bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole-exome sequencing of plasma cell-free DNA portrays the somatic mutation landscape of refractory metastatic colorectal cancer and enables the discovery of mutatedKDR/VEGFR2 receptors as modulators of anti-angiogenic therapies
Authors: Toledo Rodrigo A. , Garralda Elena , Mitsi Maria , Pons Tirso , Monsech Jorge , Vega Estela , Otero Álvaro , Albarran Maria I. , Baños Natalia , Durán Yolanda , Bonilla Victoria , Sarno Francesca , Camacho-Artacho Marta , Sanchez-Perez Tania , Perea Sofia , Álvarez Rafael , De Martino Alba , Lietha Daniel , Blanco-Aparicio Carmen , Cubillo Antonio , Domínguez Orlando , Martínez-Torrecuadrada Jorge L. , Hidalgo Manuel 
Published: August 2017

ABSTRACTThe non-invasive detection of cancer mutations is a breakthrough in oncology. Here, we applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on aRAS/BRAF/PIK3CAwild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens including VEGFR inhibitors. Using WES-cfDNA, we could detect 73% (54/74) of the somatic mutations uncovered by WES-tumor including a variety of mutation types: frameshift (indels), missense, noncoding (splicing), and nonsense mutations. Additionally, WES-cfDNA discovered 14 high-confidence somatic mutations not identified by WES-tumor. Importantly, in the absence of the tumor specimen, WES-cfDNA could identify 68 of the 88 (77.3%) total mutations that could be identified by both techniques. Of tumor biology relevance, we identified the novelKDR/VEGFR2 L840F somatic mutation, which we showed was a clonal mutation event in this tumor. Comprehensivein vitroandin vivofunctional assays confirmed that L840F causes strong resistance to anti-angiogenic drugs, whereas theKDR/VEGFR2 hot-spot mutant R1032Q confers sensitivity to cabozantinib. Moreover, we found a 1-3% of recurrentKDRsomatic mutations across large and non-overlapping cancer sequencing projects, and the majority of these mutations were located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK, suggesting a functional role.In summary, the current study highlights the capability of exomic sequencing of cfDNA from plasma of cancer patients as a powerful platform for somatic landscape analysis and discovery of resistance-associated cancer mutations. Because of its advantage to generate results highly concordant to those of tumor sequencing without the hurdle of conventional tumor biopsies, we anticipate that WES-cfDNA will become frequently used in oncology. Moreover, our study identified for the first-timeKDR/VEGFR2 somatic mutations as potential genetic biomarkers of response to anti-angiogenic cancer therapies and will serve as reference for further studies on the topic.
The Epstein-Barr virus episome maneuvers between nuclear chromatin compartments during reactivation
Authors: Moquin Stephanie A. , Thomas Sean , Whalen Sean , Warburton Alix , Fernanadez Samantha G. , McBride Alison A. , Pollard Katherine S. , Miranda JJ L. 
Published: August 2017

ABSTRACTThe human genome is structurally organized in three-dimensional space to facilitate functional partitioning of transcription. We learned that the latent episome of the human Epstein-Barr virus (EBV) preferentially associates with gene-poor chromosomes and avoids gene-rich chromosomes. Kaposi’s sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not. Contacts localize on the EBV side to OriP, the latent origin of replication. This genetic element, and the EBNA1 protein that binds there, are sufficient to reconstitute chromosome association preferences of the entire episome. Contacts localize on the human side to gene-poor regions of chromatin distant from transcription start sites. Upon reactivation from latency, however, the episome moves away from repressive heterochromatin and toward active euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during reactivation. Involvement of a myriad of interchromosomal associations also suggests a role for this type of long - range association in gene regulation.IMPORTANCEThe human genome is structurally organized in three-dimensional space, and this structure functionally affects transcriptional activity. We set out to investigate whether a double stranded DNA virus, Epstein-Barr virus (EBV), uses similar mechanisms as the human genome to regulate transcription. We found that the EBV genome associates with repressive compartments of the nucleus during latency and active compartments during reactivation. This study is advances our knowledge of the EBV life cycle, adding three-dimensional re-localization as a novel component to the molecular events that occur during reactivation. Furthermore, the data adds to our understanding of nuclear compartments, showing that disperse interchromosomal interactions may be important for regulating transcription.
Investigating the existence of periodicity in activity of neural network by novel neural signal processing technique - quantifying induced learning in cell culture
Authors: Biswas Sayan 
Published: August 2017

AbstractThe network forming ability of neurons are huge for their sparking ability to form new connections and break existing ones. This sheer ability allows dynamic nature of the network for which this network are ever changing. The neurons being cells that are chemically and electrically excitable, electrical excitation of these cells cause variation of voltage in vicinity of the active neurons. These variation captured through electrical recording device records to activity points in the network. Cultured neuron cells on Multi electrode array dish is used to study disassociated cultures. A novel integrative model of neural signal processing termed as Activity Index is applied. AI variation is plotted graphically to show the evidence in periodicity of network analysis. The finding on periodicity are discussed along with how could it be used as a potential parameter to quantify learning ability of a cell culture.Index Termsneurons, dynamic, variation of voltage, Multi electrode array, Activity Index train, Periodicity, learning
Sequence-dependent nucleosome sliding in rotation-coupled and uncoupled modes revealed by molecular simulations
Authors: Niina Toru , Brandani Giovanni B. , Tan Cheng , Takada Shoji 
Published: August 2017

AbstractWhile nucleosome positioning on eukaryotic genome play important roles for genetic regulation, molecular mechanisms of nucleosome positioning and sliding along DNA are not well understood. Here we investigated thermally-activated spontaneous nucleosome sliding mechanisms developing and applying a coarse-grained molecular simulation method that incorporates both long-range electrostatic and short-range hydrogen-bond interactions between histone octamer and DNA. The simulations revealed two distinct sliding modes depending on the nucleosomal DNA sequence. A uniform DNA sequence showed frequent sliding with one base pair step in a rotation-coupled manner, akin to screw-like motions. On the contrary, a strong positioning sequence, the so-called 601 sequence, exhibits rare, abrupt transitions of five and ten base pair steps without rotation. Moreover, we evaluated the importance of hydrogen bond interactions on the sliding mode, finding that strong and weak bonds favor respectively the rotation-coupled and -uncoupled sliding movements.Author summaryNucleosomes are fundamental units of chromatin folding consisting of double-stranded DNA wrapped ∼1.7 times around a histone octamer. By densely populating the eukaryotic genome, nucleosomes enable efficient genome compaction inside the cellular nucleus. However, the portion of DNA occupied by a nucleosome can hardly be accessed by other DNA-binding proteins, obstructing fundamental cellular processes such as DNA replication and transcription. DNA compaction and access by other proteins can simultaneously be achieved via the dynamical repositioning of nucleosomes, which can slide along the DNA sequence. In this study, we developed and used coarse-grained molecular dynamics simulations to reveal the molecular details of nucleosome sliding. We find that the sliding mode is highly dependent on the underlying DNA sequence. Specifically, a sequence with a strong nucleosome positioning signal slides via large jumps by five and ten base pairs, preserving the optimal DNA bending profile. On the other hand, uniform sequences without the positioning signal slide via a screw-like motion of DNA, one base pair at the time. These results show that sequence has a large effect not only on the formation of nucleosomes, but also on the kinetics of repositioning.
CTCF, WAPL and PDS5 proteins control the formation of TADs and loops by cohesin
Authors: Wutz Gordana , Várnai Csilla , Nagasaka Kota , Cisneros David A , Stocsits Roman , Tang Wen , Schoenfelder Stefan , Jessberger Gregor , Muhar Matthias , Hossain M Julius , Walther Nike , Koch Birgit , Kueblbeck Moritz , Ellenberg Jan , Zuber Johannes , Fraser Peter , Peters Jan-Michael 
Published: August 2017

AbstractMammalian genomes are organized into compartments, topologically-associating domains (TADs) and loops to facilitate gene regulation and other chromosomal functions. Compartments are formed by nucleosomal interactions, but how TADs and loops are generated is unknown. It has been proposed that cohesin forms these structures by extruding loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here we show that cohesin suppresses compartments but is essential for TADs and loops, that CTCF defines their boundaries, and that WAPL and its PDS5 binding partners control the length of chromatin loops. In the absence of WAPL and PDS5 proteins, cohesin passes CTCF sites with increased frequency, forms extended chromatin loops, accumulates in axial chromosomal positions (vermicelli) and condenses chromosomes to an extent normally only seen in mitosis. These results show that cohesin has an essential genome-wide function in mediating long-range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.
Delayed activation of the DNA replication licensing system in Lgr5(+) intestinal stem cells
Authors: Carroll T.D. , Newton I.P. , Chen Y. , Blow J.J. , Näthke I. 
Published: August 2017

ABSTRACTDuring late mitosis and early G1, replication origins are licensed for replication by binding to double hexamers of MCM2-7. Here, we investigate how licensing and proliferative commitment are coupled in the small-intestinal epithelium. We developed a method for identifying cells in intact tissue containing DNA-bound MCM2-7. Interphase cells above the transit-amplifying compartment had no DNA-bound MCM2-7, but still expressed MCM2-7 protein, suggesting that licensing is inhibited immediately upon differentiation. Strikingly, we found most proliferative Lgr5(+) stem cells are in an unlicensed state. This suggests that the elongated cell-cycle of intestinal stem-cells is caused by an increased G1length, characterised by dormant periods with unlicensed origins. Significantly, the unlicensed state is lost InApcmutant epithelium, which lacks a functional restriction point, causing licensing immediately upon G1entry. We propose that the unlicensed G1of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.
BUSCO applications from quality assessments to gene prediction and phylogenomics
Authors: Waterhouse Robert M. , Seppey Mathieu , Simão Felipe A. , Manni Mosè , Ioannidis Panagiotis , Klioutchnikov Guennadi , Kriventseva Evgenia V. , Zdobnov Evgeny M. 
Published: August 2017

ABSTRACTGenomics promises comprehensive surveying of genomes and metagenomes, but rapidly changing technologies and expanding data volumes make evaluation of completeness a challenging task. Technical sequencing quality metrics can be complemented by quantifying completeness in terms of the expected gene content of Benchmarking Universal Single-Copy Orthologs (BUSCO,http://busco.ezlab.org). Now in its third release, BUSCO utilities extend beyond quality control to applications in comparative genomics, gene predictor training, metagenomics, and phylogenomics.
Single-cell RNA sequencing reveals cell-type specificcis-eQTLs in peripheral blood mononuclear cells
Authors: van der Wijst M.G.P. , Brugge H. , de Vries D.H. , Franke L.H. 
Published: August 2017

AbstractMost disease-associated genetic risk factors are regulatory. Here, we generated single-cell RNA-seq data of ∼25,000 peripheral blood mononuclear cells from 45 donors to identify how genetic variants affect gene expression. We validated this approach by replicating previously published whole blood RNA-seqcis-expression quantitative trait loci effects (cis-eQTLs), but also identified new cell type-specificcis-eQTLs. These eQTLs give additional insight into the downstream consequences of genetic risk factors for immune-mediated diseases.
Measuring functional connectivity in stroke – approaches and considerations
Authors: Siegel Joshua S. , Shulman Gordon L. , Corbetta Maurizio 
Published: August 2017

AbstractRecent research has demonstrated the importance of global changes to the functional organization of brain network following stroke. Resting functional MRI (R-fMRI) is a non-invasive tool that enables the measurement of functional connectivity (FC) across the entire brain while placing minimal demands on the subject. For these reasons, it is a uniquely appealing tool for studying the distant effects of stroke. However, R-fMRI studies rely on a number of premises that cannot be assumed without careful validation in the context of stroke. Here, we describe strategies to identify and mitigate confounds specific to R-fMRI research in cerebrovascular disease. Five main topics are discussed: 1) achieving adequate co-registration of lesioned brains, 2) identifying and removing hemodynamic lags in resting BOLD, 3) identifying other vascular disruptions that affect the resting BOLD signal, 4) selecting an appropriate control cohort, and 5) acquiring sufficient fMRI data to reliably identify FC changes. For each topic, we provide evidence-based guidelines for steps to improve the interpretability and reproducibility of FC-stroke research. We include a table of confounds and approaches to identify and mitigate each. Our recommendations extend to any research using R-fMRI to study diseases that might alter cerebrovascular flow and dynamics or brain anatomy.
A non-catalytic role of TET3 promotes open chromatin and enhances global transcription
Authors: Krueger Christel , Peat Julian R. , Eckersley-Maslin Melanie A. , Hore Timothy A. , Mohammed Hisham , Andrews Simon R. , Dean Wendy , Reik Wolf 
Published: August 2017

AbstractThe methylcytosine dioxygenase Tet3 is highly expressed as a specific isoform in oocytes and zygotes but essentially absent from later stages of mouse preimplantation development. Here, we show that Tet3 expression promotes transdifferentiation of embryonic stem cells to trophoblast-like stem cells. By genome-wide analyses we demonstrate that TET3 associates with and co-occupies chromatin with RNA Polymerase II. Tet3 expression induces a global increase of transcription and total RNA levels, and its presence further enhances chromatin accessibility in regions open for transcription. This novel function of TET3 is not specific to the oocyte isoform, independent of its catalytic activity, the CXXC domain, or its interaction with OGT, and is localised in its highly conserved exon 4. We propose a more general role for TET3 promoting open chromatin and enhancing global transcription during changes of cellular identity, separate from its catalytic function.
Dynamic, non-contact 3D sample rotation for microscopy
Authors: Berndt Frederic , Shah Gopi , Brugués Jan , Huisken Jan 
Published: August 2017

AbstractIn vivoimaging of growing and developing samples requires a dynamic adaptation of the sample orientation to continuously achieve optimal performance. Here, we present how, after the injection of magnetic beads, a sample can be freely positioned by applying a magnetic field. We demonstrate its performance for zebrafish on an epi-fluorescence microscope and on a light sheet system for superior multi-view acquisition.
Replication of early and recent Zika virus isolates throughout mouse brain development
Authors: Rosenfeld Amy B , Doobin David J , Warren Audrey L , Racaniello Vincent R , Vallee Richard B 
Published: August 2017

AbstractFetal infection with Zika virus (ZIKV) can lead to congenital Zika virus syndrome (cZVS), which includes cortical malformations and microcephaly. The aspects of cortical development that are affected during virus infection are unknown. Using organotypic brain slice cultures generated from embryonic mice of various ages, sites of ZIKV replication including the neocortical proliferative zone and radial columns, as well as the developing midbrain, were identified. The infected radial units are surrounded by uninfected cells undergoing apoptosis, suggesting that programmed cell death may limit viral dissemination in the brain and may constrain virus associated injury. Therefore, a critical aspect of ZIKV induced neuropathology may be defined by death of uninfected cells. All ZIKV isolates assayed replicated efficiently in early and mid-gestation cultures, and two isolates examined replicated in late-gestation tissue. Alteration of neocortical cytoarchitecture, such as disruption of the highly-elongated basal processes of the radial glial progenitor cells, and impairment of postmitotic neuronal migration were also observed. These data suggest that all lineages of ZIKV tested are neurotropic, and that ZIKV infection interferes with multiple aspects of neurodevelopment that contribute to the complexity of cZVS.SignificanceZika virus infection has been associated with multiple pathologies of the central nervous system (CNS) including microcephaly, Guillain-Barré syndrome, lissencephaly, the loss of white and grey matter volume and acute myelitis. Using organotypic brain slice cultures, we determined that ZIKV replicates across different embryonic developmental stages, and viral infection can disrupt proper brain development leading to congenital CNS complications. These data illustrate that all lineages of ZIKV tested are neurotropic, and that infection may disrupt neuronal migration during brain development. The results expand our understanding of neuropathologies associated with congenital Zika virus syndrome.
Academic stratospheres-cum-underworlds: when highs and lows of publication cultures meet
Authors: Stöckelová Tereza , Vostal Filip 
Published: August 2017

Purpose
The purpose of this paper is to link up and think through two bodies of literature, namely the critique of predatory publishing practices and the critique of political economy of established publishers, while introducing a reflection on the dynamic asymmetries of geopolitics and economics of globalizing knowledge production.

Design/methodology/approach
The authors deploy a conceptual approach developed with reference to a case study in order to explore the embedded logic of the current system of academic publishing.

Findings
The analysis shows that rather than examining two seemingly different issues (predatory publishing vs established publishers) as conflictual dualism, it is more productive to conceive them in associative and mutually constitutive fashion.

Research limitations/implications
A nuanced and multidimensional research approach is needed if we are to understand the dynamics of contemporary academic landscape.

Originality/value
The originality of the contribution lies in its problematizing of three established approaches that feature debates on the transformation of the academy. It moves beyond a micro-level explanation by (the lack of) individual morality as well as a structural explanatory framework preoccupied with publishing infrastructure and culturalist approach based on ready-made dichotomies of west/north vs south/east. Instead, the analysis provides an account that engages both with morality and geopolitics whilst tackling them as dynamic processes in making.
Publish or impoverish
Authors: Quan Wei , Chen Bikun , Shu Fei 
Published: August 2017

Purpose
The purpose of this paper is to present the landscape of the cash-per-publication reward policy in China and reveal its trend since the late 1990s.

Design/methodology/approach
This study is based on the analysis of 168 university documents regarding the cash-per-publication reward policy at 100 Chinese universities.

Findings
Chinese universities offer cash rewards from USD30 to USD165,000 for papers published in journals indexed by Web of Science, and the average reward amount has been increasing for the past ten years.

Originality/value
The cash-per-publication reward policy in China has never been systematically studied and investigated before except for in some case studies. This is the first paper that reveals the landscape of the cash-per-publication reward policy in China.
On the quest for currencies of science
Authors: Costas Rodrigo , Perianes-Rodríguez Antonio , Ruiz-Castillo Javier 
Published: August 2017

Purpose
The introduction of “altmetrics” as new tools to analyze scientific impact within the reward system of science has challenged the hegemony of citations as the predominant source for measuring scientific impact. Mendeley readership has been identified as one of the most important altmetric sources, with several features that are similar to citations. The purpose of this paper is to perform an in-depth analysis of the differences and similarities between the distributions of Mendeley readership and citations across fields.

Design/methodology/approach
The authors analyze two issues by using in each case a common analytical framework for both metrics: the shape of the distributions of readership and citations, and the field normalization problem generated by differences in citation and readership practices across fields. In the first issue the authors use the characteristic scores and scales method, and in the second the measurement framework introduced in Crespo et al. (2013).

Findings
There are three main results. First, the citations and Mendeley readership distributions exhibit a strikingly similar degree of skewness in all fields. Second, the results on “exchange rates (ERs)” for Mendeley readership empirically supports the possibility of comparing readership counts across fields, as well as the field normalization of readership distributions using ERs as normalization factors. Third, field normalization using field mean readerships as normalization factors leads to comparably good results.

Originality/value
These findings open up challenging new questions, particularly regarding the possibility of obtaining conflicting results from field normalized citation and Mendeley readership indicators; this suggests the need for better determining the role of the two metrics in capturing scientific recognition.