bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping and dynamics of regulatory DNA in maturing seeds
Authors: Sullivan Alessandra M. , Arsovski Andrej A. , Thompson Agnieszka , Sandstrom Richard , Thurman Robert E. , Neph Shane , Johnson Audra K. , Sullivan Shawn T. , Sabo Peter J. , Neri Fidencio V. , Weaver Molly , Diegel Morgan , Nemhauser Jennifer L. , Stamatoyannopoulos John A. , Bubb Kerry L. , Queitsch Christine 
Published: January 2018

AbstractThe genome is reprogrammed during development to produce diverse cell types, largely through altered expression and activity of key transcription factors. The accessibility and critical functions of epidermal cells have made them a model for connecting transcriptional events to development in a range of model systems. In Arabidopsis thaliana and many other plants, fertilization triggers differentiation of specialized epidermal seed coat cells that have a unique morphology caused by large extracellular deposits of pectin. Here, we used DNase I-seq to generate regulatory landscapes of A. thaliana seeds at two critical time points in seed coat maturation, enriching for seed coat cells with the INTACT method. We found over 3000 developmentally dynamic regulatory DNA elements and explored their relationship with nearby gene expression. The dynamic regulatory elements were enriched for motifs for several transcription factors families; most notably the TCP family at the earlier time point and the MYB family at the later one. To assess the extent to which the observed regulatory sites in seeds added to previously known regulatory sites in A. thaliana, we compared our data to 11 other data sets generated with seven-day-old seedlings for diverse tissues and conditions. Surprisingly, over a quarter of the regulatory, i.e. accessible, bases observed in seeds were novel. Notably, in this comparison, development exerted a stronger effect on the plant regulatory landscape than extreme environmental perturbations, highlighting the importance of extending studies of regulatory landscapes to other tissues and cell types during development.
Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation
Authors: Nielsen Jonas B. , Thorolfsdottir Rosa B. , Fritsche Lars G. , Zhou Wei , Skov Morten W. , Graham Sarah E. , Herron Todd J. , McCarthy Shane , Schmidt Ellen M. , Sveinbjornsson Gardar , Surakka Ida , Mathis Michael R. , Yamazaki Masatoshi , Crawford Ryan D. , Gabrielsen Maiken E. , Skogholt Anne Heidi , Holmen Oddgeir L. , Lin Maoxuan , Wolford Brooke N. , Dey Rounak , Dalen Håvard , Sulem Patrick , Chung Jonathan H. , Backman Joshua D. , Arnar David O. , Thorsteinsdottir Unnur , Baras Aris , O’Dushlaine Colm , Holst Anders G. , Wen Xiaoquan , Hornsby Whitney , Dewey Frederick E. , Boehnke Michael , Kheterpal Sachin , Lee Seunggeun , Kang Hyun M. , Holm Hilma , Kitzman Jacob , Shavit Jordan A. , Jalife José , Brummett Chad M. , Teslovich Tanya M. , Carey David J. , Gudbjartsson Daniel F. , Stefansson Kari , Abecasis Goncalo R. , Hveem Kristian , Willer Cristen J. 
Published: January 2018

SummaryTo understand the genetic variation underlying atrial fibrillation (AF), the most common cardiac arrhythmia, we performed a genome-wide association study (GWAS) of > 1 million people, including 60,620 AF cases and 970,216 controls. We identified 163 independent risk variants at 111 loci and prioritized 165 candidate genes likely to be involved in AF. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans or mice (MYH6, NKX2-5, PITX2, TBC1D32, TBX5),1,2 or near genes important for striated muscle function and integrity (e.g. MYH7, PKP2, SSPN, SGCA). Experiments in rabbits with heart failure and left atrial dilation identified a heterogeneous distributed molecular switch from MYH6 to MYH7 in the left atrium, which resulted in contractile and functional heterogeneity and may predispose to initiation and maintenance of atrial arrhythmia.
The Tudor protein Veneno assembles the ping-pong amplification complex that 1 produces viral piRNAs in Aedes mosquitoes
Authors: Joosten Joep , Miesen Pascal , Pennings Bas , Jansen Pascal W.T.C. , Huynen Martijn A. , Vermeulen Michiel , Van Rij Ronald P. 
Published: January 2018

SummaryTUDOR-domain containing proteins facilitate PIWI interacting (pi)RNA biogenesis in Drosophila melanogaster and other model organisms. In Aedes aegypti mosquitoes, a somatically active piRNA pathway generates piRNAs from viral RNA during acute infection with cytoplasmic RNA viruses. Viral piRNA biogenesis requires ping-pong amplification by the PIWI proteins Ago3 and Piwi5. We hypothesized that Tudor proteins are required for viral piRNA production and performed a knockdown screen targeting all Ae. aegypti Tudor genes. Knockdown of several Tudor genes resulted in reduced viral piRNA levels, with silencing of AAEL012437 having the strongest effect. This protein, which we named Veneno, associates directly with Ago3 in an sDMA-dependent manner and localizes in cytoplasmic foci reminiscent of piRNA processing granules of Drosophila. Veneno-interactome analyses reveal a network of co-factors including the orthologs of the Drosophila piRNA pathway components Vasa and Yb, which in turn interacts directly with Piwi5. We propose that Veneno assembles a multi-protein complex for ping-pong dependent piRNA production from exogenous viral RNA.
Sleep-like bistability, loss of causality and complexity in the brain of Unresponsive Wakefulness Syndrome patients
Authors: Rosanova M. , Fecchio M. , Casarotto S. , Sarasso S. , Casali A.G. , Pigorini A. , Comanducci A. , Seregni F. , Devalle G. , Bodart O , Boly M. , Gosseries O. , Laureys S. , Massimini M. 
Published: January 2018

AbstractUnresponsiveness Wakefulness Syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and responsive to sensory stimuli. In these patients, Transcranial Magnetic Stimulation combined with electroencephalography (TMS/EEG) also reveals preserved cortical reactivity, but in most cases, the residual thalamocortical circuits fail to engage complex causal interactions, as assessed by the perturbational complexity index (PCI).Another condition during which thalamocortical circuits are intact, active and reactive, yet unable to generate complex responses, is physiological non-rapid eye movement (NREM) sleep. The underlying mechanism is bistability: the tendency of cortical neurons to fall into a silent period (OFF-period) upon receiving an input.Here we tested whether a pathological form of bistability may be responsible for loss of brain complexity in UWS patients. Time-frequency decomposition analysis of TMS/EEG responses in UWS patients revealed the occurrence of OFF-periods (detected as a transient suppression of high-frequency oscillations in the EEG) similar to the ones evoked by TMS in the cortex of healthy sleeping subjects. Pathological OFF-periods were detected in any cortical area, significantly impaired local causal interactions (as measured by PLF) and prevented the buildup of global complexity (as measured by PCI) in the brain of UWS patients.Our results draw a first link between neuronal events (OFF-periods) and global brain dynamics (complexity) in UWS patients. To the extent that sleep-like bistability represents the common functional endpoint of loss of complexity, detecting its presence and tracking its evolution over time, may offer a valuable read-out to devise, guide and titrate therapeutic strategies aimed at restoring consciousness.
Unrelated Donor Selection for Stem Cell Transplants using Predictive Modelling
Authors: Sivasankaran Adarsh , Williams Eric , Maiers Martin , Cherkassky Vladimir 
Published: January 2018

AbstractUnrelated Donor selection for a Hematopoietic Stem Cell Transplant is a complex multi-stage process. Choosing the most suitable donor from a list of Human Leukocyte Antigen (HLA) matched donors can be challenging to even the most experienced physicians and search coordinators. The process involves experts sifting through potentially thousands of genetically compatible donors based on multiple factors. We propose a Machine Learning approach to donor selection based on historical searches performed and selections made for these searches. We describe the process of building a computational model to mimic the donor selection decision process and show benefits of using the proposed model in this study.
Putative bovine topological association domains and CTCF binding motifs can reduce the search space for causative regulatory variants of complex traits
Authors: Wang Min , Hancock Timothy P , Chamberlain Amanda J. , Vander Jagt Christy J. , Pryce Jennie E , Cocks Benjamin G , Goddard Mike E , Hayes Benjamin J 
Published: January 2018

AbstractBackgroundTopological association domains (TADs) are chromosomal domains characterised by frequent internal DNA-DNA interactions. The transcription factor CTCF binds to conserved DNA sequence patterns called CTCF binding motifs to either prohibit or facilitate chromosomal interactions. TADs and CTCF binding motifs control gene expression, but they are not yet well defined in the bovine genome. In this paper, we sought to improve the annotation of bovine TADs and CTCF binding motifs, and assess whether the new annotation can reduce the search space for cis-regulatory variants.ResultsWe used genomic synteny to map TADs and CTCF binding motifs from humans, mice, dogs and macaques to the bovine genome. We found that our mapped TADs exhibited the same hallmark properties of those sourced from experimental data, such as housekeeping gene, tRNA genes, CTCF binding motifs, SINEs, H3K4me3 and H3K27ac. Then we showed that runs of genes with the same pattern of allele-specific expression (ASE) (either favouring paternal or maternal allele) were often located in the same TAD or between the same conserved CTCF binding motifs. Analyses of variance showed that when averaged across all bovine tissues tested, TADs explained 14% of ASE variation (standard deviation, SD: 0.056), while CTCF explained 27% (SD: 0.078). Furthermore, we showed that the quantitative trait loci (QTLs) associated with gene expression variation (eQTLs) or ASE variation (aseQTLs), which were identified from mRNA transcripts from 141 lactating cows’ white blood and milk cells, were highly enriched at putative bovine CTCF binding motifs. The most significant aseQTL and eQTL for each genic target were located within the same TAD as the gene more often than expected (Chi-Squared test P-value ≤ 0.001).ConclusionsOur results suggest that genomic synteny can be used to functionally annotate conserved transcriptional components, and provides a tool to reduce the search space for causative regulatory variants in the bovine genome.
Efficient neural decoding of self-location with a deep recurrent network
Authors: Tampuu Ardi , Matiisen Tambet , Ólafsdóttir H. Freyja , Barry Caswell , Vicente Raul 
Published: January 2018

AbstractPlace cells in the mammalian hippocampus signal self-location with sparse spatially stable firing fields. Based on observation of place cell activity it is possible to accurately decode an animal’s location. The precision of this decoding sets a lower bound for the amount of information that the hippocampal population conveys about the location of the animal. In this work we use a novel recurrent neural network (RNN) decoder to infer the location of freely moving rats from single unit hippocampal recordings. RNNs are biologically plausible models of neural circuits that learn to incorporate relevant temporal context without the need to make complicated assumptions about the use of prior information to predict the current state. When decoding animal position from spike counts in 1D and 2D-environments, we show that the RNN consistently outperforms a standard Bayesian model with flat priors. In addition, we also conducted a set of sensitivity analysis on the RNN decoder to determine which neurons and sections of firing fields were the most influential. We found that the application of RNNs to neural data allowed flexible integration of temporal context, yielding improved accuracy relative to a commonly used Bayesian approach and opens new avenues for exploration of the neural code.Author summaryBeing able to accurately self-localize is critical for most motile organisms. In mammals, place cells in the hippocampus appear to be a central component of the brain network responsible for this ability. In this work we recorded the activity of a population of hippocampal neurons from freely moving rodents and carried out neural decoding to determine the animals’ locations. We found that a machine learning approach using recurrent neural networks (RNNs) allowed us to predict the rodents’ true positions more accurately than a standard Bayesian method with flat priors. The RNNs are able to take into account past neural activity without making assumptions about the statistics of neuronal firing. Further, by analyzing the representations learned by the network we were able to determine which neurons, and which aspects of their activity, contributed most strongly to the accurate decoding.
Mutational landscape of a chemically-induced mouse model of liver cancer
Authors: Connor Frances , Rayner Tim F. , Feig Christine , Aitken Sarah J. , Lukk Margus , Odom Duncan T. 
Published: January 2018

AbstractCarcinogen-induced mouse models of liver cancer are used extensively to study the pathogenesis of the disease and have a critical role in validating candidate therapeutics. These models can recapitulate molecular and histological features of human disease. However, it is not known if the spectra of genomic alterations driving these mouse tumour genomes are comparable to those found in humans. Here, we provide a detailed characterisation of the exome-wide pattern of mutations in tumours from mice exposed to diethylnitrosamine (DEN), a commonly used model of hepatocellular carcinoma (HCC). DEN-initiated tumours had a high, uniform number of somatic single nucleotide variants (SNVs), with very few insertions, deletions or copy number alterations, consistent with the known genotoxic action of DEN. Exposure of hepatocytes to DEN left a reproducible mutational imprint in resulting tumour exomes which we could computationally reconstruct using six known COSMIC mutational signatures. The tumours carried a high diversity of low-incidence, non-synonymous point mutations in many oncogenes and tumour suppressors, reflecting the stochastic introduction of SNVs into the hepatocyte genome by the carcinogen. We identified four recurrently mutated genes that were putative oncogenic drivers of HCC in this model. Every neoplasm carried activating hotspot mutations either in codon 61 of Hras, in codon 584 of Braf or in codon 254 of Egfr. Truncating mutations of Apc occurred in 21% of neoplasms, which were exclusively carcinomas supporting a role for deregulation of Wnt/β-catenin signalling in cancer progression. Conclusion: Our study provides detailed insight into the mutational landscape of tumours arising in a commonly-used carcinogen model of hepatocellular carcinoma, facilitating the future use of this model to understand the human disease.
Long Noncoding RNA- Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension
Authors: Xing Yan , Zheng Xiaodong , Fu Yao , Qi Jing , Li Minghui , Peng Haisheng , Wang Shuang , Li Shuzhen , Zhu Daling 
Published: January 2018

ABSTRACTThe expression and function of long noncoding RNAs (lncRNAs) in the development of hypoxic pulmonary hypertension, especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs) are largely unknown. Here, we characterized the expression of lncRNA-maternally expressed gene 3 (lncRNA-MEG3) was significantly increased and primarily located in the cytoplasm of PASMCs by hypoxia. LncRNA-MEG3 knockdown by lung-specific delivery of small interfering RNAs (siRNAs) significantly prevented the development of hypoxic pulmonary hypertension in vivo. Silencing of lncRNA-MEG3 by siRNAs and gapmers attenuated PASMC responses to hypoxia in vitro. Mechanically, we found that lncRNA-MEG3 acts as a molecular sponge of microRNA-328 (miR-328); upon hypoxia, lncRNA-MEG3 interacts and sequesters miR-328, leading to the upregulation of insulin-like growth factor 1 receptor (IGF1R). Additionally, higher expression of lncRNA-MEG3 and IGF1R, and lower expression of miR-328 were observed in PASMCs of iPAH patients. These data provide insight into the contribution of lncRNA-MEG3 in hypoxia pulmonary hypertension. Upregulation of lncRNA-MEG3 sequesters cytoplasmic miR-328, eventually leading to the expression of IGF1R, revealing a regulatory mechanism by lncRNAs in hypoxia-induced PASMC proliferation.
PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation
Authors: Ronson George E. , Piberger Ann Liza , Higgs Martin R. , Olsen Anna L. , Stewart Grant S. , McHugh Peter J. , Petermann Eva , Lakin Nicholas D. 
Published: January 2018

AbstractPARP1 regulates the repair of DNA single strand breaks (SSBs) generated directly, or during base excision repair (BER). However, the role of PARP2 in these and other repair mechanisms is unknown. Here, we report a requirement for PARP2 in stabilising replication forks that encounter BER intermediates through Fbh1-dependent regulation of Rad51. Whilst PARP2 is dispensable for tolerance of cells to SSBs or homologous recombination dysfunction, it is redundant with PARP1 in BER. Therefore, combined disruption of PARP1 and PARP2 leads to defective BER, resulting in elevated levels of replication associated DNA damage due to an inability to stabilise Rad51 at damaged replication forks and prevent uncontrolled DNA resection. Together, our results demonstrate how PARP1 and PARP2 regulate two independent, but intrinsically linked aspects of DNA base damage tolerance by promoting BER directly, and through stabilising replication forks that encounter BER intermediates.
Target Control in Logical Models Using the Domain of Influence of Nodes
Authors: Yang Gang , Zañudo Jorge G. T. , Albert Réka 
Published: January 2018

ABSTRACTDynamical models of biomolecular networks are successfully used to understand the mechanisms underlying complex diseases and to design therapeutic strategies. Network control, and its special case of target control, is a promising avenue toward developing disease therapies. In target control it is assumed that a small subset of nodes is most relevant to the system’s state and the goal is to drive the target nodes into their desired states. An example of target control would be driving a cell to commit to apoptosis (programmed cell death). From the experimental perspective, gene knockout, pharmacological inhibition of proteins and providing sustained external signals are among practical intervention techniques. We identify methodologies to use the stabilizing effect of sustained interventions for target control in logical models of biomolecular networks. Specifically, we define the domain of influence of a node (in a certain state) to be the nodes (and their corresponding states) that will be ultimately stabilized by the sustained state of this node regardless of the initial state of the system. We also define the related concept of the logical domain of influence of a node, and develop an algorithm for its identification using an auxiliary network that incorporates the regulatory logic. This way a solution to the target control problem is a set of nodes whose domain of influence can cover the desired target node states. We perform greedy randomized adaptive search in state space to find such solutions. We apply our strategy to several biological networks to demonstrate its effectiveness.
Exhibition and preservation of non-fiction interactive and transmedia forms of expression
Authors: Gifreu-Castells Arnau 
Published: January 2018

Purpose
The constant updating and unstoppable advance of technologies, mixing of platforms, programs and codes and the new trends in funding, among other factors, have led us to a present-future full of interactive, collaborative, participatory and co-creative digital artefacts and works. Games, experimental projects, short films and interactive video clips, in relation to fictional and non-fictional narrative, like documentary and journalism mainly, generate a complex body of works that depend on a series of compatibilities between technologies and languages to work properly and keep up with the times. The main purpose of this article is to analyse how the expression forms of interactive nonfiction narrative can be exhibited and preserved, looking at four main genres: documentary, journalism, museums and education.

Design/methodology/approach
At the methodological level, a study of analogue and digital forms in the proposed areas was performed, and a series of projects as case studies were analysed. In addition, a series of initiatives and institutions developing preservation methods are listed and ten effective strategies have been proposed to preserve interactive and transmedia nonfiction works.

Findings
The results make it possible to propose new ways of exhibiting and preserving valuable digital non-fiction works that need to be catalogued and safeguarded for the future.

Originality/value
For non-digital artistic forms of expression, copies were the main way of ensuring their preservation, but how does this process work for digital art forms? This area is a virgin field that urgently needs to be studied to determine and generate structures for preserving these types of works.
The obsessive and harmonious nature of entrepreneurial passion
Authors: Fisher Rosemary , Merlot Elizabeth , Johnson Lester W. 
Published: January 2018

Purpose
The purpose of this paper is to examine the nature of entrepreneurial passion and in doing so explores the relationship between harmonious and obsessive passion (OP) and resilience. A pathway between passion and entrepreneurial success (ES) that is mediated by sustained entrepreneurial commitment (SEC) and resilience is tested.

Design/methodology/approach
An online questionnaire survey was completed by (n=215) Australian entrepreneurs. Results were based on structural equation modelling analysis.

Findings
Harmonious passion contributes directly and indirectly to perceptions of ES through resilience; OP contributes to SEC which contributes to success through resilience.

Research limitations/implications
Limitations stem from the survey methodology used. Implications for incorporating harmonious and OP into training to ensure well developed entrepreneurs are raised.

Originality/value
This study is one of the few studies to test the theoretical constructs of passion and resilience in the entrepreneurship context, and seemingly the first to do so on an Australian sample of entrepreneurs. This research finds that both types of passion are important to individual level resilience and ultimately to ES. An OP for one’s venture is an important contributor to persisting with the venture.