bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analyzing the heterogeneity of rule-based EHR phenotyping algorithms in CALIBER and the UK Biobank
Authors: Denaxas Spiros , Parkinson Helen , Fitzpatrick Natalie , Sudlow Cathie , Hemingway Harry 
Published: June 2019

AbstractElectronic Health Records (EHR) are data generated during routine interactions across healthcare settings and contain rich, longitudinal information on diagnoses, symptoms, medications, investigations and tests. A primary use-case for EHR is the creation of phenotyping algorithms used to identify disease status, onset and progression or extraction of information on risk factors or biomarkers. Phenotyping however is challenging since EHR are collected for different purposes, have variable data quality and often require significant harmonization. While considerable effort goes into the phenotyping process, no consistent methodology for representing algorithms exists in the UK. Creating a national repository of curated algorithms can potentially enable algorithm dissemination and reuse by the wider community. A critical first step is the creation of a robust minimum information standard for phenotyping algorithm components (metadata, implementation logic, validation evidence) which involves identifying and reviewing the complexity and heterogeneity of current UK EHR algorithms. In this study, we analyzed all available EHR phenotyping algorithms (n=70) from two large-scale contemporary EHR resources in the UK (CALIBER and UK Biobank). We documented EHR sources, controlled clinical terminologies, evidence of algorithm validation, representation and implementation logic patterns. Understanding the heterogeneity of UK EHR algorithms and identifying common implementation patterns will facilitate the design of a minimum information standard for representing and curating algorithms nationally and internationally.
Higher stochasticity of microbiota composition in seedlings of domesticated wheat compared to wild wheat
Authors: Özkurt Ezgi , Hassani M. Amine , Sesiz Uğur , Künzel Sven , Dagan Tal , Özkan Hakan , Stukenbrock Eva H. 
Published: June 2019

AbstractPlants constitute an ecological niche for microbial communities that colonize different plant tissues and explore the plant habitat for reproduction and dispersal. The association of microbiota and plant may be altered by ecological and evolutionary changes in the host population. Seedborne microbiota, expected to be largely vertically-transferred, have the potential to co-adapt with their host over generations. Reduced host diversity because of strong directional selection and polyploidization during plant domestication and cultivation may have impacted the assembly and transmission of seed-associated microbiota. Nonetheless, the effect of plant domestication on the diversity of their associated microbes is poorly understood. Here we show that microbial communities in domesticated wheat,Triticum aestivum, are less diverse but more inconsistent among individual plants compared to the wild wheat species,T. dicoccoides. We found that diversity of microbes in seeds overall is low, but comparable in different wheat species, independent of their genetic and geographic origin. However, the diversity of seedborne microbiota that colonize the roots and leaves of the young seedling is significantly reduced in domesticated wheat genotypes. Moreover, we observe a higher variability between replicates ofT. aestivumsuggesting a stronger effect of chance events in microbial colonization and assembly. We also propagated wild and domesticated wheat in two different soils and found that different factors govern the assembly of soil-derived and seedborne microbial communities. Overall, our results demonstrate that the role of stochastic processes in seedborne microbial community assembly is larger in domesticated wheat compared to the wild wheat. We suggest that the directional selection on the plant host and polyploidization events during domestication may have decreased the degree of wheat-microbiota interactions and consequently led to a decreased stable core microbiota.
Local rewiring of genome - nuclear lamina interactions by transcription
Authors: Brueckner Laura , Zhao Peiyao A , van Schaik Tom , Leemans Christ , Sima Jiao , Peric-Hupkes Daniel , Gilbert David M , van Steensel Bas 
Published: June 2019

AbstractTranscriptionally inactive genes are often positioned at the nuclear lamina (NL), as part of large lamina-associated domains (LADs). Activation of such genes is often accompanied by repositioning towards the nuclear interior. How this process works and how it impacts flanking chromosomal regions is poorly understood. We addressed these questions by systematic manipulation of gene activity and detailed analysis of NL interactions. Activation of genes inside LADs typically causes detachment of the entire transcription unit but rarely more than 50-100 kb of flanking DNA, even when multiple neighboring genes are activated. The degree of detachment depends on the expression level and the length of the activated gene. Loss of NL interactions coincides with a switch from late to early replication timing, but the latter can involve longer stretches of DNA. These findings show how NL interactions can be shaped locally by transcription and point to a remarkable flexibility of interphase chromosomes.
Towards automated control of embryonic stem cell pluripotency
Authors: Khazim Mahmoud , Postiglione Lorena , Pedone Elisa , Rocca Dan L. , Zahra Carine , Marucci Lucia 
Published: June 2019

AbstractMouse embryonic stem cells (mESCs) have been shown to exist in three distinct pluripotent states (ground, naïve and primed pluripotent states), depending on culture conditions. External feedback control strategies have been, so far, mainly used to automatically regulate gene expression in bacteria and yeast. Here, we exploit a microfluidics/microscopy platform and segmentation and external feedback control algorithms for the automatic regulation of pluripotency phenotypes in mESCs. We show feasibility of automatically controlling, in living mESCs, levels of an endogenous pluripotency gene, Rex1, through a fluorescent reporter, used as control output, and drugs commonly used to modulate pluripotency (i.e. MEK kinase and Gsk3β inhibitors) as control inputs. Our results will ultimately aid in the derivation of superior protocols for pluripotency maintenance and differentiation of mouse and human stem cells.
MitoFinder: efficient automated large-scale extraction of mitogenomic data in target enrichment phylogenomics
Authors: Allio Rémi , Schomaker-Bastos Alex , Romiguier Jonathan , Prosdocimi Francisco , Nabholz Benoit , Delsuc Frédéric 
Published: June 2019

AbstractThanks to the development of high-throughput sequencing technologies, target enrichment sequencing of nuclear ultraconserved DNA elements (UCEs) now allows routinely inferring phylogenetic relationships from thousands of genomic markers. Recently, it has been shown that mitochondrial DNA (mtDNA) is frequently sequenced alongside the targeted loci in such capture experiments. Despite its broad evolutionary interest, mtDNA is rarely assembled and used in conjunction with nuclear markers in capture-based studies. Here, we developed MitoFinder, a user-friendly bioinformatic pipeline, to efficiently assemble and annotate mitogenomic data from hundreds of UCE libraries. As a case study, we used ants (Formicidae) for which 501 UCE libraries have been sequenced whereas only 29 mitogenomes are available. We compared the efficiency of four different assemblers (IDBA-UD, MEGAHIT, MetaSPAdes, and Trinity) for assembling both UCE and mtDNA loci. Using MitoFinder, we show that metagenomic assemblers, in particular MetaSPAdes, are well suited to assemble both UCEs and mtDNA. Mitogenomic signal was successfully extracted from all 501 UCE libraries allowing confirming species identification using COI barcoding. Moreover, our automated procedure retrieved 296 cases in which the mitochondrial genome was assembled in a single contig, thus increasing the number of available ant mitogenomes by an order of magnitude. By leveraging the power of metagenomic assemblers, MitoFinder provides an efficient tool to extract complementary mitogenomic data from UCE libraries, allowing testing for potential mito-nuclear discordance. Our approach is potentially applicable to other sequence capture methods, transcriptomic data, and whole genome shotgun sequencing in diverse taxa.
Bacteria associated with flowers affect the reproductive success ofBrassica napusL.viascent-mediated interactions with pollinators
Authors: Farré-Armengol Gerard , Junker Robert R. 
Published: June 2019

AbstractFlowers are colonized by specific bacterial communities that have been shown to affect floral scent emission and pollinator behavior. Whether these effects translate into changes in the plants’ reproductive success remains unknown. In our study, flowers ofBrassica napuswere inoculated with the phyllospheric bacteriaPantoea agglomeransandPseudomonas syringae. Next-generation 16S rRNA gene amplicon sequencing of bacterial communities associated with flowers showed that inoculation was efficient and affected bacterial communities throughout the flowering time of individual flowers. Flowers ofB. napusinoculated withP. agglomeransandP. syringaewere preferred by pollinators in the field or in olfactometer assays. Presumably due to the increased visitation rates, inoculated plants produced more seeds of tendentially higher quality per flower. Floral scent emissions were affected by time after inoculation and by treatment with bacterial strains, potentially explaining the behavioral responses of pollinators. Controlled laboratory experiments showed that bacteria emit volatiles through their own metabolism and that the concentrations of some floral volatiles can be reduced by bacteria. Furthermore, our results also suggest that bacteria can use floral scent compounds as carbon sources. Our results demonstrate a significant effect of floral bacteria on the pollination and reproduction of entomophilous plants that is at least partly mediated by their effects on floral chemical signaling.
Genome-wide analysis reveals a switch in the translational program upon oocyte meiotic resumption
Authors: Luong Xuan G. , Daldello Enrico Maria , Rajkovic Gabriel , Yang Cai-Rong , Conti Marco 
Published: June 2019

SummaryDuring oocyte maturation, changes in gene expression depend exclusively on translation and degradation of maternal mRNAs rather than transcription. Execution of this translation program is essential for assembling the molecular machinery required for meiotic progression, fertilization, and embryo development. With the present study, we used a RiboTag/RNA-Seq approach to explore the timing of maternal mRNA translation in quiescent oocytes as well as in oocytes progressing through the first meiotic division. This genome-wide analysis reveals a global switch in maternal mRNA translation coinciding with oocyte re-entry into the meiotic cell cycle. Messenger RNAs whose translation is highly active in quiescent oocytes invariably become repressed during meiotic re-entry, whereas transcripts repressed in quiescent oocytes become activated. Experimentally, we have defined the exact timing of the switch, the repressive function of CPE elements, and identified a novel role for CPEB1 in maintaining constitutive translation of a large group of maternal mRNAs during maturation.
Hypoxia-Induced PIM Kinase and Laminin-Activated Integrin α6 Mediate Resistance to PI3K Inhibitors in Bone-Metastatic CRPC
Authors: Toth Rachel K. , Tran Jack D. , Muldong Michelle T. , Nollet Eric A. , Schulz Veronique V. , Jensen Corbin , Hazelhurst Lori A. , Corey Eva , Durden Donald , Jamieson Christina , Miranti Cindy K. , Warfel Noel A. 
Published: June 2019

ABSTRACTBone-metastatic castration-resistant prostate cancer (CRPC) is lethal due to inherent resistance to androgen deprivation therapy, chemotherapy, and targeted therapies. Despite the fact that a majority of CRPC patients (approximately 70%) harbor a constitutively active PI3K survival pathway, targeting the PI3K/mTOR pathway has failed to increase overall survival in clinical trials. Here, we identified two separate and independent survival pathways induced by the bone tumor microenvironment that are hyperactivated in CRPC and confer resistance to PI3K inhibitors. The first pathway involves integrin α6β1-mediated adhesion to laminin and the second involves hypoxia-induced expression of PIM kinases. In vitro and in vivo models demonstrate that these pathways transduce parallel but independent signals that promote survival by reducing oxidative stress and preventing cell death. We further demonstrate that both pathways drive resistance to PI3K inhibitors in PTEN-negative tumors. These results provide preclinical evidence that combined inhibition of integrin α6β1 and PIM kinase in CRPC is required to overcome tumor microenvironment-mediated resistance to PI3K inhibitors in PTEN-negative tumors within the hypoxic and laminin-rich bone microenvironment.
Deconvoluting signals downstream of growth and immune receptor kinases by phosphocodes of the BSU1 family phosphatases
Authors: Park Chan Ho , Bi Yang , Youn Ji-Hyun , Kim So-Hee , Kim Jung-Gun , Xu Nicole Y. , Shrestha Ruben , Burlingame Alma L , Xu Shou-Ling , Mudgett Mary Beth , Kim Seong-Ki , Kim Tae-Wuk , Wang Zhi-Yong 
Published: June 2019

AbstractHundreds of leucine-rich repeat receptor kinases (LRR-RKs) have evolved to control diverse processes of growth, development, and immunity in plants; the mechanisms that link LRR-RKs to distinct cellular responses are not understood. Here we show that two LRR-RKs, the brassinosteroid hormone receptor BRI1 (BRASSINOSTEROID INSENSITIVE 1) and the flagellin receptor FLS2 (FLAGELLIN SENSING 2), regulate downstream glycogen synthase kinase 3 (GSK3) and mitogen-activated protein (MAP) kinases, respectively, through phosphocoding of the BRI1-SUPPRESSOR1 (BSU1) phosphatase. BSU1 was previously identified as a component that inactivates GSK3s in the BRI1 pathway. We found surprisingly that loss of the BSU1 family phosphatases activates effector-triggered immunity (ETI) and impairs flagellin-triggered MAP kinase activation and immunity. The flagellin-activated BOTRYTIS-INDUCED KINASE 1 (BIK1) phosphorylates BSU1 at serine-251. Mutation of serine-251 reduces the ability of BSU1 to mediate flagellin-induced MAP kinase activation and immunity, but not its abilities to suppress ETI and interact with GSK3, which is enhanced through the phosphorylation of BSU1 at serine-764 upon brassinosteroid signaling. These results demonstrate that BSU1 plays an essential role in immunity and transduces brassinosteroid-BRI1 and flagellin-FLS2 signals using different phosphorylation sites. Our study illustrates that phosphocoding in shared downstream components provides signaling specificities for diverse plant receptor kinases.
CD44 alternative splicing is a sensor of intragenic DNA methylation in tumors
Authors: Batsché Eric , Mauger Oriane , Kornobis Etienne , Hopkins Benjamin , Hanmer-Lloyd Charlotte , Muchardt Christian 
Published: June 2019

ABSTRACTDNA methylation (meDNA) is a suspected modulator of alternative splicing, while splicing in turn is involved in tumour formations nearly as frequently as DNA mutations. Yet, the impact of meDNA on tumorigenesis via its effect on splicing has not been thoroughly explored. Here, we find that HCT116 colon carcinoma cells inactivated for the DNA methylases DNMT1 and DNMT3b undergo a partial epithelial to mesenchymal transition (EMT) associated with alternative splicing of the CD44 transmembrane receptor. The skipping of CD44 variant exons is in part explained by altered expression or splicing of splicing and chromatin factors. A direct effect of meDNA on alternative splicing was sustained by transient depletion of DNMT1 and the methyl-binding genes MBD1, MBD2, and MBD3. Yet, local changes in intragenic meDNA also altered recruitment of MBD1 protein and of the chromatin factor HP1γ known to alter transcriptional pausing and alternative splicing decisions. We further tested if meDNA level has sufficiently strong direct impact on the outcome of alternative splicing to have a predictive value in the MCF10A model for breast cancer progression and in patients with acute lymphoblastic leukemia (B ALL). We found that a small number of differentially spliced genes mostly involved in splicing and signal transduction is systematically correlated with local meDNA. Altogether, our observations suggest that, although DNA methylation has multiple avenues to alternative splicing, its indirect effect may be also mediated through alternative splicing isoforms of these sensors of meDNA.
A systems-biology approach to molecular machines: Exploration of alternative transporter mechanisms
Authors: George August , Bisignano Paola , Rosenberg John M. , Grabe Michael , Zuckerman Daniel M. 
Published: June 2019

AbstractMotivated by growing evidence for pathway heterogeneity and alternative functions of molecular machines, we demonstrate a computational approach for investigating two questions: (1) Are there multiple mechanisms (state-space pathways) by which a machine can perform a given function, such as cotransport across a membrane? (2) How can additional functionality, such as proofreading/error-correction, be built into machine function using standard biochemical processes? Answers to these questions will aid both the understanding of molecular-scale cell biology and the design of synthetic machines. Focusing on transport in this initial study, we sample a variety of mechanisms by employing Metropolis Markov chain Monte Carlo. Trial moves adjust transition rates among an automatically generated set of conformational and binding states while maintaining fidelity to thermodynamic principles and a user-supplied fitness/functionality goal. Each accepted move generates a new model. The simulations yield both single and mixed reaction pathways for cotransport in a simple environment with a single substrate along with a driving ion. In a “competitive” environment including an additional decoy substrate, several qualitatively distinct reaction pathways are found which are capable of extremely high discrimination coupled to a leak of the driving ion, akin to proofreading. The array of functional models would be difficult to find by intuition alone in the complex state-spaces of interest.Author summaryMolecular machines, which operate on the nanoscale, are proteins/complexes that perform remarkable tasks such as the selective absorption of nutrients into the cell by transporters. These complex machines are often described using a fairly simple set of states and transitions that may not account for the stochasticity and heterogeneity generally expected at the nanoscale at body temperature. New tools are needed to study the full array of possibilities. This study presents a novel in silico method to systematically generate testable molecular-machine kinetic models and explore alternative mechanisms, applied first to membrane transport proteins. Our initial results suggest these transport machines may contain mechanisms which ‘detoxify’ the cell of an unwanted toxin, as well as significantly discriminate against the import of the toxin. This novel approach should aid the experimental study of key physiological processes such as renal glucose re-absorption, rational drug design, and potentially the development of synthetic machines.
Accurate and efficient discretisations for stochastic models providing near agent-based spatial resolution at low computational cost
Authors: Fadai Nabil T. , Baker Ruth E. , Simpson Matthew J. 
Published: June 2019

AbstractUnderstanding how cells proliferate, migrate, and die in various environments is essential in determining how organisms develop and repair themselves. Continuum mathematical models, such as the logistic equation and the Fisher-Kolmogorov equation, can describe the global characteristics observed in commonly-used cell biology assays, such as proliferation and scratch assays. However, these continuum models do not account for single-cell-level mechanics observed in high-throughput experiments. Mathematical modelling frameworks that represent individual cells, often called agent-based models, can successfully describe key single-cell-level features of these assays, but are computationally infeasible when dealing with large populations. In this work, we propose an agent-based model with crowding effects that is computationally efficient and matches the logistic and Fisher-Kolmogorov equations in parameter regimes relevant to proliferation and scratch assays, respectively. This stochastic agent-based model allows multiple agents to be contained within compartments on an underlying lattice, thereby reducing the computational storage compared to existing agent-based models that allow one agent per site only. We propose a systematic method to determine a suitable compartment size. Implementing this compartment-based model with this compartment size provides a balance between computational storage, local resolution of agent behaviour, and agreement with classical continuum descriptions.
Decomposing social networking site regret: a uses and gratifications approach
Authors: Islam A.K.M. Najmul , Mäntymäki Matti , Kefi Hajer 
Published: June 2019

Purpose
Regret is an undesirable yet very common outcome of social networking site (SNS) use. To date, the literature has examined SNS regret at an aggregate level. The purpose of this paper is to decompose the dimensions and constituents of SNS regret into networking regret and brand page regret, to better understand it, and examine how the two facets of regret are created by SNS use intensity and gratification. The authors also decomposed SNS activities into networking activities and brand page activities and positioned them as predictors of networking regret and brand page regret, respectively.

Design/methodology/approach
The authors drew on uses and gratifications theory and positioned interpersonal connectivity and exhibitionism as the antecedents of networking activities as well as informational value and exhibitionism as the antecedents of brand page activities. The authors collected data from 246 Facebook users from France and analyzed the data using the partial least squares approach.

Findings
The results show that use intensity has a marginal effect on both brand page and networking regret. However, exhibitionism was found to reinforce the effect of use intensity on both brand page and networking regret. It also had a positive effect on both networking and brand page activities. The other two gratifications, interpersonal connectivity and informational value, had a positive effect on networking and brand page activities, respectively.

Originality/value
To date, empirical attempts at investigating decomposed SNS regret have been rare. The paper fills this theoretical and empirical gap and contributes to the literature on regret in an SNS use context.
The None in Three Victim Responsiveness Assessment (Ni3: VRA): a new outcome measure for intimate partner violence (IPV) prevention programs
Authors: Debowska Agata , Boduszek Daniel , Willmott Dominic , Jones Adele D. 
Published: June 2019

Purpose
The purpose of this paper is to develop and validate the None in Three Victim Responsiveness Assessment (Ni3: VRA) examining affective and cognitive responsiveness toward victims of intimate partner violence.

Design/methodology/approach
Data were collected at two time points in a sample of 359 young people from Barbados and Grenada (56.27 percent female; M age=12.73 years).

Findings
Confirmatory factor analysis results indicated that the Ni3: VRA scores are best captured by a two-factor solution, including affective and cognitive dimensions. A test-retest correlation confirmed the reliability of the Ni3: VRA over time. Affective responsiveness formed a significant positive association with caring/cooperative behavior.

Originality/value
The Ni3: VRA can be used for the evaluation of preventive strategies aimed at reducing the rates of IPV.