bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving Venous Thromboembolism Prophylaxis Administration in an Acute Surgical Unit
Authors: Allaway Matthew G. R. , Eslick Guy D. , Kwok Grace T. Y. , Cox Michael R. 
Published: July 2018

Objectives
Venous thromboembolism (VTE) prophylaxis regimes frequently have a wide variation in application. Nepean acute surgical unit was established in 2006 as a novel model for emergency surgical care. As part of the model’s rollout, there were several areas of clinical management targeted for improvement, one being VTE prophylaxis compliance. It was decided all patients older than 18 years treated for a variety of acute surgical conditions within the acute surgical unit should be administered routine VTE prophylaxis with heparin and compression stockings. A novel multifaceted intervention was implemented at the time to achieve this goal. The primary aim of this study was to determine VTE prophylaxis administration rates before and after this intervention.

Methods
A before-after study conducted as a retrospective review of medical records of all patients 18 years or older, having an appendicectomy in 3 periods: Before acute surgical unit (ASU) (November 2004 to October 2006), Early ASU (November 2006 to October 2008), and Established ASU (January 2012 to December 2013). Outcomes were mechanical and pharmacological VTE prophylaxis administration rates for each group.

Results
There were 1149 patients included in the study: Before ASU, 167; Early ASU, 375; and Established ASU, 607. There was a significant stepwise increase in parmacological VTE prophylaxis administration: Before ASU, 54.5%; Early ASU, 74.7%; and Established ASU, 96.9% (Before versus Early: odds ratio [OR], 2.46; 95% confidence interval [CI], 1.68–3.61; P < 0.001; Early versus Established: OR, 10.500; 95% CI, 6.29–17.53; P < 0.001). Mechanical VTE prophylaxis was significantly increased in the established group (Before versus Established: OR, 47.18; 95% CI, 25.61–86.91; P < 0.001).

Conclusions
There was a significant increase in VTE prophylaxis administration after the implementation of our multifaceted intervention. Allocating a responsible provider dedicated to VTE prophylaxis prescription and compliance checking was a key component to this intervention.
Development of a Clinical Decision Support System for Living Kidney Donor Assessment Based on National Guidelines
Authors: Knight Simon R. , Cao Khoa N. , South Matthew , Hayward Nicki , Hunter James P. , Fox John 
Published: July 2018

Background
Live donor nephrectomy is an operation that places the donor at risk of complications without the possibility of medical benefit. Rigorous donor selection and assessment is therefore essential to ensure minimization of risk and for this reason robust national guidelines exist. Previous studies have demonstrated poor adherence to donor guidelines.

Methods
We developed a clinical decision support system (CDSS), based on national living donor guidelines, to facilitate the identification of contraindications, additional investigations, special considerations, and the decision as to nephrectomy side in potential living donors. The CDSS was then tested with patient data from 45 potential kidney donors.

Results
The CDSS comprises 17 core tasks completed by either patient or nurse, and 17 optional tasks that are triggered by certain patient demographics or conditions. Decision rules were able to identify contraindications, additional investigations, special considerations, and predicted operation side in our patient cohort. Seventeen of 45 patients went on to donate a kidney, of whom 7 had major contraindications defined in the national guidelines, many of which were not identified by the clinical team. Only 43% of additional investigations recommended by national guidelines were completed, with the most frequently missed investigations being oral glucose tolerance testing and routine cancer screening.

Conclusions
We have demonstrated the feasibility of turning a complex set of national guidelines into an easy-to-use machine-readable CDSS. Comparison with real-world decisions suggests that use of this CDSS may improve compliance with guidelines and informed consent tailored to individual patient risks.
Synthetic mammalian pattern formation driven by differential diffusivity of Nodal and Lefty
Authors: Sekine Ryoji , Shibata Tatsuo , Ebisuya Miki 
Published: July 2018

AbstractPattern formation is fundamental for embryonic development. Although synthetic biologists have created several patterns, a synthetic mammalian reaction-diffusion pattern has yet to be realized. TGF-β family proteins Nodal and Lefty have been proposed to meet the conditions for reaction-diffusion patterning: Nodal is a short-range activator that enhances the expression of Nodal and Lefty whereas Lefty acts as a long-range inhibitor against Nodal. However, the pattern forming possibility of the Nodal-Lefty signaling has never been directly tested, and the underlying mechanisms of differential diffusivity of Nodal and Lefty remain unclear. Here, through a combination of synthetic biology and theoretical modeling, we show that a reconstituted minimal network of the Nodal-Lefty signaling spontaneously gives rise to a pattern in mammalian cell culture. Surprisingly, extracellular Nodal was confined underneath the cells as small clusters, resulting in a narrow distribution range compared with Lefty. We further found that the finger 1 domain of the Nodal protein is responsible for its short-range distribution. By transplanting the finger 1 domain of Nodal into Lefty, we converted the originally long-range distribution of Lefty to a short-range one, successfully preventing the pattern formation. These results indicate that the differences in the localization and domain structures between Nodal and Lefty, combined with the activator-inhibitor topology, are sufficient for reaction-diffusion pattern formation in mammalian cells.
Crispr/Cas9 Targeted Capture of Mammalian Genomic Regions for Characterization by NGS
Authors: Slesarev Alexei , Viswanathan Lakshmi , Tang Yitao , Borgschulte Trissa , Achtien Katherine , Razafsky David , Onions David , Chang Audrey , Cote Colette 
Published: July 2018

ABSTRACTThe robust detection of structural variants in mammalian genomes remains a challenge. It is particularly difficult in the case of genetically unstable Chinese hamster ovary (CHO) cell lines with only draft genome assemblies available. We explore the potential of the CRISPR/Cas9 system for the targeted capture of genomic loci containing integrated vectors in CHO-K1-based cell lines, and compare it to popular target-enrichment methods and to whole genome sequencing (WGS). The CRISPR/Cas9-based techniques allow for amplification-free capture of genomic regions, which reduces the possibility of sequencing artifacts. Other advantages of these methods are the ease of bioinformatics analysis, potential for multiplexing, and the production of longer sequencing templates for real-time sequencing. The utility of these protocols has been proven by identification of transgene integration sites and flanking sequences in a number of CHO cell lines. However, data produced by these and other targeted capture methods are not always sufficient to analyze complex genomic rearrangements (CGRs) or unexpected sequences introduced into genome by vector integration events. In contrast, WGS provides complete information about vector integration sites, vector copy number, CGRs, and foreign DNA-but despite these benefits, WGS is not easily implemented due to the cost and complexity of the analysis.
Q-FADD: A mechanistic approach for modeling the accumulation of proteins at sites of DNA damage by free diffusion
Authors: Mahadevan Jyothi , Rudolph Johannes , Jha Asmita , Tay Jian Wei , Dragavon Joe , Grumstrup Erik M. , Luger Karolin 
Published: July 2018

AbstractThe repair of DNA damage requires the ordered recruitment of many different proteins that are responsible for signaling and subsequent repair. A powerful tool for studying the orchestrated accumulation of these proteins at damage sites is laser microirradiation in live cells, followed by monitoring of the accumulation of the fluorescently labeled protein in question. Despite the widespread use of this approach, there exists no rigorous method for characterizing this process quantitatively. Here we introduce a free diffusion model that explicitly accounts for the unique topology of individual nuclei and quantitatively describes the accumulation of two test proteins, poly-ADP-ribose polymerases 1 and 2. Application of our model to other proteins will yield novel insights into the timing and mechanism of DNA repair.
Response to early drought stress and identification of QTLs controlling biomass production under drought in pearl millet
Authors: Debieu M , Sine B , Passot S , Grondin A , Akata AE , Gangashetty P , Vadez V , Gantet P , Foncéka D , Cournac L , Hash CT , Kane NA , Vigouroux Y , Laplaze L 
Published: July 2018

AbstractPearl millet plays a major role in food security in arid and semi-arid areas of Africa and India. However, it lags behind the other cereal crops in terms of genetic improvement. The recent sequencing of its genome opens the way to the use of modern genomic tools for breeding. Our study aimed at identifying genetic components involved in early drought stress tolerance as a first step toward the development of improved pearl millet varieties or hybrids. A panel of 188 inbred lines from West Africa was phenotyped under early drought stress and well-irrigated conditions. We found a strong impact of drought stress on yield components. This impact was variable between inbred lines. We then performed an association analysis with a total of 392,493 SNPs identified using Genotyping-by-Sequencing (GBS). Correcting for genetic relatedness, genome wide association study identified QTLs for biomass production in early drought stress conditions and for stay-green trait. In particular, genes involved in the sirohaem and wax biosynthesis pathways were found to co-locate with association loci. Our results open the way to use genomic selection to breed pearl millet lines with improved yield under drought stress.
Thecis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements inDrosophila
Authors: Zandvakili Arya , Uhl Juli , Campbell Ian , Song Yuntao Charlie , Gebelein Brian 
Published: July 2018

AbstractHox genes encode a family of transcription factors that, despite having similarin vitroDNA binding preferences, regulate distinct genetic programs along the metazoan anterior-posterior axis. To better define mechanisms of Hox specificity, we compared and contrasted the ability of abdominal Hox factors to regulate twocis-regulatory elements within theDrosophilaembryo. Both the Ultrabithorax (Ubx) and Abdominal-A (Abd-A) Hox factors form cooperative complexes with the Extradenticle (Exd) and Homothorax (Hth) transcription factors to repress thedistal-lessleg selector gene via theDCRE, whereas only Abd-A interacts with Exd and Hth on theRhoAelement to activate arhomboidserine protease gene that stimulates Epidermal Growth Factor secretion. By swapping binding sites between these elements, we found that theRhoAExd/Hth/Hox site configuration that mediates Abd-A specific activation can also convey transcriptional repression by both Ubx and Abd-A when placed into theDCRE,but only in one orientation. We further show that the orientation and spacing of Hox sites relative to additional transcription factor binding sites within theRhoAandDCREelements is critical to mediate appropriate cell- and segment-specific output. These results indicate that the interaction between Hox, Exd, and Hth neither determines activation vs repression specificity nor defines Ubx vs Abd-A specificity. Instead the precise integration of Hox sites with additional TF inputs is required for accurate transcriptional output. Taken together, these studies provide new insight into the mechanisms of Hox target and regulatory specificity as well as the constraints placed on regulatory elements to convey appropriate outputs.Author SummaryThe Hox genes encode a family of transcription factors that give cells within each region along the developing body plan a unique identity in animals from worms to mammals. Surprisingly, however, most of the Hox factors bind the same or highly similar DNA sequences. These findings raise a paradox: How can proteins that have highly similar DNA binding properties perform different functions in the animal by regulating different sets of target genes? In this study, we address this question by studying how two Hox factors regulate the expression of target genes that specify leg development and the making of liver-like cells in the developing fly. By comparing and contrasting how Hox target genes are activated and/or repressed, we found that the same Hox binding sites can mediate either activation or repression in a manner that depends upon context. In addition, we found that a Hox binding site that is normally regulated by only one Hox factor, can also be used by more than one Hox factor swapped into another target gene. These findings indicate that the specificity of a Hox factor to regulate target genes does not rely solely upon DNA binding specificity but also requires regulatory specificity.
Signalling pathways drive heterogeneity of ground state pluripotency
Authors: McEwen Kirsten R. , Linnett Sarah , Leitch Harry G. , Srivastava Prashant , Al-Zouabi Lara , Huang Tien-Chi , Rotival Maxime , Sardini Alessandro , Chan Thalia E. , Filippi Sarah , Stumpf Michael P.H. , Petretto Enrico , Hajkova Petra 
Published: July 2018

AbstractPluripotent stem cells (PSCs) can self-renew indefinitely while maintaining the ability to generate all cell types of the body. This plasticity is proposed to require heterogeneity in gene expression, driving a metastable state which may allow flexible cell fate choices. Contrary to this, naive PSC grown in fully defined ‘2i’ environmental conditions, containing small molecule inhibitors of MEK and GSK3 kinases, show homogenous pluripotency and lineage marker expression. However, here we show that 2i induces greater genome-wide heterogeneity than traditional serum-containing growth environments at the population level across both male and female PSCs. This heterogeneity is dynamic and reversible over time, consistent with a dynamic metastable equilibrium of the pluripotent state. We further show that the 2i environment causes increased heterogeneity in the calcium signalling pathway at both the population and single-cell level. Mechanistically, we identify loss of robustness regulators in the form of negative feedback to the upstream EGF receptor. Our findings advance the current understanding of the plastic nature of the pluripotent state and highlight the role of signalling pathways in the control of transcriptional heterogeneity. Furthermore, our results have critical implications for the current use of kinase inhibitors in the clinic, where inducing heterogeneity may increase the risk of cancer metastasis and drug resistance.
Modelling predation and mortality rates from the fossil record of gastropods
Authors: Budd Graham E. , Mann Richard P. 
Published: July 2018

AbstractGastropods often show signs of unsuccessful attacks by predators in the form of healed scars in their shells. As such, fossil gastropods can be taken as providing a record of predation through ge-ological time. However, interpreting the number of such scars has proved to be problematic - would a low number of scars mean a low rate of attack, or a high rate of success, for example? Here we develop a model of scar formation, and formally show that in general these two variables cannot be disambiguated without further information about population structure. Nevertheless, by making the probably reasonable assumptions that the non-predatory death rate is both constant and low, we show that it is possible to use relatively small assemblages of gastropods to produce accurate estimates of both attack and success rates, if the overall death rate can be estimated. We show in addition what sort of information would be required to solve this problem in more general cases. However, it is unlikely that it will be possible to extract the relevant information easily from the fossil record: a variety of important collection and taphonomic biases are likely to intervene to obscure the data that gastropod assemblages may yield.
De Novoassembly of the goldfish (Carassius auratus) genome and the evolution of genes after whole genome duplication
Authors: Chen Zelin , Omori Yoshihiro , Koren Sergey , Shirokiya Takuya , Kuroda Takuo , Miyamoto Atsushi , Wada Hironori , Fujiyama Asao , Toyoda Atsushi , Zhang Suiyuan , Wolfsberg Tyra G. , Kawakami Koichi , Phillippy Adam M. ,   NISC Comparative Sequencing Program, Mullikin James C. , Burgess Shawn M. 
Published: July 2018

SummaryFor over a thousand years throughout Asia, the common goldfish (Carassius auratus) was raised for both food and as an ornamental pet. Selective breeding over more than 500 years has created a wide array of body and pigmentation variation particularly valued by ornamental fish enthusiasts. As a very close relative of the common carp (Cyprinus carpio), goldfish shares the recent genome duplication that occurred approximately 14-16 million years ago (mya) in their common ancestor. The combination of centuries of breeding and a wide array of interesting body morphologies is an exciting opportunity to link genotype to phenotype as well as understanding the dynamics of genome evolution and speciation. Here we generated a high-quality draft sequence of a “Wakin” goldfish using 71X PacBio long-reads. We identified 70,324 coding genes and more than 11,000 non-coding transcripts. We found that the two sub-genomes in goldfish retained extensive synteny and collinearity between goldfish and zebrafish. However, “ohnologous” genes were lost quickly after the carp whole-genome duplication, and the expression of 30% of the retained duplicated gene diverged significantly across seven tissues sampled. Loss of sequence identity and/or exons determined the divergence of the expression across all tissues, while loss of conserved, non-coding elements determined expression variance between different tissues. This draft assembly also provides an important resource for comparative genomics with the very commonly used zebrafish model (Danio rerio), and for understanding the underlying genetic causes of goldfish variants.
Subjective perceptual experience tracks the neural signature of sensory evidence accumulation during decision formation
Authors: Tagliabue Chiara F. , Veniero Domenica , Benwell Christopher S. Y. , Cecere Roberto , Savazzi Silvia , Thut Gregor 
Published: July 2018

AbstractHow neural representations of low-level visual information are accessed by higher-order processes to inform decisions and give rise to conscious experience is a longstanding question. Research on perceptual decision making has revealed a late event-related EEG potential (the Centro-Parietal Positivity, CPP) to be a correlate of the accumulation of sensory evidence. We tested to what extent this evidence accumulation signal is driven by externally presented (physical) versus internally experienced (subjective) sensory evidence. The results show that the known relationship between external evidence and the evidence accumulation signal (reflected in the CPP amplitude) is mediated by the level of subjective awareness. Additionally, the CPP closely tracks the subjective perceptual evidence during both correct and incorrect trials. Hence, a remarkably close relationship exists between the evidence accumulation process (i.e. CPP) and subjective perceptual experience, suggesting that neural decision processes and components of conscious experience are tightly linked.
Structural determinants and genetic modifications enhance BMP2 stability and extracellular secretion
Authors: Khattar Vinayak , Lee Joo Hyoung , Wang Hong , Bastola Soniya , Ponnazhagan Selvarangan 
Published: July 2018

ABSTRACTThe short half-life and use of recombinant bone morphogentic protein (BMP)-2 in large doses poses major limitations in the clinic. Events regulating post-translational processing and degradation of BMP2 in situ, linked to its secretion, have not been understood. Towards identifying mechanisms regulating intracellular BMP2 stability, we first discovered that inhibiting proteasomal degradation enhances both intracellular BMP2 level and its extracellular secretion. Next, we identified BMP2 degradation occurs through an ubiquitin-mediated mechanism. Since ubiquitination precedes proteasomal turnover and mainly occurs on lysine residues of nascent proteins, we systematically mutated individual lysine residues within BMP2 and tested them for enhanced stability. Results revealed that substitutions on four lysine residues within the pro-BMP2 region and three in the mature region increased both BMP2 turnover and extracellular secretion. Structural modeling revealed key lysine residues involved in proteasomal degradation occupy a lysine cluster near proprotein convertase cleavage site. Interestingly, mutations within these residues did not affect biological activity of BMP2. These data suggest preventing intracellular proteasomal loss of BMP2 through genetic modifications can overcome limitations related to its short half-life.
EphB2 and ERK signaling are required for heterotypic contact inhibition of locomotion to drive cell sorting
Authors: Brayford Simon , Serna-Morales Eduardo , Luchici Andrei , Hiratsuka Toru , Stramer Brian M. 
Published: July 2018

SummaryInteractions between different cell-types can induce distinct contact inhibition of locomotion (CIL) responses that are hypothesized to control population-wide behaviors during embryogenesis [1, 2]. However, our understanding of the signals that lead to cell-type specific repulsion, and the precise capacity of heterotypic CIL responses to drive emergent behaviors is lacking. Using a new in vitro model of heterotypic CIL between epithelial and mesenchymal cells, we show that fibrosarcoma cells (HT1080), but not fibroblasts (NIH3T3), are actively repelled by epithelial cells in culture. We show that knocking down EphB2 in fibrosarcoma cells specifically leads to disruption of the repulsion phase of CIL in response to interactions with epithelial cells. Furthermore, this heterotypic interaction requires ERK activation, downstream of EphB2 signaling. We also examine the population-wide effects when these various cell combinations, and their specific heterotypic CIL responses, are allowed to interact in culture. Mixtures of fibrosarcoma and epithelial cells – unlike fibroblasts and epithelial cells – lead to complete sorting and segregation of the two populations, and inhibiting their distinct CIL response by knocking down EphB2 or ERK in fibrosarcoma cells disrupts this emergent sorting behavior. Our understanding of the mechanisms underlying developmental behaviors such as cell sorting is lacking as predominant sorting hypotheses, such as differential adhesion, have recently been found inadequate in predicting the sorting of mesenchymal cells [3, 4]. These data suggest that heterotypic CIL responses, in conjunction with processes such as differential adhesion, may aid the sorting of cell populations during embryogenesis.