bluuebunny/crossref_metadata_2025 huggingface dataset:
Does relaxing the infinite sites assumption give better tumor phylogenies? An ILP-based comparative approach
Authors: Bonizzoni Paola , Ciccolella Simone , Della Vedova Gianluca , Soto Mauricio
Published: December 2017

Most of the evolutionary history reconstruction approaches are based on the infinite site assumption, which is underlying the Perfect Phylogeny model and whose main consequence is that acquired mutation can never lost. This results in the clonal model used to explain cancer evolution. Some recent results gives a strong evidence that recurrent and back mutations are present in the evolutionary history of tumors [5,21], thus showing that more general models then the Perfect Phylogeny are required. We propose a new approach that incorporates the possibility of losing a previously acquired mutation, extending the Persistent Phylogeny model [1].

We exploit our model to provide an ILP formulation of the problem of reconstructing trees on mixed populations, where the input data consists of the fraction of cells in a set of samples that have a certain mutation. This is a fundamental problem in cancer genomics, where the goal is to study the evolutionary history of a tumor. An experimental analysis shows the usefulness of allowing mutation losses, by studying some real and simulated datasets where our ILP approach provides a better interpretation than the one obtained under perfect phylogeny assumption. Finally, we show how to incorporate multiple back mutations and recurrent mutations in our model.
ProteomeVis: a web app for exploration of protein properties from structure to sequence evolution across organisms’ proteomes
Authors: Gilson Amy I. , Durfee Niamh , Razban Rostam M. , Strobelt Hendrick , Dinkla Kasper , Choi Jeong-Mo , Pfister Hanspeter , Shakhnovich Eugene
Published: December 2017

Motivation

Protein evolution spans time scales and its effects span the length of an organism. A web app named ProteomeVis is developed to provide a comprehensive view of protein evolution in the S.cerevisiaeandE. coliproteomes. ProteomeVis interactively creates protein chain graphs, where edges between nodes represent structure and sequence similarities within user-defined ranges, to study the long time scale effects of protein structure evolution. The short time scale effects of protein sequence evolution is studied by sequence evolutionary rate (ER) correlation analyses with protein properties that span from the molecular to the organismal level.

Results

We demonstrate the utility and versatility of ProteomeVis by investigating the distribution of edges per node in organismal protein chain universe graphs (oPCUGs) and putative ER determinants. S.cerevisiaeand E.colioPCUGs are scale-free with scaling constants of 1.78 and 1.50, respectively. Both scaling constants can be explained by a previously reported theoretical model describing protein structure evolution (Dokholyanet al.,2002). Protein abundance most strongly correlates with ER among properties in ProteomeVis, with Spearman correlations of −0.51 (p-value<10−10) and −0.46 (p-value<10−10) for S.cerevisiaeandE. coli, respectively. This result is consistent with previous reports that found protein expression to be the most important ER determinant (Zhang and Yang, 2015).

Availability

ProteomeVis is freely accessible athttp://proteomevis.chem.harvard.edu/proteomevis/.

Contact

shakhnovich@chemistry.harvard.edu

Supplementary information

Available to download on bioRxiv.
Quantifying and visualising divergence between pairs of phylogenetic trees: implications for phylogenetic reconstruction
Authors: Smith Martin R.
Published: December 2017

Tree topologies are a primary output of phylogenetic analysis. It is important to understand how such outputs are influenced by the choice of phylogenetic method, and the nature and quality of input data. This often entails the measurement of how closely an output corresponds to an ideal tree topology. The symmetric difference (partition) metric is the only widely-used measure that is defined for trees that contain polytomies, but expresses undesirable behaviour in certain situations.

Here I propose a divergence metric for unweighted tree topologies based on quartet statements, which measures the topological information common to two trees. This metric reflects the contributions of both accuracy and precision to tree quality; these components can be decomposed through the use of ternary diagrams. This approach is implemented in a new package for the R statistical environment, and applied to a recent controversy, where it provides a new perspective on the relative merits of Bayesian and parsimony approaches to morphological phylogenetics.
Volatility estimates increase choice switching and relate to prefrontal activity in schizophrenia
Authors: Deserno L. , Boehme R. , Mathys C. , Katthagen T. , Kaminski J. , Stephan K. E. , Heinz A. , Schlagenhauf F.
Published: December 2017

Background

Reward-based decision-making is impaired in patients with schizophrenia (PSZ) as reflected by increased choice switching. The underlying cognitive and motivational processes as well as associated neural signatures remain unknown. Reinforcement Learning (RL) and hierarchical Bayesian learning account for choice switching in different ways. We hypothesized that enhanced choice switching, as seen in PSZ during reward-based decision-making, relates to higher-order beliefs about environmental volatility and examined the associated neural activity.

Methods

46 medicated PSZ and 43 healthy controls (HC) performed a reward-based decision-making task requiring flexible responses to changing action-outcome contingencies during functional Magnetic Resonance Imaging (fMRI). Detailed computational modeling of choice data was performed, including RL and the hierarchical Gaussian filter (HGF). Trajectories of learning from computational modeling informed the analysis of fMRI data.

Results

A three-level HGF accounted best for the observed choice data. This model revealed a heightened initial belief about environmental volatility and a stronger influence of volatility on lower-level learning of action-outcome contingencies in PSZ as compared to HC. This was replicated in an independent sample of non-medicated PSZ. Beliefs about environmental volatility were reflected by higher activity in dorsolateral prefrontal cortex of PSZ as compared to HC.

Conclusions

Our study suggests that PSZ inferred the environment as overly volatile, which may explain increased choice switching. In PSZ, activity in dorsolateral prefrontal cortex was more strongly related to beliefs about environmental volatility. Our computational phenotyping approach may provide useful information to dissect clinical heterogeneity and could improve prediction of outcome.
The physiological regulation of macropinocytosis duringDictyosteliumgrowth and development
Authors: Williams Thomas D. , Kay Robert R.
Published: December 2017

Macropinocytosis is a conserved endocytic process used byDictyosteliumamoebae for feeding on liquid medium. To furtherDictyosteliumas a model for macropinocytosis, we developed a high-throughput flow cytometry assay for macropinocytosis, and used it to identify inhibitors and investigate the physiological regulation of macropinocytosis.Dictyosteliumhas two feeding states: phagocytic and macropinocytic. When cells are switched from phagocytic growth on bacteria to liquid media, the rate of macropinocytosis slowly increases, due to increased size and frequency of macropinosomes. Upregulation is triggered by a minimal medium of 3 amino acids plus glucose and likely depends on macropinocytosis itself. Bacteria suppress macropinocytosis while their product, folate, partially suppresses upregulation of macropinocytosis. Starvation, which initiates development, does not of itself suppress macropinocytosis: this can continue in isolated cells, but is shut down by a conditioned-medium factor or activation of PKA signalling. Thus macropinocytosis is a facultative ability ofDictyosteliumcells, regulated by environmental conditions that are identified here.

A high-throughput flow cytometry assay shows that macropinocytosis inD. discoideumis upregulated in the presence of nutrients and absence of bacteria. Development and bacteria induce cells to downregulate macropinocytosis.
Unlocking the biological potential ofEuglena gracilis: evolution, cell biology and significance to parasitism
Authors: Ebenezer ThankGod E. , Zoltner Martin , Burrel Alana , Nenarokova Anna , Vanclová Anna M. G. Novák , Prasad Binod , Soukal Petr , Santana-Molina Carlos , O’Neill Ellis , Nankissoor Nerissa N. , Vadakedath Nithya , Daiker Viktor , Obado Samson , Jackson Andrew P. , Devos Damien , Lukeš Julius , Lebert Michael , Vaughan Sue , Hampl Vladimir , Carrington Mark , Ginger Michael L. , Dacks Joel B. , Kelly Steven , Field Mark C.
Published: December 2017

Photosynthetic euglenids are major components of aquatic ecosystems and relatives of trypanosomes.Euglena gracilishas considerable biotechnological potential and great adaptability, but exploitation remains hampered by the absence of a comprehensive gene catalogue. We address this by genome, RNA and protein sequencing: theE. gracilisgenome is >2Gb, with 36,526 predicted proteins. Large lineage-specific paralog families are present, with evidence for flexibility in environmental monitoring, divergent mechanisms for metabolic control, and novel solutions for adaptation to extreme environments. Contributions from photosynthetic eukaryotes to the nuclear genome, consistent with the shopping bag model are found, together with transitions between kinetoplastid and canonical systems. Control of protein expression is almost exclusively post-transcriptional. These data are a major advance in understanding the nuclear genomes of euglenids and provide a platform for investigating the contributions ofE. gracilisand its relatives to the biosphere.
Cancer subtype identification using somatic mutation data
Authors: Kuijjer Marieke L. , Paulson Joseph N. , Salzman Peter , Ding Wei , Quackenbush John
Published: December 2017

BACKGROUND

With the onset of next generation sequencing technologies, we have made great progress in identifying recurrent mutational drivers of cancer. As cancer tissues are now frequently screened for specific sets of mutations, a large amount of samples has become available for analysis. Classification of patients with similar mutation profiles may help identifying subgroups of patients who might benefit from specific types of treatment. However, classification based on somatic mutations is challenging due to the sparseness and heterogeneity of the data.

METHODS

Here, we describe a new method to de-sparsify somatic mutation data using biological pathways. We applied this method to 23 cancer types from The Cancer Genome Atlas, including samples from 5, 805 primary tumors.

RESULTS

We show that, for most cancer types, de-sparsified mutation data associates with phenotypic data. We identify poor prognostic subtypes in three cancer types, which are associated with mutations in signal transduction pathways for which targeted treatment options are available. We identify subtype-drug associations for 14 additional subtypes. Finally, we perform a pan-cancer subtyping analysis and identify nine pan-cancer subtypes, which associate with mutations in four overarching sets of biological pathways.

CONCLUSIONS

This study is an important step towards understanding mutational patterns in cancer.
Interpretation of biological experiments changes with evolution of Gene Ontology and its annotations
Authors: Tomczak Aurelie , Mortensen Jonathan M. , Winnenburg Rainer , Liu Charles , Alessi Dominique T. , Swamy Varsha , Vallania Francesco , Lofgren Shane , Haynes Winston , Shah Nigam H. , Musen Mark A. , Khatri Purvesh
Published: December 2017

Gene Ontology (GO) enrichment analysis is ubiquitously used for interpreting high throughput molecular data and generating hypotheses about underlying biological phenomena of experiments. However, the two building blocks of this analysis — the ontology and the annotations — evolve rapidly. We used gene signatures derived from 104 disease analyses to systematically evaluate how enrichment analysis results were affected by evolution of the GO over a decade. We found low consistency between enrichment analyses results obtained with early and more recent GO versions. Furthermore, there continues to be strong annotation bias in the GO annotations where 58% of the annotations are for 16% of the human genes. Our analysis suggests that GO evolution may have affected the interpretation and possibly reproducibility of experiments over time. Hence, researchers must exercise caution when interpreting GO enrichment analyses and should reexamine previous analyses with the most recent GO version.
Multiplex Confounding Factor Correction for Genomic Association Mapping with Squared Sparse Linear Mixed Model
Authors: Wang Haohan , Liu Xiang , Xiao Yunpeng , Xu Ming , Xing Eric P.
Published: December 2017

Genome-wide Association Study has presented a promising way to understand the association between human genomes and complex traits. Many simple polymorphic loci have been shown to explain a significant fraction of phenotypic variability. However, challenges remain in the non-triviality of explaining complex traits associated with multifactorial genetic loci, especially considering the confounding factors caused by population structure, family structure, and cryptic relatedness. In this paper, we propose a Squared-LMM (LMM2) model, aiming to jointly correct population and genetic confounding factors. We offer two strategies of utilizing LMM2 for association mapping: 1) It serves as an extension of univariate LMM, which could effectively correct population structure, but consider each SNP in isolation. 2) It is integrated with the multivariate regression model to discover association relationship between complex traits and multifactorial genetic loci. We refer to this second model as sparse Squared-LMM (sLMM2). Further, we extend LMM2/sLMM2 by raising the power of our squared model to the LMMn/sLMMn model. We demonstrate the practical use of our model with synthetic phenotypic variants generated from genetic loci of Arabidopsis Thaliana. The experiment shows that our method achieves a more accurate and significant prediction on the association relationship between traits and loci. We also evaluate our models on collected phenotypes and genotypes with the number of candidate genes that the models could discover. The results suggest the potential and promising usage of our method in genome-wide association studies.
A novel method for estimating LDC levels: total cholesterol and non-HDLC can be used to predict the normal LDLC level in apparently healthy population
Authors: Zhang Guo-Ming , Bai Shumei , Zhang Gao-Ming , Ma Xiao-Bo
Published: December 2017

Background

Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), and low-density lipoprotein cholesterol (LDLC) are usually ordered together to test lipid metabolism in physical examination and clinical application. LDLC is a component of TC and its change is closely correlated to TC.

Objective

We aim to predict the normal LDLC level by using TG, TC, HDLC and non-HDLC (nonHDLC) in this study.

Methods

TG, TC, HDLC, and LDLC data were obtained from Laboratory Information System (LIS) based on 4 years (Octo, 1, 2013-Sept, 30, 2017) period health check-up TG, TC, HDLC, and LDLC(direct clearance method) were measured using TBA2000FR biochemical analyzer. The nonHDLC was calculated with TC minus HDLC. Correlation between TG, TC, nonHDLC, and LDLC were analyzed using Spearman’s rank approach. Receiver operating characteristics curve analysis was used to evaluate the predictive of TG, TC and nonHDLC for the normal LDLC level(less than 130mg/dL).

Results

Both TC(r = 0.870) and nonHDLC (r = 0.893) were significantly positively correlated with LDLC. Area under curve of TC and nonHDLC can be used to predict normal LDLC level. Optimal thresholds were 182.5 mg/dL(4.72 mmol/L) for TC and 135.3 mg/dL(3.50 mmol/L) for nonHDLC. Based on these optimal thresholds, less than 0.5% and 0.4% of tests with elevated LDLC might be missed, but the missing elevated LDLC is not too high(less than 147.3 mg/dL).

Conclusion

If the nonHDLC is less than 135.3mg/dL(3.50 mmol/L) and/or TC is less than 182.5mg/dL(4.72 mmol/L) for the apparently healthy populations the LDLC level will be less than 130mg/dL(3.36 mmol/L). Total cholesterol and non-HDLC can be used to predict the normal LDLC level in apparently healthy population is a novel method for estimating LDC level.
Altered transcription factor binding events predict personalized gene expression and confer insight into functional cis-regulatory variants
Authors: Shi Wenqiang , Fornes Oriol , Wasserman Wyeth W.
Published: December 2017

Deciphering the functional roles of cis-regulatory variants is a critical challenge in genome analysis and interpretation. We hypothesize that altered transcription factor (TF) binding events are a central mechanism by which cis-regulatory variants impact gene expression. We present TF2Exp, the first gene-based framework (to our knowledge) to predict the impact of altered TF binding on personalized gene expression based on cis-regulatory variants. Using data from lymphoblastoid cell lines, TF2Exp models achieved suitable performance for 3,060 genes. Alterations within DNase I hypersensitive, CTCF-bound, and tissue-specific TF-bound regions were the greatest contributors to the models. Our cis-regulatory variant-based TF2Exp models performed as well as the state-of-the-art SNP-based models, both in cross-validation and external validation. In addition, unlike SNP-based models, our TF2Exp models have the unique advantages to evaluate impact of uncommon variants and distinguish the functional roles of variants in linkage disequilibrium, showing broader utility for future human genetic studies.
Dynamical model of the CLC-2 ion channel exhibits a two-step gating mechanism
Authors: McKiernan Keri A. , Koster Anna K. , Maduke Merritt , Pande Vijay S.
Published: December 2017

This work reports a dynamical Markov state model of CLC-2 “fast” (pore) gating, based on 600 microseconds of molecular dynamics (MD) simulation. In the starting conformation of our CLC-2 model, both outer and inner channel gates are closed. The first conformational change in our dataset involves rotation of the inner-gate backbone along residues S168-G169-I170. This change is strikingly similar to that observed in the cryo-EM structure of the bovine CLC-K channel, though the volume of the intracellular (inner) region of the ion conduction pathway is further expanded in our model. From this state (inner gate open and outer gate closed), two additional states are observed, each involving a unique rotameric flip of the outer-gate residue GLUex. Both additional states involve conformational changes that orient GLUexaway from the extracellular (outer) region of the ion conduction pathway. In the first additional state, the rotameric flip of GLUexresults in an open, or near-open, channel pore. The equilibrium population of this state is low (∼1%), consistent with the low open probability of CLC-2 observed experimentally in the absence of a membrane potential stimulus (0 mV). In the second additional state, GLUexrotates to occlude the channel pore. This state, which has a low equilibrium population (∼1%), is only accessible when GLUexis protonated. Together, these pathways model the opening of both an inner and outer gate within the CLC-2 selectivity filter, as a function of GLUexprotonation. Collectively, our findings are consistent with published experimental analyses of CLC-2 gating and provide a high-resolution structural model to guide future investigations.

Author summary

In the brain, the roles and mechanisms of sodium-, potassium-, and calcium-selective ion channels are well established. In contrast, chloride-selective channels have been studied much less and are not sufficiently understood, despite known associations of chloride-channel defects with brain disorders. The most broadly expressed voltage-activated chloride channel in the brain is CLC-2 (one of 9 human CLC homologs). In this work, we use simulations to model the conformational dynamics of the CLC-2 chloride ion channel selectivity filter (SF), which is the part of the protein that controls whether the channel is in an ion-conducting or non-conducting state. Our analysis identifies four primary conformational states and a specific progression through these states. Our results are consistent with structural and functional data in the literature and provide a high-resolution model for guiding further studies of CLC-2. These results will inform our understanding of how CLC-2 governs electrical activity and ion homeostasis in the brain.
Social and non-social autism symptom and trait domains are genetically dissociable
Authors: Warrier Varun , Toro Roberto , Won Hyejung , Leblond Claire S , Cliquet Freddy , Delorme Richard , De Witte Ward , Bralten Janita , Chakrabarti Bhismadev , Børglum Anders D , Grove Jakob , Poelmans Geert ,   the 23andMe Research Team, Hinds David A. , Bourgeron Thomas , Baron-Cohen Simon
Published: December 2017

The core diagnostic criteria for autism comprise two symptom domains – social and communication difficulties, and unusually repetitive and restricted behaviour, interests and activities. There is some evidence to suggest that these two domains are dissociable, yet, this hypothesis has not been tested using molecular genetics. We test this using a GWAS of a non-social autistic trait, systemizing (N = 51,564), defined as the drive to analyse and build systems. We demonstrate that systemizing is heritable and genetically correlated with autism. In contrast, we do not identify significant genetic correlations between social autistic traits and systemizing. Supporting this, polygenic scores for systemizing are significantly positively associated with restricted and repetitive behaviour but not with social difficulties in autistic individuals. These findings strongly suggest that the two core domains of autism are genetically dissociable, and point at how to fractionate the genetics of autism.
On-line Optimization of Hamiltonian Replica Exchange Simulations
Authors: MacCallum Justin L. , Muniyat Mir Ishruna , Gaalswyk Kari
Published: December 2017

Replica exchange is a widely used sampling strategy in molecular simulation. While a variety of methods exist for optimizing temperature replica exchange, less is known about how to optimize more general Hamiltonian replica exchange simulations. We present an algorithm for the on-line optimization of both temperature and Hamiltonian replica exchange simulations that draws on techniques from the optimization of deep neural networks in machine learning. We optimize a heuristic-based objective function capturing the efficiency of replica exchange. Our approach is general, and has several desirable properties, including: (1) it makes few assumptions about the system of interest; (2) optimization occurs on-line wihout the requirement of pre-simulation; and (3) it readily generalizes to systems where there are multiple control parameters per replica. We explore some general properties of the algorithm on a simple harmonic oscillator system, and demonstrate its effectiveness on a more complex data-guided protein folding simulation.
Combined aptamer and transcriptome sequencing of single cells
Authors: Delley Cyrille L. , Liu Leqian , Sarhan Maen F. , Abate Adam R.
Published: December 2017

The transcriptome and proteome encode distinct information that is important for characterizing heterogeneous biological systems. We demonstrate a method to simultaneously characterize the transcriptomes and proteomes of single cells at high throughput using aptamer probes and droplet-based single cell sequencing. With our method, we differentiate distinct cell types based on aptamer surface binding and gene expression patterns. Aptamers provide advantages over antibodies for single cell protein characterization, including rapid, in vitro, and high-purity generation via SELEX, and the ability to amplify and detect them with PCR and sequencing.
Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington’s disease
Authors: Song Wan , Zsindely Nóra , Faragó Anikó , Marsh J. Lawrence , Bodai László
Published: December 2017

Huntington’s Disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in aDrosophila melanogasterHD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT induced pathology while reducing PRC2 complex core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.
Downstream promoter interactions of TFIID TAFs facilitate transcription reinitiation
Authors: Joo Yoo Jin , Ficarro Scott B. , Soares Luis M. , Chun Yujin , Marto Jarrod A. , Buratowski Stephen
Published: December 2017

TFIID binds promoter DNA to recruit RNA polymerase II and other basal factors for transcription. Although the TATA-binding protein (TBP) subunit of TFIID is necessary and sufficient for in vitro transcription, the TBP-associated factor (TAF) subunits recognize downstream promoter elements, act as coactivators, and interact with nucleosomes. In yeast nuclear extracts, transcription induces stable TAF binding to downstream promoter DNA, promoting subsequent activator-independent transcription reinitiation. In vivo, promoter responses to TAF mutations correlate with the level of downstream, rather than overall, Taf1 cross-linking. We propose a new model in which TAFs function as reinitiation factors, accounting for the differential responses of promoters to various transcription factor mutations.
Disruptive innovation at the base-of-the-pyramid
Authors: Adegbile Abiodun , Sarpong David
Published: December 2017

Purpose

The authors aim to examine the potential opportunities and challenges multinationals operating in Africa are likely to encounter when they seek to pioneer disruptive innovations at the base of the pyramid (BoP) in African emerging markets.

Design/methodology/approach

Drawing on the extant literature on the BoP, disruptive innovation and the African business context, the authors explore the pioneering of disruptive innovations in the African socio-economic context.

Findings

This study develops various hypotheses to extend our understanding of disruptive innovations at the BoP. The authors also delineate potential managerial and institutional challenges multinational corporations (MNCs) are likely to encounter in their efforts to pioneering disruptive innovations for BoP customers in African emerging markets.

Practical implications

The authors develop some recommendations for MNCs on how to create and capture value from disruptive innovations in African emerging markets

Originality/value

The authors delineate African context-specific managerial and institutional challenges that MNCs might encounter when seeking to develop disruptive innovation at the BoP.
How do Italian vocational teachers educate for a sense of initiative and entrepreneurship? Development and initial application of the SIE questionnaire
Authors: Morselli Daniele
Published: December 2017

Purpose

The purpose of this paper is to examine how educators can teach the key competence of a sense of initiative and entrepreneurship (SIE) as a cross-curricular subject in compulsory education. It draws both on the literature relating to entrepreneurial education and on competence-based education to set out five features of entrepreneurial teaching. For illustrative purposes, these five characteristics are explored in a questionnaire put to a small group of teaching staff.

Design/methodology/approach

This study employs a qualitative approach, seeking to understand the personal perspectives of participants, and drawing out the complexities of their behaviour, whilst also providing a holistic interpretation of such behaviour.

Findings

The literature review identifies five features of entrepreneurial teaching: embedding learning outcomes for a SIE within taught subjects; active entrepreneurial teaching; educating for entrepreneurial attitudes; networking activities; being entrepreneurial as part of lifelong learning. It can be hypothesised that teaching staff teach different aspects of the SIE depending on the subject they teach (vocational or more traditional) and their role (teacher or workshop assistant).

Originality/value

Development of the SIE and the five characteristics of entrepreneurial teaching is a first step towards understanding how secondary vocational teachers and workshop assistants understand and teach the SIE as cross-curricular subject. In line with Fayolle and Gailly who called for deeper investigation of the most effective combinations of objectives, content and teaching methods, the paper seeks to establish a relationship between teaching methods, development of entrepreneurial attitudes and assessment.
Information as signs
Authors: Thellefsen Martin Muderspach , Thellefsen Torkild , Sørensen Bent
Published: December 2017

Purpose

The purpose of this paper is to formulate an analytical framework for the information concept based on the semiotic theory.

Design/methodology/approach

The paper is motivated by the apparent controversy that still surrounds the information concept. Information, being a key concept within LIS, suffers from being anchored in various incompatible theories. The paper suggests that information is signs, and it demonstrates how the concept of information can be understood within C.S. Peirce’s phenomenologically rooted semiotic. Hence, from there, certain ontological conditions as well epistemological consequences of the information concept can be deduced.

Findings

The paper argues that an understanding of information, as either objective or subjective/discursive, leads to either objective reductionism and signal processing, that fails to explain how information becomes meaningful at all, or conversely, information is understood only relative to subjective/discursive intentions, agendas, etc. To overcome the limitations of defining information as either objective or subjective/discursive, a semiotic analysis shows that information understood as signs is consistently sensitive to both objective and subjective/discursive features of information. It is consequently argued that information as concept should be defined in relation to ontological conditions having certain epistemological consequences.

Originality/value

The paper presents an analytical framework, derived from semiotics, that adds to the developments of the philosophical dimensions of information within LIS.
Effect of Hazardous Alcohol Use During Pregnancy on Growth Outcomes at Birth: Findings from a South African Cohort Study
Authors: Myers Bronwyn , Koen Nastassja , Donald Kirsten A. , Nhapi Raymond T. , Workman Lesley , Barnett Whitney , Hoffman Nadia , Koopowitz Sheri , Zar Heather J. , Stein Dan J.
Published: December 2017

Background

Cohort studies have noted associations between hazardous alcohol use during pregnancy and infant growth outcomes, but many have not controlled for potential psychosocial confounders. To assess the unique contribution of hazardous alcohol use, we examined its effect on infant growth outcomes while controlling for maternal psychosocial stressors and hazardous tobacco and drug use in a cohort of 986 pregnant South African women enrolled into the Drakenstein Child Health Study between 2012 and 2015.

Methods

Data on psychosocial stressors and maternal risk behaviors were collected between 28 and 32 weeks of gestation. Participants were categorized as hazardous alcohol users if they obtained moderate or high scores (>10) on the Alcohol, Smoking and Substance Involvement Screening Test at this assessment or retrospectively reported drinking at least 2 drinks weekly during any trimester of pregnancy. Infant growth outcomes were recorded at delivery. Multivariable regression models examined correlates of hazardous alcohol use and associations between hazardous alcohol use and birth outcomes.

Results

Overall, 13% of mothers reported hazardous alcohol use. Recent exposure to intimate partner violence (adjusted odds ratio (aOR) = 2.08; 95% confidence interval (CI): 1.37, 3.18) and hazardous tobacco use (aOR = 5.03; 95% CI: 2.97, 8.52) were significant correlates of hazardous alcohol use. After controlling for potential psychosocial confounders, hazardous alcohol use remained associated with lower infant weight‐for‐age (B = −0.35, 95% CI: −0.56, −0.14), height‐for‐age (B = −0.46, 95% CI: −0.76, −0.17), and head‐circumference‐for‐age z‐scores (B = −0.43, 95% CI: −0.69, −0.17).

Conclusions

Interventions to reduce hazardous alcohol use among pregnant women in South Africa are needed to prevent alcohol‐related infant growth restrictions. As these growth deficits may lead to neurodevelopmental consequences, it is critical to identify alcohol‐related growth restrictions at birth and link exposed infants to early interventions for neurodevelopment.
Intra‐ocular diathermy forceps
Authors: van Overdam Koen A. , Kilic Emine , Verdijk Robert M. , Manning Sonia
Published: December 2017

Purpose

The purpose of this study was to develop intra‐ocular diathermy forceps and test them on perfused porcine cadaver eyes.

Methods

We designed two types of 23‐gauge intra‐ocular bipolar diathermy forceps by modifying commercially available membrane peeling forceps. In the first type, the emitting electrode is connected to one‐half of the core and the return electrode to the other half, with one jaw of the forceps attached to each half. In the second type, the emitting electrode is attached to the core and both jaws of the forceps, and the return electrode to the surrounding tube. We compared the new diathermy forceps to conventional intra‐ocular diathermy, on perfused porcine cadaver eyes. First‐order retinal artery and vein closure was confirmed both by a perfusion study and by histology of the treated vessels.

Results

Type 1 diathermy forceps closed retinal arteries and veins more successfully (five of five and five of five successful treatments, respectively) than Type 2 diathermy forceps (five of five and four of five, respectively) and conventional diathermy (three of five and four of five, respectively). Less energy was used with Type 1 compared to Type 2 and conventional for artery closure (1.5 ± 0.0 versus 4.6 ± 3.3 versus 2.1 ± 0.8 joules, respectively) and vein closure (1.5 ± 0.0 versus 5.4 ± 4.6 versus 2.4 ± 0.8 joules, respectively). Histology of the treated vessels confirmed the perfusion study results.

Conclusion

We designed two types of a new multifunctional intra‐ocular instrument with the ability to peel membranes and to grasp, compress and coagulate retinal blood vessels. Both types pose operational advantages compared to current conventional intra‐ocular diathermy.
High‐intensity interval training improves insulin sensitivity in older individuals
Authors: Søgaard D. , Lund M. T. , Scheuer C. M. , Dehlbæk M. S. , Dideriksen S. G. , Abildskov C. V. , Christensen K. K. , Dohlmann T. L. , Larsen S. , Vigelsø A. H. , Dela F. , Helge J. W.
Published: December 2017

Aim

Metabolic health may deteriorate with age as a result of altered body composition and decreased physical activity. Endurance exercise is known to counter these changes delaying or even preventing onset of metabolic diseases. High‐intensity interval training (HIIT) is a time efficient alternative to regular endurance exercise, and the aim of this study was to investigate the metabolic benefit of HIIT in older subjects.

Methods

Twenty‐two sedentary male (n = 11) and female (n = 11) subjects aged 63 ± 1 years performed HIIT training three times/week for 6 weeks on a bicycle ergometer. Each HIIT session consisted of five 1‐minute intervals interspersed with 1½‐minute rest. Prior to the first and after the last HIIT session whole‐body insulin sensitivity, measured by a hyperinsulinaemic‐euglycaemic clamp, plasma lipid levels, HbA1c, glycaemic parameters, body composition and maximal oxygen uptake were assessed. Muscle biopsies were obtained wherefrom content of glycogen and proteins involved in muscle glucose handling were determined.

Results

Insulin sensitivity (P = .011) and maximal oxygen uptake increased (P < .05) in both genders, while plasma cholesterol (P < .05), low‐density lipoprotein (P < .05), visceral fat mass (P < .05) and per cent body fat (P < .05) decreased after 6 weeks of HIIT. HbA1c decreased only in males (P = .001). Muscle glycogen content increased in both genders (P = .001) and in line GLUT4 (P < .05), glycogen synthase (P = .001) and hexokinase II (P < .05) content all increased.

Conclusion

Six weeks of HIIT significantly improves metabolic health in older males and females by reducing age‐related risk factors for cardiometabolic disease.
Characterization of the properties of a selective, orally bioavailable autotaxin inhibitor in preclinical models of advanced stages of liver fibrosis
Authors: Baader Manuel , Bretschneider Tom , Broermann Andre , Rippmann Joerg F , Stierstorfer Birgit , Kuttruff Christian A , Mark Michael
Published: December 2017

Background and Purpose

Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non‐alcoholic steatohepatitis (NASH) remains unclear.

Experimental Approach

The relevance of ATX in the pathogenesis of liver fibrosis was investigated by oral administration of Ex_31, a selective ATX inhibitor, in a 10 week model of carbon tetrachloride‐induced liver injury and in a 14 week model of choline‐deficient amino acid‐defined diet‐induced liver injury in rats.

Key Results

Oral administration of Ex_31, a selective ATX inhibitor, at 15 mg·kg−1 twice daily in therapeutic intervention mode resulted in efficient ATX inhibition and more than 95% reduction in plasma LPA levels in both studies. Treatment with Ex_31 had no effect on biomarkers of liver function, inflammation, or fibrosis and did not result in histological improvements in diseased animals.

Conclusions and Implications

Our findings question the role of ATX in the pathogenesis of hepatic fibrosis and the potential of small molecule ATX inhibitors for the treatment of patients with NASH and advanced stages of liver fibrosis.
The national burden of influenza‐associated severe acute respiratory illness hospitalization in Rwanda, 2012‐2014
Authors: Nyamusore José , Rukelibuga Joseph , Mutagoma Mwumvaneza , Muhire Andrew , Kabanda Alice , Williams Thelma , Mutoni Angela , Kamwesiga Julius , Nyatanyi Thierry , Omolo Jared , Kabeja Adeline , Koama Jean Baptiste , Mukarurangwa Agrippine , Umuringa Jeanne d'Arc , Granados Carolina , Gasana Michel , Moen Ann , Tempia Stefano
Published: December 2017

Background

Estimates of influenza‐associated hospitalization are severely limited in low‐ and middle‐income countries, especially in Africa.

Objectives

To estimate the national number of influenza‐associated severe acute respiratory illness (SARI) hospitalization in Rwanda.

Methods

We multiplied the influenza virus detection rate from influenza surveillance conducted at 6 sentinel hospitals by the national number of respiratory hospitalization obtained from passive surveillance after adjusting for underreporting and reclassification of any respiratory hospitalizations as SARI during 2012‐2014. The population at risk was obtained from projections of the 2012 census. Bootstrapping was used for the calculation of confidence intervals (CI) to account for the uncertainty associated with all levels of adjustment. Rates were expressed per 100 000 population. A sensitivity analysis using a different estimation approach was also conducted.

Results

SARI cases accounted for 70.6% (9759/13 813) of respiratory admissions at selected hospitals: 77.2% (6783/8786) and 59.2% (2976/5028) among individuals aged <5 and ≥5 years, respectively. Overall, among SARI cases tested, the influenza virus detection rate was 6.3% (190/3022): 5.7% (127/2220) and 7.8% (63/802) among individuals aged <5 and ≥5 years, respectively. The estimated mean annual national number of influenza‐associated SARI hospitalizations was 3663 (95% CI: 2930‐4395—rate: 34.7; 95% CI: 25.4‐47.7): 2637 (95% CI: 2110‐3164—rate: 168.7; 95% CI: 135.0‐202.4) among children aged <5 years and 1026 (95% CI: 821‐1231—rate: 11.3; 95% CI: 9.0‐13.6) among individuals aged ≥5 years. The estimates obtained from both approaches were not statistically different (overlapping CIs).

Conclusions

The burden of influenza‐associated SARI hospitalizations was substantial and was highest among children aged <5 years.
The impact of silver nanoparticles integration on biofilm formation and mechanical properties of glass ionomer cement
Authors: El‐Wassefy Noha A. , El‐Mahdy Rasha H. , El‐Kholany Naglaa R.
Published: December 2017

Objectives

To study the effect of silver nanoparticles incorporation to glass ionomer cement (GIC) on the Staphylococcus aureus biofilm in terms of bacterial growth and evaluate the incorporating effect on hardness and compressive strength.

Methods

Silver nanopowder was added in concentration 0, 1, 3, and 5 wt% to the conventional powder of GIC Fuji IX GP and then the powder is added to the liquid and mixed together with the recommended Powder/liquid ratio of 3.6:1 g. One hundred and twenty disc and cylindrical‐shaped specimens were prepared using teflon molds. The specimens were put in tissue culture plate wells contained S. aureus in brain–heart infusion broth. The plate was incubated at 37°C for 24 h. Specimens were then washed, fixed, dehydrated, and air dried. The spatial distribution of biofilm was examined via scanning electron microscope. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were also evaluated. After setting, the specimens were stored in distilled water for 24 h before testing for microhardness and compressive strength.

Results

Scanning electron photomicrographs of biofilm formed on the control GIC, showed a consistent biofilm with a thick sheet of cells, whereas those formed were less dense at 3 wt% and below the detection limit at 5 wt% silver nanoparticles. MIC and MBC of S. aureus were 25 and 50 µg/mL, respectively. The microhardness and compressive strength values of tested groups showed a nonsignificant decrease from the control group, P = .58 and .82, respectively.

Conclusion

Incorporation of silver nanoparticles with GIC can limit S. aureus biofilm formation with an insignificant effect on mechanical properties and noticeable influence on its coloration, which restrict its usage in areas where esthetic is not of major concern.

Clinical significance

As the modification of GIC with silver nanoparticles improved the antibiofilm properties without altering its mechanical properties, it could be used as a restoration of root carious lesion mainly in nonesthetic areas, a base under composite restorations in deep posterior cavities and as a core material in caries susceptible patients.
Oro‐facial pain and temporomandibular disorders classification systems: A critical appraisal and future directions
Authors: Klasser G. D. , Manfredini D. , Goulet J.‐P. , De Laat A.
Published: December 2017

It is a difficult undertaking to design a classification system for any disease entity, let alone for oro‐facial pain (OFP) and more specifically for temporomandibular disorders (TMD). A further complication of this task is that both physical and psychosocial variables must be included. To augment this process, a two‐step systematic review, adhering to PRISMA guidelines, of the classification systems published during the last 20 years for OFP and TMD was performed. The first search step identified 190 potential citations which ultimately resulted in only 17 articles being included for in‐depth analysis and review. The second step resulted in only 5 articles being selected for inclusion in this review. Five additional articles and four classification guidelines/criteria were also included due to expansion of the search criteria. Thus, in total, 14 documents comprising articles and guidelines/criteria (8 proposals of classification systems for OFP; 6 for TMD) were selected for inclusion in the systematic review. For each, a discussion as to their advantages, strengths and limitations was provided. Suggestions regarding the future direction for improving the classification process with the use of ontological principles rather than taxonomy are discussed. Furthermore, the potential for expanding the scope of axes included in existing classification systems, to include genetic, epigenetic and neurobiological variables, is explored. It is therefore recommended that future classification system proposals be based on combined approaches aiming to provide archetypal treatment‐oriented classifications.
Priming of Nicotiana benthamiana antioxidant defences using brown seaweed extracts
Authors: Esserti Siham , Smaili Amal , Makroum Kacem , Belfaiza Malika , Rifai Lalla Aicha , Koussa Tayeb , Kasmi Imane , Faize Mohamed
Published: December 2017

Extracts from the brown seaweeds Cystoseira myriophylloides, Laminaria digitata and Fucus spiralis were evaluated as plant defence inducers against the wild fire disease of Nicotiana benthamiana. Seeds’ imbibition in aqueous seaweed extracts (SE) results in plants with reduced disease severity. In addition, bacterial populations were significantly reduced in these plants when compared to those germinated in sterile distilled water. They primed N. benthamiana for H2O2 accumulation and for enhanced activity of several antioxidant enzymes including catalase, ascorbate peroxidase, guaiacol peroxidase and polyphenol oxidase. These results revealed that soaking of seeds in SE before sowing allows N. benthamiana to reduce pathogen attack and can be easily applied in practice.