bluuebunny/crossref_metadata_2025 huggingface dataset:
OCSANA+: Optimal Control and Simulation of Signaling Networks from Network Analysis
Authors: Marazzi Lauren , Gainer-Dewar Andrew , Vera-Licona Paola
Published: October 2019

OCSANA+ is a Cytoscape app for identifying nodes to drive the system towards a desired long-term behavior, prioritizing combinations of interventions in large scale complex networks, and estimating the effects of node perturbations in signaling networks, all based on the analysis of the network’s structure. OCSANA+ includes an update to OCSANA (optimal combinations of interventions from network analysis) software tool with cutting-edge and rigorously tested algorithms, together with recently-developed structure-based control algorithms for non-linear systems and an algorithm for estimating signal flow. All these algorithms are based on the network’s topology. OCSANA+ is implemented as a Cytoscape app to enable a user interface for running analyses and visualizing results.

Availability and Implementation

OCSANA+ app and its tutorial can be downloaded from the Cytoscape App Store or https://veraliconaresearchgroup.github.io/OCSANA-Plus/. The source code and computations are available in https://github.com/VeraLiconaResearchGroup/OCSANA-Plus_SourceCode.
Selective 40S footprinting reveals that scanning ribosomes remain cap-tethered in human cells
Authors: Bohlen Jonathan , Fenzl Kai , Kramer Günter , Bukau Bernd , Teleman Aurelio A.
Published: October 2019

Translation regulation occurs largely during initiation. Currently, translation initiation can be studied in vitro, but these systems lack features present in vivo and on endogenous mRNAs. Here we develop selective 40S footprinting for visualizing initiating 40S ribosomes on endogenous mRNAs in vivo. It pinpoints where on an mRNA initiation factors join the ribosome to act, and where they leave. We discover that in human cells most scanning ribosomes remain attached to the 5’ cap. Consequently, only one ribosome scans a 5’UTR at a time, and 5’UTR length affects translation efficiency. We discover that eIF3B, eIF4G1 and eIF4E remain on translating 80S ribosomes with a decay half-length of ∼12 codons. Hence ribosomes retain these initiation factors while translating short upstream Open Reading Frames (uORFs), providing an explanation for how ribosomes can re-initiate translation after uORFs in humans. This method will be of use for studying translation initiation mechanisms in vivo.

HIGHLIGHTS

Selective 40S FPing visualizes regulation of translation initiation on mRNAs in vivo

Scanning ribosomes are cap-tethered in human cells

Only one ribosome scans a 5’UTR at a time in human cells

Ribosomes retain eIFs during early translation, allowing reinitiation after uORFs
A selective inference approach for FDR control using multi-omics covariates yields insights into disease risk
Authors: Yurko Ronald , G’Sell Max , Roeder Kathryn , Devlin Bernie
Published: October 2019

To correct for a large number of hypothesis tests, most researchers rely on simple multiple testing corrections. Yet, new methodologies of selective inference could potentially improve power while retaining statistical guarantees, especially those that enable exploration of test statistics using auxiliary information (covariates) to weight hypothesis tests for association. We explore one such method, adaptive p-value thresholding (Lei & Fithian 2018, AdaPT), in the framework of genome-wide association studies (GWAS) and gene expression/coexpression studies, with particular emphasis on schizophrenia (SCZ). Selected SCZ GWAS association p-values play the role of the primary data for AdaPT; SNPs are selected because they are gene expression quantitative trait loci (eQTLs). This natural pairing of SNPs and genes allow us to map the following covariate values to these pairs: GWAS statistics from genetically-correlated bipolar disorder, the effect size of SNP genotypes on gene expression, and gene-gene coexpression, captured by subnetwork (module) membership. In all 24 covariates per SNP/gene pair were included in the AdaPT analysis using flexible gradient boosted trees. We demonstrate a substantial increase in power to detect SCZ associations using gene expression information from the developing human prefontal cortex (Werling et al. 2019). We interpret these results in light of recent theories about the polygenic nature of SCZ. Importantly, our entire process for identifying enrichment and creating features with independent complementary data sources can be implemented in many different high-throughput settings to ultimately improve power.
Integrating citizen science data with expert surveys increases accuracy and spatial extent of species distribution models
Authors: Robinson O.J. , Ruiz-Gutierrez V. , Reynolds M.D. , Golet G.H. , Strimas-Mackey M. , Fink D.
Published: October 2019

Information on species’ habitat associations and distributions, across a wide range of spatial and temporal scales, are a fundamental source of ecological knowledge. However, collecting biological information at relevant scales if often cost prohibitive, although it is essential for framing the broader context of more focused research and conservation efforts. Citizen-science data has been signaled as an increasingly important source of biological information needed to fill in data gaps needed to make more comprehensive and robust inferences on species distributions. However, there are perceived trade-offs of combining highly structured, scientific survey data with largely unstructured, citizen-science data. As a result, the focus of most methodological advances to combine these sources of information has been on treating these sources as independent. The degree to which each source of information is allowed to directly inform a common underlying process (e.g. species distribution) depends on the perceived quality of the data. In this paper, we explore these trade-offs by applying a simplified approach of filtering citizen-science data to resemble structured survey data, and analyze both sources of data under a common framework. To accomplish this, we explored ways of integrating high-resolution survey data on shorebirds in the northern Central Valley of California with observations in eBird for the entire region that were filtered to improve their quality. The integration of survey data with the filtered citizen-science data in eBird resulted in improved inference and predictive ability, and increased the extent and accuracy of inferences on shorebirds for the Central Valley. The structured surveys were found to improve the overall accuracy of ecological inference based only on citizen-science data, by increasing the representation of data collected from high quality habitats for shorebirds (e.g. rice fields). The practical approach we have shown for data integration can be also be used to improve the efficiency of designing biological surveys in the context of larger, citizen-science monitoring efforts, ultimately reducing the financial and time expenditures typically required of monitoring programs and focused research. The simple processing and filtering method we present can be used to integrate other types of data (e.g. camera traps) with more localized efforts (e.g. research projects), ultimately improving our ecological knowledge on the distribution and habitat associations of species of conservation concern worldwide.
Principles of RNA processing from analysis of enhanced CLIP maps for 150 RNA binding proteins
Authors: Van Nostrand Eric L , Pratt Gabriel A , Yee Brian A , Wheeler Emily , Blue Steven M , Mueller Jasmine , Park Samuel S , Garcia Keri E , Gelboin-Burkhart Chelsea , Nguyen Thai B , Rabano Ines , Stanton Rebecca , Sundararaman Balaji , Wang Ruth , Fu Xiang-Dong , Graveley Brenton R , Yeo Gene W
Published: October 2019

A critical step in uncovering rules of RNA processing is to study the in vivo regulatory networks of RNA binding proteins (RBPs). Crosslinking and immunoprecipitation (CLIP) methods enabled mapping RBP targets transcriptome-wide, but methodological differences present challenges to large-scale integrated analysis across datasets. The development of enhanced CLIP (eCLIP) enabled the large-scale mapping of targets for 150 RBPs in K562 and HepG2, creating a unique resource of RBP interactomes profiled with a standardized methodology in the same cell types. Here we describe our analysis of 223 enhanced (eCLIP) datasets characterizing 150 RBPs in K562 and HepG2 cell lines, revealing a range of binding modalities, including highly resolved positioning around splicing signals and mRNA untranslated regions that associate with distinct RBP functions. Quantification of enrichment for repetitive and abundant multi-copy elements reveals 70% of RBPs have enrichment for non-mRNA element classes, enables identification of novel ribosomal RNA processing factors and sites and suggests that association with retrotransposable elements reflects multiple RBP mechanisms of action. Analysis of spliceosomal RBPs indicates that eCLIP resolves AQR association after intronic lariat formation (enabling identification of branch points with single-nucleotide resolution) and provides genome-wide validation for a branch point-based scanning model for 3’ splice site recognition. Further, we show that eCLIP peak co-occurrences across RBPs enables the discovery of novel co-interacting RBPs. Finally, we present a protocol for visualization of RBP:RNA complexes in the eCLIP workflow using biotin and standard chemiluminescent visualization reagents, enabling simplified confirmation of ribonucleoprotein enrichment without radioactivity. This work illustrates the value of integrated analysis across eCLIP profiling of RBPs with widely distinct functions to reveal novel RNA biology. Further, our quantification of both mRNA and other element association will enable further research to identify novel roles of RBPs in regulating RNA processing.
Genomic analyses of population structure reveal metabolism as a primary driver of local adaptation in Daphnia pulex
Authors: Maruki Takahiro , Ye Zhiqiang , Lynch Michael
Published: October 2019

Elucidating population structure is important for understanding evolutionary features of an organism. In the freshwater microcrustacean Daphnia pulex, an emerging model system in evolutionary genomics, previous studies using a small number of molecular markers indicated that genetic differentiation among populations is high. However, the dispersal ability of D. pulex is potentially high, and evolutionary forces shaping genetic differentiation among populations are not understood well. In this study, we carried out genomic analyses using high-throughput sequencing to investigate the population structure of D. pulex. We analyzed 10 temporary-pond populations widely distributed across the midwestern United States, with each sample consisting of 71 to 93 sexually reproducing individuals. The populations are generally in Hardy-Weinberg equilibrium and have relatively large effective sizes. The genetic differentiation among the populations is moderate and positively correlated with geographic distance. To find outlier regions showing significantly high or low genetic differentiation, we carried out a sliding-window analysis of the differentiation estimates using the bootstrap. Genes with significantly high genetic differentiation show striking enrichment of gene ontology terms involved in food digestion, suggesting that differences in food quality and/or quantity among populations play a primary role in driving local adaptation of D. pulex.
Identification of scavenger receptor B1 as the airway microfold cell receptor forMycobacterium tuberculosis
Authors: Khan Haaris S. , Nair Vidhya R. , Ruhl Cody R. , Alvarez-Arguedas Samuel , Galvan Resendiz Jorge L. , Franco Luis H. , Huang Linzhang , Shaul Philip W. , Mitchell Ron B. , Shiloh Michael U.
Published: October 2019

Mycobacterium tuberculosis(Mtb) can enter the body through multiple routes, including via specialized transcytotic cells called microfold cells (M cell). However, the mechanistic basis for M cell entry remains undefined. Here, we show that M cell transcytosis depends on the Mtb Type VII secretion machine and its major virulence factor EsxA. We identify scavenger receptor B1 (SR-B1) as an EsxA receptor on airway M cells. SR-B1 is required for Mtb binding to and translocation across M cells in mouse and human tissue. Together, our data demonstrate a previously undescribed role for Mtb EsxA in mucosal invasion and identify SR-B1 as the airway M cell receptor for Mtb.
Inter-reader agreement of 18F-FDG PET/CT for the quantification of carotid artery plaque inflammation
Authors: Johnsrud Kjersti , Seierstad Therese , Russell David , Revheim Mona-Elisabeth
Published: October 2019

Background

A significant proportion of ischemic strokes are caused by emboli from unstable atherosclerotic carotid artery plaques with inflammation being a key feature of plaque instability and stroke risk. Positron emission tomography (PET) depicting the uptake of 2-deoxy-2-(18F)-fluoro-D-glucose (18F-FDG) in carotid artery plaques is a promising technique to quantify plaque inflammation. A consensus on the methodology for plaque localization and quantification of inflammation by 18F-FDG PET/computed tomography (CT) in atherosclerosis has not been established. High inter-reader agreement is essential if 18F-FDG PET/CT is to be used as a clinical tool for the assessment of unstable plaques and stroke risk. The aim of our study was to assess the inter-reader variability of different methods for quantification of 18F-FDG uptake in carotid atherosclerotic plaques with a separate CT angiography (CTA) providing anatomical guidance.

Methods and results

Forty-three patients with carotid artery stenosis ≥70% underwent 18F-FDG PET/CT. Two independent readers separately delineated the plaque in all axial PET slices containing the atherosclerotic plaque and the maximum standardized uptake value (SUVmax) from each slice was measured. Uptake values with and without background correction were calculated. Intraclass correlation coefficients were highest for uncorrected uptake values (0.97-0.98) followed by those background corrected by subtraction (0.89-0.94) and lowest for those background corrected by division (0.74-0.79). There was a significant difference between the two readers definition of plaque extension, but this did not affect the inter-reader agreement of the uptake parameters.

Conclusions

Quantification methods without background correction have the highest inter-reader agreement for 18F-FDG PET of carotid artery plaque inflammation. The use of the single highest uptake value (max SUVmax) from the plaque will facilitate the method’s clinical utility in stroke prevention.
Phosphorylation of the ancestral histone variant H3.3 amplifies stimulation-induced transcription
Authors: Armache Anja , Yang Shuang , Robbins Lexi E , Durmaz Ceyda , Daman Andrew W , Jeong Jin Q , Martínez de Paz Alexia , Ravishankar Arjun , Arslan Tanja , Lin Shu , Panchenko Tanya , Garcia Benjamin A. , Hake Sandra B. , Li Haitao , Allis C. David , Josefowicz Steven Z.
Published: October 2019

Complex organisms are able to rapidly induce select genes among thousands in response to diverse environmental cues. This occurs in the context of large genomes condensed with histone proteins into chromatin. The macrophage response to pathogen sensing, for example, rapidly engages highly conserved signaling pathways and transcription factors (TFs) for coordination of inflammatory gene induction1–3. Enriched integration of histone H3.3, the ancestral histone H3 variant, is a feature of inflammatory genes and, in general, dynamically regulated chromatin and transcription4–7. However, little is known of how chromatin is regulated at rapidly induced genes and what features of H3.3, conserved from yeast to human, might enable rapid and high-level transcription. The amino-terminus of H3.3 contains a unique serine residue as compared with alanine residues found in “canonical” H3.1/2. We find that this H3.3-specific serine residue, H3.3S31, is phosphorylated (H3.3S31ph) in a stimulation-dependent manner along the gene bodies of rapidly induced response genes in mouse macrophages responding to pathogen sensing. Further, this selective mark of stimulation-responsive genes directly engages histone methyltransferase (HMT) SETD2, a component of the active transcription machinery. Our structure-function studies reveal that a conserved positively charged cleft in SETD2 contacts H3.3S31ph and specifies preferential methylation of H3.3S31ph nucleosomes. We propose that features of H3.3 at stimulation induced genes, including H3.3S31ph, afford preferential access to the transcription apparatus. Our results provide insight into the function of ancestral histone variant H3.3 and the dedicated epigenetic mechanisms that enable rapid gene induction, with implications for understanding and treating inflammation.
The human CD8 T stem cell-like memory phenotype appears in the acute phase in Yellow Fever virus vaccination
Authors: Fuertes Marraco Silvia A. , Bovay Amandine , Nassiri Sina , Maby-El Hajjami Hélène , Ouertatani-Sakouhi Hajer , Held Werner , Speiser Daniel E.
Published: October 2019

Long-term memory is a fundamental feature of cytotoxic CD8 T cell immunity. Yet when do memory cells arise, especially in humans, is poorly documented, the pathways of effector / memory cell differentiation being largely debated. Based on a cross-sectional study, we previously reported that the live-attenuated Yellow Fever virus vaccine YF-17D induces a stem cell-like memory (SCM) CD8 T cell population persisting for at least 25 years. Here we present longitudinal data revealing that an activated SCM phenotype is distinctly detectable early on following YF-17D vaccination, i.e. at the same time as activated effector cells. In the long-run, the cells that express the transcription factor T cell factor 1 (TCF1) preferentially persist, consistent with the role of TCF1 in memory establishment. By performing t-distributed Stochastic Neighbour Embedding of flow cytometry data on standard differentiation and activation markers, we obtained a time-lapse representation of the dynamics of the CD8 T cell response: SCM cells appear early and remain closely related to the baseline Naive cells, while effector cells burst out of baseline and gradually contract after the peak of the response. Altogether, we observe heterogeneity in differentiation phenotypes in both the acute phase and the decade-long-term phases, including cells with memory phenotypes very early in the response. As opposed to models where memory cells develop from effector cells, our data support differentiation models where long-term memory cells are established by the early decision to retain proximity to the Naive state in a memory-dedicated pool of cells.
Chinese reverse M&As in the Netherlands: Chinese managers’ trust building practices
Authors: Sun Zhe , Zhao Liang
Published: October 2019

Purpose

Building trust is critical in reverse mergers and acquisitions (M&As), attributed to the divergence of governance and culture between the East and the West. This paper aims to explore the barriers and trust-building practices of Chinese managers in reverse M&As in developed countries.

Design/methodology/approach

The primary data set of this research contains case studies of two Chinese M&A deals and in-depth interviews with managers and advisories in the Netherlands.

Findings

This research finds that the divergences of decision-making structure, communication style and trust orientation generate barriers to the trust building in Chinese reverse M&As. The third-party advisory participation helps to build cognition-based trust of acquired company managers on Chinese acquiring company managers through providing information and explanation, fitting Chinese buyers in the Western M&A procedure and offering communication. It also helps to build affect-based trust through bridging the divergence of trust orientation and filling the cultural voids. Meanwhile, the invisible integration helps to build cognition-based trust through maintaining the core business, offering great help to acquired companies for their business expansion and selecting the business collaboration areas in the long term. It also helps to build affect-based trust through granting a high degree of governance independence and enabling a balanced status in acquired companies.

Originality/value

This research unveils the “black box” of Chinese reverse M&As from an inter-personal trust perspective and advances the nuanced understanding of trust and trust-building practices in Chinese reverse M&As. It also provides practical tools for both Chinese companies and acquired companies in developed countries.
A conservative, piecewise–analytical, transversal method of lines for reaction–diffusion equations
Authors: Ramos J.I.
Published: October 2019

Purpose

The purpose of this paper is to develop a new transversal method of lines for one-dimensional reaction–diffusion equations that is conservative and provides piecewise–analytical solutions in space, analyze its truncation errors and linear stability, compare it with other finite-difference discretizations and assess the effects of the nonlinear diffusion coefficients, reaction rate terms and initial conditions on wave propagation and merging.

Design/methodology/approach

A conservative, transversal method of lines based on the discretization of time and piecewise analytical integration of the resulting two-point boundary-value problems subject to the continuity of the dependent variables and their fluxes at the control-volume boundaries, is presented. The method provides three-point finite difference expressions for the nodal values and continuous solutions in space, and its accuracy has been determined first analytically and then assessed in numerical experiments of reaction-diffusion problems, which exhibit interior and/or boundary layers.

Findings

The transversal method of lines presented here results in three-point finite difference equations for the nodal values, treats the diffusion terms implicitly and is unconditionally stable if the reaction terms are treated implicitly. The method is very accurate for problems with the interior and/or boundary layers. For a system of two nonlinearly-coupled, one-dimensional reaction–diffusion equations, the formation, propagation and merging of reactive fronts have been found to be strong function of the diffusion coefficients and reaction rates. For asymmetric ignition, it has been found that, after front merging, the temperature and concentration profiles are almost independent of the ignition conditions.

Originality/value

A new, conservative, transversal method of lines that treats the diffusion terms implicitly and provides piecewise exponential solutions in space without the need for interpolation is presented and applied to someone.
The impact of different play activity designs on students’ embodied learning
Authors: Davis Bria , Tu Xintian , Georgen Chris , Danish Joshua A. , Enyedy Noel
Published: October 2019

Purpose

This paper aims to build on work that has demonstrated the value of play or game-based learning environments and to further unpack how different kinds of play activities can support learning of academic concepts. To do so, this paper explores how students learn complex science concepts through collective embodied play by comparing two forms of play labeled as Inquiry Play and Game Play.

Design/methodology/approach

This study builds off of previous research that uses the Science Through Technology Enhanced Play (STEP) technology platform (Authors et al., 2015). STEP is a mixed reality platform that allows learners to playfully explore science phenomena, such as the rules of particle behavior in solid, liquid and gas, through collective embodied activity. A combination of interaction analysis and qualitative coding of teacher and student interactions are used to examine patterns in the learning processes during embodied play activities.

Findings

Both forms of play led to similar learning gains. However, Inquiry Play promoted more emergent, flexible modeling of underlying mechanisms while Game Play oriented students more towards “winning”.

Originality/value

By contrasting play environments, this paper provides new insights into how different features of play activities, as well as how teachers orient their students according to these different features, support students’ learning in collective activity. As a result, these findings can provide insights into the design of future play-based learning environments that are intended to support the learning of academic concepts.
Opportunity cost of time, income, education and food away from home consumption expenditures by type of facility in Albania
Authors: Seidu Ayuba
Published: October 2019

Purpose

The purpose of this paper is to provide a detailed analysis of the socioeconomic and demographic determinants driving food away from home (FAFH) consumption expenditures at full service and fast food restaurants in transition Albania.

Design/methodology/approach

Using a nationally representative data set, this study estimates a system of full service and fast food restaurant consumption expenditures under sample selection framework. The system estimator exploits full information about the error correlations for gain in efficiency.

Findings

The results indicate that future growth of the foodservice industry in Albania will be driven by increased spending at full service restaurants due to rising opportunity cost of the food manager’s time at home, household income and years of formal schooling of Albanians.

Research limitations/implications

The findings of this study can inform policy deliberations in designing nutrition and education programs for the Albanian Government to combat rising obesity rates. Moreover, the findings can inform marketing strategies by foodservice firms in Albania. On FAFH–obesity debate, future research can focus on the analysis of FAFH consumption expenditures on obesity rates in Albania.

Originality/value

Consumption of FAFH is fast evolving in developing and transition economies. Albania, a typical transition country, is no exception. Concurrently, Albania is under epidemiological transition facing increased incidence of non-communicable diseases and obesity. Any intervention program by the Albanian Government aimed at reversing the rising obesity trend by targeting FAFH consumption should be based on sound empirical findings. Analysis of FAFH consumption expenditures across different foodservice facilities is an under-researched topic for Albania in the literature.
Effect of pre-disclosure information leakage by block traders
Authors: Kim Tai-Young
Published: October 2019

Purpose

This paper aims to investigate pre-disclosure information leakage by block traders and market reactions to disclosures of off-hours block trading compared to off-market trading.

Design/methodology/approach

Stock responses were analyzed based on timely disclosures regarding Korean firms’ decisions to dispose of their own shares to improve their financial structures.

Findings

The results showed that pre-disclosure abnormal returns were generated in off-hours block trading. In contrast, on disclosure days, the returns for off-hours block trading were significantly lower than those for off-market trading. It was consistent with prior studies, indicating that block traders were related to information leakage and caused moral hazard problems.

Originality/value

The comparison between off-hours block trading and off-market trading provides important insights regarding block traders’ behavior. This study’s findings on the leakage of information from block traders indicate the need for firms to exercise caution when using block traders.
Oil, elections and fiscal transparency
Authors: AASKOVEN LASSE
Published: October 2019

How does governments’ ability to gain financing from oil income affect their behaviour? Numerous studies have explored the effects of oil wealth on countries’ political characteristics, especially the level of democracy. Oil has also been associated with a significant electoral incumbency advantage across different political regimes. However, the relationship between oil wealth and incumbent governments’ behaviour, including election‐year fiscal manipulation, has been studied to a lesser extent. This article argues that higher oil rents increase election‐year public spending as they provide national governments both with direct revenue and increased financing opportunities. However, fiscal transparency mitigates this effect. Consequently, oil‐induced electoral budget cycles decrease as fiscal transparency increases. Using a high‐quality measure of fiscal transparency in a panel of countries, robust evidence in favour of this argument is found. The findings suggest that many of the previous results on the political effects of oil, including incumbency advantage, might run through an election‐year spending channel, and that fiscal institutions might matter substantially for the political effects of oil.
Magnate Counsel and Parliament, c.1340–76: The Place of the Lords in the Era of the Commons
Authors: Raven Matt
Published: October 2019

The mid 14th century has long been identified as a crucial period in the emergence of the Commons. Its rise fundamentally reconfigured the traditional landscape of representation, in which the magnates embodied the ‘community of the realm’. It is the place of the Commons that has drawn the bulk of scholarly attention. Through a close examination of the surviving Parliament Rolls for the period 1340–76, this article argues that magnate counsel, especially on the interrelated themes of warfare, diplomacy, and supply, remained integral to meetings of parliament in the ‘era of the Commons’. Parliament formed a crucial ‘point of contact’ between the king and a broad political society that actively pushed the practice and performance of noble advice‐giving, in line with common assumptions about the ideal social composition of the king's counsellors.
Association of prevalence of electronic cigarette use with smoking cessation and cigarette consumption in England: a time–series analysis between 2006 and 2017
Authors: Beard Emma , West Robert , Michie Susan , Brown Jamie
Published: October 2019

Aims

To provide up‐to‐date estimates of how changes in the prevalence of electronic cigarette (e‐cigarette) use in England have been associated with changes in smoking cessation activities and daily cigarette consumption among smokers in England.

Design

Time–series analysis of population trends.

Setting

England.

Participants

Participants came from the Smoking Toolkit Study, which involves repeated, cross‐sectional household surveys of individuals aged 16 years and older in England. Data were aggregated on approximately 1200 past‐year smokers each quarter (total n = 50 498) between 2007 and 2017.

Measurements

Prevalence of e‐cigarette use in current smokers was used to predict (a) prevalence of quit attempts among last‐year smokers, (b) overall quit rates among last‐year smokers and (c) mean cigarette consumption per day among current smokers. Prevalence of e‐cigarette use during a quit attempt among last‐year smokers was used to predict (a) quit success rate among last‐year smokers and (b) overall quit rates among last‐year smokers.

Findings

Overall quit rates increased by 0.054% [95% confidence interval (CI) = 0.032–0.076, P < 0.001] and 0.050% (95% CI = 0.031–0.069, P < 0.001) respectively for every 1% increase in the prevalence of e‐cigarette use by smokers and e‐cigarette use during a quit attempt. Quit success rates increased by 0.060% (95% CI = 0.043–0.078, P < 0.001) for every 1% increase in the prevalence of e‐cigarette use during a quit attempt. No clear evidence was found for an association between e‐cigarette use and either prevalence of quit attempt (BAdj = 0.011, 95% CI = −0.046 to 0.069, P = 0.698) or cigarette consumption (BAdj = 0.019, 95% CI = −0.043 to 0.082, P = 0.542).

Conclusion

Changes in prevalence of e‐cigarette use in England have been positively associated with the overall quit rates and quit success rates but not clearly associated with the prevalence of quit attempts and mean cigarette consumption.
Ideological Competition and Conflict in the Judicial Hierarchy
Authors: Strayhorn Joshua A.
Published: October 2019

Circuit splits, or conflicting rules across multiple U.S. Courts of Appeals, have important policy implications and dramatic effects on Supreme Court case selection, yet we know little about the incentives ideological lower courts face when deciding whether to initiate conflict. This article develops a formal model of a judicial hierarchy where lower court judges are subject to review by a high court with distaste for unresolved conflict, termed “split‐intolerance,” and with uncertain preferences over policy. Lower courts may compete by investing costly effort in legal quality to make their rules more attractive. In equilibrium, lower courts may initiate conflict even when the odds of success before the high court are remote. Surprisingly, lower courts grow more likely to create conflict as the high court's split‐intolerance increases; however, split‐intolerance can also incentivize greater lower court effort. I present qualitative evidence illustrating the model's explanatory power.
Attracting junior doctors to rural centres: A national study of work‐life conditions and satisfaction
Authors: Lennon Matthew , O’Sullivan Belinda , McGrail Matthew , Russell Deborah , Suttie Joseph , Preddy John
Published: October 2019

Objective

Junior doctors, in their first four years of medical work, are an important part of the health care team. Attracting and retaining these doctors to rural areas underpins the development of the future rural workforce. This is the first national‐scale study about satisfaction of junior doctors, based on their work location, to inform recruitment and retention.

Design

Repeat cross‐sectional data 2008 and 2015, pooled for analysis.

Setting

Medicine in Australia: Balancing Employment and Life survey.

Participants

First responses of 4581 pre‐vocational doctors working as interns up to their fourth postgraduate year.

Main outcome measures

Differences between metropolitan and rural respondents in satisfaction and positivity on two inventories.

Results

Overall work satisfaction was approximately 85% amongst rural and metropolitan junior doctors, but controlling for other factors rural junior doctors had significantly higher overall satisfaction. Rural junior doctors were significantly more satisfied with their work‐life balance, ability to obtain desired leave and leave at short notice, personal study time and access to leisure interests compared with metropolitan junior doctors. Metropolitan junior doctors were more satisfied with the network of doctors supporting them and the opportunities for family.

Conclusion

While both metropolitan and rural junior doctors are generally satisfied, many professional and personal aspects of satisfaction differ considerably by work location. In order to attract early career doctors, the benefits of rural work should be emphasised and perceived weaknesses mitigated.
High‐carbon steel and ancient sword‐making as observed in a double‐edged sword from an Iron Age megalithic burial in Tamil Nadu, India
Authors: Park J.‐S. , Rajan K. , Ramesh R.
Published: October 2019

An iron sword from an Iron Age megalithic burial at Thelunganur in Tamil Nadu, India, was examined using metallographic techniques. The sword was made of ultra‐high‐carbon steel with a fairly uniform microstructure consisting primarily of fine cementite particles in a ferrite background free of notable non‐metallic inclusions. The morphological control, however, was not perfect and frequently allowed cementite to precipitate in the form of a network along austenite grain boundaries. It was also observed that carbide particles of varying size and shape often caused microscopic layers to develop, forming a visible pattern to the naked eye on the polished and etched surface of the iron sword. This pattern likely inspired the later development of various surface markings such as the damask. This paper presents a detailed account of the analytical data to show that the iron sword under consideration was an early example of high‐carbon steel employed in the manufacture of a functional object where the divorced eutectoid transformation technique, rediscovered recently, was used for the control of cementite morphology. It is also proposed that technologies for making and handling high‐carbon steel were in existence at a much earlier date than previously supposed.
Novel heterozygous sequence variant in the GLI1 underlies postaxial polydactyly
Authors: Yousaf Maryam , Ullah Asmat , Azeem Zahid , Isani Majeed Ayesha , Memon Muhammad Iqbal , Ghous Tahseen , Basit Sulman , Ahmad Wasim
Published: October 2019

Polydactyly is one of the most common congenital abnormal phenotype of autopod, which is characterized by extra supernumerary digit in hands/feet with or without well‐developed bony structure within the digits. Preaxial polydactyly (PPD), postaxial polydactyly (PAP), and meso‐axial (central) polydactyly are three different isoforms of polydactyly. Genetically, at least 10 genes have been identified causing nonsyndromic polydactyly. In the present study, we have investigated a large family segregating autosomal dominant form of nonsyndromic polydactyly. Whole exome sequencing followed by Sanger sequencing revealed a novel heterozygous missense variant (NM_005269.3; c.1064C>A; p.(Thr355Asn) in the gene GLI1 segregating with the disease phenotype within the family. This study presents first familial case of autosomal dominant form of polydactyly caused by the GLI1 variant.
An experimental test of community‐based strategies for mitigating human–wildlife conflict around protected areas
Authors: Branco Paola S. , Merkle Jerod A. , Pringle Robert M. , King Lucy , Tindall Tosca , Stalmans Marc , Long Ryan A.
Published: October 2019

Natural habitats are rapidly being converted to cultivated croplands, and crop‐raiding by wildlife threatens both wildlife conservation and human livelihoods worldwide. We combined movement data from GPS‐collared elephants with camera‐trap data and local reporting systems in a before–after‐control‐impact design to evaluate community‐based strategies for reducing crop raiding outside Mozambique's Gorongosa National Park. All types of experimental fences tested (beehive, chili, beehive and chili combined, and procedural controls) significantly reduced the number of times elephants left the Park to raid crops. However, placing beehive fences at a subset of key crossing locations reduced the odds that elephants would leave the Park by up to 95% relative to unfenced crossings, and was the most effective strategy. Beehive fences also created opportunities for income generation via honey production. Our results provide experimental evidence that working with local communities to modify both animal behavior and human attitudes can mitigate conflict at the human–wildlife interface.
Distinguishing ataxia from developmental coordination disorder
Authors: Baxter Peter
Published: October 2019

This commentary is on the original article by Lawerman et al. on pages 75‐82 of this issue.
Feasibility and accuracy of tricuspid annular displacement assessed by speckle tracking echocardiography and Doppler tissue imaging
Authors: Tan Yuan , Manouras Aristomenis , Lund Lars H. , Venkateshvaran Ashwin
Published: October 2019

Background

Tricuspid annular plane systolic excursion (TAPSE) is a recommended quantitative measure of right ventricular (RV) longitudinal function assessed by M‐mode echocardiography. Offline alternatives are desirable when TAPSE is unavailable. This study aimed to assess the feasibility, reliability, and agreement between retrospectively obtained measures of tricuspid annular displacement using Doppler tissue imaging (TADDTI) and speckle tracking echocardiography (TADSTE) compared with reference TAPSE.

Methods

Consecutive subjects referred for evaluation of heart failure were enrolled. Subjects in atrial fibrillation, significant valvular disease, or with poor image quality were excluded. TAPSE was measured during the examination using M‐mode. TADSTE was measured as the maximal longitudinal displacement of the RV basal segment in systole using speckle strain imaging. TADDTI was derived offline from color‐DTI superimposed grayscale images.

Results

107 subjects (age 60 ± 16; 48% female) were analyzed. Both TADDTI and TADSTE demonstrated good feasibility and excellent intra‐ and inter‐observer concordances. Although both measures demonstrated strong association with TAPSE, TADDTI showcased lower specificity to identify RV dysfunction and higher false positives. Bland‐Altman analysis revealed a tendency of TADDTI to underestimate TAPSE (bias = 1.40; SD = 2.74 mm) as compared with TADSTE (bias = 0.27; SD = 2.30mm). Wide limits of agreement were observed for both methods.

Conclusions

TADSTE and TADDTI provide reproducible and feasible quantification of RV function. However, TADDTI significantly underestimates TAPSE limiting the interchangeability of these modalities.
Comparison of 3D echocardiographic‐derived indices using fully automatic left ventricular endocardial tracing (heart model) and semiautomatic tracing (3DQ‐ADV)
Authors: D’Elia Nicholas , Appadurai Vinesh , Mallouhi Michael , Ng Jun , Marwick Thomas , Wahi Sudhir
Published: October 2019

Aims

The availability of a true 3D dataset provides an opportunity for automation of left ventricular (LV) and left atrial (LA) measurements. Although manual and automated measurements of 3D volumes are known to correlate, the variance is an important parameter for the individual patient. The reasons for discrepancies remain unexplained. We hence aim to explain the disagreement between automated and manual LV and LA volumes.

Methods and Results

A total of 355 patients underwent standard clinical echo, with offline analysis in both fully‐ (Heart Model, Philips) and semiautomated (3DQ‐Adv, Philips) assessment of routine indices of LV and LA function and shape. Each image was classified according to quality using a 4‐point scale as well as the American Society for Echocardiography guidelines for appropriate use of contrast. Bland‐Altman plots were used to assess agreement, and t tests were used to assess differences in agreement. Predictors of volume discrepancy were sought with linear regression. Measures of LV and LA volumes were greater with automatic than semiautomatic assessment. The difference in left ventricular end‐diastolic volume was dependent on the number of regional wall‐motion abnormalities (RWMA) (β = 0.59, P < .04) and image quality (β = 19.71, P = .02). RWMA predicted the difference in left ventricular end‐systolic volume (β = 0.83, P < .01) and left atrial end‐systolic volume (β = −1.01 P < .01).

Conclusion

LV and LA volumes were higher with automatic than semiautomatic assessment. Image quality and RWMA may contribute to this discrepancy. These limitations need to be addressed before fully automatic assessment of 3D echocardiograms can be used in the clinic.
Integrated population model reveals that kestrels breeding in nest boxes operate as a source population
Authors: Fay Rémi , Michler Stephanie , Laesser Jacques , Schaub Michael
Published: October 2019

The identification of the source–sink status of a population is critical for the establishment of conservation plans and enacting smart management decisions. We developed an integrated population model to formally assess the source status of a kestrelFalco tinnunculuspopulation breeding in nest boxes in Switzerland. We estimated juvenile and adult survival, reproduction and net dispersal (emigration/immigration) by jointly analyzing capture–recapture, dead recovery, breeding monitoring and population survey data. We also investigated the role of nest boxes on kestrel demography and assessed the contributions of vital rates to realized population growth rates. The results indicate that the kestrel population breeding in nest boxes has acted as a source over the 15 years of the study duration. A quantitative approach suggests that a substantial number of individuals have emigrated annually from this population likely affecting the population dynamics outside the management area. Variation in fecundity explained 34% of the temporal variability of the population growth rate. Moreover, a literature review suggests that kestrel pairs produce on average 1.4 chicks more per breeding attempt in nest boxes compared to natural open nests. Together, these findings suggest that fecundity was an important driver for the dynamics of this population and that nest boxes have contributed to its raise. Nest boxes are regularly used as an efficient tool for conservation management. We suggest that such a conservation action can result in the establishment of a source population being beneficial for populations both inside and outside the managed area.
Pseudokinases: a tribble‐edged sword
Authors: Richmond Laura , Keeshan Karen
Published: October 2019

Advances in the understanding of the Tribbles family of pseudokinases (TRIB1, TRIB2 and TRIB3) reveal these proteins as potentially valuable biomarkers of disease diagnosis, prognosis, prediction and clinical strategy. In their role as signalling mediators and scaffolding proteins, TRIBs lead to changes in protein stability and activity, which impact on diverse cellular processes such as proliferation, differentiation, cell cycle and cell death. We review the role of TRIB proteins as promising therapeutic targets, with an emphasis on their role in cancer, and as biomarkers, with potential application across diverse pathological processes.
The redox‐active site of thioredoxin is directly involved in apoptosis signal‐regulating kinase 1 binding that is modulated by oxidative stress
Authors: Psenakova Katarina , Hexnerova Rozalie , Srb Pavel , Obsilova Veronika , Veverka Vaclav , Obsil Tomas
Published: October 2019

Apoptosis signal‐regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen‐activated protein kinase kinase kinase 5, which mediates various stress signals including oxidative stress. The catalytic activity of ASK1 is tightly controlled by oligomerization and binding of several cofactors. Among these cofactors, thioredoxin stands out as the most important ASK1 inhibitor, but only the reduced form of thioredoxin inhibits ASK1 by direct binding to its N‐terminal domain. In addition, oxidation‐driven thioredoxin dissociation is the key event in oxidative stress‐mediated ASK1 activation. However, the structural mechanism of ASK1 regulation by thioredoxin remains unknown. Here, we report the characterization of the ASK1 domain responsible for thioredoxin binding and its complex using NMR spectroscopy and chemical cross‐linking, thus providing the molecular basis for ASK1: thioredoxin complex dissociation under oxidative stress conditions. Our data reveal that the N‐terminal domain of ASK1 adopts a fold resembling the thioredoxin structure while retaining substantial conformational plasticity at the thioredoxin‐binding interface. Although oxidative stress induces relatively moderate structural changes in thioredoxin, the formation of intramolecular disulfide bridges leads to a considerable conformational rearrangement of the thioredoxin‐binding interface on ASK1. Moreover, the cysteine residue at position 250 of ASK1 is the key element of this molecular switch. Finally, our results show that the redox‐active site of thioredoxin is directly involved in ASK1 binding that is modulated by oxidative stress, thereby identifying a key target for the structure‐based drug design.