bluuebunny/crossref_metadata_2025 huggingface dataset:
Untangling the environmental from the dietary: dust does not matter
Authors: Merceron Gildas , Ramdarshan Anusha , Blondel Cécile , Boisserie Jean-Renaud , Brunetiere Noël , Francisco Arthur , Gautier Denis , Milhet Xavier , Novello Alice , Pret Dimitri
Published: September 2016

Both dust and silica phytoliths have been shown to contribute to reducing tooth volume during chewing. However, the way and the extent to which they individually contribute to tooth wear in natural conditions is unknown. There is still debate as to whether dental microwear represents a dietary or an environmental signal, with far-reaching implications on evolutionary mechanisms that promote dental phenotypes, such as molar hypsodonty in ruminants, molar lengthening in suids or enamel thickening in human ancestors. By combining controlled-food trials simulating natural conditions and dental microwear textural analysis on sheep, we show that the presence of dust on food items does not overwhelm the dietary signal. Our dataset explores variations in dental microwear textures between ewes fed on dust-free and dust-laden grass or browse fodders. Browsing diets with a dust supplement simulating Harmattan windswept environments contain more silica than dust-free grazing diets. Yet browsers given a dust supplement differ from dust-free grazers. Regardless of the presence or the absence of dust, sheep with different diets yield significantly different dental microwear textures. Dust appears a less significant determinant of dental microwear signatures than the intrinsic properties of ingested foods, implying that diet plays a critical role in driving the natural selection of dental innovations.
A heterogeneous landscape does not guarantee high crop pollination
Authors: Samnegård Ulrika , Hambäck Peter A. , Lemessa Debissa , Nemomissa Sileshi , Hylander Kristoffer
Published: September 2016

The expansion of pollinator-dependent crops, especially in the developing world, together with reports of worldwide pollinator declines, raises concern of possible yield gaps. Farmers directly reliant on pollination services for food supply often live in regions where our knowledge of pollination services is poor. In a manipulative experiment replicated at 23 sites across an Ethiopian agricultural landscape, we found poor pollination services and severe pollen limitation in a common oil crop. With supplementary pollination, the yield increased on average by 91%. Despite the heterogeneous agricultural matrix, we found a low bee abundance, which may explain poor pollination services. The variation in pollen limitation was unrelated to surrounding forest cover, local bee richness and bee abundance. While practices that commonly increase pollinators (restricted pesticide use, flower strips) are an integral part of the landscape, these elements are apparently insufficient. Management to increase pollination services is therefore in need of urgent investigation.
Size, longevity and cancer: age structure
Authors: Wensink Maarten J.
Published: September 2016

There is significant recent interest in Peto's paradox and the related problem of the evolution of large, long-lived organisms in terms of cancer robustness. Peto's paradox refers to the expectation that large, long-lived organisms have a higher lifetime cancer risk, which is not the case: a paradox. This paradox, however, is circular: large, long-lived organisms are large and long-lived
because
they are cancer robust. Lifetime risk, meanwhile, depends on the age distributions of both cancer and competing risks: if cancer strikes before competing risks, then lifetime risk is high; if not, not. Because no set of competing risks is generally prevalent, it is instructive to temporarily dispose of competing risks and investigate the pure age dynamics of cancer under the multistage model of carcinogenesis. In addition to augmenting earlier results, I show that in terms of cancer-free lifespan large organisms reap greater benefits from an increase in cellular cancer robustness than smaller organisms. Conversely, a higher cellular cancer robustness renders cancer-free lifespan more resilient to an increase in size. This interaction may be an important driver of the evolution of large, cancer-robust organisms.
Background complexity and the detectability of camouflaged targets by birds and humans
Authors: Xiao Feng , Cuthill Innes C.
Published: September 2016

Remaining undetected is often key to survival, and camouflage is a widespread solution. However, extrinsic to the animal itself, the complexity of the background may be important. This has been shown in laboratory experiments using artificially patterned prey and backgrounds, but the mechanism remains obscure (not least because ‘complexity’ is a multifaceted concept). In this study, we determined the best predictors of detection by wild birds and human participants searching for the same cryptic targets on trees in the field. We compared detection success to metrics of background complexity and ‘visual clutter’ adapted from the human visual salience literature. For both birds and humans, the factor that explained most of the variation in detectability was the textural complexity of the tree bark as measured by a metric of feature congestion (specifically, many nearby edges in the background). For birds, this swamped any effects of colour match to the local surroundings, although for humans, local luminance disparities between the target and tree became important. For both taxa, a more abstract measure of complexity, entropy, was a poorer predictor. Our results point to the common features of background complexity that affect visual search in birds and humans, and how to quantify them.
Close genetic relationships between a spousal pair with autism-affected children and high minor allele content in cases in autism-associated SNPs
Authors: Zhu Zuobin , Lu Xitong , Yuan Dejian , Huang Shi
Published: September 2016

Parents of children affected with autism spectrum disorders (ASD) often have mild forms of autistic-like characteristics. Past studies have focused on searching for individual genetic risk loci of ASD. Here we studied the overall properties of the genomes of ASD trios by using previously published genome-wide data for common SNPs. The pairwise genetic distance (PGD) between a spousal pair with ASD-affected children was found smaller than that of a random pair selected among the spouses in the ASD trios, and spousal relatedness correlated with severe forms of ASD. Furthermore, for a set of 970 ASD associated SNPs, cases showed higher homozygous minor allele content than parents. These results indicate new genetic elements in the broad phenotypes of parents with ASD-affected offspring and in ASD pathogenesis.

Highlights

The overall properties of the genomes of ASD trios show ASD specific features.

A spousal pair with ASD-affected children showed smaller genetic distance than that of a randomly selected pair among the spouses in the ASD trios.

Minor allele contents in ASD-associated SNPs in ASD cases were greater than those in the parents of cases.
MathIOmica: an integrative platform for dynamic omics
Authors: Mias George I. , Yusufaly Tahir , Roushangar Raeuf , Brooks Lavida R. K. , Singh Vikas V. , Christou Christina
Published: September 2016

Multiple omics data are rapidly becoming available, necessitating the use of new methods to integrate different technologies and interpret the results arising from multimodal assaying. The MathIOmica package forMathematicaprovides one of the first extensive introductions to the use of the Wolfram Language to tackle such problems in bioinformatics. The package particularly addresses the necessity to integrate multiple omics information arising from dynamic profiling in a personalized medicine approach. It provides multiple tools to facilitate bioinformatics analysis, including importing data, annotating datasets, tracking missing values, normalizing data, clustering and visualizing the classification of data, carrying out annotation and enumeration of ontology memberships and pathway analysis. We anticipate MathIOmica to not only help in the creation of new bioinformatics tools, but also in promoting interdisciplinary investigations, particularly from researchers in mathematical, physical science and engineering fields transitioning into genomics, bioinformatics and omics data integration.
A phenomenological spatial model for macro-ecological patterns in species-rich ecosystems
Authors: Peruzzo Fabio , Azaele Sandro
Published: September 2016

Over the last few decades, ecologists have come to appreciate that key ecological patterns, which describe ecological communities at relatively large spatial scales, are not only scale dependent, but also intimately intertwined. The relative abundance of species – which informs us about the commonness and rarity of species – changes its shape from small to large spatial scales. The average number of species as a function of area has a steep initial increase, followed by decreasing slopes at large scales. Finally, if we find a species in a given location, it is more likely we find an individual of the same species close-by, rather than farther apart. Such spatial turnover depends on the geographical distribution of species, which often are spatially aggregated. This reverberates on the abundances as well as the richness of species within a region, but so far it has been difficult to quantify such relationships.

Within a neutral framework – which considers all individuals competitively equivalent – we introduce a spatial stochastic model, which phenomenologically accounts for birth, death, immigration and local dispersal of individuals. We calculate the pair correlation function – which encapsulates spatial turnover – and the conditional probability to find a species with a certain population within a given circular area. Also, we calculate the macro-ecological patterns, which we have referred to above, and compare the analytical formulæ with the numerical integration of the model. Finally, we contrast the model predictions with the empirical data for two lowland tropical forest inventories, showing always a good agreement.
Properties of compostite feedback-feedforward pulse generating motifs
Authors: Iyengar Bharat Ravi
Published: September 2016

Negative feedbacks and incoherent feedforward loops are known to give rise to a pulse in response to a step change in the input. In this article, I present a study of composite motifs made of coupled feedback and feedforward loops, acting via different regulatory mechanisms. In these motifs, the effect of input and output on the controller is realized via either an AND-gate or an OR-gate. Using a simplistic model of gene expression and a common parameter set, I have studied the effect of global parameter variation on the dynamic and steady-state properties of different motifs, in response to a step change in the input. These metrics include steady state gain, response time, overshoot, peak time and peak duration. For the motifs with a negative feedback component, it can be seen that AND-gated motifs show a “feedforward-like” property whereas the OR-gated motifs show a “feedback-like” property. Motifs with a positive feedback component show hypersensitivity of gain, to parameters. Overshoot correlates negatively with peak time whereas peak duration correlates concavely with peak time, a property that is also observed for uncoupled feedback and feedforward motifs. This indicates that this relationship between overshoot, peak duration and peak time, seems to be a universal property of pulse-generating motifs.
Simulation model for dynamics of three types of annual plants
Authors: Pękalski Andrzej
Published: September 2016

A Monte Carlo type model describing dynamics of three pairs of annual plants living in a homogeneous habitat is presented and discussed. Each plant follows its own history with growing, fecundity and survival chances determined individually as functions of the plant’s condition and environment. The three plants -Valerianella locusta, Mysotis ramosissimaandCerastium semidecandrumdiffer by the weight of their seeds, which in the model determines the competition preference. Heavier seeds have a better chance for germination from a site containing seeds of different plants. Better colonisers produce more seeds and disperse them over a larger distance. I show that without absolute asymmetry in the impact effects between better competitors and better colonisers and in a spatially and temporarily homogeneous habitat, coexistence of species is possible, however only in a limited time. This is different from statements coming from models using mean-field type methods. I demonstrate also that in a system of two species clustering of plants of the same type are more frequent. From the calculated survival chances of seedlings and adult plants it follows that elimination of plants occur mostly at the early stages of the plants life cycle, which agrees with the field data.I show that this competition/colonisation trade-off model is sufficient to maintain coexistence and I determine the conditions for dominance of one type of plants. I show that the time of extinction of the weaker species goes down with increasing observation time as a power function with the exponent independent of the type of plants.
ANumerusPopulation Viability and Harvesting Analyses Web App
Authors: Getz Wayne M. , Muellerklein Oliver , Salter Richard , Carlson Colin J. , Lyons Andrew J. , Seidel Dana
Published: September 2016

Population viability analysis (PVA) is used to assess the probability that a biological population will persist for a specified period of time. Such models are typically cast as Markov processes that may include age, stage, sex and metapopulation structures, density-dependence and ecological interaction processes. They may also include harvesting, stocking, and thresholds that trigger interventions. Here we present Numerus PVA, which is a web app that includes extensible user-selected options. Specifically, Numerus PVA allows for the specification of one to ten age classes, one or two sexes, single population or metapopulation configurations with 2 or 3 subpopulations, as well as density-dependent settings for inducing region-specific carrying capacities. Movement among subpopulations can be influenced by age, metapopulation connectivity, and attractivity of regions based on the relative fitness of the youngest age classes in each region. Simulations can be carried out deterministically or stochastically, with a user-specified combination of demographic and environmental processes. Numerus PVA is freely available athttp://www.numerusinc.com/webapps/pvafor running directly on any browser and device. Numerus PVA is easily modified by users familiar with the NovaModeler Software Platform.
Rapid metagenomic next-generation sequencing during an investigation of hospital-acquired human parainfluenza virus 3 infections
Authors: Greninger Alexander L. , Zerr Danielle M , Qin Xuan , Adler Amanda L. , Englund Janet A. , Jerome Keith R.
Published: September 2016

Metagenomic next-generation sequencing (mNGS) is increasingly used for the unbiased detection of viruses, bacteria, fungi, and eukaryotic parasites in clinical samples. Whole genome sequencing (WGS) of clinical bacterial isolates has been shown to inform hospital infection prevention practices, but the use of this technology during potential respiratory virus outbreaks has not been taken advantage of. Here, we report on the use of mNGS to inform the real-time infection prevention response to a cluster of hospital-acquired human parainfluenza 3 virus (HPIV3) infections at a children’s hospital. Isolates from 3 patients with hospital-acquired HPIV3 identified over a 12-day period on a general medical unit and 10 temporally-associated isolates from patients with community-acquired of HPIV3 were analyzed. Our sample-to-sequencer time was <24 hours while our sample-to-answer turn-around time was <60 hours with a hands-on time of approximately 6 hours. Eight (2 case isolates and 6 control isolates) of 13 samples had sufficient sequencing coverage to yield whole genomes for HPIV3, while 10 (2 cases and 8 controls) of 13 samples gave partial genomes and all 13 samples had >1 read to HPIV3. Phylogenetic clustering revealed the presence of identical HPIV3 genomic sequence in the two of the cases with hospital-acquired infection, consistent with the concern for recent transmission within the medical unit. Adequate sequence coverage was not recovered for the third case. This work demonstrates the promise of mNGS to provide actionable information for infection control in addition to microbial detection.
Genome-wide reconstruction of complex structural variants using read clouds
Authors: Spies Noah , Weng Ziming , Bishara Alex , McDaniel Jennifer , Catoe David , Zook Justin M. , Salit Marc , West Robert B. , Batzoglou Serafim , Sidow Arend
Published: September 2016

Recently developed methods that utilize partitioning of long genomic DNA fragments, and barcoding of shorter fragments derived from them, have succeeded in retaining long-range information in short sequencing reads. These so-called read cloud approaches represent a powerful, accurate, and cost-effective alternative to single-molecule long-read sequencing. We developed software, GROC-SVs, that takes advantage of read clouds for structural variant detection and assembly. We apply the method to two 10x Genomics data sets, one chromothriptic sarcoma with several spatially separated samples, and one breast cancer cell line, all Illumina-sequenced to high coverage. Comparison to short-fragment data from the same samples, and validation by mate-pair data from a subset of the sarcoma samples, demonstrate substantial improvement in specificity of breakpoint detection compared to short-fragment sequencing, at comparable sensitivity, and vice versa. The embedded longrange information also facilitates sequence assembly of a large fraction of the breakpoints; importantly, consecutive breakpoints that are closer than the average length of the input DNA molecules can be assembled together and their order and arrangement reconstructed, with some events exhibiting remarkable complexity. These features facilitated an analysis of the structural evolution of the sarcoma. In the chromothripsis, rearrangements occurred before copy number amplifications, and using the phylogenetic tree built from point mutation data we show that single nucleotide variants and structural variants are not correlated. We predict significant future advances in structural variant science using 10x data analyzed with GROC-SVs and other read cloud-specific methods.
Distributed representation of context by intrinsic subnetworks in prefrontal cortex
Authors: Waskom Michael L. , Wagner Anthony D.
Published: September 2016

Human prefrontal cortex supports flexible decision-making by representing abstract information about task context. The organizational basis of these context representations, and of representations underlying other higher-order processes, is unknown. Here, we use multivariate decoding and analyses of spontaneous correlations to show that context representations are distributed across subnetworks within prefrontal cortex. Examining targeted prefrontal regions, we found that pairs of voxels with similar context preferences exhibited spontaneous correlations that were approximately twice as large as those between pairs with opposite context preferences. This subnetwork organization was stable across task-engaged and resting states, suggesting that abstract context representations are constrained by an intrinsic functional architecture. These results reveal a principle of fine-scaled functional organization in association cortex.
Director trading, or lack thereof, and acquiring firm performance
Authors: Hossain Md Mosharraf , Heaney Richard Arthur , Koh SzeKee
Published: September 2016

Purpose

This paper aims to address the question of whether acquiring firm directors trading, prior to a merger or acquisition (M&A) announcement, predicts the share market reaction on M&A announcement.

Design/methodology/approach

Event studies and cross-section regression were used in this analysis.

Findings

This paper finds that acquiring firms with no director trading and firms with net director purchases in the 12 months prior to the M&A announcement earn positive abnormal returns. It is also found that share market reaction to M&A announcements is considerably larger for acquiring firms whose directors do not trade relative to those companies with directors who do trade over the prior 12 months. This director non-trading result is further born out in regression analysis.

Research limitations/implications

The absence of pre-M&A announcement director trading could reflect lower agency costs for the acquiring firm and this might explain to stronger announcement day effect for this group of firms.

Practical implications

The fact that directors choose not to trade in their shares prior to a M&A transaction appears to be viewed as good news by the market.

Social implications

Director trading is value relevant for the acquiring firm and so it is critical that director trading is transparent.

Originality/value

To the best of the authors' knowledge, this question has not been addressed in the literature before, particularly the finding for firms with no director trading in the period prior to the M&A announcement.
Not just a pretty picture: visual literacy education through art for young children
Authors: Lopatovska Irene , Hatoum Sarah , Waterstraut Saebra , Novak Lisa , Sheer Sara
Published: September 2016

Purpose

The purpose of this paper is to understand young children’s knowledge of visual literacy elements as well as their ability to comprehend newly introduced visual literacy concepts. The study also examined existing support for visual literacy programs from parents and educators.

Design/methodology/approach

The study explored the knowledge of basic visual literacy elements of young children enrolled in two private schools in the New York City metropolitan area. The authors interviewed 17 children, aged four to six years old, about fine art paintings using a semi-structured interview format. Children’s responses were qualitatively analyzed to determine their initial level of visual literacy and their ability to learn and retain the concepts of visual literacy after receiving basic instruction. The children’s educators and parents completed online questionnaires that were quantitatively analyzed to determine their level of support for visual literacy programs.

Findings

The findings show that young children exhibited extensive knowledge of simple visual literacy elements (color, shape, line), and limited understanding of more abstract elements (perspective and salience). Children’s knowledge of visual elements improved after instruction. Parents and educators expressed support for incorporating visual literacy instruction in early childhood education.

Research limitations/implications

The study relied on a sample of children and adults drawn from two private schools. The sample’s demographics might have affected study findings. More studies are needed using a larger and more diverse sample.

Practical implications

The study suggests that young children are ready to receive instruction on visual literacy elements using art images. Children reacted positively to the images and were engaged in the discussions about them, supporting the use of fine art paintings as an instrument to introduce visual literacy concepts to young children. Survey of children’s parents and teachers indicated strong interest in, and support for such programs.

Social implications

With the increase of visual information production and consumption, it is important to introduce visual literacy early in life. The study advances research in methods for developing visual literacy instruction for young children.

Originality/value

There are no previously reported studies that have examined pre-kindergarten children’s knowledge of basic visual literacy elements and reactions to visual literacy instruction.
Information seeking and searching strategies as plans and patterns of action
Authors: Savolainen Reijo
Published: September 2016

Purpose

The purpose of this paper is to elaborate the picture of strategies for information searching and seeking by reviewing the conceptualizations on this topic in the field of library and information science (LIS).

Design/methodology/approach

The study draws on Henry Mintzberg’s idea of strategy as plan and strategy as pattern in a stream of actions. Conceptual analysis of 57 LIS investigations was conducted to find out how researchers have approached the above aspects in the characterizations of information search and seeking strategies.

Findings

In the conceptualizations of information search and information seeking strategies, the aspect of strategy as plan is explicated most clearly in text-book approaches describing the steps of rational web searching. Most conceptualizations focus on the aspect of strategy as pattern in a stream of actions. This approach places the main emphasis on realized strategies, either deliberate or emergent. Deliberate strategies indicate how information search or information seeking processes were oriented by intentions that existed previously. Emergent strategies indicate how patterns in information seeking and seeking developed in the absence of intentions, or despite them.

Research limitations/implications

The conceptualizations of the shifts in information seeking and searching strategies were excluded from the study. Similarly, conceptualizations of information search or information retrieval tactics were not examined.

Originality/value

The study pioneers by providing an in-depth analysis of the ways in which the key aspects of strategy are conceptualized in the classifications and typologies of information seeking and searching strategies. The findings contribute to the elaboration of the conceptual space of information behaviour research.
The impact of intellectual capital on start-up expectations
Authors: Matricano Diego
Published: September 2016

Purpose

According to an emerging research trend, which seeks to apply the concept of intellectual capital (IC) to the field of entrepreneurship, the purpose of this paper is to test whether IC can affect the start-up expectations of aspiring entrepreneurs.

Design/methodology/approach

Binary logistic regression models, based on empirical data derived from the Global Entrepreneurship Monitor website and referring to Italy over the years 2005-2010, are used to test the influence of IC (comprising human, structural and relational capital) on start-up expectations.

Findings

Binary logistic regression models reveal robust results. Human, structural and relational capitals affect start-up expectations in Italy. Only in 2010 did structural capital fail to do so.

Research limitations/implications

This study has three main limitations. The first concerns the need for further research to confirm the influence of IC on start-up expectations. The second concerns in-depth, more exhaustive analyses that cannot be carried out due to the use of second- hand data. The third deals with the reference only to Italy, over a limited time-span (2005-2010).

Originality/value

To the best knowledge of the author, this is one of the first empirical studies that investigate whether IC can affect start-up expectations. Results revealed by the regression models might steer other scholars’ interest toward this research path (linking IC and entrepreneurship) that has not yet been properly considered.
Towards environmental management accounting for trade-offs
Authors: Christ Katherine Leanne , Burritt Roger , Varsei Mohsen
Published: September 2016

Purpose

Environmental Management Accounting (EMA) information has become synonymous with win-win decision settings, but this paper aims to consider how EMA support can be extended to company managers who face the dynamics of win-wins and trade-offs.

Design/methodology/approach

Based on extant literature, the paper suggests an important extension of the use of EMA in support of management decision-making. The need for extended consideration and use of EMA to help overcome trade-offs is illustrated using the case of a wine bottling plant location decision by an Australian company in a global supply chain transporting wine from Australia to North America and Europe.

Findings

Results confirm the need to add to the broader use of EMA to assist managers attempting to solve real world trade-off problems between economic performance, carbon equivalent emissions reduction and water risk reduction.

Research limitations/implications

Generalisation of the single wine company case illustration to other companies and similar industry settings remains to be investigated.

Practical implications

Trade-offs are considered between economic benefit and two environmental performance matters of concern to the company, carbon equivalent emissions reduction and water risk reduction.

Originality/value

The paper introduces the notion of extending the use of EMA as a pragmatic way for managers to assess trade-off situations with environmental alternatives where no optimal solution is available. Value is added through the real case study of an Australian wine company.
Modelling effects of nonbreeders on population growth estimates
Authors: Lee Aline M. , Reid Jane M. , Beissinger Steven R.
Published: September 2016

Adult individuals that do not breed in a given year occur in a wide range of natural populations. However, such nonbreeders are often ignored in theoretical and empirical population studies, limiting our knowledge of how nonbreeders affect realized and estimated population dynamics and potentially impeding projection of deterministic and stochastic population growth rates.

We present and analyse a general modelling framework for systems where breeders and nonbreeders differ in key demographic rates, incorporating different forms of nonbreeding, different life histories and frequency‐dependent effects of nonbreeders on demographic rates of breeders.

Comparisons of estimates of deterministic population growth rate, λ, and demographic variance, , from models with and without distinct nonbreeder classes show that models that do not explicitly incorporate nonbreeders give upwardly biased estimates of , particularly when the equilibrium ratio of nonbreeders to breeders, , is high. Estimates of λ from empirical observations of breeders only are substantially inflated when individuals frequently re‐enter the breeding population after periods of nonbreeding.

Sensitivity analyses of diverse parameterizations of our model framework, with and without negative frequency‐dependent effects of nonbreeders on breeder demographic rates, show how changes in demographic rates of breeders vs. nonbreeders differentially affect λ. In particular, λ is most sensitive to nonbreeder parameters in long‐lived species, when , and when individuals are unlikely to breed at several consecutive time steps.

Our results demonstrate that failing to account for nonbreeders in population studies can obscure low population growth rates that should cause management concern. Quantifying the size and demography of the nonbreeding section of populations and modelling appropriate demographic structuring is therefore essential to evaluate nonbreeders' influence on deterministic and stochastic population dynamics.
The emerging role of calmodulin regulation of RyR2 in controlling heart rhythm, the progression of heart failure and the antiarrhythmic action of dantrolene
Authors: Walweel Kafa , Oo Ye Win , Laver Derek R
Published: September 2016

Cardiac output and rhythm depend on the release and the take‐up of calcium from the sarcoplasmic reticulum (SR). Excessive diastolic calcium leak from the SR due to dysfunctional calcium release channels (RyR2) contributes to the formation of delayed after‐depolarizations, which underlie the fatal arrhythmias that occur in heart failure and inherited syndromes. Calmodulin (CaM) is a calcium‐binding protein that regulates target proteins and acts as a calcium sensor. CaM is comprised of two calcium‐binding EF‐hand domains and a flexible linker. CaM is an accessory protein that partially inhibits RyR2 channel activity. CaM is critical for normal cardiac function, and altered CaM binding and efficacy may contribute to defects in SR calcium release. The present paper reviews CaM binding to RyR2 and how it regulates RyR2 channel activity. It then goes on to review how mutations in the CaM amino acid sequence give rise to inherited syndromes such as Catecholaminergic Polymorphic Ventricular Tachychardia (CPVT) and long QT syndrome (LQTS). In addition, the role of reduced CaM binding to RyR2 that results from RyR2 phosphorylation or from oxidation of either RyR2 or CaM contributes to the progression of heart failure is reviewed. Finally, this manuscript reviews recent evidence that CaM binding to RyR2 is required for the inhibitory action of a pharmaceutical agent (dantrolene) on RyR2. Dantrolene is a clinically used muscle relaxant that has recently been found to exert antiarrhythmic effects against SR Ca2+ overload arrhythmias.
The impact of ovarian stimulation on the outcome of intrauterine insemination treatment: an analysis of 8893 cycles
Authors: Liu Jinyong , Li Tin‐Chiu , Wang Jing , Wang Wei , Hou Zhen , Liu Jiayin
Published: September 2016

Objective

To evaluate the impact of ovarian stimulation on the outcome of intrauterine insemination (IUI).

Design

Retrospective analysis.

Setting

A single university‐based centre.

Population

A total of 5109 couples with 8893 cycles.

Methods

The outcome of IUI with different protocols for ovarian stimulation was examined.

Main outcome measures

The live birth rate (LBR), twin pregnancy rate and ovarian hyperstimulation syndrome (OHSS).

Results

In ovulatory women without ovarian stimulation, the LBR was 7.6%. Stimulation with clomifene citrate (CC), letrozole (LE), human menopausal gonadotrophin (HMG), CC or LE combined with HMG achieved LBRs of 6.1, 5, 7.9, 8 and 12.2%, respectively. LE combined with HMG achieved a significantly improved LBR compared with no stimulation. HMG stimulation was associated with a higher rate of twins (7.4%) than no stimulation (0%, P < 0.01). In ovulatory women, the LBR appeared lower in CC and LE compared with no stimulation (P > 0.05). In anovulatory women, ovarian stimulation with CC, LE, HMG, CC or LE combined with HMG achieved LBRs of 11.3, 5.1, 11.8, 12.6 and 13.6%, respectively. No significant difference was observed. There were no triplet pregnancies or OHSS in stimulated cycles.

Conclusions

In ovulatory women, ovarian stimulation with LE combined with HMG achieved a significantly improved live birth rate. HMG stimulation resulted in a high risk for twins.

Tweetable abstract

In ovulatory women, ovarian stimulation with letrozole and HMG resulted in a significantly improved LBR.
Trade law and alcohol regulation: what role for a global Alcohol Marketing Code?
Authors: Mitchell Andrew D. , Casben Jessica
Published: September 2016

Background and aims

Following calls for restrictions and bans on alcohol advertising, and in light of the tobacco industry's challenge to Australia's tobacco plain packaging measure, a tobacco control measure finding support in the World Health Organization (WHO) Framework Convention on Tobacco Control, this paper considers what role, if any, an international alcohol marketing code might have in preventing or reducing the risk of challenges to domestic alcohol marketing restrictions under trade rules.

Methods

Narrative review of international trade and health instruments and international trade court judgements regarding alcohol products and marketing restrictions.

Findings

The experience of European trade courts in the litigation of similar measures suggests that World Trade Organization rules have sufficient flexibility to support the implementation of alcohol marketing restrictions. However, the experience also highlights the possibility that public health measures have disproportionate and unjustifiable trade effects and that the ability of a public health measure to withstand a challenge under trade rules will turn on its particular design and implementation.

Conclusion

Measures implemented pursuant to international public health instruments are not immune to trade law challenges. Close collaboration between health policymakers, trade officials and lawyers, from as early as the research stage in the development of a measure to ensure a robust evidence base, will ensure the best chance of regulatory survival for an international marketing code.
Three‐dimensional culture system can induce expression of casein in immortalized bovine mammary epithelial cells
Authors: Zhan Kang , Lin Miao , Liu MingMei , Sui YangNan , Babekir Haitham Mohammed , Zhao GuoQi
Published: September 2016

Primary bovine mammary epithelial cells (BMECs) are not ideal models for long‐term studies of lactation mechanisms because these cells in a monolayer culture system cannot be polarized to simulate the physiological functions in vitro. We investigate the effects of different culture models and karyotypes on casein expression in a three‐dimensional (3D) culture system. The immortalized cells' karyotypes were analyzed at passages 10, 20, 30 and 40 to detect the effects of chromosome stability. Western blotting examined that whether or not the immortalized cells at passages 5, 10, 20, 30, 40 and 50 could induce expression of casein in a 3D culture system. The proper polarization of the acinar structures was monitored. BMECs were successfully immortalized. The cell karyotype at passage 30 remained at 60 chromosomes and the average value was 57.1 ± 0.40 after passage 40. The polarized protein's levels were up‐regulated in 3D culture compared to 2D culture. Expression of αs1, β and κ‐casein could be detectable in a passage range in 3D culture. Expression of αs2‐casein was undetectable in all experimental groups. However, all casein expressions were barely detectable in traditional 2D culture system. Therefore, 3D culture system is an important tool for the long‐term study of lactation mechanisms in vitro.
Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment
Authors: Okusaka Takuji , Otsuka Taiga , Ueno Hideki , Mitsunaga Shuichi , Sugimoto Rie , Muro Kei , Saito Isao , Tadayasu Yusuke , Inoue Kohei , Loembé Arsene‐Bienvenu , Ikeda Masafumi
Published: September 2016

This phase I, dose‐escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinoma were enrolled to groups, depending on whether liver impairment was mild (group I, aspartate aminotransferase and alanine aminotransferase ≤2× upper limit of normal and Child–Pugh score 5 [n = 14] or 6 [n = 2]) or moderate (group II, Child–Pugh score 5–6 and aspartate aminotransferase or alanine aminotransferase >2× to ≤5× upper limit of normal [n = 7] or Child–Pugh score 7 [n = 7]); 22 patients had prior sorafenib treatment. Nintedanib was given twice daily in 28‐day cycles until disease progression or unacceptable adverse events, starting at 150 mg (group I) or 100 mg (group II) and escalating to 200 mg. The primary objective was to define the maximum tolerated dose based on occurrence of dose‐limiting toxicities during cycle 1 (grade ≥3 non‐hematological and grade 4 hematological adverse events). No dose‐limiting toxicities were reported during cycle 1 and the maximum tolerated dose for both groups was 200 mg twice daily. The most frequent adverse events were gastrointestinal (diarrhea, nausea, vomiting, and decreased appetite). No patients discontinued nintedanib due to adverse events; 31% of group I and 21% of group II had dose reductions. Median time to progression was 2.8 months (95% confidence interval, 1.05–5.52) for group I and 3.2 months (95% confidence interval, 0.95–6.70) for group II. Nintedanib showed a manageable safety profile and efficacy signals, including in patients previously treated with sorafenib. Clinical trial registration NCT01594125; 1199.120 (ClinicalTrials.gov).
EWSR1/ELF5 induces acute myeloid leukemia by inhibiting p53/p21 pathway
Authors: Endo Akifumi , Tomizawa Daisuke , Aoki Yuki , Morio Tomohiro , Mizutani Shuki , Takagi Masatoshi
Published: September 2016

The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the association of EWSR1 chimeric fusion genes with leukemia has rarely been reported. We identified a novel EWSR1‐associated chimeric fusion gene in a patient with acute myeloid leukemia harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired‐end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation‐specific transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21‐dependent pathway. The injection of EWSR1/ELF5‐transduced NIH3T3 cells into NSG‐SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5.
Assessing Individual Income Growth
Authors: Jenkins Stephen P. , Van Kerm Philippe
Published: September 2016

We develop methods for describing distributions of income growth across individuals and for comparing changes in growth distributions over time. The methods include graphical devices (‘income growth profiles’) and dominance conditions, and also summary indices, together with associated methods of estimation and inference. Taking an explicitly longitudinal perspective, our approach illuminates clearly who are the gainers and the losers, and also provides distributionally‐sensitive assessments—ones that allow the income growth for different individuals to be weighted differently. Our empirical application shows that the pattern of income growth in Britain over the period 1992–6 was less pro‐poor than that for 1998–2002, and not significantly different from the pattern for 2001–5.
Resilient Leaders and Institutional Reform: Theory and Evidence
Authors: Besley Timothy , Persson Torsten , Reynal‐Querol Marta
Published: September 2016

Strengthening executive constraints is one of the key means of improving political governance. This paper argues that resilient leaders who face a lower probability of being replaced are less likely to reform institutions in the direction of constraining executive power. We test this idea empirically using data on leaders since 1875 using two proxies of resilience: whether a leader survives long enough to die in office, and whether recent natural disasters occur during the leader's tenure. We show that both are associated with lower rates of leader turnover and a lower probability of a transition to strong executive constraints. This effect is robust across a wide range of specifications. Moreover, in line with the theory, it is specific to strengthening executive constraints rather than generalized political reform.
Relationships between individual‐tree mortality and water‐balance variables indicate positive trends in water stress‐induced tree mortality across North America
Authors: Hember Robbie A. , Kurz Werner A. , Coops Nicholas C.
Published: September 2016

Accounting for water stress‐induced tree mortality in forest productivity models remains a challenge due to uncertainty in stress tolerance of tree populations. In this study, logistic regression models were developed to assess species‐specific relationships between probability of mortality (Pm) and drought, drawing on 8.1 million observations of change in vital status (m) of individual trees across North America. Drought was defined by standardized (relative) values of soil water content (Ws,z) and reference evapotranspiration (ETr,z) at each field plot. The models additionally tested for interactions between the water‐balance variables, aridity class of the site (AC), and estimated tree height (h). Considering drought improved model performance in 95 (80) per cent of the 64 tested species during calibration (cross‐validation). On average, sensitivity to relative drought increased with siteAC(i.e. aridity). Interaction between water‐balance variables and estimated tree height indicated that drought sensitivity commonly decreased during early height development and increased during late height development, which may reflect expansion of the root system and decreasing whole‐plant, leaf‐specific hydraulic conductance, respectively. Across North America, predictions suggested that changes in the water balance caused mortality to increase from 1.1% yr−1in 1951 to 2.0% yr−1in 2014 (a net change of 0.9 ± 0.3% yr−1). Interannual variation in mortality also increased, driven by increasingly severe droughts in 1988, 1998, 2006, 2007 and 2012. With strong confidence, this study indicates that water stress is a common cause of tree mortality. With weak‐to‐moderate confidence, this study strengthens previous claims attributing positive trends in mortality to increasing levels of water stress. This ‘learn‐as‐we‐go’ approach – defined by sampling rare drought events as they continue to intensify – will help to constrain the hydraulic limits of dominant tree species and the viability of boreal and temperate forest biomes under continued climate change.
Reference curves for CD4 T‐cell count response to combination antiretroviral therapy in HIV‐1‐infected treatment‐naïve patients
Authors: Bouteloup V , Sabin C , Mocroft A , Gras L , Pantazis N , Le Moing V , d'Arminio Monforte A , Mary‐Krause M , Roca B , Miro JM , Battegay M , Brockmeyer N , Berenguer J , Morlat P , Obel N , De Wit S , Fätkenheuer G , Zangerle R , Ghosn J , Pérez‐Hoyos S , Campbell M , Prins M , Chêne G , Meyer L , Dorrucci M , Torti C , Thiébaut R ,   The Standard Reference Distribution of CD4 Response to HAART Project Team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord
Published: September 2016

Objectives

The aim of this work was to provide a reference for the CD4 T‐cell count response in the early months after the initiation of combination antiretroviral therapy (cART) in HIV‐1‐infected patients.

Methods

All patients in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) cohort who were aged ≥ 18 years and started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV‐1 RNA copies/mL at 6 months (± 3 months) after cART initiation were included in the study. Unadjusted and adjusted references curves and predictions were obtained using quantile regressions.

Results

A total of 28 992 patients were included in the study. The median CD4 T‐cell count at treatment initiation was 249 [interquartile range (IQR) 150, 336] cells/μL. The median observed CD4 counts at 6, 9 and 12 months were 382 (IQR 256, 515), 402 (IQR 274, 543) and 420 (IQR 293, 565) cells/μL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL is generally required in order that patients stay ‘on track’ (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those starting with CD4 counts in the higher percentiles. Individual predictions adjusted for factors influencing CD4 count were more precise.

Conclusions

Reference curves aid the evaluation of the immune response early after antiretroviral therapy initiation that leads to viral control.