bluuebunny/crossref_metadata_2025_split huggingface dataset:
A vacuum-actuated microtissue stretcher for long-term exposure to oscillatory strain within a 3D matrix
Authors: Walker Matthew , Godin Michel , Pelling Andrew E. 
Published: June 2017

AbstractAlthough our understanding of cellular behavior in response to extracellular biological and mechanical stimuli has greatly advanced using conventional 2D cell culture methods, these techniques lack physiological relevance. We developed the microtissue vacuum-actuated stretcher (MVAS) to probe cellular behavior within a 3D multicellular environment composed of innate matrix protein, and in response to continuous uniaxial stretch. The MVAS consists of an array of fifty self-assembled microtissues bordered by vacuum chambers. When a vacuum is applied, the microtissues stretch in plane allowing live imaging. The MVAS is highly suitable for biomedical research and pharmaceutical discovery due to a high-throughput array format and scalable fabrication steps outlined in this paper. We validated our approach by characterizing the bulk microtissue strain, the microtissue strain field and single cell strain, and by assessing F-actin expression in response to chronic cyclic strain of 10%. The MVAS was shown to be capable of delivering reproducible dynamic bulk strain amplitudes up to 13% and the strain field had local maxima around each of the cantilevers. The strain at the single cell level was found to be 10.4% less than the microtissue axial strain due to cellular rotation. Chronic cyclic strain produced a 35% increase in F-actin expression consistent with previously observed cytoskeletal reinforcement in 2D cell culture. The MVAS may further our understanding of the reciprocity shared between cells and their environment, which is critical to meaningful biomedical research and successful therapeutic approaches.
Akt/PKB enhances non-canonical Wnt signals by compartmentalizing β-Catenin
Authors: Aznar Nicolas , Sun Nina , Dunkel Ying , Ear Jason , Buschman Matthew D. , Ghosh Pradipta 
Published: June 2017

AbstractCellular proliferation is antagonistically regulated by canonical and non-canonical Wnt signals; their dysbalance triggers cancers. It is widely believed that the PI3-K→ Akt pathway enhances canonical Wnt signals by affecting transcriptional activity and stability of β-catenin. Here we demonstrate that the PI3-K→Akt pathway also enhances non-canonical Wnt signals by compartmentalizing β-catenin. By phosphorylating the phosphoinositide(PI)-binding domain of a multimodular signal transducer, Daple, Akt abolishes Daple’s ability to bind PI3-P-enriched endosomes that engage dynein motor complex for long-distance trafficking of β-catenin/E-cadherin complexes to pericentriolar recycling endosomes (PCREs). Phosphorylation compartmentalizes Daple/β-catenin/E-cadherin complexes to cell-cell contact sites, enhances non-canonical Wnt signals, and thereby, suppresses colony growth. Dephosphorylation compartmentalizes β-catenin on PCREs, a specialized compartment for prolonged unopposed canonical Wnt signaling, and enhances colony growth. Cancer-associated Daple mutants that are insensitive to Akt mimic a constitutively dephosphorylated state. This work not only identifies Daple as a platform for crosstalk between Akt and the non-canonical Wnt pathway, but also reveals the impact of such crosstalk during cancer initiation and progression.
Evolutionary persistence of DNA methylation for millions of years after ancient loss of ade novomethyltransferase
Authors: Catania Sandra , Dumesic Phillip A. , Pimentel Harold , Nasif Ammar , Stoddard Caitlin I. , Burke Jordan E. , Diedrich Jolene K. , Cook Sophie , Shea Terrance , Geinger Elizabeth , Lintner Robert , Yates John R. , Hajkova Petra , Narlikar Geeta J. , Cuomo Christina A. , Pritchard Jonathan K. , Madhani Hiten D. 
Published: June 2017

SUMMARYCytosine methylation of DNA is a widespread modification of DNA that plays numerous critical roles, yet has been lost many times in diverse eukaryotic lineages. In the yeastCryptococcus neoformans, CG methylation occurs in transposon-rich repeats and requires the DNA methyltransferase, Dnmt5. We show that Dnmt5 displays exquisite maintenance-type specificityin vitroandin vivoand utilizes similarin vivocofactors as the metazoan maintenance methylase Dnmt1. Remarkably, phylogenetic and functional analysis revealed that the ancestral species lost the gene for ade novomethylase, DnmtX, between 50-150 MYA. We examined how methylation has persisted since the ancient loss of DnmtX. Experimental and comparative studies reveal efficient replication of methylation patterns inC. neoformans, rare stochastic methylation loss and gain events, and the action of natural selection. We propose that an epigenome has been propagated for >50 MY through a process analogous to Darwinian evolution of the genome.
Synaptic mechanisms of interference in working memory
Authors: Kilpatrick Zachary P 
Published: June 2017

SummaryInformation from preceding trials of cognitive tasks can bias performance in the current trial, a phenomenon referred to as interference. Subjects performing visual working memory tasks exhibit interference in their trial-to-trial response correlations: the recalled target location in the current trial is biased in the direction of the target presented on the previous trial. We present modeling work that (a) develops a probabilistic inference model of this history-dependent bias, and (b) links our probabilistic model to computations of a recurrent network wherein short-term facilitation accounts for the dynamics of the observed bias. Network connectivity is reshaped dynamically during each trial, providing a mechanism for generating predictions from prior trial observations. Applying timescale separation methods, we can obtain a low-dimensional description of the trial-to-trial bias based on the history of target locations. The model has response statistics whose mean is centered at the true target location across many trials, typical of such visual working memory tasks. Furthermore, we demonstrate task protocols for which the plastic model performs better than a model with static connectivity: repetitively presented targets are better retained in working memory than targets drawn from uncorrelated sequences.
Non-competitive resource exploitation within-mosquito shapes evolution of malaria virulence
Authors: Costa G. , Gildenhard M. , Eldering M. , Lindquist R.L. , Hauser A.E. , Sauerwein R. , Goosmann C. , Brinkmann V. , Levashina E.A. 
Published: June 2017

AbstractMalaria is a fatal human parasitic disease transmitted by a mosquito vector. The evolution of within-host malaria virulence has been the focus of many empirical and theoretical studies. However, the vector’s contribution to virulence evolution is not well understood. Here we explored how within-vector resource exploitation impacts evolutionary trajectories of within-hostPlasmodiumvirulence. We developed a nested model of within-vector dynamics and malaria epidemiology, which predicted that non-competitive resource exploitation within-vector restricts within-host parasite virulence. To validate our model, we experimentally manipulated mosquito lipid trafficking and gauged within-vector parasite development, within-host infectivity and virulence. We found that mosquito-derived lipids determine within-host parasite virulence by shaping development and metabolic activity of transmissible sporozoites. Our findings uncover the role of within-vector environment in regulating within-hostPlasmodiumvirulence and identifyPlasmodiummetabolic traits that may contribute to the evolution of malaria virulence.
NetMHCpan 4.0: Improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data
Authors: Jurtz Vanessa , Paul Sinu , Andreatta Massimo , Marcatili Paolo , Peters Bjoern , Nielsen Morten 
Published: June 2017

AbstractCytotoxic T cells are of central importance in the immune system’s response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC (major histocompatibility complex) class I molecules. Peptide binding to MHC molecules is the single most selective step in the antigen presentation pathway. On the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has therefore attracted large attention.In the past, predictors of peptide-MHC interaction have in most cases been trained on binding affinity data. Recently an increasing amount of MHC presented peptides identified by mass spectrometry has been published containing information about peptide processing steps in the presentation pathway and the length distribution of naturally presented peptides. Here, we present NetMHCpan-4.0, a method trained on both binding affinity and eluted ligand data leveraging the information from both data types. Large-scale benchmarking of the method demonstrates an increased predictive performance compared to state-of-the-art when it comes to identification of naturally processed ligands, cancer neoantigens, and T cell epitopes.
Challenges in estimating heritability of phase polyphenism: insights from measured and simulated data in the desert locust
Authors: Jourdan-Pineau Hélène , Pélissié Benjamin , Chapuis Elodie , Chardonnet Floriane , Pagès Christine , Foucart Antoine , Blondin Laurence , Piou Cyril , Chapuis Marie-Pierre 
Published: June 2017

AbstractQuantitative genetics experiments aim at understanding and predicting the evolution of phenotypic traits. Running such experiments often bring the same questions: Should I bother with maternal effects? Could I estimate those effects? What is the best crossing scheme to obtain reliable estimates? Can I use molecular markers to spare time in the complex task of keeping track of the experimental pedigree?We explored those practical issues in the desert locust,Schistocerca gregariausing morphologic and coloration traits, known to be influenced by maternal effects. We ran quantitative genetic analyses with an experimental dataset and used simulations to explore i) the efficiency of animal models to accurately estimate both heritability and maternal effects, ii) the influence of crossing schemes on the precision of estimates and iii) the performance of a marker-based method compared to the pedigree-based method.The simulations indicated that maternal effects deeply affect heritability estimates and very large datasets are required to properly distinguish and estimate maternal effects and heritabilities. In particular, ignoring maternal effects in the animal model resulted in overestimation of heritabilities and a high rate of false positives whereas models specifying maternal variance suffer from lack of power. Maternal effects can be estimated more precisely than heritabilities but with low power. To obtain better estimates, bigger datasets are required and, in the presence of maternal effects, increasing the number of families over the number of offspring per families is recommended. Our simulations also showed that, in the desert locust, using relatedness based on available microsatellite markers may allow reasonably reliable estimates while rearing locusts in group.In the light of the simulation results, our experimental dataset suggested that maternal effects affected various phase traits. However the statistical limitations, revealed by the simulation approach, didn’t allow precise variance estimates. We stressed out that doing simulations is a useful step to design an experiment in quantitative genetics and interpret the outputs of the statistical models.
An optimized pipeline for parallel image-based quantification of gene expression and genotyping afterin situhybridization
Authors: Dobrzycki Tomasz , Krecsmarik Monika , Bonkhofer Florian , Patient Roger , Monteiro Rui 
Published: June 2017

ABSTRACTAdvances in genome engineering have resulted in the generation of numerous zebrafish mutant lines. A commonly used method to assess gene expression in the mutants is in situ hybridization (ISH). Because the embryos can be distinguished by genotype after ISH, comparing gene expression between wild type and mutant siblings can be done blinded and in parallel. Such experimental design reduces the technical variation between samples and minimises the risk of bias. This approach, however, requires an efficient method of genomic DNA extraction from post-ISH fixed zebrafish samples to ascribe phenotype to genotype. Here we describe a method to obtain PCR-quality DNA from 95-100% of zebrafish embryos, suitable for genotyping after ISH. In addition, we provide an image analysis protocol for quantifying gene expression of ISH-probed embryos, adaptable for the analysis of different expression patterns. Finally, we show that intensity-based image analysis enables accurate representation of the variability of gene expression detected by ISH and that it can complement quantitative methods like qRT-PCR. By combining genotyping after ISH and computer-based image analysis, we have established a high-confidence, unbiased methodology to assign gene expression levels to specific genotypes, and applied it to the analysis of molecular phenotypes of newly generatedlmo4amutants.SUMMARY STATEMENTOur optimized protocol to genotype zebrafish mutant embryos after in situ hybridization and digitally quantify the in situ signal will help to standardize existing experimental designs and methods of analysis.
Loss of CaMKI function disrupts salt aversive learning inC. elegans
Authors: Lim Jana P. , Fehlauer Holger , Glauser Dominique A. , Brunet Anne , Goodman Miriam B. 
Published: June 2017

AbstractThe ability to adapt behavior to environmental fluctuations is critical for survival of organisms ranging from invertebrates to mammals.Caenorhabditis eleganscan learn to avoid sodium chloride when it is paired with starvation. This behavior is likely advantageous to avoid areas without food. While some genes have been implicated in this salt aversive learning behavior, critical genetic components, and the neural circuit in which they act, remain elusive. Here, we show that the sole worm ortholog of mammalian CaMKI/IV, CMK-1, is essential for salt aversive learning behavior inC. elegans. We find that CMK-1 acts in the primary salt-sensing ASE neurons to regulate this behavior. By characterizing the intracellular calcium dynamics in ASE neurons using microfluidics, we find that loss ofcmk-1leads to an altered pattern of sensory-evoked calcium responses that may underlie salt aversive learning. Our study implicates the conserved CaMKI/CMK-1 as an essential cell-autonomous regulator for behavioral plasticity to environmental salt inC. elegans.Significance StatementLike other animals, the nematodeCaenorhabditis elegansdepends on salt for survival and navigates toward high concentrations of this essential mineral. Because salt generates osmotic stress at high concentrations, it also threatens the survival of small terrestrial animals likeC. elegans. A growing body of evidence indicates thatC. elegansbalances these factors through a process called salt aversive learning. We show that this behavior depends on expression of a calcium/calmodulin-dependent kinase, CMK-1, in the ASE salt sensing neurons and that salt-induced calcium signals in the ASE neurons are less sensitive to salt conditioning in animals lacking CMK-1 function. Our study identifies CMK-1 and sensory neurons as key factors in this form of behavioral plasticity.
Dopamine, Inference, and Uncertainty
Authors: Gershman Samuel J. 
Published: June 2017

AbstractThe hypothesis that the phasic dopamine response reports a reward prediction error has become deeply entrenched. However, dopamine neurons exhibit several notable deviations from this hypothesis. A coherent explanation for these deviations can be obtained by analyzing the dopamine response in terms of Bayesian reinforcement learning. The key idea is that prediction errors are modulated by probabilistic beliefs about the relationship between cues and outcomes, updated through Bayesian inference. This account can explain dopamine responses to inferred value in sensory preconditioning, the effects of cue pre-exposure (latent inhibition) and adaptive coding of prediction errors when rewards vary across orders of magnitude. We further postulate that orbitofrontal cortex transforms the stimulus representation through recurrent dynamics, such that a simple error-driven learning rule operating on the transformed representation can implement the Bayesian reinforcement learning update.
Egr1 deficiency induces browning of inguinal subcutaneous white adipose tissue in mice
Authors: Milet Cécile , Bléher Marianne , Allbright Kassandra , Orgeur Mickael , Coulpier Fanny , Duprez Delphine , Havis Emmanuelle 
Published: June 2017

AbstractBeige adipocyte differentiation within white adipose tissue, referred to as browning, is seen as a possible mechanism for increasing energy expenditure. The molecular regulation underlying the thermogenic browning process has not been entirely elucidated. Here, we identify the zinc finger transcription factor EGR1 as a negative regulator of the beige fat program. Loss ofEgr1in mice promotes browning in the absence of external stimulation and activatesUcp1that encodes the key thermogenic mitochondrial uncoupling protein-1. Moreover, EGR1 is recruited to the proximal region of theUcp1promoter in subcutaneous inguinal white adipose tissue. Transcriptomic analysis of subcutaneous inguinal white adipose tissue in the absence ofEgr1identifies the molecular signature of white adipocyte browning downstream ofEgr1deletion and highlights a concomitant increase of beige differentiation marker and decrease in extracellular matrix gene expression. Conversely,Egr1overexpression in mesenchymal stem cells decreases beige adipocyte differentiation, while increasing extracellular matrix production. These results uncover the role ofEgr1in blocking energy expenditure via directUcp1transcription regulation and highlightEgr1as a therapeutic target for counteracting obesity.
Daily stress and coping among emergency response officers: a case study
Authors: Rodrigues Susana , Kaiseler Mariana , Queirós Cristina , Basto-Pereira Miguel 
Published: June 2017

Purpose
Police in Europe are facing increased demands and diminished resources, and this is particularly prominent among emergency response officers (EROs) working in poorer countries such as Portugal. Considering that daily stress and limited coping skills can result in detrimental consequences for officers’ health and society welfare, the purpose of this paper is to investigate stress and coping among Portuguese EROs.

Design/methodology/approach
EROs completed daily diaries over 11 working days. Each diary entry included an open-ended stressor, coping section and a Likert-type scale to evaluate coping effectiveness. Data were analyzed using inductive and deductive content analysis procedures. The frequency of stressors, coping and coping effectiveness were calculated.

Findings
EROs reported facing more operational stressors, particularly public disorder situations. However, gun situations were perceived as the most intense stressor. Emotion-focused coping (i.e. peer support) was more used than problem-focused. Despite variation in coping effectiveness in accordance to stressor experienced, longitudinal analysis suggests that problem-focused coping is more effective.

Research limitations/implications
Longitudinal methodologies should contemplate stress appraisal and coping effectiveness in order to fully understand stress and coping. Future studies should employ this methodology at a larger scale and over longer periods.

Practical implications
Intervention programs for EROs should be multidimensional, targeting work conditions and resources, stress management, and coping effectiveness.

Originality/value
Findings provide strong recommendations for future research and applied implications for stress prevention and effective coping interventions.
Family firms’ management decision to export/not to export: a resource-based view
Authors: Duarte Alonso Abel , O’Brien Seamus 
Published: June 2017

PurposeThe purpose of this paper is to address some knowledge gaps in the family entrepreneurship literature, examining the cases of seven Western Australian family firms with various degrees of export involvement, including no involvement. In this process, the study incorporates the resource-based view of the firm (RBVF).Design/methodology/approachFace-to-face and telephone interviews conducted with firm co-owners and one manager of seven family firms. Content analysis and word association were employed to analyse the data gathered.FindingsThe interviews revealed the significance of various key resources regardless of firms’ extent of export involvement. Indeed, alignments with the RBVF emerged, with firms’ strategies resting on valuable, rare, perfectly immobile and non-substitutable resource attributes. More lucrative consumer markets, diversifying, product recognition and minimising the impact of domestic competitors were main reasons to export. In contrast, rising costs, unfavourable currency exchanges or mediocre previous experiences were motives for discontinuing exports. Nonetheless, building on their resource foundation, non-exporting firms’ strategies focussed on strengthening their involvement in the domestic market, perceived as a valued alternative.Originality/valueThe academic literature identifies various knowledge gaps concerning family firm entrepreneurship, including research focussing on family firms’ internationalisation process. By addressing this under-researched area, the study provides an element of originality and value. In addition, despite Western Australia’s proximity to neighbouring markets, limited contemporary research on family firms has been conducted in this state; hence, the study provides an original component. Finally, the study seeks to refine the RBVF in the context of family firm research.
Competition and innovation with horizontal R&D spillovers
Authors: Khazabi Massoud , Quyen Nguyen Van 
Published: June 2017

Purpose
The purpose of this paper is to extend a theoretical framework for analyzing competition and innovation in the presence of horizontal spillovers.

Design/methodology/approach
A theoretical analysis approach is adopted to drive the paper’s findings.

Findings
It is shown that when firms behave non-cooperatively in both the R&D and production stages, the degree of spillover has a negative relationship with the effective and respective R&D expenditures of each firm as well as the level of social welfare. An inverted-U relationship between competition and social welfare also holds. When firms behave cooperatively in the R&D stage, and non-cooperatively in the production stage the relationship between the R&D expenditure of the joint research lab and the number of firms in the market is negative.

Originality/value
In the literature on R&D spillovers and process innovation, efforts are mostly focused on the comparative R&D expenditures and the relative social welfare between non-cooperative and cooperative R&D. The question of the effectiveness of R&D technology on the optimal number of firm, however, is not explicitly addressed. The paper is intended to address this lacuna.