bluuebunny/crossref_metadata_2025_split huggingface dataset:
EpiSAFARI: Sensitive detection of valleys in epigenetic signals for enhancing annotations of functional elements
Authors: Harmanci Arif , Harmanci Akdes Serin , Swaminathan Jyothishmathi , Gopalakrishnan Vidya 
Published: March 2019

AbstractThe genomewide signal profiles from functional genomics experiments are dense information sources for annotating the regulatory elements. These profiles measure epigenetic activity at the nucleotide resolution and they exhibit distinct patterns along the genome. Most notable of these patterns are the valley patterns that are prevalently observed in many epigenetic assays such as ChIP-Seq and bisulfite sequencing. Valleys mark locations of cis-regulatory elements such as enhancers. Systematic identification of the valleys provides novel information for delineating the annotation of regulatory elements using epigenetic data. Nevertheless, the valleys are generally not reported by analysis pipelines. Here, we describe EpiSAFARI, a computational method for sensitive detection of valleys from diverse types of epigenetic profiles. EpiSAFARI employs a novel smoothing method for decreasing noise in signal profiles and accounts for technical factors such as sparse signals, mappability, and nucleotide content. In performance comparisons, EpiSAFARI performs favorably in terms of accuracy. The histone modification and DNA methylation valleys detected by EpiSAFARI exhibit high conservation, transcription factor binding, and they are enriched in nascent transcription. In addition, the large clusters of histone valleys are found to be enriched at the promoters of the developmentally associated genes.
Distinct oligodendrocyte populations have spatial preference and injury-specific responses
Authors: Floriddia Elisa M. , Zhang Shupei , van Bruggen David , Gonçalves dos Santos João P. , Altinkök Müge , Llorens-Bobadilla Enric , Frisén Jonas , Castelo-Branco Gonçalo 
Published: March 2019

AbstractOligodendrocytes (OLs), the myelinating cells of the central nervous system, are transcriptionally heterogeneous,1 the origin and functional consequences of which are unknown. Functional heterogeneity of MOLs might correlate with the local environment or their interactions with different neuron types.2 Here, we show that distinct MOL populations have spatial preference in the mammalian central nervous system and differential susceptibility to traumatic spinal cord injury. We also show that the generation of distinct MOL populations is independent of the OPC developmental origin. We found that OPCs originating from the previously described developmental waves3–5 have comparable potential to differentiate into the main MOL populations. Furthermore, we found that MOL type 2 (MOL2) is enriched in the spinal cord and almost absent in the brain, while MOL5/6 is enriched with age in all analyzed regions. MOL2 and MOL5/6 also have differential preference for motor and sensory tracts in the spinal cord. In the context of disease, we found that MOL2 and MOL5/6 have differential susceptibility to traumatic spinal cord injury, where MOL2 are lost and MOL5/6 increased their contribution to the OL lineage. Importantly, MOL2 susceptibility is disease specific, as we found MOL2 is not lost in a mouse model of multiple sclerosis. Our results demonstrate that the MOL populations, previously described by single-cell transcriptomics,1 have distinct spatial preference and responses. We anticipate our study to pave the way for a better understanding of the MOL populations-specific functional roles in development, health, and disease, allowing for better targeting of the OL subtypes important for the regeneration and repair of the central nervous system.
Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data
Authors: Wu Yang , Qi Ting , Wang Huanwei , Zhang Futao , Zheng Zhili , Phillips-Cremins Jennifer E. , Deary Ian J. , McRae Allan F. , Wray Naomi R. , Zeng Jian , Yang Jian 
Published: March 2019

AbstractPromoter-anchored chromatin interactions (PAIs) play a pivotal role in transcriptional regulation. Current high-throughput technologies for detecting PAIs, such as promoter capture Hi-C, are not scalable to large cohorts. Here, we present an analytical approach that uses summary-level data from cohort-based DNA methylation (DNAm) quantitative trait locus (mQTL) studies to predict PAIs. Using mQTL data from human peripheral blood (n=1,980), we predicted 34,797 PAIs which showed strong overlap with the chromatin contacts identified by previous experimental assays. The promoter-interacting DNAm sites were enriched in enhancers or near expression QTLs. Genes whose promoters were involved in PAIs were more actively expressed, and gene pairs with promoter-promoter interactions were enriched for co-expression. Integration of the predicted PAIs with GWAS data highlighted interactions among 601 DNAm sites associated with 15 complex traits. This study demonstrates the use of mQTL data to predict PAIs and provides insights into the role of PAIs in complex trait variation.
Aromatic polyketide biosynthesis: fidelity, evolution and engineering
Authors: Qin Zhiwei , Devine Rebecca , Hutchings Matthew I. , Wilkinson Barrie 
Published: March 2019

AbstractWe report the formicapyridines which are structurally and biosynthetically related to the pentacyclic fasamycin and formicamycin aromatic polyketides but comprise a rare pyridine moiety. These new compounds are trace level metabolites formed by derailment of the major biosynthetic pathway. Inspired by evolutionary logic we show that rational mutation of a single gene in the biosynthetic gene cluster leads to a significant increase both in total formicapyridine production and their enrichment relative to the fasamycins/formicamycins. Our observations broaden the polyketide biosynthetic landscape and identify a non-catalytic role for ABM superfamily proteins in type II polyketide synthase assemblages for maintaining biosynthetic pathway fidelity.
The autophagic response toStaphylococcus aureusprovides an intracellular niche in neutrophils
Authors: Prajsnar Tomasz K. , Serba Justyna J. , Dekker Bernice M. , Gibson Josie F. , Masud Samrah , Fleming Angeleen , Johnston Simon A. , Renshaw Stephen A. , Meijer Annemarie H. 
Published: March 2019

ABSTRACTStaphylococcus aureusis a major human pathogen causing multiple pathologies, from cutaneous lesions to life-threatening sepsis. Although neutrophils contribute to immunity againstS. aureus, multiple lines of evidence suggest that these phagocytes can provide an intracellular niche for staphylococcal dissemination. However, the mechanism of neutrophil subversion by intracellularS. aureusremains unknown. Targeting of intracellular pathogens by autophagy is recognised as an important component of host innate immunity, but whether autophagy is beneficial or detrimental toS. aureus-infected hosts remains controversial. Here, using larval zebrafish we show thatS. aureusis rapidly decorated by the autophagy marker Lc3 following engulfment by macrophages and neutrophils. Upon phagocytosis by neutrophils, Lc3-positive, non-acidified spacious phagosomes are formed. This response is dependent on phagocyte NADPH oxidase as bothcybaknockdown and diphenyleneiodonium (DPI) treatment inhibited Lc3 decoration of phagosomes. Importantly, NADPH oxidase inhibition diverted neutrophilS. aureusprocessing into tight acidified vesicles, which resulted in increased host resistance to the infection. Some intracellular bacteria within neutrophils were also tagged by p62-GFP fusion protein and loss of p62 impaired host defence. Taken together, we have shown that intracellular handling ofS. aureusby neutrophils is best explained by Lc3-associated phagocytosis (LAP), which appears to provide an intracellular niche for bacterial pathogenesis, while the selective autophagy receptor p62 is host-protective. The antagonistic roles of LAP and p62-mediated pathways inS. aureus-infected neutrophils may explain the conflicting reports relating to anti-staphylococcal autophagy and provide new insights for therapeutic strategies against antimicrobial resistant staphylococci.
Long-term reduction of short wavelength light affects sustained attention and visuospatial working memory
Authors: Domagalik Aleksandra , Oginska Halszka , Beldzik Ewa , Fafrowicz Magdalena , Marek Tadeusz 
Published: March 2019

ABSTRACTThe short wavelength, i.e. blue light, is crucial for non-image forming effects such as entrainment of circadian system. Moreover, many studies showed that blue light enhances alertness and performance in cognitive tasks. However, most of scientific reports in this topic is based on studies using short exposure to blue or blue-enriched light and only few focused on the effects of its reduced transmittance, especially in longer period. The latter could potentially give insight into understanding if age-related sleep problems and cognitive decline are related to less amount of blue light reaching the retina, as our lenses become more yellow with age. In this study, we investigated the effects of prolonged blocking of blue light on cognitive functioning, in particular - sustained attention and visuospatial working memory, and sleep. We used amber contact lenses reducing transmittance of blue light by approximately 90% for the period of four weeks on a group of young, healthy participants. No changes were observed for measurements related to sleep and sleep-wake rhythm. The significant effect was shown both for sustained attention and visuospatial memory, i.e. the longer blocking the blue light lasted, the greater decrease in performance was observed. Additionally, the follow-up session was conducted (approximately one week after taking off the blue-blocking lenses) and revealed that in case of sustained attention this detrimental effect of blocking BL is fully reversible. Our findings provide evidence that prolonged reduction of BL exposure directly affects human cognitive functioning regardless of sleep-related conditions.
Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors
Authors: Perpetuini Andrea Cerquone , Reggio Alessio , Cerretani Mauro , Giuliani Giulio , Santoriello Marisabella , Stefanelli Roberta , Palma Alessandro , Harper Steven , Castagnoli Luisa , Bresciani Alberto , Cesareni Gianni 
Published: March 2019

AbstractMuscle resident fibro-adipogenic progenitors (FAPs), support muscle regeneration by releasing cytokines that stimulate the differentiation of myogenic stem cells. However, in non-physiological contexts (myopathies, atrophy, aging) FAPs cause fibrotic and fat infiltrations that impair muscle function. We set out to perform a fluorescence microscopy-based screening to identify compounds that perturb the differentiation trajectories of these multipotent stem cells. From a primary screen of 1120 FDA/EMA approved drugs, we identified 34 compounds as potential inhibitors of adipogenic differentiation of FAPs isolated from the murine model (mdx) of Duchenne muscular dystrophy (DMD). The hit list from this screen was surprisingly enriched with compounds from the glucocorticoid (GCs) chemical class, drugs that are known to promote adipogenesis in vitro and in vivo. To shed light on these data, three GCs identified in our screening efforts were characterized by different approaches. We found that like dexamethasone, budesonide inhibits adipogenesis induced by insulin in subconfluent FAPs. However, both drugs have a proadipogenic impact when the adipogenic mix contains factors that increase the concentration of cAMP. Gene expression analysis demonstrated that treatment with glucocorticoids induces the transcription of Gilz/Tsc22d3, an inhibitor of the adipogenic master regulator PPARγ, only in anti-adipogenic conditions. Additionally, alongside their anti-adipogenic effect, GCs are shown to promote terminal differentiation of satellite cells. Both the anti-adipogenic and pro-myogenic effects are mediated by the glucocorticoid receptor and are not observed in the presence of receptor inhibitors. Steroid administration currently represents the standard treatment for DMD patients, the rationale being based on their anti-inflammatory effects. The findings presented here offer new insights on additional glucocorticoid effects on muscle stem cells that may affect muscle homeostasis and physiology.
Statistical context dictates the relationship between feedback-related EEG signals and learning
Authors: Nassar Matthew R. , Bruckner Rasmus , Frank Michael J. 
Published: March 2019

AbstractSuccessful decision-making requires learning expectations based on experienced outcomes. This learning should be calibrated according to the surprise associated with an outcome, but also to the statistical context dictating the most likely source of surprise. For example, when occasional changepoints are expected, surprising outcomes should be weighted heavily, demanding increased learning. In contrast, when signal corruption is expected to occur occasionally, surprising outcomes can suggest a corrupt signal that should be ignored by learning systems. Here we dissociate surprising outcomes from the degree to which they demand learning using a predictive inference task and computational modeling. We show that the updating P300, a stimulus-locked electrophysiological response previously associated with adjustments in learning behavior, does so conditionally on the source of surprise. Larger P300 signals predicted greater learning in a changing context, but predicted less learning in a context where surprise was indicative of a one-off outlier (oddball). The conditional predictive relationship between the P300 and learning behavior was persistent even after adjusting for known sources of learning rate variability. Our results suggest that the P300 provides a surprise signal that is interpreted by downstream learning processes differentially according to statistical context in order to appropriately calibrate learning across complex environments.
Corticolimbic Circuit Structure Moderates an Association Between Early Life Stress and Later Trait Anxiety
Authors: Kim M. Justin , Farber Madeline J. , Knodt Annchen R. , Hariri Ahmad R. 
Published: March 2019

AbstractChildhood adversity is associated with a wide range of negative behavioral and neurodevelopmental consequences. However, individuals vary substantially in their sensitivity to such adversity. Here, we examined how individual variability in structural features of the corticolimbic circuit, which plays a key role in emotional reactivity, moderates the association between childhood adversity and later trait anxiety in 798 young adult university students. Consistent with prior research, higher self-reported childhood adversity was significantly associated with higher self-reported trait anxiety. However, this association was attenuated in participants with higher microstructural integrity of the uncinate fasciculus and greater thickness of the orbitofrontal cortex. These structural properties of the corticolimbic circuit may capture a neural profile of relative resiliency to early life stress, especially against the negative effects of childhood adversity on later trait anxiety. More generally, our findings highlight the potential utility in the simultaneous consideration of qualitatively different brain structural measures in explaining complex behavioral associations in future research.
Integrative network modeling reveals mechanisms underlying T cell exhaustion
Authors: Bolouri Hamid , Young Mary , Beilke Joshua , Johnson Rebecca , Fox Brian , Huang Lu , Santini Cristina Costa , Hill Christopher Mark , van der Vuurst de Vries Anne-Renee , Shannon Paul , Dervan Andrew , Sivakumar Pallavur , Trotter Matthew , Bassett Douglas , Ratushny Alexander 
Published: March 2019

AbstractFailure to clear antigens causes CD8+T cells to become increasingly hypo-functional, a state known as exhaustion. We combined manually extracted information from published literature with gene expression data from diverse model systems to infer a set of molecular regulatory interactions that underpin exhaustion. Topological analysis and simulation modeling of the network suggests CD8+T cells undergo 2 major transitions in state following stimulation. The time cells spend in the earlier proliferative/pro-memory (PP) state is a fixed and inherent property of the network structure. Transition to the second state is necessary for exhaustion. Combining insights from network topology analysis and simulation modeling, we predict the extent to which each node in our network drives cells towards an exhausted state. We demonstrate the utility of our approach by experimentally testing the prediction that druginduced interference with EZH2 function increases the proportion of proliferative/pro-memory cells in the early days post-activation.
Novel insights into the morphology ofPlesiochelys biglerifrom the early Kimmeridgian of Northwestern Switzerland
Authors: Raselli Irena , Anquetin Jérémy 
Published: March 2019

AbstractPlesiochelyidae were relatively large coastal marine turtles, which inhabited the epicontinental seas of Western Europe during the Late Jurassic. Their fossil record can be tracked in Germany, Switzerland, the United Kingdom, France, Spain and Portugal. The Jura Mountains, in northwestern Switzerland, have been the main source for the study of this group, mostly thanks to the rich and famous historical locality of Solothurn. In the last two decades, numerous plesiochelyid remains have been collected from Kimmeridgian deposits (LowerVirgulaMarls and Banné Marls) in the area of Porrentruy (Canton of Jura, Switzerland). This material was revealed by construction works of the A16 Transjurane highway between 2000 and 2011, and led to the recent description of the new speciesPlesiochelys bigleri. In the years 2014 and 2016, new fragmentary turtle material was collected from the Banné Marls (Reuchenette Formation, lower Kimmeridgian) near the village of Glovelier, Canton of Jura, Switzerland. The new material consists of a complete shell, additional shell elements, a few bones from the appendicular and vertebral skeleton, and a fragmentary basicranium. This material can be confidently assigned to the speciesP. bigleri. It supports the presence of this species in the Banné Marls, slightly extends its spatial distribution and confirms the differences with the closely related speciesP. etalloni.The new material reveals that the split between the cerebral and palatine branches of the internal carotid artery occurs in a vertical plane inP. bigleri. This condition could not be observed in the type material due to poor preservation. This new character clearly distinguishesP. biglerifromP. etalloniand seems to be unique among thalassochelydians.
Relation of seasonal birth pulses and maternal immunity with viral invasion and persistence: A case study of Hendra virus infection in a population of black flying foxes (Pteropus alecto)
Authors: Jeong Jaewoon , Peel Alison J. , Plowright Raina K. , Restif Olivier , Mccallum Hamish 
Published: March 2019

AbstractIncreasing outbreaks of emerging infectious diseases, originating from wildlife, has intensified interest in understanding the dynamics of these diseases in their wildlife reservoir hosts. Until recently, the effect of seasonal birth pulses and subsequent waning of maternally derived antibodies on epidemics in a wild mammal population has received little attention and has remained obscure. In this study, we explore how population structure, influenced by seasonal breeding and maternally derived immunity, affects viral invasion and persistence, using a hypothetical system loosely based on Hendra virus infection in black flying foxes (Pteropus alecto). We used deterministic epidemic models to simulate transient epidemics, following viral introduction into an infection-free population, with a variety of timings within a year and different levels of pre-existing herd immunity. Moreover, we applied different levels of birth synchrony and different modelling methods of waning maternal immunity to examine the effect of birth pulses and maternally derived immunity, both individually and in combination. The presence of waning maternal immunity dispersed the supply time of susceptible individuals in seasonally breeding populations, hence diminishing the effect of birth pulse. Dampened epidemics, caused by waning maternal immunity, made viral invasion and persistence easier. This study enhanced our understanding of viral invasion, persistence, and timing of epidemics in wildlife populations.
Value relevance of earnings and book values in the Qatari Stock Exchange
Authors: Almujamed Hesham I. , Alfraih Mishari M. 
Published: March 2019

Purpose
The study of developed capital markets suggests that information provided in financial statements has lost its value relevance to equity holders. The purpose of this paper is to explore this issue in the emerging market of Qatar.

Design/methodology/approach
Following other studies in the literature, the study examines the value relevance of earnings and book values using the price valuation model provided by Ohlson (1995). A total of 215 observations were collected from all firms listed on the Qatari Stock Exchange over a period of five years (2012–2016).

Findings
This study suggests that the value relevance of both earnings and book values has noticeably decreased over the sample period. However, its results show that the decline in the value relevance of earnings favored book values.

Research limitations/implications
Like other studies, this one has limitations that suggest areas for future research. For example, in Qatar, like other emerging markets, a lack of data prevents the performance of deep analysis. Additionally, the authors only use Ohlson’s (1995) model as a framework for evaluation. It would be interesting to explore the changes when examining alternative valuation models. Another limitation is that the authors examine only two accounting measures: earnings and book values. Further research could explore changes in the value relevance of other measures, such as cash flow.

Practical implications
These findings provide empirical evidence regarding the value relevance of earnings and book values in an emerging market.

Originality/value
To the authors’ knowledge, this paper provides the first empirical evidence regarding the value relevance of earnings and book values in the emerging capital market of Qatar.
Open innovation practices and related internal dynamics: case studies of Italian ICT SMEs
Authors: Santoro Gabriele , Ferraris Alberto , Winteler Daniel John 
Published: March 2019

PurposeThe purpose of this paper is to shed light on challenges and facilitating factors of open innovation practices (OIP) implemented by small- and medium-sized enterprises (SMEs).Design/methodology/approachThe empirical research has been conducted on eight SMEs operating in the ICT sector, through a qualitative approach involving comparative case studies.FindingsThe findings drawn from the interviews indicate that each OIP established entails specific challenges and facilitating factors that SMEs have to face to sustain the open innovation journey and foster competitiveness. These findings helped to draw some important managerial implications and provide insights to SMEs willing to open innovation processes.Originality/valueThe study identifies OIP used in empirical studies to explore specific challenges and facilitators for each OIP, in the context of SMEs. Previous studies mostly focussed on open innovation sources and scarcely investigated internal dynamics of specific OIP.