bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-particle view of stress-promoters induction dynamics: an interplay between MAPK signaling, chromatin and transcription factors
Authors: Wosika Victoria , Pelet Serge 
Published: August 2019

AbstractPrecise regulation of gene expression in response to environmental changes is crucial for cell survival, adaptation and proliferation. In eukaryotic cells, extracellular signal integration is often carried out by Mitogen-Activated Protein Kinases (MAPK). Despite a robust MAPK signaling activity, downstream gene expression can display a great variability between single cells. Using a live mRNA reporter, we monitored the dynamics of transcription in Saccharomyces cerevisiae upon hyper-osmotic shock. The transient activity of the MAPK Hog1 opens a temporal window where stress-response genes can be activated. Here we show that the first minutes of Hog1 activity are essential to control the activation of a promoter. The chromatin repression on a locus slows down this transition and contributes to the variability in gene expression, while binding of transcription factors increases the level of transcription. However, soon after Hog1 activity peaks, negative regulators promote chromatin closure of the locus and transcription progressively stops.
The association between caesarean section delivery and later life obesity in 21-24 year olds in an Urban South African birth cohort
Authors: Sogunle Eniola , Masukume Gwinyai , Nelson Gill 
Published: August 2019

AbstractBackgroundObesity is an important public health problem and rates have reached epidemic proportions in many countries. Studies have explored the association between infants delivered by caesarean section and their later life risk of obesity, in many countries outside Africa. As a result of the increasing caesarean section and obesity rates in South Africa, we investigated the association in this country.MethodsThis was a retrospective analysis of data that were collected from a prospective South African birth cohort (Birth to Twenty Plus), established in 1990. A total of 889 young adults aged 21-24 years were included in the analysis. Multiple logistic regression models were fitted to assess the association between mode of delivery and early adulthood obesity.ResultsOf the 889 young adults, 106 (11.9%) were obese while 72 (8.1%) were delivered by CS; of which 14 (19.4%) were obese. Caesarean section delivery was significantly associated with obesity in young adults after adjusting for potential confounders like gestational age (at delivery), birth weight, sex, maternal age, parity and education (OR 1.99, 95% CI 1.00–3.94, p=0.049).ConclusionThe association of caesarean section with early adulthood obesity should be interpreted with caution because data on certain key confounding factors such as mothers’ pre-pregnancy body mass index and gestational diabetes were not available. Further research from Africa, with larger sample sizes and databases with useful linking of maternal and infant data, should be conducted.
Paternal Indifference and neglect in early life and Creativity: Exploring the Moderating Role ofTPH1genotype and Offspring’s Gender
Authors: Yu Qi , Si Si , Zhang Shun , Zhang Jinghuan 
Published: August 2019

AbstractFor further understanding the joint contribution of environment, heredity and gender to creativity, the present research examined the prospective impact of paternal indifference & neglect in early life,TPH1rs623580, offspring’s gender, and the interaction effects thereof on creativity in five hundred and thirty-nine unrelated healthy Chinese undergraduate students. Paternal indifference & neglect in early life was assessed on the Parental Bonding Instrument (PBI) and creativity on the Runco Creativity Assessment Battery (rCAB). Results showed significant paternal indifference & neglect ×TPH1genotype andTPH1genotype × offspring’s gender interaction effects when predicting creativity. Specifically, paternal indifference & neglect in early life negatively predicted creativity in youth when individuals carry A allele ofTPH1(rs623580). In addition, male individuals who carry A allele were linked with lower level of flexibility compared to TT homozygote individuals. No significant three-way interaction was found. Findings from the current study suggested that the A allele ofTPH1(rs623580) might be a risk allele for creativity, and the long-term negative influence of paternal indifference & neglect in early life on individuals’ creativity in youth depending onTPH1genotype.
Oxidative stress in alpha and beta cells as a selection criterion for biocompatible biomaterials
Authors: Sthijns Mireille M.J.P.E. , Jetten Marlon J. , Mohammed Sami G. , Claessen Sandra M.H. , de Vries Rick , Stell Adam , de Bont Denise , Engelse Marten A. , Mumcuoglu Didem , van Blitterswijk Clemens A. , Dankers Patricia Y.W. , de Koning Eelco J.P. , van Apeldoorn Aart A. , LaPointe Vanessa L.S. 
Published: August 2019

AbstractThe clinical success of islet transplantation is limited by factors including acute ischemia, stress upon transplantation, and delayed vascularization. Islets experience high levels of oxidative stress due to delayed vascularization after transplantation and this can be further aggravated by their encapsulation and undesirable cell-biomaterial interactions. To identify biomaterials that would not further increase oxidative stress levels and that are also suitable for manufacturing a beta cell encapsulation device, we studied five clinically approved polymers for their effect on oxidative stress and islet (alpha and beta cell) function. We found that 300 poly(ethylene oxide terephthalate) 55/poly(butylene terephthalate) 45 (PEOT/PBT300) was more resistant to breakage and more elastic than other biomaterials, which is important for its immunoprotective function. In addition, PEOT/PBT300 did not induce oxidative stress or reduce viability in MIN6 beta cells, and even promoted protective endogenous antioxidant expression over 7 days. Importantly, PEOT/PBT300 is one of the biomaterials we studied that did not interfere with insulin secretion in human islets. These data indicate that PEOT/PBT300 may be a suitable biomaterial for an islet encapsulation device.
Cyclin Dependent Kinase 5 (CDK5) Regulates the Circadian Clock
Authors: Brenna Andrea , Olejniczak Iwona , Chavan Rohit , Ripperger Jürgen A. , Langmesser Sonja , Cameroni Elisabetta , Hu Zehan , De Virgilio Claudio , Dengjel Jörn , Albrecht Urs 
Published: August 2019

AbstractCircadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down ofCdk5in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Therefore, CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by the circadian clock.
Polygenic risk scores of several subtypes of epilepsies in a founder population
Authors: Moreau Claudia , Rébillard Rose-Marie , Wolking Stefan , Michaud Jacques , Tremblay Frédérique , Girard Alexandre , Bouchard Joanie , Minassian Berge , Laprise Catherine , Cossette Patrick , Girard Simon 
Published: August 2019

ABSTRACTImportanceEpilepsy is defined as a group of neurological disorders characterized by epileptic seizures, brief episodes of symptoms that are caused by abnormal or excessive neuronal activity in the brain. Epilepsy affects around 3 percent of individuals. In the past 10 years, many groups have been working to better understand the complex genetic mechanisms underlying epilepsy. Together, they studied many different genetic mechanisms, but there is still a substantial missing heritability component in epilepsy genetics.ObjectiveHere, we used polygenic risk scores (PRS) to quantify the cumulative effects of a number of variants, which may individually have a very small effect on susceptibility.DesignWe calculated PRS in 522 French-Canadian epilepsy patients divided into seven subtypes and French-Canadian controls.SettingAll study participants (cases and controls) were selected based on their French-Canadian ancestry.ParticipantsThe epilepsy cohort was composed of families of at least three affected individuals with Idiopathic Generalized Epilepsy (IGE) or Non-acquired Focal Epilepsy (NAFE) previously collected and diagnosed by neurologists following the International League Against Epilepsy (ILAE) criteria.ExposuresAll samples were processed on a common genotyping array.Main outcomes and ResultsWe show that the area under the curve (AUC) is almost always slightly greater than 0.5, especially in patients with IGE and subtypes. We also looked at the association of the PRS with the different phenotypes using a linear mixed effects model estimated by generalized estimating equation (GEE) with the pairwise identity-by-descent (IBD) matrix as a random effect. P-values of GEE were consistent with AUC calculations.Conclusions and RelevanceGlobally, we support the notion that PRS and SNP-based heritability provide reliable measures to rightfully estimate the contribution of genetic factors to the pathophysiological mechanism of epilepsies, but further studies are needed on PRS before they can be used clinically.
Constraints and limitations on the transcriptional response downstream of the Bicoid morphogen gradient
Authors: Tran Huy , Walczak Aleksandra M. , Dostatni Nathalie 
Published: August 2019

AbstractThe regulation of thehunchbackpromoter expression by the maternal Bicoid gradient has been studied as a model system in development for many years. Yet, at the level of quantitative agreement between data and theoretical models, even the first step of this regulation, transcription, continues to be challenging. This situation is slowly progressing, thanks to quantitative live-imaging techniques coupled to advanced statistical data analysis and modelling. Here we outline the current state of our knowledge of this apparently “simple” step, highlighting the newly appreciated role of bursty transcription dynamics and its regulation.
Assessment of the Utility of Gene Positioning Biomarkers in the Stratification of Prostate Cancers
Authors: Meaburn Karen J. , Misteli Tom 
Published: August 2019

AbstractIn eukaryotic cells, the genome is spatially organized in a non-random fashion within the confines of the interphase nucleus, and most genes occupy preferred nuclear positions. For some genomic loci these positioning patterns are context specific, reflected in the distinct location of certain genes and chromosomes in different cell types and in disease. Disease-related differential spatial positioning of genes has led to the hypothesis that the spatial reorganization of the genome may be utilized as a diagnostic biomarker. In keeping with this possibility, the positioning patterns of specific genes can be used to reproducibly discriminate benign tissues from cancerous ones. In addition to the use of spatial genome organization for diagnostic purposes, we explore here the potential use of spatial genome organization as a prognostic tool. This is a pressing need since in many cancer types there is a lack of accurate markers to predict the aggressiveness of individual tumors. We find that directional repositioning of SP100 and TGFB3 gene loci stratifies prostate cancers of differing Gleason scores. A more peripheral position of SP100 and TGFB3 in the nucleus, compared to benign tissues, is associated with low Gleason score cancers, whereas more internal positioning correlates with higher Gleason scores. Conversely, LMNA is more internally positioned in many non-metastatic prostate cancers, while its position is indistinguishable from benign tissue in metastatic cancer. Our findings of subtype-specific gene positioning patterns in prostate cancer provides a proof-of-concept for the potential usefulness of spatial gene positioning as a prognostic biomarker.
Multiple changes underlie allelic divergence of CUP2 between Saccharomyces species
Authors: Li Xueying C. , Fay Justin C. 
Published: August 2019

AbstractUnder the model of micromutationism, phenotypic divergence between species is caused by accumulation of many small-effect changes. While mapping the causal changes to single nucleotide resolution could be difficult for diverged species, genetic dissection via chimeric constructs allows us to evaluate whether a large-effect gene is composed of many small-effect nucleotide changes. In a previously described non-complementation screen, we found allele difference of CUP2, a copper-binding transcription factor, underlie divergence in copper resistance between Saccharomyces cerevisiae and S. uvarum. Here, we tested whether the allele effect of CUP2 was caused by multiple nucleotide changes. By analyzing chimeric constructs containing four separate regions in the CUP2 gene, including its distal promoter, proximal promoter, DNA binding domain and transcriptional activation domain, we found that all four regions of the S. cerevisiae allele conferred copper resistance, with the proximal promoter showing the largest effect, and that both additive and epistatic effects are likely involved. These findings support a model of multiple changes underlying evolution and suggest an important role of both protein coding and cis-regulatory changes in evolution.
Atypical neuromagnetic resting activity associated with thalamic volume and cognitive outcome in very preterm children
Authors: Nunes Adonay S. , Kozhemiako Nataliia , Hutcheon Evan , Chau Cecil , Ribary Urs , Grunau Ruth E , Doesburg Sam M 
Published: August 2019

AbstractChildren born very preterm, even in the absence of overt brain injury or major impairment, are at risk of cognitive difficulties. This risk is associated with disruption of ongoing critical periods involving development of the thalamocortical system while in the neonatal intensive care unit. The thalamus is an important structure that not only relays sensory information but acts as a hub integrating cortical activity, and through this integration, it regulates cortical power at different frequency bands. In this study, we investigate the association between atypical power at rest in children born very preterm at school age, neurocognitive function and structural alterations related to the thalamus. Our results indicate that children born extremely preterm have higher power at low frequencies and lower power at high frequencies, compared to controls born full-term. A similar pattern of spectral power was found to be associated with poorer neurocognitive outcomes. This pattern of spectral power was also associated with normalized T1 intensity and the volume of the thalamus. Overall, this study provides evidence of the relation between structural alterations related to very preterm birth, atypical oscillatory power at rest and neurocognitive difficulties at school-age children born very preterm.
Negative frequency-dependent selection maintains coexisting genotypes during fluctuating selection
Authors: Turner Caroline B. , Buskirk Sean W. , Harris Katrina B. , Cooper Vaughn S. 
Published: August 2019

AbstractNatural environments are rarely static; rather selection can fluctuate on time scales ranging from hours to centuries. However, it is unclear how adaptation to fluctuating environments differs from adaptation to constant environments at the genetic level. For bacteria, one key axis of environmental variation is selection for planktonic or biofilm modes of growth. We conducted an evolution experiment withBurkholderia cenocepacia, comparing the evolutionary dynamics of populations evolving under constant selection for either biofilm formation or planktonic growth with populations in which selection fluctuated between the two environments on a weekly basis. Populations evolved in the fluctuating environment shared many of the same genetic targets of selection as those evolved in constant biofilm selection, but were genetically distinct from the constant planktonic populations. In the fluctuating environment, mutations in the biofilm-regulating geneswspAandrpfRrose to high frequency in all replicate populations. A mutation inwspAfirst rose rapidly and nearly fixed during the initial biofilm phase but was subsequently displaced by a collection ofrpfRmutants upon the shift to the planktonic phase. ThewspAandrpfRgenotypes coexisted via negative frequency-dependent selection around an equilibrium frequency that shifted between the environments. The maintenance of coexisting genotypes in the fluctuating environment was unexpected. Under temporally fluctuating environments coexistence of two genotypes is only predicted under a narrow range of conditions, but the frequency-dependent interactions we observed provide a mechanism that can increase the likelihood of coexistence in fluctuating environments.
Cryptococcus neoformansrecovered from olive trees (Olea europaea) in Turkey reveal allopatry with African and South American lineages
Authors: Ergin Çağrı , Şengül Mustafa , Aksoy Levent , Döğen Aylin , Sun Sheng , Averette Anna F. , Cuomo Christina A. , Seyedmousavi Seyedmojtaba , Heitman Joseph , Ilkit Macit 
Published: August 2019

ABSTRACTCryptococcusspecies are life-threatening human fungal pathogens that cause cryptococcal meningoencephalitis in both immunocompromised and healthy hosts. The natural environmental niches ofCryptococcusinclude pigeon (Columba livia) guano, soil, and a variety of tree species such asEucalyptus camaldulensis, Ceratonia siliqua, Platanus orientalis, andPinusspp. Genetic and genomic studies of extensive sample collections have provided insights into the population distribution and composition of differentCryptococcusspecies in geographic regions around the world. However, few such studies examinedCryptococcusin Turkey. We sampled 388Olea europaea(olive) and 132E. camaldulensistrees from 7 locations in coastal and inland areas of the Aegean region of Anatolian Turkey in September 2016 to investigate the distribution and genetic diversity present in the naturalCryptococcuspopulation. We isolated 84Cryptococcus neoformansstrains (83MATα and 1MATa) and 3Cryptococcus deneoformansstrains (allMATa) from 87 (22.4% of surveyed)O. europaeatrees; a total of 32C. neoformansstrains were isolated from 32 (24.2%) of theE. camaldulensistrees, all of which wereMATα. A statistically significant difference was observed in the frequency ofC. neoformansisolation between coastal and inland areas (P< 0.05). Thus,O. europaeatrees could represent a novel niche forC. neoformans. Interestingly, theMATaC. neoformansisolate was fertile in laboratory crosses with VNI and VNBMATα tester strains and produced robust hyphae, basidia, and basidiospores, thus suggesting potential sexual reproduction in the natural population. Sequencing analyses of theURA5gene identified at least 5 different genotypes among the isolates. Population genetics and genomic analyses revealed that most of the isolates in Turkey belong to the VNBII lineage ofC. neoformans, which is predominantly found in southern Africa; these isolates are part of a distinct minor clade within VNBII that includes several isolates from Zambia and Brazil. Our study provides insights into the geographic distribution of differentC. neoformanslineages in the Mediterranean region and highlights the need for wider geographic sampling to gain a better understanding of the natural habitats, migration, epidemiology, and evolution of this important human fungal pathogen.
Scalable probabilistic PCA for large-scale genetic variation data
Authors: Agrawal Aman , Chiu Alec M. , Le Minh , Halperin Eran , Sankararaman Sriram 
Published: August 2019

AbstractPrincipal component analysis (PCA) is a key tool for understanding population structure and controlling for population stratification in genome-wide association studies (GWAS). With the advent of large-scale datasets of genetic variation, there is a need for methods that can compute principal components (PCs) with scalable computational and memory requirements. We present ProPCA, a highly scalable method based on a probabilistic generative model, which computes the top PCs on genetic variation data efficiently. We applied ProPCA to compute the top five PCs on genotype data from the UK Biobank, consisting of 488,363 individuals and 146,671 SNPs, in less than thirty minutes. Leveraging the population structure inferred by ProPCA within the White British individuals in the UK Biobank, we scanned for SNPs that are not well-explained by the PCs to identify several novel genome-wide signals of recent putative selection including missense mutations in RPGRIP1L and TLR4.Author SummaryPrincipal component analysis is a commonly used technique for understanding population structure and genetic variation. With the advent of large-scale datasets that contain the genetic information of hundreds of thousands of individuals, there is a need for methods that can compute principal components (PCs) with scalable computational and memory requirements. In this study, we present ProPCA, a highly scalable statistical method to compute genetic PCs efficiently. We systematically evaluate the accuracy and robustness of our method on large-scale simulated data and apply it to the UK Biobank. Leveraging the population structure inferred by ProPCA within the White British individuals in the UK Biobank, we identify several novel signals of putative recent selection.