bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global reference mapping and dynamics of human transcription factor footprints
Authors: Vierstra Jeff , Lazar John , Sandstrom Richard , Halow Jessica , Lee Kristen , Bates Daniel , Diegel Morgan , Dunn Douglas , Neri Fidencio , Haugen Eric , Rynes Eric , Reynolds Alex , Nelson Jemma , Johnson Audra , Frerker Mark , Buckley Michael , Kaul Rajinder , Meuleman Wouter , Stamatoyannopoulos John A. 
Published: February 2020

AbstractCombinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, yet it remains challenging to distinguish variants that impact regulatory function2. Genomic DNase I footprinting enables quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin3–5. However, to date only a small fraction of such sites have been precisely resolved on the human genome sequence5. To enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate at nucleotide resolution ~4.5 million compact genomic elements encoding transcription factor occupancy. We map the fine-scale structure of ~1.6 million DHS and show that the overwhelming majority is populated by well-spaced sites of single transcription factor:DNA interaction. Cell context-dependent cis-regulation is chiefly executed by wholesale actuation of accessibility at regulatory DNA versus by differential transcription factor occupancy within accessible elements. We show further that the well-described enrichment of disease- and phenotypic trait-associated genetic variants in regulatory regions1,6is almost entirely attributable to variants localizing within footprints, and that functional variants impacting transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find that the global density of human genetic variation is markedly increased within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a new framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation.
Slope-Hunter: A robust method for index-event bias correction in genome-wide association studies of subsequent traits
Authors: Mahmoud Osama , Dudbridge Frank , Smith George Davey , Munafo Marcus , Tilling Kate 
Published: February 2020

AbstractBackgroundStudying genetic associations with prognosis (e.g. survival, disability, subsequent disease events) is problematic due to selection bias - also termed index event bias or collider bias - whereby selection on disease status can induce associations between causes of incidence with prognosis. A current method for adjusting genetic associations for this bias assumes there is no genetic correlation between incidence and prognosis, which may not be a plausible assumption.MethodsWe propose an alternative, the ‘Slope-Hunter’ approach, which is unbiased even when there is genetic correlation between incidence and prognosis. Our approach has two stages. First, we use cluster-based techniques to identify: variants affecting neither incidence nor prognosis (these should not suffer bias and only a random sub-sample of them are retained in the analysis); variants affecting prognosis only (excluded from the analysis). Second, we fit a cluster-based model to identify the class of variants only affecting incidence, and use this class to estimate the adjustment factor.ResultsSimulation studies showed that the Slope-Hunter method reduces type-1 error by between 49%-85%, increases power by 1%-36%, reduces bias by 17%-47% compared to other methods in the presence of genetic correlation and performs as well as previous methods when there is no genetic correlation. Slope-Hunter and the previous methods perform less well as the proportion of variation in incidence explained by genetic variants affecting only incidence decreases.ConclusionsThe key assumption of Slope-Hunter is that the contribution of the set of genetic variants affecting incidence only to the heritability of incidence is at least as large as the contribution of those affecting both incidence and prognosis. When this assumption holds, our approach is unbiased in the presence of genetic correlation between incidence and progression, and performs no worse than alternative approaches even when there is no correlation. Bias-adjusting methods should be used to carry out causal analyses when conditioning on incidence.
An evolutionary trade-off between parasite virulence and dispersal at experimental invasion fronts
Authors: Nørgaard Louise Solveig , Zilio Giacomo , Saade Camille , Gougat-Barbera Claire , Hall Matthew D. , Fronhofer Emanuel A. , Kaltz Oliver 
Published: February 2020

ABSTRACTEco-evolutionary processes may play an important role in the spatial spread of infectious disease. Current theory predicts more exploitative parasites to evolve in highly connected populations or at the front of spreading epidemics. However, many parasites rely on host dispersal to reach new populations. This may lead to conflict between local transmission and global spread, possibly counteracting selection for higher virulence. Here, we used the freshwater hostParamecium caudatumand its bacterial parasiteHolospora undulatato investigate parasite evolution under an experimental range expansion scenario with natural host dispersal. We find that parasites evolving at experimental range fronts favoured higher dispersal rates of infected hosts than did parasites evolving in core populations. Front parasites further showed lower levels of virulence (host division and survival) and delayed development of infection, consistent with parameter estimates from an epidemiological model that we fitted on experimental time-series data. This combined evidence suggests an evolutionary trade-off between virulence and host-mediated dispersal, with a concomitant reduction in the investment into horizontal transmission. Our experiment illustrates how parasite evolution can be shaped by divergent selection encountered in different segments of an epidemic wave. Such an interplay between demography and spatial selection has important implications for the understanding and management of emerging diseases, and, more generally, for biological invasions and other non-equilibrium scenarios of spreading populations.SIGNIFICANCE STATEMENTWhat drives parasite evolution in spatially expanding epidemics? Many parasites require dispersal of infected hosts to reach new patches, and this may produce specific adaptations enhancing spatial spread. We performed experimental range expansions in an aquatic model system, with natural dispersal of infected hosts. Parasites from experimental range fronts were less virulent and interfered less with host dispersal, but also invested less in horizontal transmission than parasites from the range core. Thus, dispersal adaptation at the front may come at a cost of reduced horizontal transmission, a trade-off rarely considered in theoretical models on parasite virulence evolution. These results have important implications in the context of emerging diseases, and for parasite evolution during biological invasions or other spatial non-equilibrium scenarios.
An adaptable analysis workflow for characterization of platelet spreading and morphology
Authors: Pike Jeremy A. , Simms Victoria A. , Smith Christopher W. , Morgan Neil V. , Khan Abdullah O. , Poulter Natalie S. , Styles Iain B. , Thomas Steven G. 
Published: February 2020

AbstractThe assessment of platelet spreading through light microscopy, and the subsequent quantification of parameters such as surface area and circularity, is a key assay for many platelet biologists. Here we present an analysis workflow which robustly segments individual platelets to facilitate the analysis of large numbers of cells while minimising user bias. Image segmentation is performed by interactive learning and touching platelets are separated with an efficient semi-automated protocol. We also use machine learning methods to robustly automate the classification of platelets into different subtypes. These adaptable and reproducible workflows are made freely available and are implemented using the open source software KNIME and ilastik.
Characterisation of factors contributing to the performance of nonwoven fibrous matrices as substrates for adenovirus vectored vaccine stabilisation
Authors: Dulal Pawan , Walters Adam A , Hawkins Nicholas , Claridge Tim DW , Kowal Katarzyna , Neill Steven , Russell Stephen J , Ritchie Adam , Ashfield Rebecca , Hill Adrian VS , Douglas Alexander D 
Published: February 2020

AbstractThe global network of fridges and freezers known as the “cold chain” can account for a significant proportion of the total cost of vaccination and is susceptible to failure. Cost-efficient techniques to enhance stability of vaccines could prevent such losses and improve vaccination coverage, particularly in low income countries. We have previously reported a novel, potentially less expensive thermostabilisation approach using a combination of simple sugars and glass micro-fibrous matrix, achieving an excellent recovery of vaccines after storage at supraphysiological temperatures. This matrix is, however, prone to fragmentation and currently not suitable for clinical translation.Here, we report an investigation of alternative, potentially GMP compatible, fibrous matrices. A number of commercially-available matrices permitted good protein recovery, quality of sugar glass and moisture content of the dried product but did not achieve the thermostabilisation performance of the original glass fibre matrix. We therefore further investigated physical and chemical characteristics of the glass fibre matrix and its components. Our investigation shows that the polyvinyl alcohol present in the glass fibre matrix assists vaccine stability. This finding enabled us to develop a custom-produced matrix with encouraging performance, as an initial step towards a biocompatible matrix for clinical translation. We discuss the path to transfer of the technology into clinical use, including potential obstacles.
Detecting sex-linked genes using genotyped individuals sampled in natural populations
Authors: Käfer Jos , Lartillot Nicolas , Marais Gabriel A.B. , Picard Franck 
Published: February 2020

AbstractWe propose a method, SDpop, able to infer sex-linkage caused by recombination suppression typical of sex chromosomes. The method is based on the modeling of the allele and genotype frequencies of individuals of known sex in natural populations. It is implemented in a hierarchical probabilistic framework, accounting for different sources of error. It allows to statistically test for the presence or absence of sex chromosomes, and to infer sex-linked genes based on the posterior probabilities in the model. Furthermore, for gametologous sequences, the haplotype and level of nucleotide polymorphism of each copy can be inferred, as well as the divergence between both. We test the method using simulated and human sequencing data, and show that, for most cases, robust predictions are obtained with 5 to 10 individuals per sex.
Less physical activity and more varied and disrupted sleep is associated with a less favorable metabolic profile in adolescents
Authors: Rognvaldsdottir Vaka , Brychta Robert J. , Hrafnkelsdottir Soffia M. , Chen Kong Y. , Arngrimsson Sigurbjorn A. , Johannsson Erlingur , Guðmundsdottir Sigridur L. 
Published: February 2020

AbstractBackgroundSleep and physical activity are modifiable behaviors that play an important role in preventing overweight, obesity, and metabolic health problems. Studies of the association between concurrent objective measures of sleep, physical activity, and metabolic risk factors among adolescents are limited.ObjectiveThe aim of the study was to examine the association between metabolic risk factors and objectively measured school day physical activity and sleep duration, quality, onset, and variability in adolescents.Materials and MethodsWe measured one school week of free-living sleep and physical activity with wrist actigraphy in 252 adolescents (146 girls), aged 15.8±0.3 years. Metabolic risk factors included body mass index, waist circumference, total body and trunk fat percentage, resting blood pressure, and fasting glucose and insulin levels. Multiple linear regression adjusted for sex, parental education, and day length was used to assess associations between metabolic risk factors and sleep and activity parameters.ResultsOn average, participants went to bed at 00:22±0.88 hours and slept 6.2±0.7 hours/night, with 0.83±0.36 hours of awakenings/night. However, night-to-night variability in sleep duration (0.87±0.57 hours) and bedtime (0.79±0.58 hours) was considerable. Neither average sleep duration nor mean bedtime was associated with any metabolic risk factors. However, greater night-to-night variability in sleep duration was associated with higher total body (β=1.9±0.9 %/h, p=0.03) and trunk fat percentage (β=1.6±0.7 %/h, p=0.02), poorer sleep quality (more hours of awakening) was associated with higher systolic blood pressure (β=4.9±2.2 mmHg/h, p=0.03), and less physical activity was associated with higher trunk fat percentage (p=0.04) and insulin levels (p=0.01).ConclusionGreater nightly variation in sleep, lower sleep quality, and less physical activity was associated with a less favorable metabolic profile in adolescents. These findings support the idea that, along with an adequate amount of sleep and physical activity, a regular sleep schedule is important to the metabolic health of adolescents.
Utilization of a cell-penetrating peptide-adaptor for delivery of HPV protein E2 into cervical cancer cells to arrest cell growth and promote cell death
Authors: LeCher Julia C. , Didier Hope L. , Dickson Robert L. , Slaughter Lauren R. , Bejarano Juana C. , Ho Steven , Nowak Scott J. , Chrestensen Carol A. , McMurry Jonathan L. 
Published: February 2020

AbstractCervical cancer is the second leading cause of cancer deaths in women worldwide. Human papillomavirus (HPV) is the causative agent of nearly all forms of cervical cancer, which arises upon viral integration into the host genome and concurrent loss of regulatory gene E2. E2 protein regulates viral oncoproteins E6 and E7. Loss of E2 upon viral integration results in unregulated expression and activity of E6 and E7, which promotes carcinogenesis. Previous studies using gene-based delivery show that reintroduction of E2 into cervical cancer cell lines can reduce proliferative capacity and promote apoptosis. However, owing in part to limitations on transfectionin vivo, E2 reintroduction has yet to achieve therapeutic usefulness. A promising new approach is protein-based delivery systems utilizing cell-penetrating peptides (CPPs). CPPs readily traverse the plasma membrane and are able to carry with them biomolecular ‘cargos’ to which they are attached. Though more than two decades of research have been dedicated to their development for delivery of biomolecular therapeutics, the full potential of CPPs has yet to be realized as the field is hindered by the tendency of CPP-linked cargos to be trapped in endosomes as well as having significant off-target potentialin vivo. Using a CPP-adaptor system that reversibly binds cargo thereby overcoming the endosomal entrapment that hampers other CPP methods, bioactive E2 protein was delivered into living cervical cancer cells, resulting in inhibition of cellular proliferation and promotion of cell death in a time- and dose-dependent manner. The results suggest that this nucleic acid- and virus-free delivery method could be harnessed to develop novel, effective protein therapeutics for treatment of cervical cancer.
Effort-based decision-making and gross motor performance: Are they linked?
Authors: Gill Simone V. , Abplanalp Samuel J. , Keegan Laura , Fulford Daniel 
Published: February 2020

AbstractThe purpose of this study was to investigate the relationship between effort-based decision making and gross motor performance. Effort-based decision making was measured using a modified version of the Effort Expenditure for Rewards Task in which participants pressed a button on a keyboard to fill a bar on a screen for a monetary reward. Gross motor performance was measured with a walking task in which participants matched their steps to the beat of an audio metronome. We hypothesized that increased effort during the effort-based decision making task would be paired with an increase in steps taken per minute during the gross motor task. However, the results of this study indicated no relationship between the effort-based decision making task and the gross motor task. Planning rather than decision-making may have been the cognitive construct that governed our gross motor task. These findings can be beneficial when thinking about potential interventions for populations who experience deficits in motor performance and cognition as well as for understanding the relationship between both cognitive and motor performance in healthy adults.
Telomere relocalization to the nuclear pore complex in response to replication stress
Authors: Pinzaru Alexandra M , Lamm Noa , al-Kareh Mike , Lazzerini-Denchi Eros , Cesare Anthony J , Sfeir Agnel 
Published: February 2020

AbstractMutations in the telomere binding protein, POT1 are associated with solid tumors and leukemias. POT1 alterations cause rapid telomere elongation, ATR kinase activation, telomere fragility, and accelerated tumor development. Here, we investigated the impact of mutant POT1 alleles through complementary genetic and proteomic approaches based on CRISPR-interference and biotin-based proximity labelling, respectively. These screens revealed that replication stress is a major vulnerability in cells expressing mutant POT1 and manifest in increased mitotic DNA synthesis (MiDAS) at telomeres. Our study also unveiled a role for the nuclear pore complex (NPC) in resolving replication defects at telomeres. Depletion of NPC subunits in the context of POT1 dysfunction increased DNA damage signaling and telomere fragility. Furthermore, we observed telomere repositioning to the nuclear periphery driven by nuclear F-actin polymerization in cells with POT1 mutations. In conclusion, our study establishes that relocalization of dysfunctional telomeres to the nuclear periphery is critical to preserve telomere repeat integrity.
Genomic novelty and process-level convergence in adaptation to whole genome duplication
Authors: Bohutínská Magdalena , Alston Mark , Monnahan Patrick , Mandáková Terezie , Bray Sian , Paajanen Pirita , Kolář Filip , Yant Levi 
Published: February 2020

AbstractWhole genome duplication (WGD) occurs across kingdoms and can promote adaptation. However, a sudden increase in chromosome number, as well as changes in physiology, are traumatic to conserved processes. Previous work in Arabidopsis arenosa revealed a coordinated genomic response to WGD, involving physically interacting meiosis proteins, as well as changes related to cell cycle and ion homeostasis. Here we ask: is this coordinated shift in the same processes repeated in another species following WGD? To answer this, we resequenced and cytologically assessed replicated populations from a diploid/autotetraploid system, Cardamine amara, and test the hypothesis that gene and process-level convergence will be prevalent between these two WGDs adaptation events. Interestingly, we find that gene-level convergence is negligible, with no more in common than would be expected by chance. This was most clear at meiosis-related genes, consistent with our cytological assessment of somewhat lower meiotic stability in C. amara, despite establishment and broad occurrence of the autotetraploid in nature. In contrast, obvious convergence at the level of functional processes, including meiotic cell cycle, chromosome organisation and stress signalling was evident. This indicates that the two autotetraploids survived challenges attendant to WGD via contrasting solutions, modifying different players from similar processes. Overall, this work gives the first insight into the salient adaptations required to cope with a genome-doubled state and brings the first genomic evidence that autopolyploids can utilize multiple trajectories to achieve adaptation to WGD. We speculate that this flexibility increases the likelihood a nascent polyploid overcomes early stringent challenges to later access the spectrum of evolutionary opportunities of polyploidy.Significance statementWhole genome duplication (WGD) is a tremendous mutation and an important evolutionary force. It also presents immediate changes to meiosis and cell physiology that nascent polyploids must overcome to survive. Given the dual facts that WGD adaptation is difficult, but many lineages nevertheless survive WGD, we ask: how constrained are the evolutionary responses to a genome-doubled state? We previously identified candidate genes for WGD adaptation in Arabidopsis arenosa, which has natural diploid and tetraploid variants. Here we test for evolutionary convergence in adaptation to WGD in a species 17 million years distant, Cardamine amara. This work gives the first genomic insight into of how autopolyploids utilize multiple adaptive trajectories to manage a genome-doubled state.
Influences of age and pubertal status on number of perineuronal nets in the rat medial prefrontal cortex
Authors: Drzewiecki Carly M. , Willing Jari , Juraska Janice M. 
Published: February 2020

AbstractThe prefrontal cortex (PFC) is a late developing region of the cortex, and its protracted maturation during adolescence may confer a period of plasticity. Closure of critical, or sensitive, periods in sensory cortices coincides with perineuronal net (PNN) expression, leading to enhanced inhibitory function and synaptic stabilization. PNN density is known to increase across adolescence in the male rodent medial PFC (mPFC). However, the trajectory of female PNN development has not been explored nor has the potential role of pubertal onset in PNN expression. Here, we examined rats at four time points spanning adolescent development to quantify the number of PNNs in the mPFC, as well as the total volume of the prefrontal white matter. Additionally, because puberty coincides with broad behavioral and neuroanatomical changes, we collected tissue from age-matched pre- and post- pubertal siblings within a litter. Results indicate that both males and females show an increase the total number of mPFC PNNs and in white matter under the mPFC between postnatal day (P) 30 and P60. Male puberty did not affect PNNs, while female pubertal onset led to an abrupt decrease in the total number of PNNs that persisted through mid-adolescence before increasing at P60. This decrease in female rats may indicate a difference in timing of maximal plasticity between the sexes during adolescence.