bluuebunny/crossref_metadata_2025_split huggingface dataset:
fuNTRp: Identifying protein positions for variation driven functional tuning
Authors: Miller Maximilian , Vitale Daniel , Kahn Peter , Rost Burkhard , Bromberg Yana 
Published: March 2019

ABSTRACTEvaluating the impact of non-synonymous genetic variants is essential for uncovering disease associations and mechanisms of evolution. Understanding corresponding sequence changes is also fundamental for synthetic protein design and stability assessments. However, the performance gain of variant effect predictors observed in recent years is not in line with the increased complexity of new methods. One likely reason for this might be that most approaches use similar sets of gene/protein features for modeling variant effect, often emphasizing sequence conservation. While high levels of conservation highlight residues essential for protein activity, much of the in vivo observable variation is arguably weaker in its impact and, thus, requires evaluation at a higher level of resolution. Here we describe function Neutral/Toggle/Rheostat predictor (funtrp), a novel computational method that categorizes protein positions based on the position-specific expected range of mutational impacts: Neutral (weak/no effects), Rheostat (function-tuning positions), or Toggle (on/off switches). We show that position types do not correlate strongly with familiar protein features such as conservation or protein disorder. We also find that position type distribution varies across different protein functions. Finally, we demonstrate that position types reflect experimentally determined functional effects and can thus improve performance of existing variant effect predictors and suggest a way forward for the development of new ones.
Early patterns of functional brain development associated with autism spectrum disorder in tuberous sclerosis complex
Authors: Dickinson Abigail , Varcin Kandice J. , Sahin Mustafa , Nelson Charles A. , Jeste Shafali S. 
Published: March 2019

Lay AbstractAround half of infants with tuberous sclerosis complex (TSC) develop autism. Here, using EEG, we find that there is a reduction in communication between brain regions during infancy in TSC, and that the infants who show the largest reductions are those who later develop autism. Being able to identify infants who show early signs of disrupted brain development may improve the timing of early prediction and interventions in TSC, and also help us to understand how early brain changes lead to autism.AbstractTuberous sclerosis complex (TSC) is a rare genetic disorder that confers a high risk for autism spectrum disorders (ASD), with behavioral predictors of ASD emerging early in life. Deviations in structural and functional neuronal connectivity are highly implicated in both TSC and ASD.For the first time, we explore whether electroencephalographic (EEG) measures of network function precede or predict the emergence of ASD in TSC. We determine whether altered brain function (1) is present in infancy in TSC, (2) differentiates infants with TSC based on ASD diagnostic status, and (3) is associated with later cognitive function.We studied 35 infants with TSC (N=35), and a group of typically developing infants (n=20) at 12 and 24 months of age. Infants with TSC were later subdivided into ASD and non-ASD groups based on clinical evaluation. We measured features of spontaneous alpha oscillations (6-12Hz) that are closely associated with neural network development: alpha power, alpha phase coherence (APC) and peak alpha frequency (PAF).Infants with TSC demonstrated reduced interhemispheric APC compared to controls at 12 months of age, and these differences were found to be most pronounced at 24 months in the infants who later developed ASD. Across all infants, PAF at 24 months was associated with verbal and non-verbal cognition at 36 months.Associations between early network function and later neurodevelopmental and cognitive outcomes highlight the potential utility of early scalable EEG markers to identify infants with TSC requiring additional targeted intervention initiated very early in life.
Analysis of patient derived xenograft studies in Oncology drug development: impact on design and interpretation of future studies
Authors: Dickinson Jake , de Matas Marcel , Dickinson Paul A , Mistry Hitesh 
Published: March 2019

AbstractBackgroundPreclinical Oncology drug development is heavily reliant on xenograft studies to assess the anti-tumour effect of new compounds. Patient derived xenograft (PDX) have become popular as they may better represent the clinical disease, however variability is greater than in cell-line derived xenografts. The typical approach of analysing these studies involves performing an un-paired t-test on the mean tumour volumes between the treated and control group at the end of the study. This approach ignores the time-series and may result in false conclusions, especially when considering the increased variability of PDX studies.AimTo test the hypothesis that a model-based analysis provides increased power than analysis of final day volumes and to provide insights into more efficient PDX study designs.MethodsData was extracted from tumour xenograft time-series data from a large publicly available PDX drug treatment database released by Novartis. For all 2-arm studies the percent tumour growth inhibition (TGI) at two time-points, day 10 and day 14 was calculated. For each study, the effect of treatment was calculated using an un-paired t-test and also a model-based analysis using the likelihood ratio-test. In addition a simulation study was also performed to assess the difference in power between the two data-analysis approaches for different levels of TGI for PDX or standard cell-line derived xenografts (CDX).ResultsThe model-based analysis had greater statistical power than the un-paired t-test approach within the PDX data-set. The model-based approach was able to detect TGI values as low as 25 percent whereas the un-paired t-test approach required at least 50 percent TGI. These findings were confirmed within the simulation study performed which also highlighted that CDX studies require less animals than PDX studies which show the equivalent level of TGI.ConclusionThe analysis of 59 2-arm PDX studies highlighted that taking a model-based approach gave increased statistical power over simply performing an un-paired t-test on the final study day. Importantly the model-based approach was able to detect smaller size of effect compared to the un-paired t-test approach is which maybe common of such studies. These findings were confirmed within simulated studies which also highlighted the same sample size used for CDX studies would lead to inadequately powered PDX studies. Application of a model-based analysis should allow studies to use less animals and run experiments for a shorter period thus providing effective insight into compound anti-tumour activity
Contribution of private gardens to habitat availability, connectivity and conservation of the common pipistrelle in Paris
Authors: Mimet Anne , Kerbiriou Christian , Simon Laurent , Julien Jean-François , Raymond Richard 
Published: March 2019

AbstractUrban sprawl is one of the greatest global changes with major negative impacts on biodiversity and human well-being. Recent policies have acknowledged the value of urban green areas in counterbalancing such impacts. These policies aim to increase the ecological value of green areas, making cities more permeable to natural populations. However, they are largely focused on the role and management of public green areas, ignoring the role and potential of private green areas for urban ecological value.This study aims to evaluate the benefits of considering private green areas for conservation efforts in cities. Using data on bat activity and information on vegetation and building height, we quantify the respective role of public and private green areas in habitat availability and connectivity for the common pipistrelle in the city of Paris, France. Our results show that despite the low proportion of private green areas in Paris (36% of the total green areas), they still contributed up to 47.9% of bat habitat availability and decrease the resistance of the city matrix by 88%. The distribution in the city matrix and vegetation composition of those areas appeared especially beneficial for bat habitat availability and connectivity. The study demonstrates the importance of private green areas in the ecological value of cities in complementing the role of public green areas. Our results confirm the need to develop more inclusive urban conservation strategies that include both public and private stakeholders.HighlightsThe urban ecological value of private gardens outweighs that of public gardensThis is true for both habitat availability and connectivityBiodiversity policies in cities should also focus on private green areasInclusive conservation strategies are also needed in cities
Lithium treatment reverses irradiation-induced changes in rodent neural progenitors
Authors: Giulia Zanni , Shinobu Goto , Giulia Gaudenzi , Vinogran Naidoo , Gabriel Levy , Elena Di Martino , Olga Dethlefsen , Angel Cedazo-Minguez , Paula Merino-Serrais , Ola Hermanson , Klas Blomgren 
Published: March 2019

ABSTRACTCranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context, and we previously showed that voluntary running introduced long after irradiation rescued hippocampal neurogenesis in young mice (Naylor et al. 2008a). Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as anti-tumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation, analogous to the voluntary running study. Female mice received a single 4 Gy whole-brain irradiation dose at postnatal day (PND) 21 and were randomized to 0.24% Li2CO3chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed at PND 77, 91 and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors and promoted neuronal integration upon its discontinuation. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with proliferation, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced impairment of hippocampal neurogenesis even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.
The complete, functional and dynamic cycle of the bacterial Initiation Factor 3
Authors: Nakamoto Jose A. , Spurio Roberto , Konevega Andrey L. , Fabbretti Attilio , Milón Pohl 
Published: March 2019

AbstractInitiation factor 3 (IF3) is an essential protein that enhances the fidelity and speed of bacterial initiation of mRNA translation. The dynamic interplay between the two independent IF3 domains, their alternative binding sites, and the mechanism that ensures translation initiation fidelity remains elusive. Here, we show that the functional positioning of IF3 domains occurs at velocities ranging over two orders of magnitude, driven by each 30S initiation ligand. IF1 and IF2 rapidly promote the accommodation of IF3 on the 30S platform with the C-terminal domain moving towards the P site. Reversion of this movement is triggered by decoding the mRNA start codon and rate limits translation initiation. Binding of the tRNA results in the concomitant accommodation of the N-terminal domain of IF3, largely dependent on the mRNA and initiator tRNA. 70S initiation complex formation promotes the closing and dissociation of IF3, recycling the factor for a new round of translation initiation. Altogether our results unveil the kinetic spectrum of IF3 conformations and highlight fundamental movements of the factor that ensure accurate translation initiation.
Eye in a Disk: eyeIntegration human pan-eye and body transcriptome database version 1.0
Authors: Swamy Vinay , McGaughey David 
Published: March 2019

AbstractPURPOSETo develop an accessible and reliable RNA-seq transcriptome database of healthy human eye tissues and a matching reactive web application to query gene expression in eye and body tissues. METHODS: We downloaded the raw sequnce data for 1375 RNA-seq samples across 54 tissues in the GTEx project as a non-eye reference set.We then queried several public repositories to find all healthy, non-perturbed, human eye-related tissue RNA-seq samples. The 916 eye and 1375 GTEx samples were sent into a Snakemake-based reproducible pipeline we wrote to quantify all known transcripts and genes, removes samples with poor sequence quality and mislabels, normalizes expression values across each tissue, performs 882 differential expression tests, calculates GO term enrichment, and outputs all as a single SQLite database file: the Eye in a Disk (EiaD) dataset. Furthermore, we rewrote the web application eyeIntegration (https://eyeIntegration.nei.nih.gov) to display EiaD.RESULTSThe new eyeIntegration portal provides quick visualization of human eye-related transcriptomes published to date by database version, gene/transcript, 19 eye tissues, and 54 body tissues. As a test of the value of this unified pan-eye dataset, we showed that fetal and organoid retina are highly similar at a pan-transcriptome level but display distinct differences in certain pathways and gene families like protocadherin and HOXB family members.CONCLUSIONThe eyeIntegration v1.0 web app serves the pan-human eye and body transcriptome dataset, EiaD. This offers the eye community a powerful and quick means to test hypotheses on human gene and transcript expression across 54 body and 19 eye tissues.
How phenotypic convergence arises in experimental evolution
Authors: Simões Pedro , Fragata Inês , Santos Josiane , Santos Marta A. , Santos Mauro , Rose Michael R. , Matos Margarida 
Published: March 2019

AbstractEvolutionary convergence is a core issue in the study of adaptive evolution, as well as a highly debated topic at present. Few studies have analyzed this issue using a “real-time” or evolutionary trajectory approach. Do populations that are initially differentiated converge to a similar adaptive state when experiencing a common novel environment?Drosophila subobscurapopulations founded from different locations and years showed initial differences and variation in evolutionary rates in several traits during short-term (∼20 generations) laboratory adaptation. Here we extend that analysis to 40 more generations to analyze (1) how differences in evolutionary dynamics between populations change between shorter and longer time spans, and (2) whether evolutionary convergence occurs after sixty generations of evolution in a common environment. We found substantial variation in longer-term evolutionary trajectories and differences between short and longer-term evolutionary dynamics. Though we observed pervasive patterns of convergence towards the character values of long-established populations, populations still remain differentiated for several traits at the final generations analyzed. This pattern might involve transient divergence, as we report in some cases, indicating that more generations should lead to final convergence. These findings highlight the importance of longer-term studies for understanding convergent evolution.
Pupillometry as an objective measure of sustained attention in young and older listeners
Authors: Zhao Sijia , Bury Gabriela , Milne Alice , Chait Maria 
Published: March 2019

AbstractThe ability to sustain attention on a task-relevant sound-source whilst avoiding distraction from other concurrent sounds is fundamental to listening in crowded environments. To isolate this aspect of hearing we designed a paradigm that continuously measured behavioural and pupillometry responses during 25-second-long trials in young (18-35 yo) and older (63-79 yo) participants. The auditory stimuli consisted of a number (1, 2 or 3) of concurrent, spectrally distinct tone streams. On each trial, participants detected brief silent gaps in one of the streams whilst resisting distraction from the others. Behavioural performance demonstrated increasing difficulty with time-on-task and with number/proximity of distractor streams. In young listeners (N=20), pupillometry revealed that pupil diameter (on the group and individual level) was dynamically modulated by instantaneous task difficulty such that periods where behavioural performance revealed a strain on sustained attention, were also accompanied by increased pupil diameter. Only trials on which participants performed successfully were included in the pupillometry analysis. Therefore, the observed effects reflect consequences of task demands as opposed to failure to attend.In line with existing reports, we observed global changes to pupil dynamics in the older group, including decreased pupil diameter, a limited dilation range, and reduced temporal variability. However, despite these changes, the older group showed similar effects of attentive tracking to those observed in the younger listeners. Overall, our results demonstrate that pupillometry can be a reliable and time-sensitive measure of the effort associated with attentive tracking over long durations in both young and (with some caveats) older listeners.
Identification of a novel gammaherpesvirus in Canada lynx (Lynx canadensis)
Authors: Hendrikse Liam D. , Kambli Ankita , Kayko Caroline , Canuti Marta , Rodrigues Bruce , Stevens Brian , Vashon Jennifer , Lang Andrew S. , Needle David B. , Troyer Ryan M. 
Published: March 2019

AbstractGammaherpesviruses (GHVs) infect many animal species and are associated with lymphoproliferative disorders in some. Previously, we identified several novel GHVs in North American felids, however a GHV had never been identified in Canada lynx (Lynx canadensis). We therefore hypothesized the existence of an unidentified GHV in lynx. Using degenerate nested and subsequently virus-specific PCR, we amplified and sequenced 3.4 kb of DNA from a novel GHV in lynx, which we namedLynx canadensisgammaherpesvirus 1 (LcaGHV1). We then estimated the prevalence of LcaGHV1 in lynx by developing a PCR-based assay and detected LcaGHV1 DNA in 36% (95% CI: 22-53%) of lynx spleen DNA samples from Maine, USA and 17% (95% CI: 8-31%) from Newfoundland, Canada. Phylogenetic analysis determined that LcaGHV1 is a distinct GHV species belonging to the genusPercavirus. The potential ecologic and pathologic consequences of this novel virus for Canada lynx populations warrant further study.
Phase-specific manipulation of neural oscillatory activity by transcranial alternating current stimulation
Authors: Fiene Marina , Schwab Bettina C. , Misselhorn Jonas , Herrmann Christoph S. , Schneider Till R. , Engel Andreas K. 
Published: March 2019

AbstractBackgroundOscillatory phase has been proposed as a key parameter defining the spatiotemporal structure of neural activity. To enhance our understanding of brain rhythms and improve clinical outcomes in pathological conditions, phase-specific modulation of oscillations by transcranial alternating current stimulation (tACS) emerged as a promising approach. However, the effectiveness of tACS in humans is still critically debated.ObjectiveHere, we investigated the phase-specificity of tACS effects on visually evoked steady state responses (SSRs) in 24 healthy human participants of either sex.MethodsTo this end, we used an intermittent electrical stimulation protocol and assessed the influence of tACS on SSR amplitude in the interval immediately following tACS.ResultsWe observed that the phase shift between flicker and tACS modulates evoked SSR amplitudes. The tACS effect size was dependent on the strength of flicker-evoked oscillatory activity, with larger effects in participants showing weaker locking of neural responses to flicker phase. Neural sources of phase-specific effects were localized in the parieto-occipital cortex within flicker-entrained regions. Importantly, the optimal phase shift between flicker and tACS associated with strongest SSRs was correlated with cortical SSR onset delays over the visual cortex.ConclusionsOverall, our data provide electrophysiological evidence for phase-specific modulations of oscillatory activity by tACS in humans. As the optimal timing of tACS application was dependent on neural conduction times as measured by SSR onset delays, data suggest that the interaction between tACS effect and SSR was cortical in nature. These findings corroborate the physiological efficacy of tACS and highlight its potential for controlled modulations of brain signals.
A Musashi-Related Protein is Essential for Gametogenesis in Arabidopsis
Authors: Moody Laura A. , Rabbinowitsch Ester , Dickinson Hugh G. , Clayton Roxaana , Emms David M. , Langdale Jane A. 
Published: March 2019

SUMMARYMusashi (Msi) proteins are an evolutionarily conserved group of RNA-binding proteins, required for targeted control of mRNA translation during many important developmental processes in animals. Most notably, Msi proteins play important roles during both spermatogenesis and oogenesis. Msi proteins also exist in plants but these are largely uncharacterized. Here we report the functional characterization of an Arabidopsis Msi orthologABORTED GAMETOPHYTE 2(AOG2), which encodes a protein containing two RNA recognition motifs and an ER-targeting signal. AOG2-GFP translational fusions were localized to the ER in transient assays, suggesting that AOG2 most likely binds to ER-targeted mRNAs. We show that disruptedAOG2function leads to a high rate of both ovule and seed abortion, and that homozygous loss of function mutants are embryo lethal. Furthermore, we demonstrate thatAOG2is required to establish asymmetry during pollen mitosis I, and that loss ofAOG2function leads to loss of pollen viability. Collectively the results reveal that AOG2 is required for the establishment of polarity and/or the progression of mitosis during gametophyte development in Arabidopsis, and thus Msi-related proteins have an evolutionarily conserved role in gametogenesis in both animals and plants.SIGNIFICANCE STATEMENTABORTED GAMETOPHYTE 2(AOG2) encodes a Musashi-related RNA-binding protein that is required for gametogenesis and embryogenesis in Arabidopsis.AOG2is required for the establishment of polarity and/or the progression of mitosis during gametophyte development in Arabidopsis, and thus Musashi-related proteins have an evolutionarily conserved role in gametogenesis in both animals and plants.