bluuebunny/crossref_metadata_2025_split huggingface dataset:
On translational control by ribosome speed inS. cerevisiae
Authors: Kazana Eleanna , von der Haar Tobias 
Published: January 2019

AbstractIn addition to the widespread and well documented control of protein synthesis by translation initiation, recent evidence suggests that translation elongation can also control protein synthesis rates. One of the proposed mechanisms leading to elongation control is the interference of slow ribosome movement around the start codon with efficient translation initiation. Here we estimate the frequency with which this mode of control occurs in baker’s yeast growing in rich medium. Genome-wide data reveal that transcripts from around 20% of yeast genes show evidence of queueing ribosomes, which may be indicative of translation elongation control. Moreover, this subset of transcripts is sensitive to distinct regulatory signals compared to initiation-controlled mRNAs, and such distinct regulation occurs for example during the response to osmotic stress.Notethe previous version 2 of this preprint contained a Decision-Tree based analysis where we attempted to relate mRNA features to the presence or absence of queueing ribosome peaks. Since releasing that version, we performed additional controls for this analysis which strongly sugest that its results are random and should be ignored. Specifically, both the overall predictability and the importance of individual features is very similar for a real dataset where genes are labelled as containing a second SSU peak or not, and for a simulated control dataset containing an equal proportion of randomly labelled genes. We have removed this figure from the current version. The analysis together with the additional control remains accessible on the accompanying Github repository (github.com/tobiasvonderhaar/ribosomespeedcontrol) in the file “Figure 3 Obsolete (Classification).ipynb”.
Altered Motor Development Following Late Gestational Alcohol and Cannabinoid Exposure in Rats
Authors: Breit Kristen R. , Zamudio Brandonn , Thomas Jennifer D. 
Published: January 2019

AbstractCannabis is the most commonly used illicit drug among pregnant women, and rates are likely to increase given recent legalization. In addition, half of pregnant women who report consuming cannabis also report drinking alcohol. However, little is known about the consequences of prenatal cannabis alone or combination with alcohol, particularly with cannabis products that are continually increasing in potency of the primary psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (THC). The current study investigated the effects of early exposure to cannabinoids during the brain growth spurt on early physical and motor development alone (Experiment 1) or in combination with alcohol (Experiment 2). In Experiment 1, Sprague-Dawley rat pups were exposed to a cannabinoid receptor agonist (CP-55,940 [CP]; 0.1, 0.25, 0.4 mg/kg/day), the drug vehicle, or a saline control from postnatal days (PD) 4-9. In Experiment 2, rat pups were exposed to CP (0.4 mg/kg/day) or the vehicle, and were additionally intubated with alcohol (11.9% v/v; 5.25 g/kg/day) or received a sham intubation. Subjects in both experiments were tested on a motor development task (PD 12-20) and a motor coordination task during adolescence (PD 30-32). Both developmental cannabinoid and alcohol exposure separately decreased body growth throughout development, and combined exposure exacerbated these effects, although only alcohol exposure induced long-term body weight reductions. Developmental cannabinoid exposure advanced early motor development, whereas alcohol exposure delayed development, and subjects given combined exposure did not differ from controls on some measures. Alcohol exposure impaired motor coordination later in life. In contrast, cannabinoid exposure, by itself did not significantly affect long-term motor coordination, but did exacerbate alcohol-related impairments in motor coordination among females. These results suggest that cannabinoid exposure may not only alter development by itself, but may exacerbate alcohol’s teratogenic effects in specific behavioral domains. These findings have important implications not only for individuals affected by prenatal exposure, but also for establishing public policy for women regarding cannabis use during pregnancy.
Scc2 counteracts a Wapl-independent mechanism that releases cohesin from chromosomes during G1 but is unnecessary during S phase for establishing cohesion
Authors: Srinivasan Madhusudhan , Petela Naomi J. , Scheinost Johanna C. , Collier James , Voulgaris Menelaos , Brunet-Roig Maurici , Beckouët Frederic , Hu Bin , Nasmyth Kim A. 
Published: January 2019

SummaryCohesin’s association with chromosomes is determined by loading dependent on the Scc2/4 complex and release due to Wapl. We show here that Scc2/4 is not merely a loading complex and that it actively maintains cohesin on chromosomes during G1. It does so by blocking a Wapl-independent release reaction that requires opening the cohesin ring at its Smc3/Scc1 interface as well as the D loop of Smc1’s ATPase. The Wapl-independent release mechanism is switched off as cells activate Cdk1 and enter G2/M and cannot be turned back on without cohesin’s dissociation from chromosomes. The latter phenomenon enabled us to show that cohesin that has already captured DNA in a Scc2-dependent manner before replication no longer requires Scc2 to capture sister DNAs during S phase.
Modulation and recruitment of TRF2 at viral telomeres during human herpesvirus 6A/B infection
Authors: Gilbert-Girard Shella , Gravel Annie , Collin Vanessa , Wight Darren J. , Kaufer Benedikt B. , Lazzerini-Denchi Eros , Flamand Louis 
Published: January 2019

AbstractHuman herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of host chromosomes. The HHV-6A/B genomes contain telomeric repeats essential for integration. Whether HHV-6A/B infections impact telomere homeostasis remains to be studied. We report that during infection, a massive increase in telomeric signals is observed. Such telomeric signals are detected in viral replication compartments (VRC) that colocalize with the viral IE2 and P41 proteins. Infection with HHV-6A mutants lacking telomeric repeats did not reproduce this phenotype. HHV-6A/B infections lead to increased expression of three shelterin genes, TRF1, TRF2 and TPP1. TRF2 was recruited to VRC and binding to the HHV-6A/B telomeric repeats demonstrated by chromatin immunoprecipitation and ELISA. Lastly, the HHV-6A IE2 protein colocalized with shelterin proteins at telomeres during infection. In summary, HHV-6A/B infections results in an excess of telomeric repeats that stimulates the expression of shelterin genes. TRF2 binds to viral telomeres during infection and localizes with HHV-6A IE2 protein. Our results highlight a potential role for shelterin complex proteins and IE2 during infection and possibly during integration of HHV-6A/B into host chromosomes.
Validating indicators of CNS disorders in a swine model of neurological disease
Authors: Swier Vicki J. , White Katherine A. , Meyerholz David K. , Chefdeville Aude , Khanna Rajesh , Sieren Jessica C. , Quelle Dawn E. , Weimer Jill M. 
Published: January 2019

AbstractGenetically modified porcine disease models are becoming increasingly important for studying molecular, physiological and pathological characteristics of human disorders. Given their limited history, there remains a great need for proven reagents in swine tissue. To provide a resource for neurological models of disease, we validated antibodies by immunohistochemistry for use in examining central nervous system (CNS) markers. To validate these tools in a relevant model, we utilized a recently developed miniswine model of neurofibromatosis type 1 (NF1). NF1 is a tumor predisposition disorder, presenting with different type of tumors. Additionally, neurological associated symptomologies may include chronic pain, cognitive impairment, and behavioral abnormalities, making this miniswine model an ideal candidate for validating CNS-relevant antibodies. We validate antibodies implicated in glial inflammation (CD68), oligodendrocyte development (NG2, O4, Olig2, and myelin PLP), and neuron differentiation and neurotransmission (doublecortin, GAD67, and tyrosine hydroxylase) by examining cellular localization and brain region specificity. Additionally, we confirm the utility of anti-GFAP, anti-Iba1, and anti-MBP antibodies, previously validated in swine, by testing their immunoreactivity across multiple brain regions in mutant NF1 samples. These validated immunostaining protocols for CNS markers provide a useful resource, furthering the utility of the genetically modified miniswine for translational and clinical applications.
Systematic analysis of dark and camouflaged genes: disease-relevant genes hiding in plain sight
Authors: Ebbert Mark T. W. , Jensen Tanner D. , Jansen-West Karen , Sens Jonathon P. , Reddy Joseph S. , Ridge Perry G. , Kauwe John S. K. , Belzil Veronique , Pregent Luc , Carrasquillo Minerva M. , Keene Dirk , Larson Eric , Crane Paul , Asmann Yan W. , Ertekin-Taner Nilufer , Younkin Steven G. , Ross Owen A. , Rademakers Rosa , Petrucelli Leonard , Fryer John D. 
Published: January 2019

AbstractBackgroundThe human genome contains ‘dark’ gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions that are ‘dark by depth’ (few mappable reads) and others that are ‘camouflaged’ (ambiguous alignment), and we assess how well long-read technologies resolve these regions. We further present an algorithm to resolve most camouflaged regions (including in short-read data) and apply it to the Alzheimer’s Disease Sequencing Project (ADSP; 13142 samples), as a proof of principle.ResultsBased on standard whole-genome lllumina sequencing data, we identified 37873 dark regions in 5857 gene bodies (3635 protein-coding) from pathways important to human health, development, and reproduction. Of the 5857 gene bodies, 494 (8.4%) were 100% dark (142 protein-coding) and 2046 (34.9%) were ≥5% dark (628 protein-coding). Exactly 2757 dark regions were in protein-coding exons (CDS) across 744 genes. Long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduced dark CDS regions to approximately 45.1%, 33.3%, and 18.2% respectively. Applying our algorithm to the ADSP, we rescued 4622 exonic variants from 501 camouflaged genes, including a rare, ten-nucleotide frameshift deletion in CR1, a top Alzheimer’s disease gene, found in only five ADSP cases and zero controls.ConclusionsWhile we could not formally assess the CR1 frameshift mutation in Alzheimer’s disease (insufficient sample-size), we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.
Dual-site high-density 4Hz transcranial alternating current stimulation applied over auditory and motor cortical speech areas does not influence auditory-motor mapping
Authors: Preisig Basil , Sjerps Matthias J. , Kösem Anne , Riecke Lars 
Published: January 2019

AbstractBackgroundVerbal repetition of auditory speech requires the mapping of a sensory acoustic input onto articulatory motor plans (auditory-motor mapping). Recent evidence indicates that auditory-motor mapping could rely on low frequency neural synchronization (i.e., theta oscillatory phase coupling) between sensory and motor speech areas.ObjectiveIn the present study, we apply dual-site high-density (HD) Transcranial Alternating Current Stimulation (TACS) above the auditory and motor cortex to induce, or disrupt, theta phase coupling between the two areas. We predicted that functionally coupling the two areas would strengthen auditory-motor mapping, compared with functionally decoupling them. We assessed the strength of auditory-motor mapping using a verbal repetition task.ResultsWe found no significant effect of TACS-induced theta phase coupling on auditory-motor mapping as indexed by verbal repetition performance.ConclusionAuditory-motor mapping may rely on a different mechanism than we hypothesized, for example, oscillatory phase-coupling outside the theta range. Alternatively, modulation of interregional theta-phase coupling may require more effective stimulation protocols, for example, TACS at higher intensities.
An incremental training method with automated, extendible T-maze for training spatial behavioral tasks in rodents
Authors: Holleman Esther , Maka Jan , Schröder Tim , Battaglia Francesco 
Published: January 2019

AbstractWe present a training procedure and a T-maze equipped with sensors and automated feeders for training spatial behavioral tasks in rodents. The maze can be transformed from an enclosed box to a maze of variable dimensions. The modularity of the protocol and setup makes it highly flexible and suitable for training a wide variety of spatial tasks, and facilitates incremental training stages of increasing maze size for more efficient learning. The apparatus, in its software and hardware, is able to adapt to animal performance, adjusting task challenges and difficulty.Two different methods of automatic behavioral scoring are evaluated against manual methods. Sensors embedded in the maze provide information regarding the order of reward locations visited and the time between the activation of the cue via the nose-poke and the activation of the reward location sensors. The distributions of these reaction times differ between correct and incorrect trials, providing an index of behavior and motivation. The automated maze system allows the trainer to operate and monitor the task away from the experimental set-up, minimizing human interference and improving the reproducibility of the experiment. We show that our method succeeds in training a binary forced-choice task in rats.
Sexual selection and the evolution of male and female cognition: a test using experimental evolution in seed beetles
Authors: Baur Julian , d’Amour Jean , Berger David 
Published: January 2019

Abstract“The mating mind hypothesis”, originally aimed at explaining human cognition, holds that the socio-sexual environment shapes cognitive abilities among animals. Similarly, general sexual selection theory predicts that mate competition should benefit individuals carrying “good genes” with beneficial pleiotropic effects on general cognitive ability. However, few experimental studies have evaluated these related hypotheses due to difficulties of performing direct tests in most taxa. Here we harnessed the empirical potential of the seed beetle study system to investigate the role of sexual selection and mating system in the evolution of cognition. We evolved replicate lines of beetle under enforced monogamy (eliminating sexual selection) or polygamy for 35 generations and then challenged them to locate and discriminate among mating partners (male assays) or host seeds (female assays). To assess learning, the same beetles performed the task in three consecutive rounds. All lines learned the task, improving both within and between trails. Moreover, polygamous males outperformed monogamous males. However, there were no differences in the rate of learning between males of the two regimes, and polygamous females showed no improvement in host search, and even signs of reduced learning. Hence, while sexual selection was a potent factor that increased cognitive performance in mate search, it did not lead to the general increase in cognitive abilities expected under the “mating mind” hypothesis or general “good genes” theory. Our results highlight sexually antagonistic (balancing) selection as a potential force maintaining genetic variation in cognitive traits.
Tau-mediated Disruption of the Spliceosome Triggers Cryptic RNA-splicing and Neurodegeneration in Alzheimer’s Disease
Authors: Hsieh Yi-Chen , Guo Caiwei , Yalamanchili Hari K. , Abreha Measho , Al-Ouran Rami , Li Yarong , Dammer Eric B. , Lah James J. , Levey Allan I. , Bennett David A. , De Jager Philip L. , Seyfried Nicholas T. , Liu Zhandong , Shulman Joshua M. 
Published: January 2019

SUMMARYIn Alzheimer’s disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal core components. InDrosophilamodels, pan-neuronal Tau expression triggers reductions in core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss-of-function inSmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA-sequencing reveals a similar profile of mRNA splicing errors inSmBmutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle pathologic burden. Our results implicate spliceosome disruption and perturbations of the neuronal transcriptome in Tau-mediated neurodegeneration in AD.
Attention hinges on tuned normalization strength within human visual cortex
Authors: Bloem Ilona M. , Ling Sam 
Published: January 2019

AbstractAlthough attention is known to increase the gain of visuocortical responses, its underlying neural computations remain unclear. Here, we used fMRI to test the hypothesis that a neural population’s ability to be modulated by attention is dependent on divisive normalization. To do so, we leveraged the feature-tuned properties of normalization and found that visuocortical responses to stimuli sharing features normalized each other more strongly. Comparing these normalization measures to measures of attentional modulation, we discovered that subpopulations that exhibited stronger normalization also exhibited larger attentional benefits. In a converging experiment, we demonstrated that attentional benefits were greatest when a subpopulation was forced into a state of stronger normalization. We propose a tuned normalization model of attention that parsimoniously accounts for many properties of our results, suggesting that the degree to which a subpopulation exhibits normalization plays a role in dictating its potential for attentional benefits.
Perception of naturally dead conspecifics impairs health and longevity through serotonin signaling in Drosophila
Authors: Chakraborty Tuhin S. , Gendron Christi M. , Lyu Yang , Munneke Allyson S. , DeMarco Madeline N. , Hoisington Zachary W. , Pletcher Scott D. 
Published: January 2019

AbstractSensory perception modulates health and aging across taxa. Understanding the nature of relevant cues and the mechanisms underlying their action may lead to novel interventions that improve the length and quality of life. In humans, psychological trauma is often associated with the recognition of dead individuals, with chronic exposure leading to persistent mental health issues including depression and post-traumatic stress disorder. The mechanisms that link mental and physical health, and the degree to which these are shared across species, remain largely unknown. Here we show that the vinegar fly, Drosophila melanogaster, has the capability to perceive dead conspecifics in its environment and that this perceptive experience induces both short- and long-term effects on health and longevity. Death perception is mediated by visual and olfactory cues, and remarkably, its effects on aging are eliminated by targeted attenuation of serotonin signaling. Our results suggest a complex perceptive ability in Drosophila that reveals deeply conserved mechanistic links between psychological state and aging, the roots of which might be unearthed using invertebrate model systems.
Calcitriol and Non-Calcemic Vitamin D Analogue, 22-Oxacalcitriol, Attenuate Developmental and Pathological Ocular Angiogenesis Ex Vivo and In Vivo
Authors: Merrigan SL , Park B , Ali Z , Jensen LD , Corson TW , Kennedy BN 
Published: January 2019

AbstractAberrant ocular blood vessel growth can underpin vision loss in leading causes of blindness, including neovascular age-related macular degeneration, retinopathy of prematurity and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, lack efficacy in some patients and are associated with poor patient compliance and tachyphylaxis. Small molecule vitamin D has de novo pro-differentiative, anti-proliferative, immunomodulatory, pro-apoptotic and anti-angiogenic properties. Here, our aim was to validate the anti-angiogenic activity of the biologically active form of vitamin D, calcitriol, and a selected vitamin D analogue, 22-oxacalcitriol, across a range of ocular angiogenesis models.First, we validated the anti-angiogenic activity of calcitriol, showing calcitriol to significantly inhibit choroidal sprouting in an ex vivo mouse choroidal fragment sprouting assay. Viability studies in human RPE cell line, ARPE-19, suggested non-calcemic vitamin D analogues have the least off-target anti-proliferative activity compared to calcitriol and additional analogues. Thereafter, the ocular anti-angiogenic activity of non-calcemic vitamin D analogue, 22-oxacalcitriol, was demonstrated in the ex vivo mouse choroidal fragment sprouting assay. In zebrafish larvae, 22-oxacalcitriol was anti-angiogenic, inducing a dose-dependent reduction in choriocapillary angiogenesis. Inhibition of mouse retinal vasculature development was not induced by systemically delivered calcitriol. However, both calcitriol and 22-oxacalcitriol administered intraperitoneally significantly attenuate choroidal neovascularisation lesion volume in the laser-induced CNV mouse model. 22-oxacalcitriol presented with a more favourable safety profile than calcitriol.In summary, calcitriol and 22-oxacalcitriol attenuate ex vivo and in vivo choroidal vasculature angiogenesis. Vitamin D has potential as a preventative or interventional treatment for ophthalmic neovascular indications.
Single-molecule live-cell imaging visualizes parallel pathways of prokaryotic nucleotide excision repair
Authors: Ghodke Harshad , Ho Han Ngoc , van Oijen Antoine M 
Published: January 2019

AbstractIn the model organismEscherichia coli, helix distorting lesions are recognized by the UvrAB damage surveillance complex in the global genomic nucleotide excision repair pathway (GGR). Alternately, during transcription-coupled repair (TCR), UvrA is recruited to Mfd at sites of RNA polymerases stalled or paused by lesions. Ultimately, damage recognition is mediated by UvrA, culminating in the loading of the damage verification enzyme UvrB. We set out to characterize the differences in the kinetics of interactions of UvrA with Mfd and UvrB. We followed functional, fluorescently tagged UvrA molecules in live cells and measured their residence times in TCR-deficient or wild-type cells. We demonstrate that the lifetimes of UvrA in Mfd-dependent or Mfd-independent interactions in the absence of exogenous DNA damage are comparable in live cells, and are governed by UvrB. Upon UV irradiation, we found that the lifetimes of UvrA strongly depended on, and matched those of Mfd. Here, we illustrate a non-perturbative, imaging-based approach to quantify the kinetic signatures of damage recognition enzymes participating in multiple pathways in cells.