bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole-body imaging of neural and muscle activity during behavior inHydra: bidirectional effects of osmolarity on contraction bursts
Authors: Yamamoto Wataru , Yuste Rafael 
Published: December 2019

AbstractThe neural code relates the activity of the nervous system to the activity of the muscles to the generation of behavior. To decipher it, it would be ideal to comprehensively measure the activity of the entire nervous system and musculature in a behaving animal. As a step in this direction, we used the cnidarianHydra vulgaristo explore how physiological and environmental conditions alter the activity of the entire neural and muscle tissue and affect behavior. We used whole-body calcium imaging of neurons and muscle cells and studied the effect of temperature, media osmolarity, nutritional state and body size on body contractions.In mountedHydra, changes in temperature, nutrition or body size did not have a major effect on neural or muscle activity, or on behavior. But changes in media osmolarity altered body contractions, increasing them in hipo-osmolar media solutions and decreasing them in hyperosmolar media. Similar effects were seen in ectodermal, but not in endodermal muscle. Osmolarity also bidirectionally changed the activity of contraction bursts neurons, but not of rhythmic potential neurons.These findings show osmolarity-dependent changes in neuronal activity, muscle activity, and contractions, consistent with the hypothesis that contraction burst neurons respond to media osmolarity, activating ectodermal muscle to generate contraction bursts. This dedicated circuit could serve as an excretory system to prevent osmotic injury. This work demonstrates the feasibility of studying the entire neuronal and muscle activity of behaving animals.Significance StatementWe imaged whole-body muscle and neuronal activity inHydrain response to different physiological and environmental conditions. Osmolarity bidirectionally alteredHydracontractile behavior. These changes were accompanied by corresponding changes in the activity of one neuronal circuit and one set of muscles. This work is a step toward comprehensive deciphering of the mechanisms of animal behavior by measuring the activity of all neurons and muscle cells.
A single-cell transcriptomic atlas of the adultDrosophilaventral nerve cord
Authors: Allen Aaron M. , Neville Megan C. , Birtles Sebastian , Croset Vincent , Treiber Christoph D. , Waddell Scott , Goodwin Stephen F. 
Published: December 2019

AbstractTheDrosophilaventral nerve cord (VNC) receives and processes descending signals from the brain to produce a variety of coordinated locomotor outputs. It also integrates sensory information from the periphery and sends ascending signals to the brain. We used single-cell transcriptomics to generate an unbiased classification of cellular diversity in the VNC of five-day old adult flies. We produced an atlas of 26,000 high-quality cells, representing more than 100 transcriptionally distinct cell types. The predominant gene signatures defining neuronal cell types reflect shared developmental histories based on the neuroblast from which cells were derived, as well as their birth order. Cells could also be assigned to specific neuromeres using adult Hox gene expression. This single-cell transcriptional atlas of the adult fly VNC will be a valuable resource for future studies of neurodevelopment and behavior.
Sequence heterochrony led to a gain of functionality in an immature stage of the central complex: a fly-beetle insight
Authors: Farnworth Max S. , Eckermann Kolja N. , Bucher Gregor 
Published: December 2019

AbstractAnimal behavior is guided by the brain. Therefore, adaptations of brain structure and function are essential for animal survival, and each species differs in such adaptations. The brain of one individual may even differ between life stages, for instance as adaptation to the divergent needs of larval and adult life of holometabolous insects. All such differences emerge during development but the cellular mechanisms behind the diversification of brains between taxa and life stages remain enigmatic. In this study, we investigated holometabolous insects, where larvae differ dramatically from the adult in both behavior and morphology. As consequence, the central complex, mainly responsible for spatial orientation, is conserved between species at the adult stage, but differs between larvae and adults as well as between larvae of different taxa. We used genome editing and established transgenic lines to visualize cells expressing the conserved transcription factorretinal homeobox,thereby marking homologousgenetic neural lineagesin both the flyDrosophila melanogasterand the beetleTribolium castaneum. This approach allowed us for the first time to compare the development of homologous neural cells between taxa from embryo to the adult. We found complex heterochronic changes including shifts of developmental events between embryonic and pupal stages. Further, we provide, to our knowledge, the first example ofsequence heterochronyin brain development, where certain developmental steps changed their position within the ontogenetic progression. We show that through thissequence heterochrony, an immature developmental stage of the central complex gains functionality inTriboliumlarvae. We discuss the bearing of our results on the evolution of holometabolous larval central complexes by regression to a form present in an ancestor.
Increasing motor skill acquisition by driving theta-gamma coupling
Authors: Akkad Haya , Dupont-Hadwen Joshua , Frese Amba , Tetkovic Irena , Barrett Liam , Bestmann Sven , Stagg Charlotte J 
Published: December 2019

AbstractSkill learning is a fundamental adaptive process, but the mechanisms remain poorly understood. Hippocampal learning is closely associated with gamma activity, which is amplitude-modulated by the phase of underlying theta activity. Whether such nested activity patterns also underpin skill acquisition in non-hippocampal tasks is unknown. Here we addressed this question by using transcranial alternating current stimulation (tACS) over sensorimotor cortex to modulate theta-gamma activity during motor skill acquisition, as an exemplar of a non-hippocampal-dependent task. We demonstrated, and then replicated, a significant improvement in skill acquisition with theta-gamma tACS, which outlasted the stimulation by an hour. Our results suggest that theta-gamma activity may be a common mechanism for learning across the brain and provides a putative novel intervention for optimising functional improvements in response to training or therapy.
Testing relationships between multimodal modes of brain structural variation and age, sex and polygenic scores for neuroticism in children and adolescents
Authors: Norbom Linn B. , Rokicki Jaroslav , van der Meer Dennis , Alnæs Dag , Doan Nhat Trung , Moberget Torgeir , Kaufmann Tobias , Andreassen Ole A. , Westlye Lars T. , Tamnes Christian K. 
Published: December 2019

AbstractHuman brain development involves spatially and temporally heterogeneous changes, detectable across a wide range of magnetic resonance imaging (MRI) measures. Investigating the interplay between multimodal MRI and polygenic scores (PGS) for personality traits associated with mental disorders in youth may provide new knowledge about typical and atypical neurodevelopment. We derived independent components across cortical thickness, cortical surface area, and gray/white matter contrast (GWC) (n=2596, 3-23 years), and tested for associations between these components and age, sex and-, in a subsample (n=878), PGS for neuroticism. Age was negatively associated with a single-modality component reflecting higher global GWC, and additionally with components capturing common variance between global thickness and GWC, and several multimodal regional patterns. Sex differences were found for components primarily capturing global and regional surface area (boys>girls), but also regional cortical thickness. For PGS for neuroticism, we found weak and bidirectional associations with a component reflecting right prefrontal surface area. These results indicate that multimodal fusion is sensitive to age and sex differences in brain structure in youth, but only weakly to polygenic load for neuroticism.
The spatial Muller’s ratchet: surfing of deleterious mutations during range expansion
Authors: Foutel-Rodier Félix , Etheridge Alison 
Published: December 2019

AbstractDuring a range expansion, deleterious mutations can “surf” on the colonisation front. The resultant decrease in fitness is known as expansion load. An Allee effect is known to reduce the loss of genetic diversity of expanding populations, by changing the nature of the expansion from “pulled” to “pushed”. We study the impact of an Allee effect on the formation of an expansion load with a new model, in which individuals have the genetic structure of a Muller’s ratchet. A key feature of Muller’s ratchet is that the population fatally accumulates deleterious mutations due to the stochastic loss of the fittest individuals, an event called a click of the ratchet. We observe fast clicks of the ratchet at the colonization front owing to small population size, followed by a slow fitness recovery due to migration of fit individuals from the bulk of the population, leading to a transient expansion load. For large population size, we are able to derive quantitative features of the expansion wave, such as the wave speed and the frequency of individuals carrying a given number of mutations. Using simulations, we show that the presence of an Allee effect reduces the rate at which clicks occur at the front, and thus reduces the expansion load.
Nuclear upregulation of PI3K p110β correlates with increased rRNA transcription in endometrial cancer cells
Authors: Gavgani Fatemeh Mazloumi , Karlsson Thomas , Tangen Ingvild L , Papdiné Morovicz Andrea , Arnesen Victoria Smith , Turcu Diana C. , Krakstad Camilla , Guillermet-Guibert Julie , Lewis Aurélia E 
Published: December 2019

AbstractGenes encoding for components of the phosphoinositide 3-kinase (PI3K) pathway are frequently mutated in cancer, including inactivating mutations ofPTENand activating mutations ofPIK3CA, encoding the PI3K catalytic subunit p110α.PIK3CB, encoding p110β, is rarely mutated, but can contribute to tumourigenesis in some PTEN-deficient tumours. The underlying molecular mechanisms are however poorly understood. By analysing cell lines and annotated clinical samples, we have previously found that p110β is highly expressed in endometrial cancer (EC) cell lines and thatPIK3CBmRNA levels increase early in primary tumours correlating with lower survival. Selective inhibition of p110α and p110β led to different effects on cell signalling and cell function, p110α activity being correlated to cell survival inPIK3CAmutant cells and p110β with cell proliferation in PTEN-deficient cells. To understand the mechanisms governing the differential roles of these isoforms, we assessed their sub-cellular localisation. p110α was cytoplasmic whereas p110β was both cytoplasmic and nuclear with increased levels in both compartments in cancer cells. Immunohistochemistry of p110β in clinically annotated patient tumour sections revealed high nuclear/cytoplasmic staining ratio, which correlated significantly with higher grades. Consistently, the presence of high levels of p110β in the nuclei of EC cells, correlated with high levels of its product phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) in the nucleus. Using immunofluorescence labelling, we observed both p110β and PtdIns(3,4,5)P3in the nucleoli of EC cell lines. The production of nucleolar PtdIns(3,4,5)P3was dependent upon p110β activity. EC cells with high levels of nuclear PtdIns(3,4,5)P3and p110β showed elevated nucleolar activity as assessed by the increase in 47S pre-rRNA transcriptional levels in a p110β-dependent manner. Altogether, these results present a nucleolar role for the PI3K pathway that may contribute to tumour progression in endometrial cancer.
Langerhans cells immunocompetency is critical for IDO1-dependent ability to induce tolerogenic T cells
Authors: Davies James , Sirvent Sofia , Vallejo Andres F. , Clayton Kalum , Porter Gemma , Stumpf Patrick , West Jonathan , Ardern-Jones Michael , Singh Harinder , MacArthur Ben , Polak Marta E 
Published: December 2019

AbstractHuman epidermal Langerhans cells (LCs) can coordinate both immunogenic and tolerogenic immune responses, creating an attractive opportunity for immunomodulation strategies. To investigate transcriptional determinants of human primary LC tolerance we applied single cells RNA-sequencing combined with transcriptional network modelling and functional analysis. Unsupervised clustering of single cell transcriptomes revealed that steady-state LCs exist in immature and immunocompetent states, and become fully immunocompetent on migration. Interestingly, LC migration, which has been shown to result in upregulation of the transcription factor IRF4, led in parallel to increased expression of a tolerogenic gene module includingIDO1,LGALS1,LAMTOR1andIL10RA,which translated to efficient induction of regulatory T cells in co-culture assays by immunocompetent LCs. Using protein expression analysis and perturbation with inhibitors, we confirmed the role of IDO1 as a mediator of LC tolerogenic responses induced during LC migration. Computational analysis of regulons and Partial Information Decomposition analyses identifiedIRF4as a key driver for LC tolerogenic programmes. The predicted IRF4-regulated genes were confirmed by analysis of CRISPR-Cas9 edited LCs. These findings suggest that efficient priming of tolerogenic responses by LCs requires upregulation of a migration-coupled maturation program which is superimposed with a tolerance-inducing genomic module.
TENET: Gene network reconstruction using transfer entropy reveals key regulatory factors from single cell transcriptomic data
Authors: Kim Junil , Jakobsen Simon Toftholm , Natarajan Kedar Nath , Won Kyoung Jae 
Published: December 2019

ABSTRACTAccurate prediction of gene regulatory rules is important towards understanding of cellular processes. Existing computational algorithms devised for bulk transcriptomics typically require a large number of time points to infer gene regulatory networks (GRNs), are applicable for a small number of genes, and fail to detect potential causal relationships effectively. Here, we propose a novel approach ‘TENET’ to reconstruct GRNs from single cell RNA sequencing (scRNAseq) datasets. Employing transfer entropy (TE) to measure the amount of causal relationships between genes, TENET predicts large-scale gene regulatory cascades/relationships from scRNAseq data. TENET showed better performance than other GRN reconstructors, in identifying key regulators from public datasets. Specifically from scRNAseq, TENET identified key transcriptional factors in embryonic stem cells (ESCs) and during direct cardiomyocytes reprogramming, where other predictors failed. We further demonstrate that known target genes have significantly higher TE values, and TENET predicted higher TE genes were more influenced by the perturbation of their regulator. Using TENET, we identified and validated that Nme2 is a culture condition specific stem cell factor. These results indicate that TENET is uniquely capable of identifying key regulators from scRNAseq data.Key PointsTENET measures putative causal relationships between genes using transfer entropy.TENET shows outstanding performance in identifying key regulators compared to existing methods.TENET can reveal previously uncharacterized regulators.
Pyk2 Overexpression in Postsynaptic Neurons Blocks Aβ1-42-induced Synaptotoxicity in a Microfluidic Co-Culture Model
Authors: Kilinc Devrim , Vreulx Anaïs-Camille , Mendes Tiago , Flaig Amandine , Marques-Coelho Diego , Verschoore Maxime , Demiautte Florie , Amouyel Philippe ,   Neuro-CEB Brain Bank, Eysert Fanny , Dourlen Pierre , Chapuis Julien , Costa Marcos Romualdo , Malmanche Nicolas , Checler Frederic , Lambert Jean-Charles 
Published: December 2019

AbstractRecent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer’s disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer’s disease, deciphering the impact of Alzheimer’s risk genes on synapse formation and maintenance is of great interest. In this paper, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid-beta (Aβ) peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein (APP). Co-culture with cells overexpressing mutated APP exposed the synapses of primary hippocampal neurons to Aβ1-42molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of Aβ suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta (Pyk2) –an Alzheimer’s disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimer’s disease brains at gene expression and protein levels–selectively in postsynaptic neurons is protective against Aβ1-42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically-relevant model of Alzheimer’s disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments.
Intracellular DNA replication and differentiation ofTrypanosoma cruziis asynchronous within individual host cellsin vivoat all stages of infection
Authors: Taylor Martin. C. , Ward Alexander , Olmo Francisco , Jayawardhana Shiromani , Francisco Amanda F. , Lewis Michael D. , Kelly John M. 
Published: December 2019

ABSTRACTInvestigations into intracellular replication and differentiation ofTrypanosoma cruziwithin the mammalian host have been restricted by limitations in our ability to detect parasitized cells throughout the course of infection. We have overcome this problem by generating genetically modified parasites that express a bioluminescent/fluorescent fusion protein. By combiningin vivoimaging and confocal microscopy, this has enabled us to routinely visualise murine infections at the level of individual host cells. These studies reveal that intracellular parasite replication is an asynchronous process, irrespective of tissue location or disease stage. Furthermore, using TUNEL assays and EdU labelling, we demonstrate that within individual infected cells, replication of both mitochondrial (kDNA) and nuclear genomes is not co-ordinated within the parasite population, and that replicating amastigotes and non-replicating trypomastigotes can co-exist in the same cell. Finally, we report the presence of distinct non-canonical morphological forms ofT. cruziin the mammalian host. These appear to represent transitional forms in the amastigote to trypomastigote differentiation process. Therefore, the intracellular life-cycle ofT. cruzi in vivois more complex than previously realised, with potential implications for our understanding of disease pathogenesis, immune evasion and drug development. Dissecting the mechanisms involved will be an important experimental challenge.AUTHOR SUMMARYChagas disease, caused by the protozoan parasite Trypanosoma cruzi, is becoming an emerging threat in non-endemic countries and establishing new foci in endemic countries. The treatment available has not changed significantly in over 40 years. Therefore, there is an urgent need for a greater understanding of parasite biology and disease pathogenesis to identify new therapeutic targets and to maximise the efficient use of existing drugs. We have used genetically modified strains ofT. cruzicarrying a bioluminescence/fluorescence dual reporter fusion gene to monitor parasite replicationin vivoduring both acute and chronic infections in a mouse model. Utilising TUNEL assays for mitochondrial DNA replication and EdU incorporation for total DNA replication, we have found that parasite division within infected cells is asynchronous in all phases of infection. Differentiation also appears to be uncoordinated, with replicating amastigotes co-existing with non-dividing trypomastigotes in the same host cell.
Scrambling the skin: Simulated Skin Re-Arrangement Using Apparent Motion
Authors: Seizova-Cajic Tatjana , Ludvigsson Sandra , Sourander Birger , Popov Melinda , Taylor Janet L 
Published: December 2019

I.ABSTRACTAn age-old hypothesis proposes that object motion across the receptor surface organizes sensory maps (Lotze, 19thcentury). Skin patches learn their relative positions from the order in which they are stimulated during motion events. We test this idea by reversing the local motion within a 6-point apparent motion sequence along the forearm. In the ‘Scrambled’ sequence, two middle locations were touched in reversed order (1-2-4-3-5-6, followed by 6-5-3-4-2-1, in a continuous loop). This created a local acceleration, a double U-turn, within an otherwise constant-velocity motion, as if the physical location of skin patches 3 and 4 was surgically swapped. The control condition, ‘Orderly’, proceeded at constant velocity at inter-stimulus onset interval (ISOI) of 120 ms. In the test, our twenty participants reported motion direction between the two middle tactors, presented on their own at 75, 120 or 190-ms ISOI. Results show degraded motion discrimination following exposure to Scrambled pattern: for the 120-ms test stimulus, it was 0.31 d’ weaker than following Orderly conditioning (p = .007). This is the aftereffect we expected; its maximal expression would be a complete reversal in perceived motion direction between locations 3 and 4 for either motion direction. We propose that the somatosensory system was beginning to ‘correct’ reversed local motion to uncurl and remove the U-turns that always occurred on the same part of the receptor surface. Such de-correlation between accelerations and their location on the sensory surface is one possible mechanism for organization of sensory maps.
The Effect of New Nurses’ Clinical Competence on Career Adaptation
Authors: Lee Kyu Ho , Lee Mi Joon 
Published: December 2019

AbstractBackgroundNew nurses need a certain period of time to adapt to the organization due to a lack of clinical competence, and also immaturity in social skill. The purpose of this study was to evaluate the effects of new nurses’ clinical competence on career adaptation in order to use the results as basic information for developing education programs to improve their adaptability in clinical practice.MethodThis study employed a descriptive survey to investigate the clinical competence and the career adaptability of new nurses working in a general hospital. The study subjects were 61 new nurses with less than one year of work experience and data was collected from June, 2018 to July, 2019. Data was analyzed using frequency analysis, descriptive statistics, t-test, ANOVA, Pearson’s correlation coefficients, and multiple regression analysis.ResultsOn average, the study subjects have worked for 11.33±1.51 months. In this study, the average clinical competence of new nurses was 2.21±0.61, and career adaptability was 3.00±0.39. The clinical competence of new nurses was positively correlated with career adaptability (r=.453, p<.001). Among the sub-categories of clinical competence, developing professional and legal implementation were found to affect career adaptability (t=2.24, p=.030).ConclusionThe clinical competence of the new nurses was shown to positively affect their career adaptability, and it was confirmed that developing professional and legal implementation in the subcategories of clinical competence affected the career adaptability of the new nurses. Thus, it is necessary to establish a program that provides support for new nurses to enable them to build professional identities that they can be proud of.