bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental function and state transitions of a gene expression oscillator inC. elegans
Authors: Meeuse Milou W.M. , Hauser Yannick P. , Hendriks Gert-Jan , Eglinger Jan , Bogaarts Guy , Tsiairis Charisios , Großhans Helge 
Published: September 2019

AbstractGene expression oscillators can structure biological events temporally and spatially. Different biological functions benefit from distinct oscillator properties. Thus, finite developmental processes rely on oscillators that start and stop at specific times; a poorly understood behavior. Here, we have characterized a massive gene expression oscillator comprising >3,700 genes inC. eleganslarvae. We report that oscillations initiate in embryos, arrest transiently after hatching and in response to perturbation, and cease in adults. Experimental observation of the transitions between oscillatory and non-oscillatory states at a resolution where we can identify bifurcation points reveals an oscillator operating near a Saddle Node on Invariant Cycle (SNIC) bifurcation. These findings constrain the architecture and mathematical models that can represent this oscillator. They also reveal that oscillator arrests occur reproducibly in a specific phase. Since we find oscillations to be coupled to developmental processes, including molting, this characteristic of SNIC bifurcations thus endows the oscillator with the potential to halt larval development at defined intervals, and thereby execute a developmental checkpoint function.
Protein ubiquitylation is essential for the schizont to merozoite transition in Plasmodium falciparum blood-stage development
Authors: Wu Yang , Encheva Vesela , Green Judith L. , Lasonder Edwin , Prommaban Adchara , Kunzelmann Simone , Christodoulou Evangelos , Grainger Munira , Truongvan Ngoc , Bothe Sebastian , Sharma Vikram , Song Wei , Pinzuti Irene , Uthaipibull Chairat , Srichairatanakool Somdet , Barault Veronique , Langsley Gordon , Schindelin Hermann , Stieglitz Benjamin , Snijders Ambrosius P. , Holder Anthony A. 
Published: September 2019

AbstractUbiquitylation is a common post translational modification of eukaryotic proteins and in the human malaria parasite, Plasmodium falciparum (Pf) overall ubiquitylation increases in the transition from intracellular schizont to extracellular merozoite stages in the asexual blood stage cycle. Here, we identify specific ubiquitylation sites of protein substrates in three intracellular parasite stages and extracellular merozoites; a total of 1464 sites in 546 proteins were identified (data available via ProteomeXchange with identifier PXD014998). 469 ubiquitylated proteins were identified in merozoites compared with only 160 in the preceding intracellular schizont stage, indicating a large increase in protein ubiquitylation associated with merozoite maturation. Following merozoite invasion of erythrocytes, few ubiquitylated proteins were detected in the first intracellular ring stage but as parasites matured through trophozoite to schizont stages the extent of ubiquitylation increased. We identified commonly used ubiquitylation motifs and groups of ubiquitylated proteins in specific areas of cellular function, for example merozoite pellicle proteins involved in erythrocyte invasion, exported proteins, and histones. To investigate the importance of ubiquitylation we screened ubiquitin pathway inhibitors in a parasite growth assay and identified the ubiquitin activating enzyme (UBA1 or E1) inhibitor MLN7243 (TAK-243) to be particularly effective. This small molecule was shown to be a potent inhibitor of recombinant PfUBA1, and a structural homology model of MLN7243 bound to the parasite enzyme highlights avenues for the development of P. falciparum specific inhibitors. We created a genetically modified parasite with a rapamycin-inducible functional deletion of uba1; addition of either MLN7243 or rapamycin to the recombinant parasite line resulted in the same phenotype, with parasite development blocked at the late schizont stage. These results indicate that the intracellular target of MLN7243 is UBA1, and this activity is essential for the final differentiation of schizonts to merozoites. The ubiquitylation of many merozoite proteins and their disappearance in ring stages are consistent with the idea that ubiquitylation leads to their destruction via the proteasome once their function is complete following invasion, which would allow amino acid recycling in the period prior to the parasite’s elaboration of a new food vacuole.
Neurovegetative symptom subtypes in young people with major depressive disorder and their structural brain correlates
Authors: Toenders Yara , Schmaal Lianne , Harrison Ben J. , Dinga Richard , Berk Michael , Davey Christopher G. 
Published: September 2019

AbstractBackgroundDepression is a leading cause of burden of disease among young people. Current treatments are not uniformly effective, in part due to the heterogeneous nature of major depressive disorder (MDD). Refining MDD into more homogeneous subtypes is an important step towards identifying underlying pathophysiological mechanisms and improving treatment of young people. In adults, symptom-based subtypes of depression identified using data-driven methods mainly differed in patterns of neurovegetative symptoms (sleep and appetite/weight). These subtypes have been associated with differential biological mechanisms, including immuno-metabolic markers, genetics and brain alterations (mainly in the ventral striatum and insular cortex).MethodsK-means clustering was applied to individual depressive symptoms from the Quick Inventory of Depressive Symptoms (QIDS) in 275 young people (15-25 years old) with MDD to identify symptom-based subtypes, and in 244 young people from an independent dataset (a subsample of the STAR*D dataset). Insula surface area and thickness and ventral striatum volume were compared between the subtypes using structural MRI.ResultsThree subtypes were identified in the discovery dataset and replicated in the independent dataset; severe depression with increased appetite, severe depression with decreased appetite and severe insomnia, and moderate depression. The severe increased appetite subtype showed lower surface area in the anterior insula compared to both healthy controls and the moderate subtype.ConclusionsOur findings in young people replicate the previously identified symptom-based depression subtypes in adults. The structural alterations of the anterior insular cortex add to the existing evidence of different pathophysiological mechanisms involved in this subtype.
Temperature fluctuations between years predict temporal allele frequency variation in a hybrid ant population
Authors: Martin-Roy R , Kulmuni J 
Published: September 2019

AbstractGenetic variability is essential for adaptation and isolated populations lacking variability can face extinction when environments change. A currently underappreciated source of genetic variability is hybridization with a closely related lineage. Hybridization can indeed facilitate adaptation e.g. via exchange of adaptive genetic material between species. Here we investigate the potential role of temperature in shaping the genetic variability in a hybrid population betweenFormica polyctenaandF. aquiloniawood ants using long term population genetic data. We find that the frequencies of both parental-like alleles in the hybrid population co-vary with temperature over the years in males but not in females. Results suggest hybridization can lead to sex-specific outcomes that are dependent on ecological factors and that genetic variability resulting from hybridization could help hybrids cope with varying temperature.
The TERB1-TERB2-MAJIN complex of mouse meiotic telomeres dates back to the common ancestor of metazoans
Authors: da Cruz Irene , Brochier-Armanet Céline , Benavente Ricardo 
Published: September 2019

AbstractBackgroundMeiosis is essential for sexual reproduction, and generates genetically diverse haploid gametes from a diploid germ cell. Reduction of ploidy depends on active chromosome movements during early meiotic prophase I. Chromosome movements require telomere attachment to the nuclear envelope. This attachment is mediated by telomere adaptor proteins. Telomere adaptor proteins have to date been identified in fission yeast and mice. In the mouse, they form a complex composed of the meiotic proteins TERB1, TERB2, and MAJIN. No sequence similarity was observed between these three mouse proteins and the adaptor proteins of fission yeast, raising the question of the evolutionary history and significance of this specific protein complex.ResultHere, we show the TERB1, TERB2, and MAJIN proteins are found throughout the Metazoa and even in early branching non-bilateral species such as Cnidaria, Placozoa and Porifera. Metazoan TERB1, TERB2, and MAJIN showed comparable domain architecture across all clades. Furthermore, the protein domains involved in the formation of the complex as well as those involved for the interaction with the telomere shelterin protein and the LINC complexes revealed high sequence similarity. Finally, gene expression in the cnidarian Hydra vulgaris provide evidence that the TERB1-TERB2-MAJIN complex is selectively expressed in the germ line.ConclusionOur results indicate that the TERB1-TERB2-MAJIN complex has an ancient origin in metazoans, suggesting conservation of meiotic functions.
EEG-based classification of natural sounds reveals specialized responses to speech and music
Authors: Zuk Nathaniel J , Teoh Emily S , Lalor Edmund C 
Published: September 2019

AbstractHumans can easily distinguish many sounds in the environment, but speech and music are uniquely important. Previous studies, mostly using fMRI, have identified separate regions of the brain that respond selectively for speech and music. Yet there is little evidence that brain responses are larger and more temporally precise for human-specific sounds like speech and music, as has been found for responses to species-specific sounds in other animals. We recorded EEG as healthy, adult subjects listened to various types of two-second-long natural sounds. By classifying each sound based on the EEG response, we found that speech, music, and impact sounds were classified better than other natural sounds. But unlike impact sounds, the classification accuracy for speech and music dropped for synthesized sounds that have identical “low-level” acoustic statistics based on a subcortical model, indicating a selectivity for higher-order features in these sounds. Lastly, the trends in average power and phase consistency of the two-second EEG responses to each sound replicated the patterns of speech and music selectivity observed with classification accuracy. Together with the classification results, this suggests that the brain produces temporally individualized responses to speech and music sounds that are stronger than the responses to other natural sounds. In addition to highlighting the importance of speech and music for the human brain, the techniques used here could be a cost-effective and efficient way to study the human brain’s selectivity for speech and music in other populations.HighlightsEEG responses are stronger to speech and music than to other natural soundsThis selectivity was not replicated using stimuli with the same acoustic statisticsThese techniques can be a cost-effective way to study speech and music selectivity
The ancestral population size conditioned on the reconstructed phylogenetic tree with occurrence data
Authors: Manceau Marc , Gupta Ankit , Vaughan Timothy , Stadler Tanja 
Published: September 2019

AbstractWe consider a homogeneous birth-death process with three different sampling schemes. First, individuals can be sampled through time and included in a reconstructed tree. Second, they can be sampled through time and only recorded as a point ‘occurrence’ along a timeline. Third, extant individuals are sampled and included in the reconstructed tree with a fixed probability. We further consider that sampled individuals can be removed or not from the process, upon sampling, with fixed probability.Given an outcome of the process, composed of the joint observation of a reconstructed phylogenetic tree and a record of occurrences not included in the tree, we derive the conditional probability distribution of the population size any time in the past. We additionally provide an algorithm to simulate ancestral population size trajectories given the observation of a reconstructed tree and occurrences.This distribution can readily be used to perform inferences of the ancestral population size in the field of epidemiology and macroevolution. In epidemiology, these results will pave the way towards jointly considering data from case count studies and reconstructed transmission trees. In macroevolution, it will foster the joint examination of the fossil record and extant taxa to reconstruct past biodiversity.
Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells
Authors: Saurty Mirca S. , Bellenger Léa , El-Habr Elias A. , Delaunay Virgile , Chneiweiss Hervé , Antoniewski Christophe , Morvan-Dubois Ghislaine , Junier Marie-Pierre 
Published: September 2019

AbstractGlioblastoma cell ability to adapt their functioning to microenvironment changes is a source of the extensive intra-tumor heterogeneity characteristic of this devastating malignant brain tumor. A systemic view of the metabolic pathways underlying glioblastoma cell functioning states is lacking. We analyzed public single cell RNA-sequencing data from glioblastoma surgical resections, which offer the closest available view of tumor cell heterogeneity as encountered at the time of patients’ diagnosis. Unsupervised analyses revealed that information dispersed throughout the cell transcript repertoires encoded the identity of each tumor and masked information related to cell functioning states. Data reduction based on an experimentally-defined signature of transcription factors overcame this hurdle. It allowed cell grouping according to their tumorigenic potential, regardless of their tumor of origin. The approach relevance was validated using an independent dataset of glioblastoma tissue transcriptomes, patient-derived cell lines and orthotopic xenografts. Overexpression of genes coding for amino acid and lipid metabolism enzymes involved in anti-oxidative, energetic and cell membrane processes characterized cells with high tumorigenic potential. Modeling of their expression network highlighted the very long chain polyunsaturated fatty acid synthesis pathway at the core of the network. Expression of its most downstream enzymatic component, ELOVL2, was associated with worsened patient survival, and required for cell tumorigenic properties in vivo. Our results demonstrate the power of signature-driven analyses of single cell transcriptomes to obtain an integrated view of metabolic pathways at play within the heterogeneous cell landscape of patient tumors.
High Resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells
Authors: Zhao Peiyao A. , Sasaki Takayo , Gilbert David M. 
Published: September 2019

ABSTRACTDNA replication in mammalian cells occurs in a defined temporal order during S phase, known as the replication timing (RT) programme. RT is developmentally regulated and correlated with chromatin conformation and local transcriptional potential. Here we present RT profiles of unprecedented temporal resolution in two human embryonic stem cell lines, human colon carcinoma line HCT116 as well as F1 subspecies hybrid mouse embryonic stem cells and their neural progenitor derivatives. Strong enrichment of nascent DNA in fine temporal windows reveals a remarkable degree of cell to cell conservation in replication timing and patterns of replication genome-wide. We identify 5 patterns of replication in all cell types, consistent with varying degrees of initiation efficiency. Zones of replication initiation were found throughout S phase and resolved to ~50kb precision. Temporal transition regions were resolved into segments of uni-directional replication punctuated with small zones of inefficient initiation. Small and large valleys of convergent replication were consistent with either termination or broadly distributed initiation, respectively. RT correlated with chromatin compartment across all cell types but correlations of initiation time to chromatin domain boundaries and histone marks were cell type specific. Haplotype phasing revealed previously unappreciated regions of allele-specific and alleleindependent asynchronous replication. Allele-independent asynchrony was associated with large transcribed genes that resemble common fragile sites. Altogether, these data reveal a remarkably deterministic temporal choreography of DNA replication in mammalian cells.Highly homogeneous replication landscape between cells in a populationInitiation zones resolved within constant timing and timing transition regionsActive histone marks enriched within early initiation zones while enrichment of repressive marks is cell type specific.Transcribed long genes replicate asynchronously.
Loss of ELK1 has differential effects on age-dependent organ fibrosis and integrin expression
Authors: Cairns Jennifer T , Habgood Anthony , Edwards-Pritchard Rochelle C , Wilkinson Chloe , Stewart Iain D , Leslie Jack , Blaxall Burns C , Susztak Katalin , Alberti Siegfried , Nordheim Alfred , Oakley Fiona , Jenkins R Gisli , Tatler Amanda L 
Published: September 2019

AbstractETS domain-containing protein-1 (ELK1) is a transcriptional repressor important in regulating αvβ6 integrin expression. αvβ6 integrins activate the profibrotic cytokine Transforming Growth Factor β1 (TGFβ1) and are increased in the alveolar epithelium in Idiopathic Pulmonary Fibrosis (IPF). IPF is a disease associated with ageing and therefore we hypothesised that aged animals lackingElk1globally would develop spontaneous fibrosis in organs where αvβ6-mediated TGFβ activation has been implicated.Here we identify thatElk1-knockout (Elk1-/0) mice aged to one year developed spontaneous fibrosis in the absence of injury in both the lung and the liver but not in the heart or kidneys. The lungs ofElk1-/0aged mice demonstrated increased collagen deposition, in particular collagen 3α1, located in small fibrotic foci and thickened alveolar walls. Despite the liver having relatively low global levels of ELK1 expression,Elk1-/0animals developed hepatosteatosis and fibrosis. The loss ofElk1also had differential effects onItgb1, Itgb5andItgb6genes expression in the four organs potentially explaining the phenotypic differences in these organs. To understand the potential causes of reduced ELK1 in human disease we exposed human cells and murine lung slices to cigarette smoke extract which lead to reduced ELK1 expression which may explain the loss of ELK1 in human disease.These data support a fundamental role for ELK1 in protecting against the development of progressive fibrosis via transcriptional regulation of beta integrin subunit genes, and demonstrate that loss of ELK1 can be caused by cigarette smoke.
Failed apoptosis enhances melanoma cancer cells aggressiveness
Authors: Berthenet K. , Castillo Ferrer C. , Popgeorgiev N. , Hernandez-Vargas H. , Ichim G. 
Published: September 2019

SummaryTriggering apoptosis remains an efficient strategy to treat cancer. However, apoptosis is no longer a final destination, since cells can undergo partial apoptosis without dying. Recent evidence shows that partial mitochondrial permeabilization and non-lethal caspase activation occur under certain circumstances, though it remains unclear how failed apoptosis impacts established cancers. Using a cancer cell model to trigger non-lethal caspase activation based on either BH3-only protein expression or chemotherapy treatment, we found that melanoma cancer cells failing to undergo complete apoptosis have a particular transcriptomic signature associated with focal adhesions, transendothelial migration and modifications of actin cytoskeleton. In line with this, cancer cells surviving apoptosis have a gain in migratory and invasive properties both in vitro (random migration, chemotaxis, wound healing and invasion assays) and in vivo (in a model of zebrafish metastasis) We further demonstrate that the failed apoptosis-associated gain in invasiveness is regulated by the c-Jun N-terminal kinase (JNK) pathway while its RNA seq signature is found in metastatic melanoma. These findings are highly significant for understanding how cell death can both cure and promote cancer.
Elements of a stochastic 3D prediction engine in larval zebrafish prey capture
Authors: Bolton Andrew D , Haesemeyer Martin , Jordi Josua , Schaechtle Ulrich , Saad Feras , Mansinghka Vikash K , Tenenbaum Joshua B , Engert Florian 
Published: September 2019

ABSTRACTMany predatory animals rely on accurate sensory perception, predictive models, and precise pursuits to catch moving prey. Larval zebrafish intercept paramecia during their hunting behavior, but the precise trajectories of their prey have never been recorded in relation to fish movements in three dimensions.As a means of uncovering what a simple organism understands about its physical world, we have constructed a 3D-imaging setup to simultaneously record the behavior of larval zebrafish, as well as their moving prey, during hunting. We show that zebrafish robustly transform their 3D displacement and rotation according to the position of their prey while modulating both of these variables depending on prey velocity. This is true for both azimuth and altitude, but particulars of the hunting algorithm in the two planes are slightly different to accommodate an asymmetric strike zone. We show that the combination of position and velocity perception provides the fish with a preferred future positional estimate, indicating an ability to project trajectories forward in time. Using computational models, we show that this projection ability is critical for prey capture efficiency and success. Further, we demonstrate that fish use a graded stochasticity algorithm where the variance around the mean result of each swim scales with distance from the target. Notably, this strategy provides the animal with a considerable improvement over equivalent noise-free strategies.In sum, our quantitative and probabilistic modeling shows that zebrafish are equipped with a stochastic recursive algorithm that embodies an implicit predictive model of the world. This algorithm, built by a simple set of behavioral rules, allows the fish to optimize their hunting strategy in a naturalistic three-dimensional environment.