bluuebunny/crossref_metadata_2025 huggingface dataset:
An insight to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis; evidence from high-throughput data integration and meta-analysis
Authors: Mozhgani Sayed-Hamidreza , Piran Mehran , Zarei-Ghobadi Mohadeseh , Jafari Mohieddin , Mokhtari-Azad Talat , Jazayeri Seyed-Mohammad , Teymoori-Rad Majid , Valizadeh Narges , Farajifard Hamid , Mirzaie Mehdi , Khamseh Azam , Rafatpanah Houshang , Rezaee Seyed-Abdolrahim , Norouzi Mehdi
Published: September 2019

Human T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the central nervous system that affected significantly spinal cord, nevertheless, the pathogenesis pathway. This study aimed to employ high throughput meta-analysis to find major genes involved in the pathogenesis of HAM/TSP. High-throughput statistical analyses identified 385, 49, and 22 differentially expressed genes for normal vs. ACs, normal vs. HAM/TSP and ACs vs. HAM/TSP groups, respectively. STRING and further network analyses highlighted 32, 29, and 13 hub genes for normal vs. ACs, normal vs. HAM/TSP, and ACs vs. HAM/TSP groups, respectively. Biological network analyses indicated the involvement of hub genes in the HAM/TSP group in many vital pathways like apoptosis and immune pathways. Moreover, the meta-analysis results disclosed three major genes including STAT1, TAP1, and PSMB8 which have function role in HAM/TSP progression. Real-time PCR revealed the meaningful down-regulation of STAT1 in HAM/TSP samples than AC and normal samples (P=0.01 and P=0.02, respectively), up-regulation of PSMB8 in HAM/TSP samples than AC and normal samples (P=0.04 and P=0.01, respectively), and down-regulation of TAP1 in HAM/TSP samples than those in AC and normal samples (P=0.008 and P=0.02, respectively). No significant difference was found among three groups in terms of percentage of T helper and cytotoxic T lymphocytes (P= 0.55 and P=0.12). Our results confirm that STAT1, TAP1, and PSMB8 are three important genes which their expressions levels were changed in three different groups. These proteins in association with other proteins can involve in the immune and apoptosis pathways.
Nested tandem duplications of the geneMelanoma antigen recognized by T-cells(Mlana) underlie the sexual dimorphism locus in domestic pigeons
Authors: Krishnan Shreyas
Published: September 2019

Birds have classic examples of exaggerated sexually dimorphic traits, including colors. Sexes among the wild rock dove and its derived domestic breeds, however, are quite indistinguishable and sex can only be ascertained through genotyping or egg laying and successful hatching of eggs. Yet, the pigeon fancy has discovered sexually dimorphic traits and harnessed some of these traits in some auto-sexing breeds. Early genetics pioneers characterized the sex-linkedStipperlocus and showed it to be linked to the pigeon Z linkedB-locus(Tyrp1). The alleles of theStipperlocus have variable dominance relative to wild-type (more severe alleles are incompletely dominant, less severe alleles are reportedly fully dominant), characterized by a continuum of lightening in homozygotes and increased variegation in heterozygotes corresponding with severity. We leveraged this positional information and population structure among breeds in a candidate gene approach to identify the genetic mechanism of de novo pigeon sex dichromatism. A large tandem duplication (77 kb) centered on the geneMelanoma antigen recognized by T cells(Mlana) is completely associated with alleles of theStipperlocus. Copy number of the 77 kb genetic lesion was not correlated with allele severity suggesting that other mechanisms, including epigenetic regulation could underlie both allele severity and degree of variegation.
A kinematic analysis ofMicruruscoral snakes reveals unexpected variation in stereotyped anti-predator displays within a mimicry system
Authors: Moore Talia Y. , Danforth Shannon M. , Larson Joanna G. , Davis Rabosky Alison R.
Published: September 2019

Warning signals in chemically defended organisms are critical components of predator-prey interactions, often requiring multiple coordinated display components for a signal to be effective. When threatened by a predator, venomous coral snakes (genusMicrurus) display a vigorous, non-locomotory thrashing behaviour that has been only qualitatively described. Given the high-contrast and often colourful banding patterns of these snakes, this thrashing display is hypothesized to be a key component of a complex aposematic signal under strong stabilizing selection across species in a mimicry system.

By experimentally testing snake response across simulated predator cues, we analysed variation in the presence and expression of a thrashing display across five species of South American coral snakes.

Although the major features of the thrash display were conserved across species, we found significant variation in the propensity to perform a display at all, the duration of thrashing, and the curvature of snake bodies that was mediated by predator cue type, snake body size, and species identity. We also found an interaction between curve magnitude and body location that clearly shows which parts of the display vary most across individuals and species.

Our results suggest that contrary to the assumption in the literature that all species and individuals perform the same display, a high degree of variation persists in thrashing behaviour exhibited byMicruruscoral snakes despite presumably strong selection to converge on a common signal. This quantitative behavioural characterization presents a new framework for analysing the non-locomotory motions displayed by snakes in a broader ecological context, especially for signalling systems with complex interaction across multiple modalities.
Mental Workload Estimation Using Wireless EEG Signals
Authors: Adewale Quadri , Panoutsos George
Published: September 2019

Previous studies have shown that electroencephalogram (EEG) can be used in estimating mental workload. However, developing fast and reliable models for cross-task, cross-subject and cross-session classifications of workload remains a challenge. In this study, a wireless Emotiv EPOC headset was used to evaluate workload in two different mental tasks: n-back task and mental arithmetic task. 0-back task and 2-back task were employed as low and high workload in the n-back task while 1-digit and 3-digit addition were used as the two different workload levels in the arithmetic task. Using power spectral density as features, a fast signal processing and feature extraction framework was developed to facilitate real-time estimation of workload. Within-session accuracies of 98.5% and 95.5% were achieved in the n-back and arithmetic tasks respectively. Adaptive subspace feature matching (ASFM) was applied for cross-session, cross-task and cross-subject classifications. The feature adaptation provided average cross-session accuracies of 80.5% and 74.4% in the n-back and the arithmetic tasks respectively. An average cross-task accuracy of 68.6% was achieved while cross-subject accuracies were 74.4% and 64.1% in the n-back and arithmetic tasks respectively. The framework generalised well across subjects and tasks, and it provided a promising approach towards developing subject and task-independent models. This study also shows that a consumer-level wireless EEG headset can be applied in cognitive monitoring for real-time estimation of workload in practice.
Statistical significance in DTI group analyses: How the choice of the estimator can inflate effect sizes
Authors: David Szabolcs , Mesri Hamed Y. , Viergever Max A. , Leemans Alexander
Published: September 2019

Diffusion magnetic resonance imaging (dMRI) is one of the most prevalent methods to investigate the micro- and macrostructure of the human brain in vivo. Prior to any group analysis, dMRI data are generally processed to alleviate adverse effects of known artefacts such as signal drift, data noise and outliers, subject motion, and geometric distortions. These dMRI data processing steps are often combined in automated pipelines, such as the one of the Human Connectome Project (HCP). While improving the performance of processing tools has clearly shown its benefits at each individual step along the pipeline, it remains unclear whether – and to what degree – choices for specific user-defined parameter settings can affect the final outcome of group analyses. In this work, we demonstrate how making such a choice for a particular processing step of the pipeline drives the final outcome of a group study. More specifically, we performed a dMRI group analysis on gender using HCP data sets and compared the results obtained with two diffusion tensor imaging estimation methods: the widely used ordinary linear least squares (OLLS) and the more reliable iterative weighted linear least squares (IWLLS). Our results show that the effect sizes for group analyses are significantly smaller with IWLLS than with OLLS. While previous literature has demonstrated higher estimation reliability with IWLLS than with OLLS using simulations, this work now also shows how OLLS can produce a larger number of false positives than IWLLS in a typical group study. We therefore highly recommend using the IWLLS method. By raising awareness of how the choice of estimator can artificially inflate effect size and thus alter the final outcome, this work may contribute to improvement of the reliability and validity of dMRI group studies.
Interacting with volatile environments stabilizes hidden-state inference and its brain signatures
Authors: Weiss Aurélien , Chambon Valérian , Lee Junseok K. , Drugowitsch Jan , Wyart Valentin
Published: September 2019

Making accurate decisions in uncertain environments requires identifying the generative cause of sensory cues, but also the expected outcomes of possible actions. Although both cognitive processes can be formalized as Bayesian inference, they are commonly studied using different experimental frameworks, making their formal comparison difficult. Here, by framing a reversal learning task either as cue-based or outcome-based inference, we found that humans perceive the same volatile environment as more stable when inferring its hidden state by interaction with uncertain outcomes than by observation of equally uncertain cues. Multivariate patterns of magnetoencephalo-graphic (MEG) activity reflected this behavioral difference in the neural interaction between inferred beliefs and incoming evidence, an effect originating from associative regions in the temporal lobe. Together, these findings indicate that the degree of control over the sampling of volatile environments shapes human learning and decision-making under uncertainty.
Isolates from ancient permafrost help to elucidate species boundaries in Acanthamoeba castellanii complex (Amoebozoa: Discosea)
Authors: Malavin Stas , Shmakova Lyubov
Published: September 2019

Acanthamoeba castellanii species complex (genotype T4) comprises of more than ten species with unclear synonymy. Its molecular phylogeny has several conflicts with published morphological data. In this paper, we analyze morphometric traits and temperature preferences in six new strains belonging to A. castellanii complex isolated from Arctic permafrost in the framework of molecular phylogeny. This integrative approach allows us to cross-link genotypic and phenotypic variability and identify species-level boundaries inside the complex. We also analyze previously known and newly found discrepancies between the nuclear and mitochondrial gene-based phylogenies. We hypothesize that one reason for these discrepancies may be the intragenomic polymorphism of ribosomal RNA genes.
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

Gene 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

Ubiquitylation 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

Background

Depression 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).

Methods

K-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.

Results

Three 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.

Conclusions

Our 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

Genetic 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

Background

Meiosis 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.

Result

Here, 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.

Conclusion

Our 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

Humans 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.

Highlights

EEG responses are stronger to speech and music than to other natural sounds

This selectivity was not replicated using stimuli with the same acoustic statistics

These 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

We 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

Glioblastoma 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

DNA 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 population

Initiation zones resolved within constant timing and timing transition regions

Active 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

ETS 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

Triggering 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

Many 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.
Genetic effect estimates in case-control studies when a continuous variable is omitted from the model
Authors: Sheng Ying , Huang Chiung-Yu , Lobach Siarhei , Zablotska Lydia , Lobach Iryna ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2019

Large-scale genome-wide analyses scans provide massive volumes of genetic variants on large number of cases and controls that can be used to estimate the genetic effects. Yet, the sets of non-genetic variables available in publicly available databases are often brief. It is known that omitting a continuous variable from a logistic regression model can result in biased estimates of odds ratios (OR) (e.g., Gail et al (1984), Neuhaus et al (1993), Hauck et al (1991), Zeger et al (1988)). We are interested to assess what information is needed to recover the bias in the OR estimate of genotype due to omitting a continuous variable in settings when the actual values of the omitted variable are not available. We derive two estimating procedures that can recover the degree of bias based on a conditional density of the omitted variable or knowing the distribution of the omitted variable. Importantly, our derivations show that omitting a continuous variable can result in either under- or over-estimation of the genetic effects. We performed extensive simulation studies to examine bias, variability, false positive rate, and power in the model that omits a continuous variable. We show the application to two genome-wide studies of Alzheimer’s disease.

Data Availability Statement

The data that support the findings of this study are openly available in the Database of Genotypes and Phenotypes at [https://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000372.v1.p1], reference number [phs000372.v1.p1] and at the Alzheimer’s Disease Neuroimaging Initiative http://adni.loni.usc.edu/.
Hyperspectral super-resolution imaging with far-red emitting fluorophores using a thin-film tunable filter
Authors: Vissa Adriano , Giuliani Maximiliano , Kim Peter K. , Yip Christopher M.
Published: September 2019

New innovations in single-molecule localization microscopy (SMLM) have revolutionized optical imaging, enabling the characterization of biological structures and interactions with unprecedented detail and resolution. However, multi-colour or hyperspectral SMLM can be particularly challenging due to non-linear image registration issues, which affect image quality and data interpretation. Many of these arise as a consequence of differences in illumination optics (beam profile, power density, polarization, point spread function) for the different light sources. This is particularly acute in evanescent-wave based approaches (TIRF) where beam shape, decay depth, and power density are important. A potential useful approach would be to use a single excitation wavelength to perform hyperspectral localization imaging.. We report herein on the use of a variable angle tunable thin-film filter to spectrally isolate far-red emitting fluorophores. This solution was integrated into a commercial microscope platform using an open-source hardware design, enabling the rapid acquisition of SMLM images with ~ 15-20 nm spectral resolution.. By characterizing intensity distributions, average intensities, and localization frequency through a range of spectral windows, we identified an optimal fluorophore pair for two-colour SMLM. Fluorophore crosstalk between the different spectral windows was assessed by examining the effect of varying the photon output thresholds on the localization frequency and fraction of data recovered. The utility of this approach was demonstrated by hyper-spectral super-resolution imaging of the interaction between the mitochondrial protein, TOM20 and the peroxisomal protein, PMP70.
Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells
Authors: Nakato Ryuichiro , Wada Youichiro , Nakaki Ryo , Nagae Genta , Katou Yuki , Tsutsumi Shuichi , Nakajima Natsu , Fukuhara Hiroshi , Iguchi Atsushi , Kohro Takahide , Kanki Yasuharu , Saito Yutaka , Kobayashi Mika , Izumi-Taguchi Akashi , Osato Naoki , Tatsuno Kenji , Kamio Asuka , Hayashi-Takanaka Yoko , Wada Hiromi , Ohta Shinzo , Aikawa Masanori , Nakajima Hiroyuki , Nakamura Masaki , McGee Rebecca C. , Heppner Kyle W. , Kawakatsu Tatsuo , Genno Michiru , Yanase Hiroshi , Kume Haruki , Senbonmatsu Takaaki , Homma Yukio , Nishimura Shigeyuki , Mitsuyama Toutai , Aburatani Hiroyuki , Kimura Hiroshi , Shirahige Katsuhiko
Published: September 2019

Background

Endothelial cells (ECs) make up the innermost layer throughout the entire vasculature. Their phenotypes and physiological functions are initially regulated by developmental signals and extracellular stimuli. The underlying molecular mechanisms responsible for the diverse phenotypes of ECs from different organs are not well understood.

Results

To characterize the transcriptomic and epigenomic landscape in the vascular system, we cataloged gene expression and active histone marks in nine types of human ECs (generating 148 genome-wide datasets) and carried out a comprehensive analysis with chromatin interaction data. We identified 3,765 EC-specific enhancers, some of which were associated with disease-associated genetic variations. We also identified various candidate marker genes for each EC type. Notably, reflecting the developmental origins of ECs and their roles in angiogenesis, vasculogenesis and wound healing.

Conclusions

While the importance of several HOX genes for early vascular development and adult angiogenesis in pathological conditions has been reported, a systematic analysis of the regulation and roles of HOX genes in mature tissue cells has been lacking. These datasets provide a valuable resource for understanding the vascular system and associated diseases.
Genome Tree of Life:Deep Burstof Organism Diversity
Authors: Choi JaeJin , Kim Sung-Hou
Published: September 2019

An organism Tree of Life (organism ToL) is a conceptual and metaphorical tree to capture a simplified narrative of the evolutionary course and kinship among the extant organisms of today. Such tree cannot be experimentally validated but may be reconstructed based on characteristics associated with the extant organisms. Since the whole genome sequence of an organism is, at present, the most comprehensivedescriptorof the organism, agenome Tolcan be an empirically derivable surrogate for the organism ToL. However, a genome ToL has been impossible to construct because of the practical reasons that experimentally determining the whole genome sequences of a large number of diverse organisms was technically impossible. Thus, for several decades,gene ToLs, based onselected genes, have been commonly used as a surrogate for the organisms ToL. This situation changed dramatically during the last several decades due to rapid advances in DNA sequencing technology. Here we describe the main features of a genome ToL that are different from those of the broadly accepted gene ToLs: (a) the first two organism groups to emerge are the founders of prokarya and eukarya, (b) they diversify into six large groups and all thefoundersof the groups haveemergedin a“Deep Burst”at the very beginning period of the emergence of Life on Earth and (c) other differences are notable in the order of emergence of smaller groups.

Significance Statement

Tree of Lifeis a conceptual and metaphorical tree that captures a simplified narrative of theevolutionary courseandkinshipamong all living organisms of today. Since the whole genome sequence information of an organism is, at present, the most comprehensive description of the organism, we reconstructed aGenome Tree of Lifeusing the proteome information from the whole genomes of over 4000 different living organisms on Earth. It suggests that (a) the first two primitive organism groups to emerge are the founders of prokarya and eukarya, (b) they diversify into six large groups, and (c) all thefoundersof the groups haveemergedin a“Deep Burst”at the very beginning period of the emergence of Life on Earth.
Colour preferences of Spotted Wing Drosophila, Drosophila suzukii, under field conditions in various crops
Authors: Fahrentrapp Johannes , Roosjen Peter , Green David R. , Gregory Billy , Panassiti Bernd
Published: September 2019

The authors have withdrawn this manuscript because of conflicting authorship views of an unnamed person claiming authorship. Therefore, the authors do not wish this work to be cited as reference for the project.

However, the original results of the withdrawn preprint remain valid. If you have any questions, please contact the corresponding author (Johannes.fahrentrapp@zhaw.ch).
The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway
Authors: Roberts Grace C. , Stonehouse Nicola J. , Harris Mark
Published: September 2019

The role of the chikungunya virus (CHIKV) non-structural protein 3 (nsP3) in the virus lifecycle is poorly understood. The protein comprises 3 domains. The N-terminus is a macro domain, biochemically characterised to bind both RNA and ADP-ribose, and to possess ADP-ribosyl hydrolase activity – an enzymatic activity that removes ADP-ribose from mono-ADP-ribosylated proteins. As ADP-ribosylation is important in the signalling pathway leading to activation of the transcription factor NF-κB, we sought to determine if the macro domain might perturb NF-κB signalling. We first show that CHIKV infection did not induce NF-κB activation, and could not block exogenous activation of the pathway via TNFα, although TNFα treatment did reduce virus titres. Ectopic expression of nsP3 was able to block TNFα-mediated NF-κB activation and this was dependent on the macro domain, as mutations previously shown to disrupt either ADP-ribose binding or hydrolase activity lost the ability to inhibit NF-κB activation. Lastly, we determined the phenotype of the macro domain mutants in the context of virus infection in a range of cell types. Our data are consistent with cell- and species-dependent roles of the macro domain, however, these phenotypes do not correlate with the ability to inhibit NF-κB activation suggesting that the macro domain plays multiple independent roles in the virus lifecycle.
OmicsOne: Associate Omics Data with Phenotypes in One-Click
Authors: Hu Yingwei , Ao Minghui , Zhang Hui
Published: September 2019

The rapid advancements of high-throughput “omics” technologies have brought huge amount of data to process during and after experiments. Multi-omic analysis facilitates a deeper interrogation of a dataset, and discovery of interesting genes, proteins, lipids, glycans, or metabolites, or pathways related to the corresponding phenotypes in a study. Many individual software tools have been developed to analyze and visualize the data. However, integrating multiple omics data analysis strategies and approaches in a single data processing pipeline is still a challenge task. OmicsOne is a software developed in R, Python and Jupyter Notebook that can achieve statistical analysis, machine learning, and data visualization on multi-‘omics’ data by taking the advantages of integrating the useful tools from individual software packages. OmicsOne can simplify “omics” data analysis, and delineate molecules, or pathways associated to interested phenotypes.
CaATP prolongs strong actomyosin binding and promotes futile myosin stroke
Authors: Ge Jinghua , Gargey Akhil , Nesmelova Irina V. , Nesmelov Yuri E.
Published: September 2019

Calcium plays an essential role in muscle contraction, regulating actomyosin interaction by binding troponin of thin filaments. There are several buffers for calcium in muscle, and those buffers play a crucial role in the formation of the transient calcium wave in sarcomere upon muscle activation. One such calcium buffer in muscle is ATP. ATP is a fuel molecule, and the important role of MgATP in muscle is to bind myosin and supply energy for the power stroke. Myosin is not a specific ATPase, and CaATP also supports myosin ATPase activity. The concentration of CaATP in sarcomeres reaches 1% of all ATP available. Since 294 myosin molecules form a thick filament, naïve estimation gives three heads per filament with CaATP bound, instead of MgATP. We found that CaATP dissociates actomyosin slower than MgATP, thus increasing the time of the strong actomyosin binding. The rate of the basal CaATPase is faster than that of MgATPase, myosin readily produces futile stroke with CaATP. When calcium is upregulated, as in malignant hyperthermia, kinetics of myosin and actomyosin interaction with CaATP suggest that myosin CaATPase activity may contribute to observed muscle rigidity and enhanced muscle thermogenesis.
Developmental Reactive Oxygen Species Target Histone Methylation to Individualize Stress resistance and Lifespan
Authors: Bazopoulou Daphne , Knoefler Daniela , Zheng Yongxin , Ulrich Kathrin , Oleson Bryndon , Xie Lihan , Kim Minwook , Kaufmann Anke , Lee Young-Tae , Dou Yali , Chen Yong , Quan Shu , Jakob Ursula
Published: September 2019

A central aspect of aging research concerns the question as to when individuality in lifespan arises and what mechanism(s) promote and potentially manifest individual differences in longevity. We have now discovered that a transient increase in reactive oxygen species (ROS), which occurs naturally during early development in a subpopulation of synchronized Caenorhabditis elegans, sets processes into motion that increase stress resistance, improve redox homeostasis and ultimately prolong lifespan in those animals. We find that these effects are linked to the global ROS-mediated decrease in developmental histone H3K4me3 levels. Studies in HeLa cells confirmed that global H3K4me3 levels are ROS-sensitive, and that depletion of H3K4me3 levels increases stress resistance in mammalian cell cultures. In vitro studies identified the Set1-MML histone methyltransferase as the redox sensitive unit of the H3K4-trimethylating COMPASS complex. Our findings imply a novel link between early-life events, ROS-sensitive epigenetic marks, stress resistance and lifespan.