bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post-transcriptional control of EMT is coordinated through combinatorial targeting by multiple microRNAs
Authors: Cursons Joseph , Pillman Katherine A , Scheer Kaitlin , Gregory Philip A , Foroutan Momeneh , Zadeh Soroor Hediyeh , Toubia John , Crampin Edmund J , Goodall Gregory J , Bracken Cameron P , Davis Melissa J 
Published: May 2017

AbstractEpithelial-mesenchymal transition (EMT) is a process whereby cells undergo reversible phenotypic change, losing epithelial characteristics and acquiring mesenchymal attributes. While EMT underlies normal, physiological programs in embryonic tissue development and adult wound healing, it also contributes to cancer progression by facilitating metastasis and altering drug sensitivity. Using a cell model of EMT (human mammary epithelial (HMLE) cells), we show that miRNAs act as an additional regulatory layer over and above the activity of the transcription factors with which they are closely associated. In this context, miRNAs serve to both enhance expression changes for genes with EMT function, whilst simultaneously reducing transcriptional noise in non-EMT genes. We find that members of the polycistronic miR-200c~141 and miR-183~182 clusters (which are decreased during HMLE cell EMT and are associated with epithelial gene expression in breast cancer patients) co-regulate common targets and pathways to enforce an epithelial phenotype. We demonstrate their combinatorial effects are apparent much closer to endogenous expression levels (and orders of magnitude lower than used in most studies). Importantly, the low levels of combinatorial miRNAs that are required to exert biological function ameliorate the “off-target” effects on gene expression that are a characteristic of supra-physiologic miRNA manipulation. We argue that high levels of over-expression characteristic of many miRNA functional studies have led to an over-estimation of the effect of many miRNAs in EMT regulation, with over 130 individual miRNAs directly implicated as drivers of EMT. We propose that the functional effects of co-regulated miRNAs that we demonstrate here more-accurately reflects the endogenous post-transcriptional regulation of pathways, networks and processes, and illustrates that the post-transcriptional miRNA regulatory network is fundamentally cooperative.
I like coffee with cream anddog?Change in an implicit probabilistic representation captures meaning processing in the brain
Authors: Rabovsky Milena , Hansen Steven S. , McClelland James L. 
Published: May 2017

AbstractThe N400 component of the event-related brain potential has aroused much interest because it is thought to provide an online measure of meaning processing in the brain. Yet, the underlying process remains incompletely understood and actively debated. Here, we present a computationally explicit account of this process and the emerging representation of sentence meaning. We simulate N400 amplitudes as the change induced by an incoming stimulus in an implicit and probabilistic representation of meaning captured by the hidden unit activation pattern in a neural network model of sentence comprehension, and we propose that the process underlying the N400 also drives implicit learning in the network. The model provides a unified account of 16 distinct findings from the N400 literature and connects human language processing with successful deep learning approaches to language processing.
Geometrical confinement guides Brachyury self-patterning in embryonic stem cells
Authors: Guillaume Blin , Picart Catherine , Thery Manuel , Puceat Michel 
Published: May 2017

AbstractDuring embryogenesis, signaling molecules initiate cell diversification, sometimes via stochastic processes, other times via the formation of long range gradients of activity which pattern entire fields of cells. Such mechanisms are not insensitive to noise (Lander, 2011), yet embryogenesis is a remarkably robust process suggesting that multiple layers of regulations secure patterning during development. In the present study, we present a proof of concept according to which an asymmetric pattern of gene expression obtained from a spatially disorganised population of cells can be guided by the geometry of the environment in a reproducible and robust manner. We used ESC as a model system whithin which multiple developmental cell states coexist (MacArthur and Lemischka, 2013; Smith, 2017; Torres-Padilla and Chambers, 2014). We first present evidence that a reciprocal regulation of genes involved in the establishment of antero-posterior polarity during peri-implantation stages of mouse development is spontaneously occuring within ESC. We then show that a population of cells with primitive streak characteristics localise in regions of high curvature and low cell density. Finally, we show that this patterning did not depend on self-organised gradients of morphogen activity but instead could be attributed to positional rearrangements. Our findings unveil a novel role for tissue geometry in guiding the self-patterning of primitive streak cells and provide a framework to further refine our understanding of symmetry breaking events occuring in ESC aggregates. Finally, this work demonstrates that the self-patterning of a specific population of ESC, Brachyury positive cells in this case, can be directed by providing engineered external geometrical cues.
Dynamic allocation of orthogonal ribosomes facilitates uncoupling of co-expressed genes
Authors: Darlington Alexander P.S. , Kim Juhyun , Jiménez José I. , Bates Declan G. 
Published: May 2017

AbstractIntroduction of synthetic circuits into host microbes creates competition between circuit and host genes for shared cellular resources, such as RNA polymerases and ribosomes. This can lead to the emergence of unwanted coupling between the expression of different genes, complicating circuit design and potentially leading to circuit failure. Here we demonstrate the ability of orthogonal ribosomes to alleviate the effects of this resource competition. We partition the ribosome pool by expressing an engineered 16S RNA with altered specificity, and use this division of specificity to build simple resource allocators which reduce the level of ribosome-mediated gene coupling. We then design and implement a dynamic resource allocation controller, which acts to increase orthogonal ribosome production as the demand for translational resources by a synthetic circuit increases. Our results highlight the potential of dynamic translational resource allocation as a means of minimising the impact of cellular limitations on the function of synthetic circuitry.
A maladaptive combination of traits contributes to the maintenance of a stable hybrid zone between two divergent species ofDrosophila
Authors: Cooper Brandon S. , Sedghifar Alisa , Nash W. Thurston , Comeault Aaron A. , Matute Daniel R. 
Published: May 2017

ABSTRACTGeographical areas where two species come into contact and hybridize serve as natural laboratories for assessing mechanisms that limit gene flow between species. The ranges of about half of all closely relatedDrosophilaspecies overlap, and the genomes of several pairs reveal signatures of past introgression. However, only two contemporary hybrid zones have been characterized in the genus, and both are recently diverged sister species (D. simulans-D. sechellia, Ks = 0.05;D. yakuba-D. santomea, Ks = 0.048). Here we present evidence of a new hybrid zone, and the ecological mechanisms that maintain it, between two highly divergentDrosophilaspecies (Ks = 0.11). On the island of Bioko in west Africa,D. teissierioccupies mostly forests,D. yakubaoccupies mostly open agricultural areas, and recently, we discovered that hybrids between these species occur near the interface of these habitats. Genome sequencing revealed that all field-sampled hybrids are F1progeny ofD. yakubafemales andD. teissierimales. We found no evidence for either advanced-generation hybrids or F1hybrids produced byD. teissierifemales andD.yakubamales. The lack of advanced-generation hybrids on Bioko is consistent with mark-recapture and laboratory experiments that we conducted, which indicate hybrids have a maladaptive combination of traits. LikeD. yakuba, hybrids behaviorally prefer open habitat that is relatively warm and dry, but likeD. teissieri, hybrids have low desiccation tolerance, which we predict leaves them physiologically ill-equipped to cope with their preferred habitat. These observations are consistent with recent findings of limited introgression in theD. yakubaclade and identify an ecological mechanism for limiting gene flow betweenD. yakubaandD. teissieri; namely, selection against hybrids that we have documented, in combination with hybrid male sterility, contributes to the maintenance of this narrow (~30m), stable hybrid zone centered on the forest-open habitat ecotone. Our results show how a deleterious combination of parental traits can result in unfit or maladapted hybrids.
Complex interaction of resource availability, life-history and demography determines the dynamics and stability of stage-structured populations
Authors: Tung Sudipta , Rajamani M. , Joshi Amitabh , Dey Sutirth 
Published: May 2017

ABSTRACTThe dynamics of stage-structured populations facing variability in resource availability and/or demographic factors like unequal sex-ratios, remains poorly understood. We addressed these issues using a stage-structured individual-based model that incorporates life-history parameters common to many holometabolous insects. The model was calibrated using time series data from a 49-generation experiment on laboratory populations ofDrosophila melanogaster, subjected to four different combinations of larval and adult nutritional levels. The model was able to capture multiple qualitative and quantitative aspects of the empirical time series across three independent studies. We then simulated the model to explore the interaction of various life-history parameters and nutritional levels in determining population stability. In all nutritional regimes, stability of the populations was reduced upon increasing egg-hatchability, critical mass and proportion of body resource allocated to female fecundity. However, the stability-effects of increasing sensitivity of female-fecundity to adult density varied across nutrition regimes. The effects of unequal sex-ratio and sex-specific culling were greatly influenced by fecundity but not by levels of juvenile nutrition. Finally, we investigated the implications of some of these insights on the efficiency of the widely-used pest control method, Sterile Insect Technique (SIT). We show that increasing the amount of juvenile food had no effects on SIT efficiency when the density-independent fecundity is low, but reduces SIT efficiency when the density-independent fecundity is high.
Differential variant calling in mutants from diverse genetic backgrounds: A case study in the nematodePristionchus pacificus
Authors: Rödelsperger Christian , Moreno Eduardo 
Published: May 2017

AbstractGenome sequencing of mutants is one of the most widely used techniques to identify genes that control traits of interest including human diseases. Traditionally, variants are called against reference genomes and various filtering techniques are applied to reduce the number of candidate mutations. However, if the genetic background of the mutant is different from the reference genome, the number of background variants may exceed the number of true mutations by several orders of magnitude resulting in candidate lists that cannot be effectively reduced.We introduce the problem of differential variant calling in mutants from diverse genetic backgrounds. In the example of a mutant strain of the nematodePristionchus pacificus, where the genetic background is not identical to the reference genome (≈1% genome-wide divergence), we show that simple intersection filtering does not effectively reduce the list of candidate mutations due to the combined effect of high number of background mutations, missing coverage in the wildtype sample, and problematic regions in the genome assembly. Although restriction to sites with coverage in mutant and wildtype sample greatly reduced the number of candidate sites, we further improved this candidate set by implementing a customized variant calling procedure. This takes the mutant sample and the control sample of same genetic background as input and calls variants exhibiting strong discriminative signals across the two samples. Intersecting the candidate mutations with an interval identfied from mapping by RAD-seq revealed a likely splice-site mutation in theP. pacificusdpy-1 gene, which has been previously shown to cause the associated morphological phenotype.Our study shows that combined analysis of mutant and wildtype samples drastically increases the potential to find true mutations. We hope that these results may be helpful for other model systems, where the identification of candidate mutants is complicated by assembly errors, lab-derived mutations, or different genetic backgrounds.
A mechanism for prime-realignment during influenza A virus replication
Authors: Oymans Judith , te Velthuis Aartjan J.W. 
Published: May 2017

AbstractThe influenza A virus genome consists of eight segments of single-stranded RNA. These segments are replicated and transcribed by a viral RNA-dependent RNA polymerase (RdRp) that is made up of the influenza virus proteins PB1, PB2 and PA. To copy the viral RNA (vRNA) genome segments and the complementary RNA (cRNA) segments, the replicative intermediate of viral replication, the RdRp must use two promoters and two differentde novoinitiation mechanisms. On the vRNA promoter, the RdRp initiates on the 3’ terminus, while on the cRNA promoter the RdRp initiates internally and subsequently realigns the nascent vRNA product to ensure that the template is copied in full. In particular the latter process, which is also used by other RNA viruses, is not understood. Here we provide mechanistic insight into prime-realignment during influenza virus replication and show that it is controlled by the priming loop and a helix-loop-helix motif of the PB1 subunit of the RdRp. Overall, these observations advance our understanding of how the influenza A virus initiates viral replication and amplifies the genome correctly.ImportanceInfluenza A viruses cause severe disease in humans and are considered a major threat to our economy and health. The viruses replicate and transcribe their genome using an enzyme called the RNA polymerases. To ensure that the genome is amplified faithfully and abundant viral mRNAs are made for viral protein synthesis, the RNA polymerase must work correctly. In this report, we provide insight into the mechanism that the RNA polymerase employs to ensure that the viral genome is copied correctly.
A 340/380 nm light emitting diode illuminator for Fura-2 AM ratiometric Ca2+ imaging of live cells with better than 5 nM precision
Authors: Tinning Peter W. , Franssen Aimee J. P.M. , Hridi Shehla U. , Bushell Trevor J. , McConnell Gail 
Published: May 2017

AbstractWe report the first demonstration of a fast wavelength-switchable 340/380 nm light emitting diode (LED) illuminator for Fura-2 ratiometric Ca2+ imaging of live cells. The LEDs closely match the excitation peaks of bound and free Fura-2 and enables the precise detection of cytosolic Ca2+ concentrations, which is only limited by the Ca2+ response of Fura-2. Using this illuminator, we have shown that Fura-2 acetoxymethyl ester (AM) concentrations as low as 250 nM can be used to detect induced Ca2+ events in tsA-201 cells and while utilizing the 150 μs switching speeds available, it was possible to image spontaneous Ca2+ transients in hippocampal neurons at a rate of 24.39 Hz that were blunted or absent at typical 0.5 Hz acquisition rates. Overall, the sensitivity and acquisition speeds available using this LED illuminator significantly improves the temporal resolution that can be obtained in comparison to current systems and supports optical imaging of fast Ca2+ events using Fura-2.
Aberrant Cortical Activity In Multiple GCaMP6-Expressing Transgenic Mouse Lines
Authors: Steinmetz Nicholas A. , Buetfering Christina , Lecoq Jerome , Lee Christian R. , Peters Andrew J. , Jacobs Elina A. K. , Coen Philip , Ollerenshaw Douglas R. , Valley Matthew T. , de Vries Saskia E. J. , Garrett Marina , Zhuang Jun , Groblewski Peter A. , Manavi Sahar , Miles Jesse , White Casey , Lee Eric , Griffin Fiona , Larkin Joshua D , Roll Kate , Cross Sissy , Nguyen Thuyanh V. , Larsen Rachael , Pendergraft Julie , Daigle Tanya , Tasic Bosiljka , Thompson Carol L. , Waters Jack , Olsen Shawn , Margolis David J. , Zeng Hongkui , Hausser Michael , Carandini Matteo , Harris Kenneth D. 
Published: May 2017

AbstractTransgenic mouse lines are invaluable tools for neuroscience but as with any technique, care must be taken to ensure that the tool itself does not unduly affect the system under study. Here we report aberrant electrical activity, similar to interictal spikes, and accompanying fluorescence events in some genotypes of transgenic mice expressing GCaMP6 genetically-encoded calcium sensors. These epileptiform events have been observed particularly, but not exclusively, in mice with Emx1-Cre and Ai93 transgenes, across multiple laboratories. The events occur at >0.1 Hz, are very large in amplitude (>1.0 mV local field potentials, >10% df/f widefield imaging signals), and typically cover large regions of cortex. Many properties of neuronal responses and behavior seem normal despite these events, though rare subjects exhibit overt generalized seizures. The underlying mechanisms of this phenomenon remain unclear, but we speculate about possible causes on the basis of diverse observations. We encourage researchers to be aware of these activity patterns while interpreting neuronal recordings from affected mouse lines and when considering which lines to study.
A theory that predicts behaviors of disordered cytoskeletal networks
Authors: Belmonte Julio , Leptin Maria , François Nédélec 
Published: May 2017

SummaryMorphogenesis in animal tissues is largely driven by tensions of actomyosin networks, generated by an active contractile process that can be reconstitutedin vitro. Although the network components and their properties are known, the requirements for contractility are still poorly understood. Here, we describe a theory that predicts whether an isotropic network will contract, expand, or conserve its dimensions. This analytical theory correctly predicts the behavior of simulated networks consisting of filaments with varying combinations of connectors, and reveals conditions under which networks of rigid filaments are either contractile or expansile. Our results suggest that pulsatility is an intrinsic behavior of contractile networks if the filaments are not stable but turn over. The theory offers a unifying framework to think about mechanisms of contractions or expansion. It provides a foundation for the study of a broad range of processes involving cytoskeletal networks, and a basis for designing synthetic networks.
Genomics and telemetry suggest a role for migration harshness in determining overwintering habitat choice, but not gene flow, in anadromous Arctic Char
Authors: Moore Jean-Sébastien , Harris Les N. , Luyer Jérémy Le , Sutherland Ben J. G. , Rougemont Quentin , Tallman Ross F. , Fisk Aaron T. , Bernatchez Louis 
Published: May 2017

AbstractMigration is a ubiquitous life history trait with profound evolutionary and ecological consequences. Recent developments in telemetry and genomics, when combined, can bring significant insights on the migratory ecology of non-model organisms in the wild. Here, we used this integrative approach to document dispersal, gene flow and potential for local adaptation in anadromous Arctic Char from six rivers in the Canadian Arctic. Acoustic telemetry data from 124 tracked individuals indicated asymmetric dispersal, with a large proportion of fish (72%) tagged in three different rivers migrating up the same short river in the fall. Population genomics data from 6,136 SNP markers revealed weak, albeit significant, population differentiation (average pairwiseFST= 0.011) and asymmetric dispersal was also revealed by population assignments. Approximate Bayesian Computation simulations suggested the presence of asymmetric gene flow, although in the opposite direction to that observed from the telemetry data, suggesting that dispersal does not necessarily lead to gene flow. These observations suggested that Arctic Char home to their natal river to spawn, but may overwinter in rivers with the shortest migratory route to minimize the costs of migration in non-breeding years. Genome scans and genetic-environment associations identified 90 outlier markers putatively under selection, 23 of which were in or near a gene. Of these, at least four were involved in muscle and cardiac function, consistent with the hypothesis that migratory harshness could drive local adaptation. Our study illustrates the power of integrating genomics and telemetry to study migrations in non-model organisms in logistically challenging environments such as the Arctic.
Predicting Protein Producibility in Filamentous Fungi
Authors: Dykstra Karmen L , Rousu Juho , Arvas Mikko 
Published: May 2017

AbstractIn this paper we study the problem of predicting the producibility of recombinant proteins in filamentous fungi, especially T. reesei, using machine learning methods. We train supervised and semi-supervised support vector machines with protein sequences, represented by their amino acid composition as well as protein family and domain information. Our results indicate, somewhat surprisingly, that quite modest amount of proteins with experimental data are required to build a state-of-the-art classifier and that additional unlabeled sequences in semi-supervised models do not bring increased predictive performance. Our experiments in cross-species prediction show that models trained for the filamentous fungus A. niger protein dataset can be generalized to predict protein producibility in T. reesei, and vice versa, without sacrificing too much accuracy, regardless of their approximately 500 millions years of divergence. However, predictors trained on E. coli and S. cerevisiae datasets gave variable performance when applied to the filamentous fungi datasets, indicating that while protein producibility prediction can be generalized accross related species, fully generic prediction tools applicable to any protein production host may not be realistic to achieve.