bluuebunny/crossref_metadata_2025_split huggingface dataset:
Termination of non-coding transcription in yeast relies on both a CTD-interaction domain and a CTD-mimic in Sen1
Authors: Han Z , Jasnovidova O , Haidara N , Tudek A , Kubicek K , Libri D , Stefl R , Porrua O. 
Published: October 2018

ABSTRACTPervasive transcription is a widespread phenomenon leading to the production of a plethora of non-coding RNAs (ncRNAs) without apparent function. Pervasive transcription poses a risk that needs to be controlled to prevent the perturbation of gene expression. In yeast, the highly conserved helicase Sen1 restricts pervasive transcription by inducing termination of non-coding transcription. However, the mechanisms underlying the specific function of Sen1 at ncRNAs are poorly understood. Here we identify a motif in an intrinsically disordered region of Sen1 that mimics the phosphorylated carboxy terminal domain (CTD) of RNA polymerase II and characterize structurally its recognition by the CTD-interacting domain of Nrd1, an RNA-binding protein that binds specific sequences in ncRNAs. In addition, we show that Sen1-dependent termination strictly requires the recognition of the CTD by the N-terminal domain of Sen1. We provide evidence that the Sen1-CTD interaction does not promote Sen1 initial recruitment but rather the capacity of Sen1 to induce the release of paused RNAPII from the DNA. Our results shed light onto the network of protein-protein interactions that control termination of non-coding transcription by Sen1.
Rationally designedmarinervectors to allow functional genomic analysis ofActinobacillus pleuropneumoniaeand other bacteria by transposon-directed insertion-site sequencing (TraDIS)
Authors: Bossé Janine T , Li Yanwen , Leanse Leon G. , Zhou Liqing , Chaudhuri Roy R , Peters Sarah E , Wang Jinhong , Maglennon Gareth A. , Holden Matthew TG , Maskell Duncan J , Tucker Alexander W , Wren Brendan W , Rycroft Andrew N , Langford Paul R ,   on behalf of the BRaDP1T consortium
Published: October 2018

AbstractTransposon Directed Insertion Sequencing (TraDIS) is a high-throughput method for mapping insertion sites in large libraries of transposon mutants. TheHimar1(mariner) transposon is ideal for generating near-saturating mutant libraries, especially in AT-rich chromosomes, as the requirement for integration is a TA dinucleotide. In this study, we generated two novelmarinervectors, pTsodCPC9 and pTlacPC9 (differing only in the promoter driving expression of the transposase gene), in order to facilitate TraDIS identification of conditionally essential genes inActinobacillus pleuropneumoniaeand other bacteria. Using the pTlacPC9 vector, we have generated, for the first time, saturatingmarinermutant libraries in bothA. pleuropneumoniaeandPasteurella multocidathat showed a near random distribution of insertions around the respective chromosomes. A preliminary screen of 5000 mutants each identified 8 and 15 genes, respectively, that are required for growth under anaerobic conditions.
TgCep250 is dynamically processed through the division cycle and essential for structural integrity of the Toxoplasma centrosome
Authors: Chen Chun-Ti , Gubbels Marc-Jan 
Published: October 2018

AbstractThe Toxoplasma centrosome is a unique bipartite structure comprising an inner- and outer-core responsible for the nuclear cycle (mitosis) and budding cycles (cytokinesis), respectively. These two cores remain associated during the cell cycle but have been proposed to function independently. Here, we describe the function of a large coiled-coil protein, TgCep250, in connecting the two centrosomal cores and promoting their structural integrity. Throughout the cell cycle TgCep250 localizes to the centrosome inner-core but resides on both inner- and outer-cores during the onset of cell division. This dynamic localization pattern is associated with proteolysis: the processed version residing on the inner-core. In the absence of TgCep250, stray centrosome inner- and outer-core foci were observed; detachment of the inner-outer-core connection resulted in nuclear partitioning defects. The detachment between centrosome inner- and outer-core was found in only one of the centrosomes during cell division, indicating distinct states of mother and daughter centrosomes. We further dissected the hierarchical organization of centrosome and kinetochore complex through depletion of kinetochore component TgNuf2, which resulted in dissociation of the intact bipolar centrosome from the nuclear periphery. Together, these data suggest that TgCep250 bridges the interaction between the centrosome cores but not between the inner-core and kinetochore.Short SummaryThe opportunistic apicomplexan parasite Toxoplasma gondii uses a bipartite centrosome to independently regulate mitosis and cytokinesis. Here we report a large coiled-coil protein that functions to integrate the two centrosomal cores for faithful cell division. This study also reveals the layered structural organization of the centrosome/kinetochore complex.
Neuronal adaptation reveals a suboptimal decoding of orientation tuned populations in the mouse visual cortex
Authors: Jin Miaomiao , Beck Jeffrey M. , Glickfeld Lindsey L. 
Published: October 2018

AbstractSensory information is encoded by populations of cortical neurons. Yet, it is unknown how this information is used for even simple perceptual choices such as discriminating orientation. To determine the computation underlying this perceptual choice, we took advantage of the robust adaptation in the mouse visual system. We find that adaptation increases animals’ thresholds for orientation discrimination. This was unexpected since optimal computations that take advantage of all available sensory information predict that the shift in tuning and increase in signal-to-noise ratio in the adapted condition should improve discrimination. Instead, we find that the effects of adaptation on behavior can be explained by the appropriate reliance of the perceptual choice circuits on target preferring neurons, but the failure to discount neurons that prefer the distractor. This suggests that to solve this task the circuit has adopted a suboptimal strategy that discards important task-related information to implement a feed-forward visual computation.
Applicability of the mutation-selection balance model to population genetics of heterozygous protein-truncating variants in humans
Authors: Weghorn Donate , Balick Daniel J. , Cassa Christopher , Kosmicki Jack , Daly Mark J. , Beier David R. , Sunyaev Shamil R. 
Published: October 2018

AbstractThe fate of alleles in the human population is believed to be highly affected by the stochastic force of genetic drift. Estimation of the strength of natural selection in humans generally necessitates a careful modeling of drift including complex effects of the population history and structure. Protein truncating variants (PTVs) are expected to evolve under strong purifying selection and to have a relatively high per-gene mutation rate. Thus, it is appealing to model the population genetics of PTVs under a simple deterministic mutation-selection balance, as has been proposed earlier [1]. Here, we investigated the limits of this approximation using both computer simulations and data-driven approaches. Our simulations rely on a model of demographic history estimated from 33,370 individual exomes of the Non-Finnish European subset of the ExAC dataset [2]. Additionally, we compared the African and European subset of the ExAC study and analyzed de novo PTVs. We show that the mutation-selection balance model is applicable to the majority of human genes, but not to genes under the weakest selection.
Using micro-CT techniques to explore the role of sex and hair in the functional morphology of bumblebee (Bombus terrestris) ocelli
Authors: Wilby David , Aarts Tobio , Tichit Pierre , Bodey Andrew , Rau Christoph , Taylor Gavin , Baird Emily 
Published: October 2018

AbstractMany insects have triplets of camera type eyes, called ocelli, whose function remains unclear for most species. Here, we investigate the ocelli of the bumblebee,Bombus terrestris, using reconstructed 3D data from X-ray micro computed-tomography scans combined with computational ray-tracing simulations. This method enables us, not only to predict the visual fields of the ocelli, but to explore for the first time the effect that hair has on them as well as the difference between worker female and male ocelli.We find that bumblebee ocellar fields of view are directed forward and dorsally, incorporating the horizon as well as the sky. There is substantial binocular overlap between the median and lateral ocelli, but no overlap between the two lateral ocelli. Hairs in both workers and males occlude the ocellar field of view, mostly laterally in the worker median ocellus and dorsally in the lateral ocelli. There is little to no sexual dimorphism in the ocellar visual field, suggesting that inB. terrestristhey confer no advantage to mating strategies.We compare our results with published observations for the visual fields of compound eyes in the same species as well as with the ocellar vision of other bee and insect species.
An enhanced-sampling MD-based protocol for molecular docking
Authors: Basciu Andrea , Malloci Giuliano , Pietrucci Fabio , Bonvin Alexandre M. J. J. , Vargiu Attilio V. 
Published: October 2018

AbstractUnderstanding molecular recognition of proteins by small molecules is key for drug design. Despite the number of experimental structures of ligand-protein complexes keeps growing, the number of available targets remains limited compared to the druggable genome, and structural diversity is generally low, which affects the chemical variance of putative lead compounds. From a computational perspective, molecular docking is widely used to mimic ligand-protein associationin silico. Ensemble-docking approaches include flexibility through a set of different conformations of the protein obtained either experimentally or from computer simulations, e.g. molecular dynamics. However, structures prone to host (the correct) ligands are generally poorly sampled by standard molecular dynamics simulations of the apo protein. In order to address this limitation, we introduce a computational approach based on metadynamics simulations (EDES -Ensemble-Docking withEnhanced-sampling of pocketShape) to generate druggable conformations of proteins only exploiting their apo structures. This is achieved by defining a set of collective variables that effectively sample different shapes of the binding site, ultimately mimicking the steric effect due to ligands to generate holo-like binding site geometries. We assessed the method on two challenging proteins undergoing different extents of conformational changes upon ligand binding. In both cases our protocol generated a significant fraction of structures featuring a low RMSD from the experimental holo conformation. Moreover, ensemble docking calculations using those conformations yielded native-like poses among the top ranked ones for both targets. This proof of concept study paves the route towards an automated workflow to generate druggable conformations of proteins, which should become a precious tool for structure-based drug design.
Silhouette width using generalized mean – a flexible method for assessing clustering efficiency
Authors: Lengyel Attila , Botta-Dukát Zoltán 
Published: October 2018

AbstractCluster analysis plays vital role in pattern recognition in several fields of science. Silhouette width is a widely used measure for assessing the fit of individual objects in the classification, as well as the quality of clusters and the entire classification. This index uses two clustering criteria, compactness (average within-cluster distances) and separation (average between-cluster distances), which implies that spherical cluster shapes are preferred over others – a property that can be seen as a disadvantage in the presence 22 of clusters with high internal heterogeneity, which is common in real situations.We suggest a generalization of the silhouette width using the generalized mean. By changing the p parameter of the generalized mean between −∞ and +∞, several specific summary statistics, including the minimum, maximum, the arithmetic, harmonic, and geometric means, can be reproduced. Implementing the generalized mean in the calculation of silhouette width allows for changing the sensitivity of the index to compactness vs. connectedness. With higher sensitivity to connectedness instead of compactness the preference of silhouette width towards spherical clusters is expected to reduce. We test the performance of the generalized silhouette width on artificial data sets and on the Iris data set. We examine how classifications with different numbers of clusters prepared by single linkage, group average, and complete linkage algorithms are evaluated, if p is set to different values.When p was negative, well separated clusters achieved high silhouette widths despite their elongated or circular shapes. Positive values of p increased the importance of compactness, hence the preference towards spherical clusters became even more detectable. With low p, single linkage clustering was deemed the most efficient clustering method, while with higher parameter values the performance of group average and complete linkage seemed better.The generalized silhouette width is a promising tool for assessing clustering quality. It allows for adjusting the contribution of compactness and connectedness criteria to the index value, thus avoiding underestimation of clustering efficiency in the presence of clusters with high internal heterogeneity.
Multi-scale Imaging Reveals Aberrant Connectome Organization and Elevated Dorsal Striatal Arc Expression in Advanced Age
Authors: Colon-Perez Luis M. , Turner Sean M. , Lubke Katelyn N. , Febo Marcelo , Burke Sara N. 
Published: October 2018

ABSTRACTThe functional connectome reflects a network architecture enabling adaptive behavior that becomes vulnerable in advanced age. The cellular mechanisms that contribute to altered functional connectivity in old age, however, are not known. Here we used a multi-scale imaging approach to link age-related changes in the functional connectome to altered expression of the activity-dependent immediate-early gene Arc as a function of training to multi-task. Aged behaviorally-impaired, but not young, rats had a subnetwork of increased connectivity between the anterior cingulate cortex and dorsal striatum. Moreover, the old rats had less stable rich club participation that increased with cognitive training. The altered functional connectome of aged rats was associated with a greater engagement of neurons in the dorsal striatum during cognitive multi-tasking. These findings point to aberrant large-scale functional connectivity in aged animals that is associated with altered cellular activity patterns within individual brain regions.
Electrospun Cellulose-Silk Composite Nanofibres Direct Mesenchymal Stem Cell Chondrogenesis in the Absence of Biological Stimulation
Authors: Begum Runa , Perriman Adam W. , Su Bo , Scarpa Fabrizio , Kafienah Wael 
Published: October 2018

AbstractSmart biomaterials with an inherent stimulating capacity that elicit specific behavioursin lieuof biological prompts would prove advantageous for regenerative medicine applications. Specific blends of the natural polymers cellulose and silk cast as films can drive the chondrogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs) uponin vitroculture. However, the true potential of such biomaterials for cartilage tissue engineering can be realised upon its three-dimensional fabrication. In this work we employ an electrospinning technique to model thein vivonanofibrous extracellular matrix (ECM). Cellulose and silk polymers at a mass ratio of 75:25 were regenerated using a trifluoroacetic acid and acetic acid cosolvent system. This natural polymer composite was directly electrospun for the first time, into nanofibers without post-spun treatment. The presence and size of fibre beading was influenced by environmental humidity. The regenerated composite retained the key chemical functionalities of its respective components. Biocompatibility of the natural polymer composite with hMSCs was demonstrated and its inherent capacity to direct chondrogenic stem cell differentiation, in the absence of stimulating growth factors, was confirmed. This physical chondrogenic stimulation was countered biochemically using fibroblast growth factor-2 (FGF-2), a growth factor used to enhance the proliferation of hMSCs. The newly fabricated scaffold provides the foundation for designing a robust, self-inductive, and cost-effective biomimetic biomaterial for cartilage tissue engineering.
No Cost of Complexity in Bacteriophages Adapting to a Complex Environment
Authors: Sackman Andrew M. , Rokyta Darin R. 
Published: October 2018

AbstractA longstanding prediction in evolutionary biology is that organisms experience a so-called “cost of complexity” manifested as a decreasing rate of adaptation in populations as organisms or selective environments become increasingly complex. This theory assumes the ubiquity of antagonistic pleiotropy, or tradeoffs in fitness, for mutations affecting multiple traits or phenotypes. A particular manifestation of antagonism thought to be at play in adaptive dynamics involves the relationship between viral growth rate and capsid stability, an interaction that may impede the adaptation of viral pathogens to novel hosts and environments. Here, we present a comparison of the genetics of adaptation for populations of bacteriophages undergoing complete adaptive walks under both simple and complex selective conditions, with complexity being determined by the number of traits under directional selection. We found no evidence for a long-term cost of complexity in viruses experiencing complex selection, with on average at least as great a rate of adaptation under more complex conditions, and rampant evidence for synergistic, rather than antagonistic, pleiotropy. The lack of evident tradeoffs between multiple phenotypes implies that emerging pathogens may be able to improve their growth in many different hosts or environments simultaneously and to do so at a faster rate than previously anticipated.
GWAS using 2b-RAD sequencing identified three mastitis important SNPs via two-stage association analysis in Chinese Holstein cows
Authors: Yang Fan , Chen Fanghui , Li Lili , Yan Li , Badri Tarig , Lv Chenglong , Yu Daolun , Chen Jie , Xing Chaofeng , Li Jie , Wang Genlin , Li Honglin , Li Jun , Cai Yafei 
Published: October 2018

AbstractBackgroundBovine mastitis is a key disease restricting developing global dairy industry. Genomic wide association studies (GWAS) provided a convenient way to understand the biological basis of mastitis and better prevent or treat the disease. 2b-RADseq is a reduced-representation sequencing that offered a powerful method for genome-wide genetic marker development and genotyping. This study, GWAS using two-stage association analysis identified mastitis important genes’ single nucleotide polymorphisms (SNP) in Chinese Holstein cows.ResultsIn the selected Chinese Holstein cows’ population, we identified 10,058 SNPs and predicted their allele frequencies. In stage I, 42 significant SNPs screened out in Chinese Holstein cows via Bayesian (P<0.001), while logistic regression model identified 51 SNPs (P<0.01). Twenty-seven significant SNPs appeared simultaneously in both analytical models, which of them only three significant SNPs (rs75762330, C>T, PIC=0.2999; rs88640083, A>G, PIC=0.1676; rs20438858, G>A, PIC=0.3366) located in non-coding region (introns and intergenic) screened out associated with inflammation or immune response. GO enrichment analysis showed that they annotated to three genes (PTK2B, SYK and TNFRSF21), respectively. Stage II? case-control study used to verify three important SNPs associated with dairy cows mastitis traits in independent population. Data suggested that the correlation between these three SNPs (rs75762330, P<0.025; rs88640083, P<0.005; rs20438858, P<0.001) and mastitis traits in dairy cows were consistent with stage I.ConclusionTwo-stage association analysis approved that three significant SNPs associated with mastitis traits in Chinese Holstein cows. Gene function analysis indicated that three genes (PTK2B, SYK and TNFRSF21) involved in inflammation and immune response of dairy cows. Suggesting that they as new candidate genes have an impact on mastitis susceptibility (PTK2B and SYK, OR>1) or resistance (TNFRSF21, OR<1) in Chinese Holstein cows.
WindSTORM: Robust online image processing for high-throughput nanoscopy
Authors: Ma Hongqiang , Xu Jianquan , Liu Yang 
Published: October 2018

AbstractHigh-throughput nanoscopy becomes increasingly important for unraveling complex biological processes from a large heterogeneous cell population at a nanoscale resolution. High-density emitter localization combined with a large field of view and fast imaging frame rate is commonly used to achieve a high imaging throughput, but the image processing speed in the dense emitter scenario remains a bottleneck. Here we present a simple non-iterative approach, referred to as WindSTORM, to achieve high-speed high-density emitter localization with robust performance for various image characteristics. We demonstrate that WindSTORM improves the computation speed by two orders of magnitude on CPU and three orders of magnitude upon GPU acceleration to realize online image processing, without compromising localization accuracy. Further, due to the embedded background correction, WindSTORM is highly robust in the presence of high and non-uniform background. WindSTORM paves the way for next generation of high-throughput nanoscopy.