bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversible Pulmonary Trunk Banding. XI: Myocardial Vascular Endothelial Growth Factor Expression in Young Goats Submitted to Ventricular Retraining
Authors: Assad Renato S. , Rocha Eduardo A. V. , Aiello Vera D. , Meniconi Tiago A. , Abduch Maria C. D. , Thomaz Petronio G. , Jatene Marcelo B. , Moreira Luiz F. P. 
Published: May 2019

ABSTRACTBackgroundVentricle retraining has been extensively studied by our laboratory. Previous studies have demonstrated that intermittent overload causes a more efficient ventricular hypertrophy. The adaptive mechanisms involved in the ventricle retraining are not completely established. This study assessed vascular endothelial growth factor (VEGF) expression in the ventricles of goats submitted to systolic overload.MethodsTwenty-one young goats were divided into 3 groups (7 animals each): control, 96-hour continuous systolic overload, and intermittent systolic overload (four 12-hour periods of systolic overload paired with 12-hour resting period). During the 96-hour protocol, systolic overload was adjusted to achieve a right ventricular (RV) / aortic pressure ratio of 0.7. Hemodynamic evaluations were performed daily before and after systolic overload. Echocardiograms were obtained preoperatively and at protocol end to measure cardiac masses thickness. At study end, the animals were killed for morphologic evaluation and immunohistochemical assessment of VEGF expression.ResultsRV-trained groups developed hypertrophy of RV and septal masses, confirmed by increased weight and thickness, as expected. In the study groups, there was a small but significantly increased water content of the RV and septum compared with those in the control group (p<0.002). VEGF expression in the RV myocardium was greater in the intermittent group (2.89% ± 0.41%) than in the continuous (1.80% ± 0.19%) and control (1.43% ± 0.18%) groups (p<0.023).ConclusionsIntermittent systolic overload promotes greater upregulation of VEGF expression in the subpulmonary ventricle, an adaptation that provides a mechanism for increased myocardial perfusion during the rapid myocardial hypertrophy of young goats.
Actin protrusions push on E-cadherin to maintain epithelial cell-cell adhesion
Authors: Li John Xiao He , Tang Vivian W. , Brieher William M. 
Published: May 2019

AbstractCadherin mediated cell-cell adhesion is actin dependent, but the precise role of actin in maintaining cell-cell adhesion is not fully understood. Actin polymerization-dependent protrusive activity is required to push distally separated cells close enough together to initiate contact. Whether protrusive activity is required to maintain adhesion in confluent sheets of epithelial cells is not known. By electron microscopy as well as live cell imaging, we have identified a population of protruding actin microspikes that operate continuously near apical junctions of polarized MDCK cells. Live imaging shows that microspikes containing E-cadherin extend into gaps between E-cadherin clusters on neighboring cells while reformation of cadherin clusters across the cell-cell boundary triggers microspike withdrawal. We identify Arp2/3, EVL, and CRMP-1 as three actin assembly factors necessary for microspike formation. Depleting these factors from cells using RNAi results in myosin II-dependent unzipping of cadherin adhesive bonds. Therefore, actin polymerization-dependent protrusive activity operates continuously at cadherin cell-cell junctions to keep them shut and to prevent myosin II-dependent contractility from tearing cadherin adhesive contacts apart.
The molecular determinants of R-roscovitine block of hERG channels
Authors: Cernuda Bryan , Fernandes Christopher , Allam Salma , Orzillo Matthew , Suppa Gabrielle , Chia Chang Zuleen , Athanasopoulos Demosthenes , Buraei Zafir 
Published: May 2019

AbstractHuman ether-à-go-go-related gene (Kv11.1, or hERG) is a potassium channel that conducts the delayed rectifier potassium current (IKr) during the repolarization phase of cardiac action potentials. hERG channels have a larger pore than other K+channels and can trap many unintended drugs, often resulting in acquired LQTS (aLQTS). R-roscovitine, a cyclin-dependent kinase (CDK) inhibitor that also inhibits L-type calcium channels, inhibits open hERG channels but does not become trapped in the pore. Two-electrode voltage clamp recordings from Xenopus oocytes expressing wild-type (WT) or mutant (T623A, S624A, Y652A, F656A) hERG channels demonstrated that, compared to WT hERG, T623A, Y652A, and F656A inhibition by 200 μM R-roscovitine was ~ 48 %, 29 %, and 73 % weaker, respectively. In contrast, S624A hERG was inhibited more potently than WT hERG, with an ~ 34 % stronger inhibition. These findings were further supported by the IC50 values, which were increased for T623A, Y652A and F656A (by ~5.5, 2.75, and 42 fold respectively) and reduced 1.3 fold for the S624A mutant. Our data suggest that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 may not be. This relatively unique feature, coupled with R-roscovitine’s tolerance in clinical trials, could guide future drug screens. We discuss our findings and how they lend support for the recent Comprehensive In Vitro Proarrhythmia Assay (CiPA) guidelines on the re-evaluation of potentially useful drugs that had failed testing due to unintended interactions with hERG.
Transplanted cells are essential for the induction but not the expression of cortical plasticity
Authors: Hoseini Mahmood S. , Rakela Benjamin , Flores-Ramirez Quetzal , Hasenstaub Andrea R. , Alvarez-Buylla Arturo , Stryker Michael P. 
Published: May 2019

AbstractTransplantation of even a small number of embryonic inhibitory neurons from the medial ganglionic eminence (MGE) into postnatal visual cortex makes it lose responsiveness to an eye deprived of vision when the transplanted neurons reach the age of the normal critical period of activity-dependent ocular dominance (OD) plasticity. The transplant might induce OD plasticity in the host circuitry or might instead construct a parallel circuit of its own to suppress cortical responses to the deprived-eye. We transplanted MGE neurons expressing archaerhodopsin, closed one eyelid for 4-5 days, and, as expected, observed transplant-induced OD plasticity. This plasticity was evident even when the activity of the transplanted cells was suppressed optogenetically, demonstrating that the plasticity was produced by changes in the host visual cortex.Significance StatementInterneuron transplantation into mouse V1 creates a window of heightened plasticity which is quantitatively and qualitatively similar to the normal critical period, i.e. short-term occlusion of either eye markedly changes ocular dominance. The underlying mechanism of this process is not known. Transplanted interneurons might either form a separate circuit to maintain the ocular dominance shift or might instead trigger changes in the host circuity. We designed experiments to distinguish the two hypotheses. Our findings suggest that while inhibition produced by the transplanted cells triggers this form of plasticity, the host circuity is entirely responsible for maintaining the ocular dominance shift.One Sentence SummaryNeuronal transplants do not just grow and connect—they induce plasticity in the adult brain.
A comparison of automatic cell identification methods for single-cell RNA-sequencing data
Authors: Abdelaal Tamim , Michielsen Lieke , Cats Davy , Hoogduin Dylan , Mei Hailiang , Reinders Marcel J.T. , Mahfouz Ahmed 
Published: May 2019

AbstractBackgroundSingle cell transcriptomics are rapidly advancing our understanding of the cellular composition of complex tissues and organisms. A major limitation in most analysis pipelines is the reliance on manual annotations to determine cell identities, which are time-consuming and irreproducible. The exponential growth in the number of cells and samples has prompted the adaptation and development of supervised classification methods for automatic cell identification.ResultsHere, we benchmarked 20 classification methods that automatically assign cell identities including single cell-specific and general-purpose classifiers. The methods were evaluated using eight publicly available single cell RNA-sequencing datasets of different sizes, technologies, species, and complexity. The performance of the methods was evaluated based on their accuracy, percentage of unclassified cells, and computation time. We further evaluated their sensitivity to the input features, their performance across different annotation levels and datasets. We found that most classifiers performed well on a variety of datasets with decreased accuracy for complex datasets with overlapping classes or deep annotations. The general-purpose SVM classifier has overall the best performance across the different experiments.ConclusionsWe present a comprehensive evaluation of automatic cell identification methods for single cell RNA-sequencing data. All the code used for the evaluation is available on GitHub (https://github.com/tabdelaal/scRNAseq_Benchmark). Additionally, we provide a Snakemake workflow to facilitate the benchmarking and to support extension of new methods and new datasets (https://github.com/tabdelaal/scRNAseq_Benchmark/tree/snakemake_and_docker).
Two different pathways for initiation ofTrichoderma reeseiRad51-only meiotic recombination
Authors: Li Wan-Chen , Chuang Yu-Chien , Chen Chia-Ling , Timofejeva Ljudmilla , Pong Wen-Li , Chen Yu-Jie , Wang Chih-Li , Wang Ting-Fang 
Published: May 2019

AbstractBackgroundMeiotic recombination is mainly, but not exclusively, initiated by Spo11-induced double strand breaks (DSBs) in some sexual eukaryotes. DSBs are repaired by one or two RecA-like recombinases (ubiquitous Rad51 and meiosis-specific Dmc1). In yeast and mammals, Dmc1 is superior to Rad51 in tolerating mismatched sequences during highly polymorphic hybrid meiosis. The mechanisms underlying Rad51-only meiotic recombination remain less studied.ResultsThe Rad51-only filamentous fungusTrichoderma reeseihas only onespo11gene. Removal ofspo11fromT. reeseigenome does not affect normal sexual development, meiosis or chromosome synapsis, but results in decrease of interhomolog recombination products to 70%, crossover homeostasis and lower genetic interference. Our results also suggest thatT. reeseiRad51, like yeast and mammalian Dmc1 (but not Rad51), can tolerate mismatched sequences during meiotic recombination. Moreover, Topoisomerase II might act redundantly (and predominantly) with Spo11 to initiate meiotic recombination.ConclusionWe suggest thatT. reeseiis an emerging model for studying Spo11-independent and Rad51-only meiosis.
In vitrocharacterization of the yeast DcpS, a scavenger mRNA decapping enzyme
Authors: Wulf Madalee G. , Buswell John , Chan Siu-Hong , Dai Nan , Marks Katherine , Martin Evan R. , Tzertzinis George , Whipple Joseph M. , Corrêa Ivan R. , Schildkraut Ira 
Published: May 2019

AbstractEukaryotic mRNAs are modified at their 5’ end early during transcription by the addition ofN7-methylguanosine (m7G), which forms the “cap” on the first 5’ nucleotide. Identification of the 5’ nucleotide on mRNA is necessary for determination of the Transcription Start Site (TSS). We explored the effect of various reaction conditions on the activity of the yeast scavenger mRNA decapping enzyme DcpS (yDcpS) and examined decapping of 30 chemically distinct cap structures varying the state of methylation, sugar, phosphate linkage, and base composition on 25mer RNA oligonucleotides. Contrary to the generally accepted belief that DcpS enzymes only decap short oligonucleotides, we found that yDcpS efficiently decaps RNA transcripts as long as 1400 nucleotides. Further, we validated the application of yDcpS for enriching capped RNA using a strategy of specifically tagging the 5’ end of capped RNA by first decapping and then recapping it with an affinity-tagged guanosine nucleotide.
Genome-wide mapping and profiling of γH2AX binding hotspots in response to different replication stress inducers
Authors: Lyu Xinxing , Chastain Megan , Chai Weihang 
Published: May 2019

AbstractBackgroundReplication stress (RS) gives rise to DNA damage that threatens genome stability. RS can originate from different sources that stall replication by diverse mechanisms. However, the mechanism underlying how different types of RS contribute to genome instability is unclear, in part due to the poor understanding of the distribution and characteristics of damage sites induced by different RS mechanisms.ResultsWe use ChIP-seq to map γH2AX binding sites genome-wide caused by aphidicolin (APH), hydroxyurea (HU), and methyl methanesulfonate (MMS) treatments in human lymphocyte cells. Mapping of γH2AX ChIP-seq reveals that APH, HU, and MMS treatments induce non-random γH2AX chromatin binding at discrete regions, suggesting that there are γH2AX binding hotspots in the genome. Characterization of the distribution and sequence/epigenetic features of γH2AX binding sites reveals that the three treatments induce γH2AX binding at largely non-overlapping regions, suggesting that RS may cause damage at specific genomic loci in a manner dependent on the fork stalling mechanism. Nonetheless, γH2AX binding sites induced by the three treatments share common features including compact chromatin, coinciding with larger-than-average genes, and depletion of CpG islands and transcription start sites. Moreover, we observe significant enrichment of SINEs in γH2AX sites in all treatments, indicating that SINEs may be a common barrier for replication polymerases.ConclusionsOur results identify the location and common features of genome instability hotspots induced by different types of RS, and help in deciphering the mechanisms underlying RS-induced genetic diseases and carcinogenesis.
Gating Mechanism of β-Ketoacyl-ACP Synthases
Authors: Mindrebo Jeffrey T. , Patel Ashay , Kim Woojoo E. , Davis Tony D. , Chen Aochiu , Bartholow Thomas G. , La Clair James J. , McCammon J. Andrew , Noel Joseph P. , Burkart Michael D. 
Published: May 2019

AbstractFormation of carbon-carbon bonds via β-ketoacyl-acyl carrier protein (ACP) synthases (KS), are key reactions duringde novofatty acid and polyketide biosynthesis. KSs recognize multiple ACPs and choreograph ping-pong mechanisms often in an iterative fashion. Therefore, KSs must limit non-productive protein-protein interactions (PPIs) to achieve high degrees of reaction fidelity. To better understand the stereochemical features governing substrate discrimination during ACP•KS PPIs, we determined x-ray crystal structures complemented by molecular dynamic simulations ofE. coliAcpP in complex with the elongating KSs, FabF and FabB. Covalently trapped substrate analogs were used to interrogate critical catalytic events accompanying carbon-carbon bond formation revealing a previously unknown gating mechanism during the binding and delivery of acyl-AcpPs. Two active site loops undergo large conformational excursions during this dynamic gating mechanism and are likely evolutionarily conserved features generally in elongating KSs.
A theory of learning to infer
Authors: Dasgupta Ishita , Schulz Eric , Tenenbaum Joshua B. , Gershman Samuel J. 
Published: May 2019

AbstractBayesian theories of cognition assume that people can integrate probabilities rationally. However, several empirical findings contradict this proposition: human probabilistic inferences are prone to systematic deviations from optimality. Puzzlingly, these deviations sometimes go in opposite directions. Whereas some studies suggest that people under-react to prior probabilities (base rate neglect), other studies find that people under-react to the likelihood of the data (conservatism). We argue that these deviations arise because the human brain does not rely solely on a general-purpose mechanism for approximating Bayesian inference that is invariant across queries. Instead, the brain is equipped with a recognition model that maps queries to probability distributions. The parameters of this recognition model are optimized to get the output as close as possible, on average, to the true posterior. Because of our limited computational resources, the recognition model will allocate its resources so as to be more accurate for high probability queries than for low probability queries. By adapting to the query distribution, the recognition model “learns to infer.” We show that this theory can explain why and when people under-react to the data or the prior, and a new experiment demonstrates that these two forms of under-reaction can be systematically controlled by manipulating the query distribution. The theory also explains a range of related phenomena: memory effects, belief bias, and the structure of response variability in probabilistic reasoning. We also discuss how the theory can be integrated with prior sampling-based accounts of approximate inference.
Differential genomic and transcriptomic events associated with high-grade transformation of Chronic Lymphocytic Leukemia
Authors: Klintman Jenny , Stamatopoulos Basile , Ridout Katie , Eyre Toby A. , Pascua Laura Lopez , Appleby Niamh , Knight Samantha J. L. , Dreau Helene , Popitsch Niko ,   The HICF2 Consortium, Ehinger Mats , Martín-Subero Jose I. , Campo Elias , Månsson Robert , Rossi Davide , Taylor Jenny C. , Vavoulis Dimitrios V. , Schuh Anna 
Published: May 2019

AbstractThe transformation of chronic lymphocytic leukemia (CLL) to high-grade diffuse large B-cell lymphoma (DLBCL), also called Richter’s Syndrome (RS), is a rare cancer with dismal prognosis. Drug discovery for RS is hampered by the lack of suitable experimental models, and effective therapies remain elusive rendering RS an area of high unmet clinical need. We performed whole genome sequencing (WGS) to interrogate paired CLL and RS samples from 17 patients enrolled in a prospective multicenter Phase 2 clinical trial (CHOP-OR) and we found that subclones affected by mutations in MAPK and PI3K pathways show a high expansion probability during transformation. We also demonstrate for the first time that non-coding mutation clusters in aPAX5enhancer, situated 330kb upstream from the transcription initiation site, correlate with transformation. Finally, we confirm our findings by employing targeted DNA sequencing (TGS) and RNA expression profiling on an extended cohort of 38 patients.Statement of significanceThrough integrated analysis of WGS, TGS and RNA expression data, we identified drivers of transformation not previously implicated in RS, which can be targeted therapeutically and tested in the clinic. Our results have informed the design of a new clinical platform study, which is now open to recruitment in the UK.
Reproducible data management and analysis using R
Authors: Fjukstad Bjørn , Shvetsov Nikita , Nøst Therese H. , Bøvelstad Hege , Halbach Till , Holsbø Einar , Hansen Knut , Lund Eiliv , Bongo Lars Ailo 
Published: May 2019

AbstractBackgroundStandardizing and documenting computational analyses are necessary to ensure reproducible results. It is especially important for large and complex projects where data collection, analysis, and interpretation may span decades. Our objective is therefore to provide methods, tools, and best practice guidelines adapted for analyses in epidemiological studies that use -omics data.ResultsWe describe an R-based implementation of data management and preprocessing. The method is well-integrated with the analysis tools typically used for statistical analysis of -omics data. We document all datasets thoroughly and use version control to track changes to both datasets and code over time. We provide a web application to perform the standardized preprocessing steps for gene expression datasets. We provide best practices for reporting data analysis results and sharing analyses.ConclusionWe have used these tools to organize data storage and documentation, and to standardize the analysis of gene expression data, in the Norwegian Women and Cancer (NOWAC) system epidemiology study. We believe our approach and lessons learned are applicable to analyses in other large and complex epidemiology projects.
Hybridization drives genetic erosion in sympatric desert fishes of western North America
Authors: Chafin Tyler K. , Douglas Marlis R. , Martin Bradley T. , Douglas Michael E. 
Published: May 2019

AbstractMany species have evolved or currently coexist in sympatry due to differential adaptation in a heterogeneous environment. However, anthropogenic habitat modifications can either disrupt reproductive barriers or obscure environmental conditions which underlie fitness gradients. In this study, we evaluated the potential for an anthropogenically-mediated shift in reproductive boundaries that separate two historically sympatric fish species (Gila cyphaandG. robusta) endemic to the Colorado River Basin using ddRAD sequencing of 368 individuals. We first examined the integrity of reproductive isolation while in sympatry and allopatry, then characterized hybrid ancestries using genealogical assignment tests. We tested for localized erosion of reproductive isolation by comparing site-wise genomic clines against global patterns and identified a breakdown in the drainage-wide pattern of selection against interspecific heterozygotes. This, in turn, allowed for the formation of a hybrid swarm in one tributary, and asymmetric introgression where species co-occur. We also detected a weak but significant relationship between genetic purity and degree of consumptive water removal, suggesting a role for anthropogenic habitat modifications in undermining species boundaries. In addition, results from basin-wide genomic clines suggested that hybrids and parental forms are adaptively non-equivalent. If so, then a failure to manage for hybridization will exacerbate the long-term extinction risk in parental populations. These results reinforce the role of anthropogenic habitat modification in promoting interspecific introgression in sympatric species by relaxing divergent selection. This, in turn, underscores a broader role for hybridization in decreasing global biodiversity within rapidly deteriorating environments.