bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opioids for breathlessness: Psychological and neural factors influencing response variability
Authors: Abdallah Sara J. , Faull Olivia K. , Wanigasekera Vishvarani , Finnegan Sarah L. , Jensen Dennis , Pattinson Kyle 
Published: June 2018

ABSTRACTEffective management of distressing bodily symptoms (such as pain and breathlessness) is an important clinical goal. However, extensive variability exists in both symptom perception and treatment response. One theory for understanding variability in bodily perception is the ‘Bayesian Brian Hypothesis’, whereby symptoms may result from the combination of sensory inputs and prior expectations. In light of this theory, we explored the relationships between opioid responsiveness, behavioural/physiological symptom modulators and brain activity during anticipation of breathlessness.MethodsWe utilised two existing opioid datasets to investigate the relationship between opioid efficacy and physiological/behavioural qualities, employing hierarchical cluster analyses in: 1) a clinical study in chronic obstructive pulmonary disease, and 2) a functional magnetic resonance brain imaging study of breathlessness in healthy volunteers. We also investigated how opioid efficacy relates to anticipatory brain activity using linear regression in the healthy volunteers.ResultsConsistent across both datasets, diminished opioid efficacy was more closely associated with negative affect than with other physiological and behavioural properties. Furthermore, in healthy individuals, brain activity in the anterior cingulate and ventromedial prefrontal cortices during anticipation of breathlessness were inversely correlated with opioid effectiveness.ConclusionDiminished opioid efficacy for relief of breathlessness may be associated with high negative affective qualities, and was correlated with the magnitude of brain activity during anticipation of breathlessness.Clinical implicationsNegative affect and symptom expectations may influence perceptual systems to become less responsive to opioid therapy.
Divergent selection and drift shape the genomes of two avian sister species spanning a saline-freshwater ecotone
Authors: Walsh Jennifer , Clucas Gemma V. , MacManes Matthew D. , Kelley Thomas W. , Kovach Adrienne I. 
Published: June 2018

AbstractThe role of species divergence due to ecologically-based divergent selection – or ecological speciation – in generating and maintaining biodiversity is a central question in evolutionary biology. Comparison of the genomes of phylogenetically related taxa spanning a selective habitat gradient enables discovery of divergent signatures of selection and thereby provides valuable insight into the role of divergent ecological selection in speciation. Tidal marsh ecosystems provide tractable opportunities for studying organisms’ adaptations to selective pressures that underlie ecological divergence. Sharp environmental gradients across the saline-freshwater ecotone within tidal marshes present extreme adaptive challenges to terrestrial vertebrates. Here we sequence 20 whole genomes of two avian sister species endemic to tidal marshes – the Saltmarsh Sparrow (Ammodramus caudacutus) and Nelson’s Sparrow (A. nelsoni) – to evaluate the influence of selective and demographic processes in shaping genome-wide patterns of divergence. Genome-wide divergence between these two recently diverged sister species was notably high (genome-wide FST = 0.32). Against a background of high genome-wide divergence, regions of elevated divergence were widespread throughout the genome, as opposed to focused within islands of differentiation. These patterns may be the result of genetic drift acting during past tidal march colonization events in addition to divergent selection to different environments. We identified several candidate genes that exhibited elevated divergence between Saltmarsh and Nelson’s sparrows, including genes linked to osmotic regulation, circadian rhythm, and plumage melanism – all putative candidates linked to adaptation to tidal marsh environments. These findings provide new insights into the roles of divergent selection and genetic drift in generating and maintaining biodiversity.
A Fully-Adjusted Two-Stage Procedure for Rank Normalization in Genetic Association Studies
Authors: Sofer Tamar , Zheng Xiuwen , Gogarten Stephanie M. , Laurie Cecelia A. , Grinde Kelsey , Shaffer John R. , Shungin Dmitry , O’Connell Jeffrey R. , Durazo-Arvizo Ramon A. , Raffield Laura , Lange Leslie , Musani Solomon , Vasan Ramachandran S. , Adrienne Cupples L. , Reiner Alexander P. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Laurie Cathy C. , Rice Kenneth M. 
Published: June 2018

AbstractWhen testing genotype-phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse consequences for rarer variants. While it has been shown that applying a rank-normalization transformation to trait values before testing may improve these statistical properties, the factor driving them is not the trait distribution itself, but its residual distribution after regression on both covariates and genotype. Because genotype is expected to have a small effect (if any) investigators now routinely use a two-stage method, in which they first regress the trait on covariates, obtain residuals, rank-normalize them, and then secondly use the rank-normalized residuals in association analysis with the genotypes. Potential confounding signals are assumed to be removed at the first stage, so in practice no further adjustment is done in the second stage. Here, we show that this widely-used approach can lead to tests with undesirable statistical properties, due to both a combination of a mis-specified mean-variance relationship, and remaining covariate associations between the rank-normalized residuals and genotypes. We demonstrate these properties theoretically, and also in applications to genome-wide and whole-genome sequencing association studies. We further propose and evaluate an alternative fully-adjusted two-stage approach that adjusts for covariates both when residuals are obtained, and in the subsequent association test. This method can reduce excess Type I errors and improve statistical power.
Vesicular delivery of the antifungal antibiotics of Lysobacter enzymogenes C3
Authors: Meers Paul R. , Liu Carol , Chen Rensa , Bartos William , Davis Julianne , Dziedzic Nicole , Orciuolo Jason , Kutyla Szymon , Pozo Maria Jose , Mithrananda Deepti , Panzera Dominick , Wang Shu 
Published: June 2018

AbstractLysobacter enzymogenes C3 is a predatory strain of gram-negative gliding bacteria that produces antifungal antibiotics by the polyketide synthetic pathway. Outer membrane vesicles (OMV) are formed as a stress response and can deliver virulence factors to host cells. The production of OMV by C3 and their role in antifungal activity are reported here. Vesicles in the range of 130-150 nm in diameter were discovered in the cell-free supernatants of C3 cultures. These OMV contain molecules characteristic of bacterial outer membranes, such as lipopolysaccharide and phospholipids. In addition, they contain chitinase activity and essentially all of the heat stable antifungal activity in cell supernatants. We show here that C3 OMV can directly inhibit growth of the yeast Saccharomyces cerevisiae as well as the filamentous fungus Fusarium subglutinans. The activity is dependent on physical contact between OMV and the cells. Furthermore, fluorescent lipid labeling of C3 OMV demonstrated transfer of the membrane-associated probe to yeast cells, suggesting the existence of a mechanism of delivery for membrane-associated molecules. Mass spectrometric analysis of C3 OMV extracts indicates the presence of molecules with molecular weights identical to some of the previously identified antifungal products of C3. These data together suggest that OMV act as an important remote mobile component of predation by Lysobacter.ImportanceThe data presented here suggest a newly discovered function of outer membrane vesicles (OMV) that are produced from the outer membrane of the bacterial species Lysobacter enzymogenes C3. We show that these OMV can be released from the surface of the cells to deliver antibiotics to target fungal organisms as a mechanism of killing or growth inhibition. Understanding the role of OMV in antibiotic delivery can generally lead to improved strategies for dealing with antibiotic-resistant organisms. These results also add to the evidence that some bacterially produced antibiotics can be discovered and purified using methods designed for isolation of nanoscale vesicles. Information on these systems can lead to better identification of active molecules or design of delivery vehicles for these molecules.
Evaluation of the Luminex ARIES® System for the Detection and Quantification of BK virus DNA in Plasma and Serum Samples from Kidney Transplant Recipients
Authors: Her Tong , Schutzbank Ted E. 
Published: June 2018

AbstractBKV nephropathy is as serious complication in renal transplant recipients due to the need for immunosuppression. Nearly 50% of renal transplant patients with BKV nephropathy experience a significant loss of function of the transplanted kidney. It is routine practice to screen renal transplant recipients regularly for BK viremi a. In this study we compared the performance of BKV qPCR analyte specific reagents (ASR) by ELITech, and Luminex for measuring BKV viral load in plasma and serum using the Roche Cobas® z480 instrument, and the Luminex ARIES® platform respectively. A total of 34 patients previously tested on the z480, with results spanning the test ‘s linear range, were analyzed on the ARIES®. The BKV DNA copy number correlation between the two methods was very good with an R2 value of 0.98. The average difference in log copy number between the two methods was −0.3, indicating that the ARIES® method may have slightly greater analytical sensitivity. BKV quantification results were closely matched between the two different methods. The workflow with the ARIES® System is greatly simplified by elimination of DNA extraction and most hands-on steps. The high degree of automation allows samples to be tested as they arrive into the laboratory, resulting in enhanced patient care due to more rapid turnaround time for results back to the ordering physician.
Identifying mixed Mycobacterium tuberculosis infection and laboratory cross-contamination during Mycobacterial sequencing programs
Authors: Wyllie David H , Robinson Esther , Peto Tim , Crook Derrick W , Ajileye Adebisi , Rathod Priti , Allen Rosemarie , Jarrett Lisa , Smith E Grace , Walker A Sarah 
Published: June 2018

ABSTRACTIntroductionDetecting laboratory cross-contamination and mixed tuberculosis infection are important goals of clinical Mycobacteriology laboratories.ObjectivesTo develop a method detecting mixtures of different M. tuberculosis lineages in laboratories performing Mycobacterial next generation sequencing (NGS).SettingPublic Health England National Mycobacteriology Laboratory Birmingham, which performs Illumina sequencing on DNA extracted from positive Mycobacterial Growth Indicator tubes.MethodsWe analysed 4,156 samples yielding M. tuberculosis from 663 MiSeq runs, obtained during development and production use of a diagnostic process using NGS. Counts of the most common (major) variant, and all other variants (non-major variants) were determined from reads mapping to positions defining M. tuberculosis lineages. Expected variation was estimated during process development.ResultsFor each sample we determined the non-major variant proportions at 55 sets of lineage defining positions. The non-major variant proportion in the two most mixed lineage defining sets (F2 metric) was compared with that in the 47 least mixed lineage defining sets (F47 metric). Three patterns were observed: (i) not mixed by either metric, (ii) high F47 metric suggesting mixtures of multiple lineages, and (iii) samples compatible with mixtures of two lineages, detected by differential F2 metric elevation relative to F47. Pattern (ii) was observed in batches, with similar patterns in the H37Rv control present in each run, and is likely to reflect cross-contamination. During production, the proportions of samples in each pattern were 97%, 2.8%, and 0.001%, respectively.ConclusionThe F2 and F47 metrics described could be used for laboratory process control in laboratories sequencing M. tuberculosis.
The heterochromatin landscape in migrating cells and the importance of H3K27me3 for migration-associated transcriptional changes
Authors: Segal Tamar , Salmon-Divon Mali , Gerlitz Gabi 
Published: June 2018

SummaryH3K9me3, H3K27me3 and H4K20me1 are epigenetic markers associated with chromatin condensation and transcriptional repression. Previously, we found that migration of melanoma cells is associated with and dependent on global chromatin condensation that includes a global increase in these markers. Taken together with more recent reports by others suggest it is a general signature of migrating cells. Here, to learn about the function of these markers in migrating cells we mapped them by ChIP-seq analysis. This analysis revealed that induction of migration leads to expansion of these markers along the genome and to an increased overlapping between them. Significantly, induction of migration led to a higher increase in H3K9me3 and H4K20me1 signals at repetitive elements than at protein-coding genes, while an opposite pattern was found for H3K27me3. Transcriptome analysis revealed that 182 altered genes following induction of migration, of which 33% are dependent on H3K27me3 for these changes. H3K27me3 was also required to prevent changes in the expression of 501 other genes upon induction of migration. Taken together our results suggest that heterochromatinization in migrating cells is global and not restricted to specific genomic loci and that H3K27me3 is a key component in executing a migration-specific transcriptional plan.
Interrupted reprogramming into induced pluripotent stem cells does not rejuvenate human mesenchymal stromal cells
Authors: Göbel Carolin , Goetzke Roman , Eggermann Thomas , Wagner Wolfgang 
Published: June 2018

AbstractReplicative senescence hampers application of mesenchymal stromal cells (MSCs) because it limits culture expansion, impairs differentiation potential, and hinders reliable standardization of cell products. MSCs can be rejuvenated by reprogramming into induced pluripotent stem cells (iPSCs), which is associated with complete erasure of age- and senescence-associated DNA methylation (DNAm) patterns. However, this process is also associated with erasure of cell-type and tissue-specific epigenetic characteristics that are not recapitulated upon re-differentiation towards MSCs. In this study, we therefore followed the hypothesis that overexpression of pluripotency factors under culture conditions that do not allow full reprogramming might reset senescence-associated changes without entering a pluripotent state. MSCs were transfected with episomal plasmids and either successfully reprogrammed into iPSCs or cultured in different media with continuous passaging every week. Overexpression of pluripotency factors without reprogramming did neither prolong culture expansion nor ameliorate molecular and epigenetic hallmarks of senescence. Notably, transfection resulted in immortalization of one cell preparation with gain of large parts of the long arm of chromosome 1. Taken together, premature termination of reprogramming does not result in rejuvenation of MSCs and harbours the risk of transformation. This approach is therefore not suitable to rejuvenate cells for cellular therapy.
Structures of the heart specific SERCA2a Ca2+-ATPase
Authors: Sitsel Aljona , Raeymaecker Joren De , Drachmann Nikolaj Düring , Derua Rita , Smaardijk Susanne , Andersen Jacob Lauwring , Vandecaetsbeek Ilse , Chen Jialin , Maeyer Marc De , Waelkens Etienne , Olesen Claus , Vangheluwe Peter , Nissen Poul 
Published: June 2018

AbstractThe isoform 2a of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) performs active reuptake of cytoplasmic Ca2+and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA2a is associated with heart failure, while restoring its function is considered as a therapeutic strategy to restore cardiac performance, but its structure was not yet determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a that were determined in the CPA-stabilized and H+-occluded [H2-3]E2-AlF4- (3.3 Å) form, arranged as parallel dimers, and the Ca2+-occluded [Ca2]E1-ATP (4.0 Å) form. We compare these new structures to similar forms of the skeletal muscle SERCA1a and address structural, functional and regulatory differences. We show that the isoform specific motifs of SERCA2a allow a distinct regulation by post-translational modifications and affect the dynamic behavior, which may explain specific properties and regulation.
BALLI: Bartlett-Adjusted Likelihood-based LInear Model Approach for Identifying Differentially Expressed Gene with RNA-seq Data
Authors: Park Kyungtaek , An Jaehoon , Gim Jungsoo , Won Sungho 
Published: June 2018

ABSTRACTMotivationTranscriptomic profiles can improve our understanding of the phenotypic molecular basis of biological research, and many statistical methods have been proposed to identify differentially expressed genes under two or more conditions with RNA-seq data. However, statistical analyses with RNA-seq data often suffer from small sample sizes, and global variance estimates of RNA expression levels have been utilized as prior distributions for gene-specific variance estimates, making it difficult to generalize the methods to more complicated settings. We herein proposed a Bartlett-Adjusted Likelihood based LInear mixed model approach (BALLI) to analyze more complicated RNA-seq data. The proposed method estimates the technical and biological variances with a linear mixed effect model, with and without adjusting small sample bias using Bartlett’s corrections.ResultsWe conducted extensive simulations to compare the performance of BALLI with those of existing approaches (edgeR, DESeq2, and voom). Results from the simulation studies showed that BALLI correctly controlled the type-1 error rates at the various nominal significance levels, and produced better statistical power and precision estimates than those of other competing methods in various scenarios. Furthermore, BALLI was robust to variation of library size. It was also successfully applied to Holstein milk yield data, illustrating its practical value.Availability and ImplementationBALLI is implemented as R package and freely available at http://healthstat.snu.ac.kr/software/balli/.Contactwon1@snu.ac.krSupplementary InformationSupplementary data are available at Bioinformatics online
General decapping activators target different subsets of inefficiently translated mRNAs
Authors: He Feng , Celik Alper , Jacobson Allan 
Published: June 2018

AbstractThe Dcp1-Dcp2 decapping enzyme and the decapping activators Pat1, Dhh1, and Lsm1 regulate mRNA decapping, but their mechanistic integration is unknown. We analyzed the gene expression consequences of deletingPAT1, LSM1,orDHH1,or theDCP2C-terminal domain, and found that: i) the Dcp2 C-terminal domain is an effector of both negative and positive regulation; ii) rather than being global activators of decapping, Pat1, Lsm1, and Dhh1 directly target specific subsets of yeast mRNAs and loss of the functions of each of these factors has substantial indirect consequences for genome-wide mRNA expression; and iii) transcripts targeted by Pat1, Lsm1, and Dhh1 exhibit only partial overlap, are generally translated inefficiently, and, as expected, are targeted to decapping-dependent decay. Our results define the roles of Pat1, Lsm1, and Dhh1 in decapping of general mRNAs and suggest that these factors may monitor mRNA translation and target unique features of individual mRNAs.
Modelling the nuclear envelope ofHeLacells
Authors: Karabağ Cefa , Jones Martin L. , Peddie Christopher J. , Weston Anne E. , Collinson Lucy M. , Reyes-Aldasoro Constantino Carlos 
Published: June 2018

AbstractThis paper describes a framework for the automatic segmentation of the nuclear envelope of cancerous HeLa cells and the modelling of the volumetric shape against an ellipsoid. The framework is automatic and unsupervised and reported a Jaccard Similarity Index of 0.968 against a manual segmentation. The modelling of the surface provides a visual display of the variations, both smooth and rugged over the surface, and measurements can be extracted with the expectation that they can correlate with the biological characteristics of the cells.
Transfer Learning for Task Adaptation of Brain Lesion Assessment and Prediction of Brain Abnormalities Progression/Regression using Irregularity Age Map in Brain MRI
Authors: Rachmadi Muhammad Febrian , Valdés-Hernández Maria del C. , Komura Taku 
Published: June 2018

AbstractThe Irregularity Age Map (IAM) for the unsupervised assessment of brain white matter hyperintensities (WMH) opens several opportunities in machine learning-based brain MRI analysis, including transfer task adaptation learning in the MRI brain lesion’s segmentation and prediction of lesion progression and regression. The lack of need for manual labels is useful for transfer learning. Whereas, the nature of IAM itself can be exploited for predicting lesion progression/regression. In this study, we propose the use of task adaptation transfer learning for WMH segmentation using CNN through weakly-training UNet and UResNet using the output from IAM and the use of IAM for predicting patterns of WMH progression and regression.
Effects of Short-time Exposure to Atrazine on miRNA Expression Profiles in the Gonad of Common Carp (Cyprinus carpio)
Authors: Wang Fang , Yang Qian-wen , Zhao Wen-Jie , Du Qi-Yan , Chang Zhong-Jie 
Published: June 2018

ABSTRACTMicroRNAs (miRNAs) are endogenous small non-coding RNAs that negatively regulate gene expression by targeting specific mRNAs; they are involved in the modulation of important mRNA networks involved in toxicity. Atrazine is a known endocrine-disrupting chemical, whose molecular mechanisms are unknown. In this study, common carp (Cyprinus carpio) gonads at two key developmental stages were exposed to 0.428 ppb atrazine for 24 hin vitro. MiRNA expression profiles were analysed to identify miRNAs related to gonad development and to reveal the atrazine mechanisms interfering with gonad differentiation. Atrazine exposure caused significant alteration of multiple miRNAs. Compared with the juvenile ovary, more miRNAs were down-regulated in juvenile testis, some of these down-regulated miRNAs target the steroid hormone biosynthesis pathway related-genes. Predicted target genes of differently-expressed miRNAs after exposure to atrazine were involved in many reproductive biology signalling pathways. We suggest that these target genes may have important roles in atrazine-induced reproductive toxicity by altering miRNAs expression. Our results also indicate that atrazine can up-regulate aromatase expression through miRNAs, which supports the hypothesis that atrazine has endocrine-disrupting activity by altering the expression of genes of the Hypothalamus-Pituitary-Gonad axis through its corresponding miRNAs. This study tells us the following conclusions: 1. Atrazine exposure results in significant alterations of miRNAs whose predicted target genes are associated with reproductive processes. 2. In the primordial gonad, atrazine promoted the expression of early gonad-determining genes by decreasing specific miRNAs. 3. In the juvenile gonad, atrazine promoted the biosynthesis of steroid hormones.