bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feature extraction approach in single-cell gene expression profiling for cell-type marker identification
Authors: Adossa Nigatu A. , Schauser Leif , Gregersen Vivi G. , Elo Laura L. 
Published: June 2019

AbstractBackgroundRecent advances in single-cell gene expression profiling technology have revolutionized the understanding of molecular processes underlying developmental cell and tissue differentiation, enabling the discovery of novel cell-types and molecular markers that characterize developmental trajectories. Common approaches for identifying marker genes are based on pairwise statistical testing for differential gene expression between cell-types in heterogeneous cell populations, which is challenging due to unequal sample sizes and variance between groups resulting in little statistical power and inflated type I errors.ResultsWe developed an alternative feature extraction method, Marker gene Identification for Cell-type Identity (MICTI) that encodes the cell-type specific expression information to each gene in every single-cell. This approach identifies features (genes) that are cell-type specific for a given cell-type in heterogeneous cell population. To validate this approach, we used (i) simulated single cell RNA-seq data, (ii) human pancreatic islet single-cell RNA-seq data and (iii) a simulated mixture of human single-cell RNA-seq data related to immune cells, particularly B cells, CD4+ memory cells, CD8+ memory cells, dendritic cells, fibroblast cells, and lymphoblast cells. For all cases, we were able to identify established cell-type-specific markers.ConclusionsOur approach represents a highly efficient and fast method as an alternative to differential expression analysis for molecular marker identification in heterogeneous single-cell RNA-seq data.
ADAMTS-1 and Syndecan-4 intersect in the regulation of cell migration and angiogenesis
Authors: Lambert Jordi , Makin Kate , Akbareian Sophia , Johnson Robert , Robinson Stephen D , Edwards Dylan R. 
Published: June 2019

AbstractThe extracellular proteoglycanase ADAMTS-1 has critical roles in organogenesis and angiogenesis. We demonstrate here the functional convergence of ADAMTS-1 and the transmembrane heparan sulfate proteoglycan syndecan-4 in influencing adhesion, migration, and angiogenesis in vitro. Knockdown of ADAMTS-1 in fibroblasts and endothelial cells resulted in a parallel reduction in cell surface syndecan-4 that was not due to altered syndecan-4 expression or internalization, but was attributable to increased expression and activity of matrix metalloproteinase-9 (MMP-9), a known syndecan-4 sheddase. Knockdown of either syndecan-4 or ADAMTS-1 led to enhanced endothelial cell responses to exogenous vascular endothelial growth factor (VEGF), and increased microvessel sprouting in ex vivo aortic ring assays, correlating with reduced ability of the cells to sequester VEGF. On fibronectin but not type 1 collagen matrices, endothelial cells with knockdown of either ADAMTS-1 or syndecan-4 elicited increased migration and showed similarly altered focal adhesion (FA) morphologies, with a higher proportion of larger FA’s and formation of long fibrillar integrin α5-containing FA’s. However, integrin α5-null endothelial cells also displayed enhanced migration in response to ADAMTS-1/syndecan-4 knockdown, indicating that integrin α5 was not the mediator of the altered migratory behaviour. Plating of naïve endothelial cells on cell-conditioned matrix from ADAMTS-1/syndecan-4 knockdown cells demonstrated that the altered behaviour was matrix dependent. Fibulin-1, a known ECM co-factor of ADAMTS-1, was expressed at reduced levels in ADAMTS-1/syndecan-4 knockdown cells. These findings support the notion that ADAMTS-1 and syndecan-4 are functionally interconnected in regulating cell migration and angiogenesis, via the involvement of MMP-9 and fibulin-1 as collaborators
Improving ATAC-seq Data Analysis with AIAP, a Quality Control and Integrative Analysis Package
Authors: Liu Shaopeng , Li Daofeng , Lyu Cheng , Gontarz Paul , Miao Benpeng , Madden Pamela , Wang Ting , Zhang Bo 
Published: June 2019

ABSTRACTATAC-seq is a technique widely used to investigate genome-wide chromatin accessibility. The recently published Omni-ATAC-seq protocol substantially improves the signal/noise ratio and reduces the input cell number. High-quality data are critical to ensure accurate analysis. Several tools have been developed for assessing sequencing quality and insertion size distribution for ATAC-seq data; however, key quality control (QC) metrics have not yet been established to accurately determine the quality of ATAC-seq data. Here, we optimized the analysis strategy for ATAC-seq and defined a series of QC metrics, including reads under peak ratio (RUPr), background (BG), promoter enrichment (ProEn), subsampling enrichment (SubEn), and other measurements. We incorporated these QC tests into our recently developed ATAC-seq Integrative Analysis Package (AIAP) to provide a complete ATAC-seq analysis system, including quality assurance, improved peak calling, and downstream differential analysis. We demonstrated a significant improvement of sensitivity (20%~60%) in both peak calling and differential analysis by processing paired-end ATAC-seq datasets using AIAP. AIAP is compiled into Docker/Singularity, and with one command line execution, it generates a comprehensive QC report. We used ENCODE ATAC-seq data to benchmark and generate QC recommendations, and developed qATACViewer for the user-friendly interaction with the QC report.
Engineering oleaginous yeast Yarrowia lipolytica for violacein production: extraction, quantitative measurement and culture optimization
Authors: Tong Yingjia , Zhou Jingwen , Zhang Liang , Xu Peng 
Published: June 2019

AbstractViolacein is a naturally occurring anticancer therapeutic with deep purple color. Yeast fermentation represents an alternative approach to efficiently manufacturing violacein from inexpensive feedstocks. In this work, we optimized the extraction protocol to improve violacein recovery ratio and purity from yeast culture, including the variations of organic solvents, the choice of mechanical shear stress, incubation time and the use of cell wall-degrading enzymes. We also established the quantitative correlation between HPLC and microplate reader method. We demonstrated that both HPLC and microplate reader are technically equivalent to measure violacein from yeast culture. Furthermore, we optimized the yeast cultivation conditions, including carbon/nitrogen ratio and pH conditions. Our results indicated that ethyl acetate is the best extraction solvent with glass beads grinding the cell pellets, the maximum violacein and deoxyviolacein production was 70.04 mg/L and 5.28 mg/L in shake flasks, respectively. Violacein purity reaches 86.92% at C/N ratio of 60, with addition of 10 g/L CaCO3 to control the media pH. Taken together, the development of efficient extraction protocol, quantitative correlation between HPLC and microplate reader, and the optimization of culture conditions set a new stage for engineering violacein production in Y. lipolytica. This information should be valuable for us to build a renewable and scalable violacein production platform from the novel host oleaginous yeast species.
Phylogenetic shifts in gene body methylation correlate with gene expression and reflect trait conservation
Authors: Seymour Danelle K. , Gaut Brandon S. 
Published: June 2019

ABSTRACTA subset of genes in plant genomes are labeled with DNA methylation specifically at CG residues. These genes, known as gene-body methylated (gbM), have a number of associated characteristics. They tend to have longer sequences, to be enriched for intermediate expression levels, and to be associated with slower rates of molecular evolution. Most importantly, gbM genes tend to maintain their level of DNA methylation between species, suggesting that this trait is under evolutionary constraint. Given the degree of conservation in gbM, we still know surprisingly little about its function in plant genomes or whether gbM is itself a target of selection. To address these questions, we surveyed DNA methylation across eight grass (Poaceae) species that span a gradient of genome sizes. We first established that genome size correlates with genome-wide DNA methylation levels, but less so for genic levels. We then leveraged genomic data to identify a set of 2,982 putative orthologs among the eight species and examined shifts of methylation status for each ortholog in a phylogenetic context. A total of 55% of orthologs exhibited a shift in gbM, but these shifts occurred predominantly on terminal branches, indicating that shifts in gbM are rarely conveyed over time. Finally, we found that the degree of conservation of gbM across species is associated with increased gene length, reduced rates of molecular evolution, and increased gene expression level, but reduced gene expression variation across species. Overall, these observations suggest a basis for evolutionary pressure to maintain gbM status over evolutionary time.
How cognitive and environmental constraints influence the reliability of simulated animats in groups
Authors: Fischer Dominik , Mostaghim Sanaz , Albantakis Larissa 
Published: July 2019

AbstractEvolving in groups can either enhance or reduce an individual’s task performance. Still, we know little about the factors underlying group performance, which may be reduced to three major dimensions: (a) the individual’s ability to perform a task, (b) the dependency on environmental conditions, and (c) the perception of, and the reaction to, other group members. In our research, we investigated how these dimensions interrelate in simulated evolution experiments using adaptive agents equipped with Markov brains (“animats”). We evolved the animats to perform a spatial-navigation task under various evolutionary setups. The last generation of each evolution simulation was tested across modified conditions to evaluate and compare the animats’ reliability when faced with change. Moreover, the complexity of the evolved Markov brains was assessed based on measures of information integration. We found that, under the right conditions, specialized animats were as reliable as animats already evolved for the modified tasks, that interaction between animats was dependent on the environment and on the design of the animats, and that the task difficulty influenced the correlation between the performance of the animat and its brain complexity. Generally, our results suggest that the interrelation between the aforementioned dimensions is complex and their contribution to the group’s task performance, reliability, and brain complexity varies, which points to further dependencies. Still, our study reveals that balancing the group size and individual cognitive abilities prevents over-specialization and can help to evolve better reliability under unknown environmental situations.Author SummaryThe ability to adapt to environmental changes is an essential attribute of organisms which have had evolutionary success. We designed a simulated evolution experiment to better understand the relevant features of such organisms and the conditions under which they evolve: First, we created diverse groups of cognitive systems by evolving simulated organisms (“animats”) acting in groups on a spatial-navigation task. Second, we post-evolutionary tested the final evolved animats in new environments–not encountered before– in order to test their reliability when faced with change. Our results imply that the ability to generalize to environments with changing task demands can have complex dependencies on the cognitive design and sensor configuration of the organism itself, as well as its social or environmental conditions.
Testing and controlling for horizontal pleiotropy with the probabilistic Mendelian randomization in transcriptome-wide association studies
Authors: Yuan Zhongshang , Zhu Huanhuan , Zeng Ping , Yang Sheng , Sun Shiquan , Yang Can , Liu Jin , Zhou Xiang 
Published: July 2019

AbstractIntegrating association results from both genome-wide association studies (GWASs) and expression quantitative trait locus (eQTL) mapping studies has the potential to shed light on the molecular mechanisms underlying disease etiology. Several statistical methods have been recently developed to integrate GWASs with eQTL studies in the form of transcriptome-wide association studies (TWASs). These existing methods can all be viewed as a form of two sample Mendelian randomization (MR) analysis, which has been widely applied in various GWASs for inferring the causal relationship among complex traits. Unfortunately, most existing TWAS and MR methods make an unrealistic modeling assumption and assume that instrumental variables do not exhibit horizontal pleiotropic effects. However, horizontal pleiotropic effects have been recently discovered to be wide spread across complex traits, and, as we will show here, are also wide spread across gene expression traits. Therefore, not allowing for horizontal pleiotropic effects can be overly restrictive, and, as we will be show here, can lead to a substantial inflation of test statistics and subsequently false discoveries in TWAS applications. Here, we present a probabilistic MR method, which we refer to as PMR-Egger, for testing and controlling for horizontal pleiotropic effects in TWAS applications. PMR-Egger relies on an MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and, with a newly developed parameter expansion version of the expectation maximization algorithm, is scalable to hundreds of thousands of individuals. With extensive simulations, we show that PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust for various types of horizontal pleiotropic effect mis-specifications, is more powerful than existing MR approaches, and, as a by-product, can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank. In these applications, we show how PMR-Egger can lead to new biological discoveries through integrative analysis.
Tuberculosis patients display a high proportion of CD8+ T cells with a high cytotoxic potential
Authors: Chávez‐Galán Leslie , Illescas‐Eugenio Jhacqueline , Alvarez‐Sekely Magaly , Baez‐Saldaña Renata , Chávez Raúl , Lascurain Ricardo 
Published: June 2019

AbstractTuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a major cause of morbidity and mortality worldwide. In the host's immune response system, T cells play a critical role in mediating protection against Mtb infection, but the role of CD8+ T cells is still controversial. We evaluated the phenotypical characterization and cytotoxic ability of CD8+ T cells by flow cytometry‐based assay. Cytokine levels in serum were measured by multiplex cytokine assay. Our data show that cells from TB patients have an increased percentage of peripheral blood CD8+αβ+ T (p = 0.02) and CD56+CD8+ T (p = 0.02) and a decreased frequency of NKG2D+CD8+ T (p = 0.02) compared with healthy donors. Unlike CD8+ T cells from healthy donors, CD8+ T cells from TB patients exhibit greater cytotoxicity, mediated by HLA class I molecules, on autologous monocytes in the presence of mycobacterial antigens (p = 0.005). Finally, TB patients have a proinflammatory profile characterized by serum high level of TNF‐α (p = 0.02) and IL‐8 (p = 0.0001), but, interestingly, IL‐4 (p = 0.002) was also increased compared with healthy donors. Our data show evidence regarding the highly cytotoxic status of CD8+ T cells in Mtb infection. These cytotoxic cells restricted to HLA‐A, B, and C could be used to optimize strategies for designing new TB vaccines or for identifying markers of disease progression.
A 3D perspective on sediment accumulation in algal turfs: Implications of coral reef flattening
Authors: Tebbett Sterling B. , Streit Robert P. , Bellwood David R. 
Published: June 2019

Abstract

Globally, coral reefs are being transformed by a suite of stressors, the foremost being climate change. Increasingly, it is expected that these reconfigured reef systems will emerge with lower‐complexity and will be dominated by algal turfs. Understanding this new operating space is vital if we are to maintain the services, such as fishable biomass production, that reefs provide. However, the functionality of these systems appears to depend on the nature of the algal turfs themselves, which is in‐turn, intimately linked to the sediments they contain.

As reefs are losing complexity, we need to understand if, and to what extent, algal turf condition and complex reef structure are connected. To address this issue we took advantage of recent developments in 3D structure‐from‐motion technology to examine how complexity metrics (elevation and surface angle) related to the nature of algal turfs on a heavily climate‐impacted coral reef. This represents a novel application of this technology in the context of coral reef ecosystems.

We found that as both elevation and surface angle decreased, the nutritional value of the epilithic algal matrix also decreased while sediment accumulation increased. Furthermore, we showed that elevated surfaces were characterized by far shorter algal turfs, and are potentially herbivory hotspots, offering fertile grounds for further exploration of herbivory dynamics at sub‐metre spatial scales.

Synthesis. This study yields new insights into the operating‐space of future reefs, and suggests that as reefs flatten, sediment accumulation is likely to increase even if sediment inputs remain unchanged, altering algal turfs fundamentally. Maintaining key services provided by climate‐transformed, low‐complexity algal turf‐dominated reefs of the future, will depend on managing the complex interactions between herbivory, sediments, algal turfs and reef structural complexity.
The Switch‐Up: An Examination of Changes in Earnings Management after Receiving SEC Comment Letters
Authors: Cunningham Lauren M. , Johnson Bret A. , Johnson E. Scott , Lisic Ling Lei 
Published: June 2019

ABSTRACTThe SEC has long asserted that earnings management practices result in adverse consequences for investors. We examine whether SEC oversight affects firms' accounting quality in terms of earnings management trade‐offs. We expect that increased firm‐specific regulatory scrutiny, in the form of an SEC comment letter, will induce management to switch from accrual‐based earnings management (AEM), which is a main focus of the SEC, to real‐activities‐based earnings management (REM), which is not likely to be commented on in the SEC's review process. Consistent with our predictions, we find that AEM is lower and REM is higher following the receipt of a comment letter, relative to non‐comment‐letter years and a propensity‐score‐matched sample of non‐comment‐letter firms. However, we do not find a significant difference in total earnings management (i.e., the sum of AEM and REM), suggesting that the higher REM acts as a substitute for lower AEM activity. We further find that our results are driven by accounting comments relating to estimates and accruals and not by classification‐only comments, which suggests that a comment letter that does not question specific issues associated with estimates and accruals is not a strong enough signal to induce the firm to change earnings management behavior. Additionally, the shift to REM is attenuated for firms with high institutional ownership. These results collectively suggest that the comment letter process effectively constrains AEM but has the unintended consequence of firms, on average, switching to REM.
Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease
Authors: Melchior Benoît , Mittapalli Gopi Kumar , Lai Carolyn , Duong‐Polk Karen , Stewart Joshua , Güner Bora , Hofilena Brian , Tjitro Amanda , Anderson Scott D. , Herman David S. , Dellamary Luis , Swearingen Christopher J. , Sunil K.C. , Yazici Yusuf 
Published: July 2019

AbstractDual‐specificity tyrosine phosphorylation‐regulated kinase‐1A (DYRK1A) is known to phosphorylate the microtubule‐associated tau protein. Overexpression is correlated with tau hyperphosphorylation and neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). This study assessed the potential of SM07883, an oral DYRK1A inhibitor, to inhibit tau hyperphosphorylation, aggregation, NFT formation, and associated phenotypes in mouse models. Exploratory neuroinflammatory effects were also studied.SM07883 specificity was tested in a kinase panel screen and showed potent inhibition of DYRK1A (IC50 = 1.6 nM) and GSK‐3β (IC50 = 10.8 nM) kinase activity. Tau phosphorylation measured in cell‐based assays showed a reduction in phosphorylation of multiple tau epitopes, especially the threonine 212 site (EC50 = 16 nM). SM07883 showed good oral bioavailability in multiple species and demonstrated a dose‐dependent reduction of transient hypothermia‐induced phosphorylated tau in the brains of wild‐type mice compared to vehicle (47%, p < 0.001). Long‐term efficacy assessed in aged JNPL3 mice overexpressing the P301L human tau mutation (3 mg/kg, QD, for 3 months) exhibited significant reductions in tau hyperphosphorylation, oligomeric and aggregated tau, and tau‐positive inclusions compared to vehicle in brainstem and spinal cord samples. Reduced gliosis compared to vehicle was further confirmed by ELISA. SM07883 was well tolerated with improved general health, weight gain, and functional improvement in a wire‐hang test compared to vehicle‐treated mice (p = 0.048).SM07883, a potent, orally bioavailable, brain‐penetrant DYRK1A inhibitor, significantly reduced effects of pathological tau overexpression and neuroinflammation, while functional endpoints were improved compared to vehicle in animal models. This small molecule has potential as a treatment for AD.
Accessing rural health services: Results from a qualitative narrative gerontological study
Authors: Neville Stephen , Napier Sara , Adams Jeffery , Shannon Kay 
Published: June 2019

AbstractObjectiveExplore how older adults’ talk about accessing rural community health services.MethodsA qualitative narrative gerontological approach explored issues related to accessing health services in their community. Semi‐structured digitally recorded individual interviews were undertaken with 32 community‐dwelling older people aged between 75 and 93 years. A narrative data analytic process was undertaken. The COnsolidated criteria for REporting Qualitative research guidelines were followed to ensure rigour in this study.ResultsThree collective narratives resulted from the data analytic process: (a) “accessing local health services”; (b) “accessing specialist services”; and (c) “accessing emergency services.”ConclusionsNarrators identified a number of issues related to accessing rural health services. These included long waiting times, lack of continuity in care provision by doctors and difficulties accessing specialist and emergency services. Nurses were frequently cited as a reliable point of contact for these older people. Expansion of nursing roles would enhance the provision of rural health‐care services.