bluuebunny/crossref_metadata_2025 huggingface dataset:
Profiling DNA Methylation Differences Between Inbred Mouse Strains on the Illumina Human Infinium MethylationEPIC Microarray
Authors: Gujar Hemant , Liang Jane W. , Wong Nicholas C. , Mozhui Khyobeni
Published: September 2017

The Illumina Infinium MethylationEPIC provides an efficient platform for profiling DNA methylation in humans at over 850,000 CpGs. Model organisms such as mice do not currently benefit from an equivalent array. Here we used this array to measure DNA methylation in mice. We defined probes targeting conserved regions and performed a comparison between the array-based assay and affinity-based DNA sequencing of methyl-CpGs (MBD-seq). Mouse samples consisted of 11 liver DNA from two strains, C57BL/6J (B6) and DBA/2J (D2), that varied widely in age. Linear regression was applied to detect differential methylation. In total, 13,665 probes (1.6% of total probes) aligned to conserved CpGs. Beta-values (β-value) for these probes showed a distribution similar to that in humans. Overall, there was high concordance in methylation signal between the EPIC array and MBD-seq (Pearson correlation r = 0.70, p-value < 0.0001). However, the EPIC probes had higher quantitative sensitivity at CpGs that are hypo-(β-value < 0.3) or hypermethylated (β-value > 0.7). In terms of differential methylation, no EPIC probe detected significant difference between age groups at a Benjamini-Hochberg threshold of 10%, and the MBD-seq performed better at detecting age-dependent change in methylation. However, the top most significant probe for age (cg13269407; uncorrected p-value = 1.8 × 10−5) is part of the clock CpGs used to estimate the human epigenetic age. For strain, 219 Infinium probes detected significant differential methylation (FDR cutoff 10%) with ∼80% CpGs associated with higher methylation in D2. This higher methylation profile in D2 compared to B6 was also replicated by the MBD-seq data. To summarize, we found only a small subset of EPIC probes that target conserved sites. However, for this small subset the array provides areliable assay of DNA methylation and can be effectively used to measure differential methylation in mice.
Transcriptional development of phospholipid and lipoprotein metabolism in different intestinal regions of Atlantic salmon (Salmo salar) fry
Authors: Jin Yang , Olsen Rolf Erik , Østensen Mari-Ann , Gillard Gareth Benjamin , Korsvoll Sven Arild , Santi Nina , Gjuvsland Arne Bjørke , Vik Jon Olav , Torgersen Jacob Seilø , Sandve Simen Rød , Olsen Yngvar
Published: September 2017

Background

It has been suggested that the high phospholipid (PL) requirement in Atlantic salmon (Salmo salar) fry is due to insufficient intestinalde-novosynthesis causing low lipoprotein (LP) production and reduced transport capacity of dietary lipids. However, there has not been performed any in-depth ontological analysis of intestinal PL and LP synthesis with development of salmon. Therefore in this paper we used RNA-seq technology to test the hypothesis that the high PL requirement in salmon fry was associated with undeveloped PL synthesis and LP formation pathways in intestine. There was a special focus on the understanding homologous genes, especially from salmonid-specific fourth vertebrate whole-genome duplication (Ss4R), contribution to salmonid specific features of regulation of PL metabolic pathways. The study was performed in stomach, pyloric caeca and hindgut at 0.16g (1 day before first-feeding), 2.5g and 10g of salmon.

Results

In general, we found an up-regulation ofde-novophosphatidylcholine (PtdCho) synthesis, phosphatidylethanolamine (PtdEtn) and LP formation pathways in pyloric caeca of salmon between 0.16g and 10g. Thirteen genes in these pathways were highly (q<0.05) up-regulated in 2.5g salmon compared to 0.16g, while only five more significant (q<0.05) genes were found when the fish grew up to 10g. Different homologous genes were found dominating in stomach, pyloric caeca and hindgut. However, the expression of dominating genes in PL and LP synthesis pathways was much higher in pyloric caeca than stomach and hindgut. Salmon-specific homologous (Ss4R) genes had similar expression during development, while other homologs had more diverged expression.

Conclusions

An increasing capacity for PL synthesis and LP formation was confirmed in pyloric caeca. The up-regulation of thede-novoPtdCho pathway confirms that the salmon fry have increasing requirement for dietary PtdCho compared to adult. The similar expressions between Ss4R homologous genes suggest that the functional divergence of these genes was incomplete compared to homologs derived from other whole genome duplication. The results of the present study have provided new information on the molecular mechanisms of phospholipid synthesis and lipoprotein formation in fish.
Quantification of cellular distribution as Poisson process in 3D matrix using a multiview light-sheet microscope
Authors: Colomb Warren , Osmond Matthew , Durfee Charles , Krebs Melissa D. , Sarkar Susanta K.
Published: September 2017

The absence of quantitativein vitrocell-extracellular matrix models represents an important bottleneck for basic research and human health. Randomness of cellular distributions provides an opportunity for the development of a quantitativein vitromodel. However, quantification of the randomness of random cell distributions is still lacking. In this paper, we have imaged cellular distributions in an alginate matrix using a multiview light-sheet microscope and developed quantification metrics of randomness by modeling it as a Poisson process, a process that has constant probability of occurring in space or time. Our light-sheet microscope can image more than 5 mm thick optically clear samples with 2.9 ±0.4μmdepth-resolution. We applied our method to image fluorescently labeled human mesenchymal stem cells (hMSCs) embedded in an alginate matrix. Simulated randomness agrees well with the experiments. Quantification of distributions and validation by simulations will enable quantitative study of cell-matrix interactions in tissue models.
The Generalized Data Model for Clinical Research
Authors: Danese Mark D. , Halperin Marc , Duryea Jennifer , Duryea Ryan
Published: September 2017

1.

1.1 Background

Most healthcare data sources store information within their own unique schemas, making reliable and reproducible research challenging. Consequently, researchers have adopted various data models to improve the efficiency of research. Transforming and loading data into these models is a labor-intensive process that can alter the semantics of the original data. Therefore, we created a data model with a hierarchical structure that simplifies the transformation process and minimizes data alteration.

1.2 Methods

There were two design goals in constructing the tables and table relationships for the Generalized Data Model (GDM). The first was to focus on clinical codes in their original vocabularies to retain the original semantic representation of the data. The second was to retain hierarchical information present in the original data while retaining provenance. The model was tested by transforming synthetic Medicare data; Surveillance, Epidemiology, and End Results data linked to Medicare claims; and electronic health records from the Clinical Practice Research Datalink. We also tested a subsequent transformation from the GDM into the Sentinel data model.

1.3 Results

The resulting data model contains 19 tables, with the Clinical Codes, Contexts, and Collections tables serving as the core of the model, and containing most of the clinical, provenance, and hierarchical information. In addition, a Mapping table allows users to apply an arbitrarily complex set of relationships among vocabulary elements to facilitate automated analyses.

1.4 Conclusions

The GDM offers researchers a simpler process for transforming data, clear data provenance, and a path for users to transform their data into other data models. The GDM is designed to retain hierarchical relationships among data elements as well as the original semantic representation of the data, ensuring consistency in protocol implementation as part of a complete data pipeline for researchers.
Resolving ESCRT-III spirals at the intercellular bridge of dividing cells using 3D STORM imaging
Authors: Goliand Inna , Dadosh Tali , Elia Natalie
Published: September 2017

The ESCRT machinery mediates membrane fission in a verity of processes in cells. According to the proposed mechanism, ESCRT-III proteins drive membrane fission by assembling into helical filaments on membranes. Yet, ESCRT-III filaments have never been directly visualized in a cellular process that utilizes this machinery for its function. Here we used 3D STORM imaging of endogenous ESCRT-III component IST1, to describe the structural organization of ESCRT-III during mammalian cytokinetic abscission. Using this approach, ESCRT-III ring and spiral assemblies were resolved at the intercellular tube of cells undergoing abscission. Characterization of these structures indicates the ESCRT-III helical filament undergoes remodeling during abscission. This work provides the first evidence that ESCRT-III proteins assemble into helical filaments in physiological context, indicating that the ESCRT-III machine indeed derives its contractile activity through spiral assemblies. Moreover, it provides new structural information on ESCRT-III filaments, which raise new mechanistic scenarios for ESCRT driven membrane constriction.
Real Time Estimation of Population Receptive Fields Using Gradient Descent
Authors: Senden Mario
Published: September 2017

A real-time population receptive field mapping procedure based on gradient descent is proposed. Model-free receptive fields produced by the algorithm are evaluated in context of simulated data exhibiting different levels of temporally autocorrelated noise and spatial point spread. As with any model-free approach, the exact shape of receptive fields produced by the real-time algorithm depends on the stimulus. Nevertheless, estimated receptive fields show good correspondence with ground-truth receptive fields in terms of both position and size. Furthermore, fitting a parametric model to the previously obtained estimates approximates the exact shape of the true underlying receptive fields well.
GLP-1 receptor agonist ameliorates obesity-induced chronic kidney injury via restoring renal lipid and energy metabolism homeostasis: revealed by metabolomics
Authors: Wang Chengshi , Li Ling , Liu Shuyun , Liao Guangneng , Chen Younan , Cheng Jingqiu , Lu Yanrong , Liu Jingping
Published: September 2017

Increasing evidence indicate that obesity is highly associated with chronic kidney disease (CKD).GLP-1 receptor (GLP-1R) agonist has shown benefits on kidney diseases, but its direct role on kidney metabolism in obesity is still not clear. This study aims to investigate the protection and metabolic modulation role of liraglutide (Lira) on kidney of obesity. Rats were induced obese by high-fat diet (HFD), and renal function and metabolism changes were evaluated by metabolomic, biological and histological methods. HFD rats exhibited metabolic disorders including elevated body weight, hyperlipidemia and impaired glucose tolerance, and remarkable renal injuries including declined renal function and inflammatory/fibrotic changes, whereas Lira significantly ameliorated these adverse effects in HFD rats. Metabolomic data showed that Lira reduced renal lipids including fatty acid residues, cholesterol, phospholipids and triglycerides, and improved mitochondria metabolites such as succinate, citrate, taurine, fumarate and NAD+in the kidney of HDF rats. Furthermore, we revealed that Lira inhibited renal lipid accumulation by coordinating lipogenic and lipolytic signals, and rescued renal mitochondria function via Sirt1/AMPK/PGC1α pathways in HDF rats. This study suggested that Lira alleviated HFD-induced kidney injury via directly restoring renal lipid and energy metabolism, and GLP-1 receptor agonist is a promising therapy for obesity-associated CKD.
Integrative Statistical Inferences for Drug Sensitivity Biomarkers in Cancer
Authors: Ullah Ehsan , Shama Saila , Muftah Noora Al , Thompson Ian Richard , Rawi Reda , Mall Raghvendra , Bensmail Halima
Published: September 2017

Personal medicine has been associated with different patient responses to different anti-cancer therapies. Recently, scientists are looking not only for new biomarkers associated with a disease such as cancer but also identifying biomarkers that predict patients who are most likely to respond to a particular cancer treatment. Orderly endeavors to relate cancer mutational information with biological conditions may encourage the interpretation of somatic mutation indexes into significant biomarkers for patient stratification.

We have screened and incorporated a board of cancer cell lines from Genomics of Drug Sensitivity in Cancer (GDSC) database to recognize genomic highlights related with drug sensitivity. We used mutation, DNA copy number variation, and gene expression information from Catalogue of Somatic Mutations in Cancer (COSMIC) and The Cancer Genome ATLAS (TCGA) for cell lines with their reactions to associate focused and cytotoxic treatments with approved drugs and drugs under clinical and preclinical examination.

We discovered mutated cancer genes were related with cell reaction to, mostly accessible, cancer medications and some mutated genes were related with sensitivity to an expansive scope of therapeutic agents. By connecting drug activity to the useful many-sided quality of cancer genomes, efficient pharmacogenomic profiling in tumor cell lines gives an intense biomarker revelation stage to guide balanced malignancy remedial systems.

Our study highlights that gene ANK2 amplification, and gene CELSER1 amplification and deletion are highly associated with anti-leukemic drug candidate LFM-A13. It also highlights that gene NUP214 and ROS1 copy number and gene NSD1 amplification are as a group highly associated with the parkinson drug Nilotinib. Finally, our study confirms that gene BRAF mutation is interacting with the BRAF-selective inhibitors drugs PLX4720 and SB590885. On the other hand, our study provides two open source analysis packages: bastah for the multitask-association analysis, and UNGeneAnno for automatic annotation of the variants.
History is written by the victors: the effect of the push of the past on the fossil record
Authors: Budd Graham E. , Mann Richard P.
Published: September 2017

Phylogenies may be modelled using “birth-death” models for speciation and extinction, but even when a homogeneous rate of diversification is used, survivorship biases can generate remarkable rate heterogeneities through time. One such bias has been termed the “push of the past”, by which the length of time a clade has survived is conditioned on the rate of diversification that happened to pertain at its origin. This creates the illusion of a secular rate slow-down through time that is, rather, a reversion to the mean. Here we model the controls on the push of the past, and the effect it has on clade origination times, and show that it largely depends on underlying extinction rates. An extra effect increasing early rates of lineage generation is also seen in large clades. These biases are important but relatively neglected influences on many aspects of diversification patterns, such as diversification spikes after mass extinctions and at the origins of clades; they also influence rates of fossilisation, changes in rates of phenotypic evolution and even molecular clocks. These inevitable features of surviving and/or large clades should thus not be generalised to the diversification process as a whole without additional study of small and extinct clades.
Transcriptional control by Sall4 in blastocysts facilitates lineage commitment of inner cell mass cells
Authors: Miller Anzy , Gharbi Sarah , Etienne-Dumeau Charles , Nishinakamura Ryuichi , Hendrich Brian
Published: September 2017

The enhancer-binding zinc finger transcription factor Sall4 is essential for early mammalian postimplantation development and plays important roles in lineage commitment of embryonic stem cells. Enhancer binding by Sall4 results in transcriptional activation of some genes, but repression of others. Exactly how cells in preimplantation stage embryos use this transcriptional modulatory activity of Sall4 during early developmental transitions has not been determined. Using single cell gene expression analyses we show that Sall4 is required to maintain the gene regulatory network in inner cell mass (ICM) cells prior to lineage commitment. Although Sall4 is not required for ICM cells to adopt a correct epiblast or primitive endoderm gene expression profile, in the absence of Sall4 early ICM cells commit to either lineage at reduced frequency. We propose a model whereby Sall4 activity sets the stage for efficient progression from the uncommitted ICM progenitor state by modulating the gene regulatory network in early ICM cells.
Kinetics of HIV-Specific CTL Responses Plays a Minimal Role in Determining HIV Escape Dynamics
Authors: Yang Yiding , Ganusov Vitaly V.
Published: September 2017

Cytotoxic T lymphocytes (CTLs) have been suggested to play an important role in controlling human immunodeficiency virus (HIV-1 or simply HIV) infection. HIV, due to its high mutation rate, can evade recognition of T cell responses by generating escape variants that can not be recognized by HIV-specific CTLs. Although HIV escape from CTL responses has been well documented, factors contributing to the timing and the rate of viral escape from T cells have not been fully elucidated. Fitness costs associated with escape and magnitude of the epitope-specific T cell response are generally considered to be the key in determining timing of HIV escape. Several previous analyses generally ignored the kinetics of T cell responses in predicting viral escape by either considering constant or maximal T cell response; several studies also considered escape from different T cell responses to be independent. Here we focus our analysis on data from two patients from a recent study with relatively frequent measurements of both virus sequences and HIV-specific T cell response to determine impact of CTL kinetics on viral escape. In contrast with our expectation we found that including temporal dynamics of epitope-specific T cell response did not improve the quality of fit of different models to escape data. We also found that for well sampled escape data the estimates of the model parameters including T cell killing efficacy did not strongly depend on the underlying model for escapes: models assuming independent, sequential, or concurrent escapes from multiple CTL responses gave similar estimates for CTL killing efficacy. Interestingly, the model assuming sequential escapes (i.e., escapes occurring along a defined pathway) was unable to accurately describe data on escapes occurring rapidly within a short-time window, suggesting that some of model assumptions must be violated for such escapes. Our results thus suggest that the current sparse measurements of temporal CTL dynamics in blood bear little quantitative information to improve predictions of HIV escape kinetics. More frequent measurements using more sensitive techniques and sampling in secondary lymphoid tissues may allow to better understand whether and how CTL kinetics impacts viral escape.
Mixed model association for biobank-scale data sets
Authors: Loh Po-Ru , Kichaev Gleb , Gazal Steven , Schoech Armin P , Price Alkes L
Published: September 2017

Biobank-based genome-wide association studies are enabling exciting insights in complex trait genetics, but much uncertainty remains over best practices for optimizing statistical power and computational efficiency in GWAS while controlling confounders. Here, we introduce a much faster version of our BOLT-LMM Bayesian mixed model association method— capable of running analyses of the full UK Biobank cohort in a few days on a single compute node—and show that it produces highly powered, robust test statistics when run on all 459K European samples (retaining related individuals). When used to conduct a GWAS for height in UK Biobank, BOLT-LMM achieved power equivalent to linear regression on 650K samples—a 93% increase in effective sample size versus the common practice of analyzing unrelated British samples using linear regression (UK Biobank documentation; Bycroft et al. bioRxiv). Across a broader set of 23 highly heritable traits, the total number of independent GWAS loci detected increased from 5,839 to 10,759, an 84% increase. We recommend the use of BOLT-LMM (retaining related individuals) for biobank-scale analyses, and we have publicly released BOLT-LMM summary association statistics for the 23 traits analyzed as a resource for all researchers.
Improved prediction of Bovine Leucocyte Antigens (BoLA) presented ligands by use of MS eluted ligands and in-vitro binding data; impact for the identification T cell epitopes
Authors: Nielsen Morten , Connelley Tim , Ternette Nicola
Published: September 2017

Peptide binding to MHC class I molecules is the single most selective step in antigen presentation and the strongest single correlate to peptide cellular immunogenicity. The cost of experimentally characterizing the rules of peptide presentation for a given MHC-I molecule is extensive, and predictors of peptide-MHC interactions constitute an attractive alternative.

Recently, an increasing amount of MHC presented peptides identified by mass spectrometry (MS ligands) has been published. Handling and interpretation of MS ligand data is in general challenging due to the poly-specificity nature of the data. We here outline a general pipeline for dealing with this challenge, and accurately annotate ligands to the relevant MHC-I molecule they were eluted from by use of GibbsClustering and binding motif information inferred fromin-silicomodels. We illustrate the approach here in the context of MHCI molecules (BoLA) of cattle. Next, we demonstrate how such annotated BoLA MS ligand data can readily be integrated within-vitrobinding affinity data in a prediction model with very high and unprecedented performance for identification of BoLA-I restricted T cell epitopes.

The approach has here been applied to the BoLA-I system, but the pipeline is readily applicable to MHC systems in other species.
Enriched pathogen diversity under host-type heterogeneity and immune-mediated competition
Authors: Martinez Pamela P. , Woods Robert J. , Pascual Mercedes
Published: September 2017

Pathogen strains can stably coexist if they specialize on different hosts. Multiple strains can also coexist on a single host through negative frequency-dependent interactions mediated by partial cross-immunity. Understanding pathogen diversity remains a challenge however when both host specificity and cross-immunity are acting and may be functionally linked, as has been proposed for rotavirus, where a single protein is both antigenically important and determines host specificity by binding to the genetically encoded human blood group antigens. This situation is akin to the more general question in ecology of species coexistence when stabilizing and equalizing mechanisms interact. We examine this interaction with a theoretical model motivated by rotavirus and apply an adaptive dynamics framework to show how these two kinds of competition, typically considered separately, affect diversity. When cross-immunity depends on host-pathogen affinity, diversity is magnified as long-term evolution allows for the coexistence of multiple semi-specialized strains, similar to observations in rotavirus. In contrast, the simultaneous co-occurrence of several semi-specialized individuals is not observed when the degree of cross-immunity is independent from affinity distance among strains. The interplay of equalizing and stabilizing mechanisms fundamentally modifies diversity patterns and should be considered when addressing strain coexistence.
Global analysis of specificity determinants in eukaryotic protein kinases
Authors: Bradley David , Viéitez Cristina , Rajeeve Vinothini , Cutillas Pedro R. , Beltrao Pedro
Published: September 2017

Protein kinases lie at the heart of cell signalling processes, constitute one of the largest human domain families and are often mutated in disease. Kinase target recognition at the active site is in part determined by a few amino acids around the phosphoacceptor residue. These preferences vary across kinases and despite the increased knowledge of target substrates little is known about how most preferences are encoded in the kinase sequence and how these preferences evolve. Here, we used alignment-based approaches to identify 30 putative specificity determinant residues (SDRs) for 16 preferences. These were studied using structural models and were validated by activity assays of mutant kinases. Mutation data from patient cancer samples revealed that kinase specificity is often targeted in cancer to a greater extent than catalytic residues. Throughout evolution we observed that kinase specificity is strongly conserved across orthologs but can diverge after gene duplication as illustrated by the evolution of the G-protein coupled receptor kinase family. The identified SDRs can be used to predict kinase specificity from sequence and aid in the interpretation of evolutionary or disease-related genomic variants.
Chronic intermittent nicotine delivery with lung alveolar region-targeted aerosol technology produces circadian blood pharmacokinetics in rats resembling human smokers
Authors: Shao Xuesi M. , Liu Siyu , Lee Eon S. , Fung David , Pei Hua , Liang Jing , Mudgway Ross , Zhang Jingxi , Feldman Jack L. , Zhu Yifang , Louie Stan , Xie Xinmin S
Published: September 2017

Introduction

Cigarette smoke is an aerosol containing microparticles that carry nicotine into lung alveolar region where nicotine is rapidly absorbed into circulation. Nicotine exposure in smokers is a chronic intermittent process, with intake during wakefulness and abstinence during sleep resulting in circadian fluctuation of blood nicotine levels. Here we present a smoking-relevant nicotine exposure device and rodent model.

Methods

We developed a computer controlled integrated platform where freely moving rodents can be exposed to episodic nicotine aerosol on an investigator-designed schedule. Rats were exposed to nicotine aerosol once every half hr in the dark phase of 12/12-hr dark/light cycles for 10 days. Plasma nicotine and its metabolite cotinine levels were determined with a LC-MS/MS method.

Results

We characterized the aerosol in the breathing zone of the rodent exposure chamber. The droplet size distribution was within the respirable diameter range. The system can generate a wide range of nicotine concentrations in air that meet a variety of experimental needs. We optimized the parameters of aerosol generation and exposure: plasma nicotine and cotinine concentrations reached 30-35 ng/ml and 190-240 ng/ml, respectively. The nicotine levels and circadian patterns resembled the pharmacokinetic pattern of human smokers.

Conclusions

We developed an aerosol system that can produce chronic intermittent nicotine exposure in unanesthetized and unrestrained rodents with route of administration and circadian blood pharmacokinetics resembling human smokers. This methodology is a novel tool for studies of behavior, pharmacology and toxicology of chronic nicotine exposure, nicotine addiction, tobacco-related diseases, teratogenicity, and for discovery of therapeutics.

Implications

We developed a method and an alveolar region-targeted aerosol system that provides chronic intermittent nicotine exposure in rodents. The method produces clinically relevant animal models with the route of administration and circadian pharmacokinetics resembling human smokers. This method is a novel tool for understanding the health effects of chronic nicotine exposures such as with tobacco cigarettes, E-cigarettes and other tobacco products, for studies of pharmacology, toxicology, nicotine addiction, tobacco-related diseases, and for discovery of medications.
The architecture and design of ecological null models
Authors: Ladau Joshua
Published: September 2017

Many questions in ecology are best addressed using observational data because they concern spatial or temporal scales where experimentation is impractical. Null models, which make predictions in the absence of a particular ecological mechanism, are instrumental for making inferences in these situations, but which null models to use or how to best test them is often unclear; this ambiguity is problematic because different null models and tests can yield different results, suggesting contradictory ecological mechanisms. To address these challenges, this paper presents an overar ching framework for the development and testing of null models, in which desirable models and tests are obtained as solutions to mathematical optimization problems. As an example of how the framework can be applied, this paper shows how it can be used to design null model tests to check for effects of interspecific interactions on species co-occurrence patterns. A minimal sufficient statistic (metric) for effects of interspecific interactions is derived, which achieves the maximal level of data compression without losing information present in the data about interspecific in teractions. Existing, intuitive statistics are shown to lack this property. The paper then derives a statistical hypothesis test that has the greatest possible power (sen sitivity) for detecting effects of competition and facilitation given a controlled false positive rate. This test is shown numerically to improve greatly over existing tests. The optimization paradigm allows the most accurate inferences possible, and should be applicable throughout ecology where null models are used to make inferences.
PharmacoDB: an integrative database for miningin vitrodrug screening studies
Authors: Smirnov Petr , Kofia Victor , Maru Alexander , Freeman Mark , Ho Chantal , El-Hachem Nehme , Adam George-Alexandru , Ba-alawi Wail , Safikhani Zhaleh , Haibe-Kains Benjamin
Published: September 2017

Recent pharmacogenomic studies profiled large panels of cancer cell lines against hundreds of approved drugs and experimental chemical compounds. The overarching goal of these screens is to measure sensitivity of cell lines to chemical perturbation, correlate these measures to genomic features, and thereby develop novel predictors of drug response. However, leveraging this valuable data is challenging due to the lack of standards for annotating cell lines and chemical compounds, and quantifying drug response. Moreover, it has been recently shown that the complexity and complementarity of the experimental protocols used in the field result in high levels of technical and biological variation in thein vitropharmacological profiles. There is therefore a need for new tools to facilitate rigorous comparison and integrative analysis of large-scale drug screening datasets. To address this issue, we have developed PharmacoDB (pharmacodb.pmgenomics.ca), a database integrating the largest pharmacogenomic studies published to date. Here, we describe how the curation of cell line and chemical compound identifiers maximizes the overlap between datasets and how users can leverage such data to compare and extract robust drug phenotypes. PharmacoDB provides a unique resource to mine a compendium of curated pharmacogenomic datasets that are otherwise disparate and difficult to integrate.

Key points

Curation of cell line and drug identifiers in the largest pharmacogenomic studies published to date

Uniform processing of drug sensitivity data to reduce heterogeneity across studies

Multiple drug response summary metrics enabling visual comparison and integrative analysis
A new model for the description of X-ray diffraction from mosaic crystals for ray-tracing calculations
Authors: Schlesiger Christopher , Anklamm Lars , Malzer Wolfgang , Gnewkow Richard , Kanngießer Birgit
Published: September 2017

This paper presents the development of a new reflection model for describing X-ray diffraction from mosaic crystals. In contrast to the well established diffraction model of Zachariasen [Zachariasen (1994),Theory of X-ray Diffraction in Crystals. Mineola: Dover Publications], it gives additional information on the spatial reflection behaviour and not just on the depth-integrated reflectivity of the crystal material. The new reflection model enables a concrete description of mosaic crystal performance in an arbitrary X-ray spectrometer configuration. Multiple reflections inside the crystal are described by splitting the calculation into a discrete number of reflections. Hence, the influence of each number of reflections is investigated, leading to a laterally resolved solution for the reflectivity. In addition, the model can use a mosaicity of arbitrary shape. This is important because the present work uses a Lorentzian-shaped mosaicity instead of a Gaussian one, which is usually the case in the most widely used simulation programs. A comparison between the new model and that of Zachariasen is performed, and it predicts a similar integrated reflectivity with a deviation lower than 0.7%. Further, a ray-tracing simulation with multiple reflections based on the new model is compared with a measurement, showing a deviation of lower than 5%.
Soil fungal abundance and plant functional traits drive fertile island formation in global drylands
Authors: Ochoa‐Hueso Raúl , Eldridge David J. , Delgado‐Baquerizo Manuel , Soliveres Santiago , Bowker Matthew A. , Gross Nicolas , Le Bagousse‐Pinguet Yoann , Quero José L. , García‐Gómez Miguel , Valencia Enrique , Arredondo Tulio , Beinticinco Laura , Bran Donaldo , Cea Alex , Coaguila Daniel , Dougill Andrew J. , Espinosa Carlos I. , Gaitán Juan , Guuroh Reginald T. , Guzman Elizabeth , Gutiérrez Julio R. , Hernández Rosa M. , Huber‐Sannwald Elisabeth , Jeffries Thomas , Linstädter Anja , Mau Rebecca L. , Monerris Jorge , Prina Aníbal , Pucheta Eduardo , Stavi Ilan , Thomas Andrew D. , Zaady Eli , Singh Brajesh K. , Maestre Fernando T.
Published: September 2017

Dryland vegetation is characterized by discrete plant patches that accumulate and capture soil resources under their canopies. These “fertile islands” are major drivers of dryland ecosystem structure and functioning, yet we lack an integrated understanding of the factors controlling their magnitude and variability at the global scale.

We conducted a standardized field survey across 236 drylands from five continents. At each site, we measured the composition, diversity and cover of perennial plants. Fertile island effects were estimated at each site by comparing composite soil samples obtained under the canopy of the dominant plants and in open areas devoid of perennial vegetation. For each sample, we measured 15 soil variables (functions) associated with carbon, nitrogen and phosphorus cycling and used the relative interaction index to quantify the magnitude of the fertile island effect for each function. In 80 sites, we also measured fungal and bacterial abundance (quantitative PCR) and diversity (Illumina MiSeq).

The most fertile islands, i.e. those where a higher number of functions were simultaneously enhanced, were found at lower elevation sites with greater soil pH values and sand content under semiarid climates, particularly at locations where the presence of tall woody species with a low‐specific leaf area increased fungal abundance beneath plant canopies, the main direct biotic controller of the fertile island effect in the drylands studied. Positive effects of fungal abundance were particularly associated with greater nutrient contents and microbial activity (soil extracellular enzymes) under plant canopies.

Synthesis. Our results show that the formation of fertile islands in global drylands largely depends on: (1) local climatic, topographic and edaphic characteristics, (2) the structure and traits of local plant communities and (3) soil microbial communities. Our study also has broad implications for the management and restoration of dryland ecosystems worldwide, where woody plants are commonly used as nurse plants to enhance the establishment and survival of beneficiary species. Finally, our results suggest that forecasted increases in aridity may enhance the formation of fertile islands in drylands worldwide.
How fast can China grow? The Middle Kingdom's prospects to 2030
Authors: Bailliu Jeannine , Kruger Mark , Toktamyssov Argyn , Welbourn Wheaton
Published: September 2017

Given its size and importance for global commodity markets, the question of how fast China can grow over the medium term is an important one. Using a Cobb–Douglas production function, we decompose the growth of trend GDP into those of the capital stock, labour, human capital and total factor productivity (TFP) and then forecast trend output growth out to 2030 using a bottom‐up approach based on forecasts that we build for each one of these factors. Our paper distinguishes itself from existing work in that we construct a forecast of Chinese TFP growth based on the aggregation of forecasts of its key determinants. In addition, our analysis is based on a carefully constructed estimate of the Chinese productive capital stock and a measure of human capital (based on Chinese wage survey data) that better reflects the returns to education in China. Our results suggest that Chinese GDP growth will slow from around 7% currently to approximately 5% by 2030, consistent with a gradual rebalancing of the Chinese economy characterized by a decline in the investment rate. Moreover, our findings underscore the growing importance of TFP growth as a driver of Chinese growth.
Impact of Statins on Arteriovenous Fistulas Outcomes: A Meta‐Analysis
Authors: Wan Qingsong , Li Li , Yang Shikun , Chu Fenfen
Published: September 2017

Statins are effective lipid‐lowering drugs with beneficial pleiotropic effects for vascular remodeling processes, statins may have a beneficial effect on the function of arteriovenous fistulas (AVFs) in hemodialysis (HD) patients. Therefore, we performed this systematic review to assess the protective effects of statin therapy in HD patients. The randomized controlled trials (RCTs) or quasi‐RCTs and retrospective cohort studies (RCS) of statin therapy for the function of AVFs in HD patients were searched from multiple databases. Relevant studies were screened according to predefined inclusion criteria and then pooled‐analyses were performed using RevMan 5.2 software. One RCT and six RCS containing 20 246 HD patients were included in this meta‐analysis, of whom 9847 were treated with statins and 10 399 were treated with placebo. Our meta‐analysis showed that there was no significant difference between statins and placebo groups, with those who received statin therapy showing similar AVF failure rates compared to control (pooled risk ratio = 0.89; 95% CI, 0.70 to 1.12, P = 0.32), and there was obvious evidence of statistical heterogeneity (P = 0.005; I2 = 68%). In addition, subgroup pooled analyses revealed that statin therapy did not ameliorate AVF failure in participants from the same racial background or similar sample size trials. There was no evidence that statins therapy could reduce the AVFs failure. However, due to methodological limitations and obvious statistical heterogeneity, high‐quality, long‐term and multicenter trials are required to fully elucidate the clinical value of statins administration for the outcomes of AVFs in HD patients.
Regional evidence and international recommendations to guide lipid management in Asian patients with type 2 diabetes with special reference to renal dysfunction
Authors: Lau Titus WL , Tan Kevin E.K. , Choo Jason C.J. , Ng Tsun‐Gun , Tavintharan Subramaniam , Chan Juliana C.N.
Published: September 2017

The anticipated increase in the prevalence and incidence of type 2 diabetes in Asia, and its associated cardiovascular–renal complications, will place a significant burden on patients, caregivers, and society. Despite the proven effectiveness of lipid management in reducing these complications, there are major treatment gaps, especially in Asian patients with young‐onset diabetes and chronic kidney disease (CKD). Recent international guidelines recommended the adoption of absolute risk estimation of atherosclerosis and cardiovascular disease to guide treatment intensity. These recommendations replaced the previous strategy of using low‐density lipoprotein cholesterol targets to guide initiation and intensification of lipid lowering, albeit still widely practiced in Asia. The latest guidelines also highlight the high risk of atherosclerosis and cardiovascular disease (ASCVD) for people with diabetes, who should be protected with statins, except for young patients without other risk factors, who will need yearly monitoring of blood lipid levels. Given the propensity of Asian patients with diabetes to develop CKD and the amplifying effect of CKD on ASCVD, the use of statins in Asian patients is particularly important. Due to interethnic differences in drug metabolism, rosuvastatin, which is largely cleared by the kidney, should be prescribed in low dosages (5–10 mg daily) in Asian populations. Conversely, epidemiological and experimental data confirm pleotropic and organ‐protective effects of atorvastatin, with proven safety in Asian populations within a daily dose range of 10–40 mg. Thus, there is a need for Asian countries to review and align their lipid‐lowering treatment guidelines to reduce the substantial burden of diabetes in the Asian region.
eSnail: A transcriptome‐based molecular resource of the central nervous system for terrestrial gastropods
Authors: Zhao Min , Wang Tianfang , Stewart Michael J. , Bose Utpal , Suwansa‐ard Saowaros , Storey Kenneth B. , Cummins Scott F.
Published: September 2017

To expand on emerging terrestrial gastropod molecular resources, we have undertaken transcriptome‐based sequencing of the central nervous system (CNS) from six ecologically invasive terrestrial gastropods. Focusing on snail species Cochlicella acuta and Helix aspersa and reticulated slugs Deroceras invadens, Deroceras reticulatum, Lehmannia nyctelia and Milax gagates, we obtained a total of 367,869,636 high‐quality reads and compared them with existing CNS transcript resources for the invasive Mediterranean snail, Theba pisana. In total, we obtained 419,289 unique transcripts (unigenes) from 1,410,569 assembled contigs, with blast search analysis of multiple protein databases leading to the annotation of 124,268 unigenes, of which 92,544 mapped to ncbi nonredundant protein databases. We found that these transcriptomes have representatives in most biological functions, based on comparison of gene ontology, kegg pathway and protein family contents, demonstrating a high range of transcripts responsible for regulating metabolic activities and molecular functions occurring within the CNS. To provide an accessible genetic resource, we also demonstrate the presence of 66,687 microsatellites and 304,693 single‐nucleotide variants, which can be used for the design of potentially thousands of unique primers for functional screening. An online “eSnail” database with a user‐friendly web interface was implemented to query all the information obtained herein (http://soft.bioinfo-minzhao.org/esnail). We demonstrate the usefulness of the database through the mining of molluscan neuropeptides. As the most comprehensive CNS transcriptome resource for terrestrial gastropods, eSnail may serve as a useful gateway for researchers to explore gastropod CNS function for multiple purposes, including for the development of biocontrol approaches.
Intensive vaginal dilation using adjuvant treatments in women with Mayer‐Rokitansky‐Kuster‐Hauser syndrome: retrospective cohort study
Authors: Ketheeswaran Ashradha , Morrisey Jennifer , Abbott Jason , Bennett Michael , Dudley Jan , Deans Rebecca
Published: September 2017

Aims

To evaluate the effect of adjuvants during intensive vaginal dilator therapy for functional and anatomical neovagina creation in women with Mayer‐Rokitansky‐Kuster‐Hauser syndrome (MRKH).

Methods

This retrospective cohort study included 75 women with MRKH undergoing intensive vaginal dilator treatment between 2000 and 2014. One specialist nurse performed non‐surgical vaginal dilation aided by adjuvants, during inpatient admissions for several dilation sessions per day. Following discharge, women continued dilation at home and were advised to attend fortnightly follow‐up appointments.

Results

Outcomes from 68 women were analysed. The median age of starting treatment was 18 years (range: 13–36). There was a mean of 3 days per admission (range 1–5) with a median of 10 dilation sessions per admission. Adjuvant treatment was used by 48/68 (71%) women: oestriol cream 29/68 (43%), 50:50 nitrous oxide and oxygen 44/68 (65%), diazepam 8/68 (12%), lidocaine ointment 26/68 (39%), paracetamol 35/68 (51%) and naproxen 2/68 (3%). There were no statistically significant differences for changes in vaginal parameters. Women receiving adjuvants had a median increase of 4.5 cm (0.5–7 cm) in neovaginal length compared with women not receiving adjuvants who had a median increase of 3.25 cm (0–7 cm) during intensive treatment. Women who received adjuvants tolerated more dilation sessions per day (10 vs 6.5 median sessions respectively) than those who did not (P < 0.001). Of those with documented length at discharge, 42/56 (75%) women had an anatomical neovagina of 7 cm or greater length.

Conclusions

Vaginal dilation delivered by intensive treatment and supplemented by adjuvant treatments in a multi‐disciplinary centre is a rapid and effective method for creation of a neovagina in women with MRKH.
The prevalence of atopic dermatitis beyond childhood: A systematic review and meta‐analysis of longitudinal studies
Authors: Abuabara K. , Yu A. M. , Okhovat J.‐P. , Allen I. E. , Langan S. M.
Published: September 2017

Background

There are sparse and conflicting data regarding the long‐term clinical course of atopic dermatitis (AD). Although often described as a childhood disease, newer population‐based estimates suggest the prevalence of pediatric and adult disease may be similar.

Methods

Our objective was to determine whether there is a decline in the prevalence of AD in population‐based cohorts of patients followed longitudinally beyond childhood. We conducted a systematic review and meta‐analysis including studies assessing AD prevalence across 3 or more points in time. The primary outcome was weighted overall risk difference (percentage decrease in AD prevalence).

Results

Of 2080 references reviewed, 7 studies with 13 515 participants were included. Participants were assessed at 3‐6 time points, ranging from age 3 months to 26 years. The percentage decrease in prevalence after age 12 was 1%, which was not significantly different from zero (95% confidence interval −2%‐5%). Similar results were found with other age cut‐offs.

Conclusion

The prevalence of AD in longitudinal birth cohort studies is similar in childhood and adolescence/early adulthood.