bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep protein methylation profiling by combined chemical and immunoaffinity approaches reveals novel PRMT1 targets
Authors: Hartel Nicolas G. , Chew Brandon , Qin Jian , Xu Jian , Graham Nicholas A. 
Published: February 2019

ABSTRACTProtein methylation has been implicated in many important biological contexts including signaling, metabolism, and transcriptional control. Despite the importance of this post-translational modification, the global analysis of protein methylation by mass spectrometry-based proteomics has not been extensively studied due to the lack of robust, well-characterized techniques for methyl peptide enrichment. Here, to better investigate protein methylation, we optimized and compared two methods for methyl peptide enrichment: immunoaffinity purification (IAP) and high pH strong cation exchange (SCX). Comparison of these methods revealed that they are largely orthogonal for monomethyl arginine (MMA), suggesting that the usage of both techniques is required to provide a global view of protein methylation. Using both IAP and SCX, we investigated changes in protein methylation downstream of protein arginine methyltransferase 1 (PRMT1) and quantified ∼1,000 methylation sites on 407 proteins. Of these methylation sites, PRMT1 knockdown resulted in significant changes to 97 arginine methylation sites on 59 proteins. In contrast, zero lysine methylation sites were significantly changed upon PRMT1 knockdown. In PRMT1 knockdown cells, 84 MMA sites were either significantly downregulated or upregulated. PRMT1 knockdown also induced significant changes in both asymmetric dimethyl arginine (ADMA) and symmetric dimethyl arginine (SDMA), suggesting that loss of PRMT1 activity allows scavenging of PRMT1 substrates by other PRMTs. Using neutral loss fragmentation ions unique to ADMA and SDMA, we annotated dimethylarginines as either ADMA or SDMA. Through integrative analysis of methyl forms, we identified 12 high confidence PRMT1 substrates, 43 putative PRMT1 substrates, and 17 methylation sites that are scavenged by other non-PRMT1 arginine methyltransferases in the absence of PRMT1 activity. Taken together, our results suggest that deep protein methylation profiling by mass spectrometry requires orthogonal enrichment techniques to identify novel PRMT1 methylation targets and highlight the dynamic interplay between methyltransferases in mammalian cells.
The length of the expressed 3’ UTR is an intermediate molecular phenotype linking genetic variants to complex diseases
Authors: Mariella Elisa , Marotta Federico , Grassi Elena , Gilotto Stefano , Provero Paolo 
Published: February 2019

AbstractIn the last decades, genome wide association studies (GWAS) have uncovered tens of thousands of associations between common genetic variants and complex diseases. However, these statistical associations can rarely be interpreted functionally and mechanistically. As the majority of the disease-associated variants are located far from coding sequences, even the relevant gene is often unclear. A way to gain insight into the relevant mechanisms is to study the genetic determinants of intermediate molecular phenotypes, such as gene expression and transcript structure. We propose a computational strategy to discover genetic variants affecting the relative expression of alternative 3’ untranslated region (UTR) isoforms, generated through alternative polyadenylation, a widespread post-transcriptional regulatory mechanism known to have relevant functional consequences. When applied to a large dataset in which whole genome and RNA sequencing data are available for 373 European individuals, 2,530 genes with alternative polyadenylation quantitative trait loci (apaQTL) were identified. We analyze and discuss possible mechanisms of action of these variants, and we show that they are significantly enriched in GWAS hits, in particular those concerning immune-related and neurological disorders. Our results point to an important role for genetically determined alternative polyadenylation in affecting predisposition to complex diseases, and suggest new ways to extract functional information from GWAS data.
Large scale automated phylogenomical analysis of bacterial whole-genome isolates and the Evergreen platform
Authors: Szarvas Judit , Ahrenfeldt Johanne , Bellod Cisneros Jose Luis , Frølund Thomsen Martin Christen , Aarestrup Frank M. , Lund Ole 
Published: February 2019

AbstractPublic health authorities whole-genome sequence thousands of pathogenic isolates each month for microbial diagnostics and surveillance of pathogenic bacteria. The computational methods have not kept up with the deluge of data and need for real-time results.We have therefore created a bioinformatics pipeline for rapid subtyping and continuous phylogenomic analysis of bacterial samples, suited for large-scale surveillance. To decrease the computational burden, a two level clustering strategy is employed. The data is first divided into sets by matching each isolate to a closely related reference genome. The reads then are aligned to the reference to gain a consensus sequence and SNP based genetic distance is calculated between the sequences in each set. Isolates are clustered together with a threshold of 10 SNPs. Finally, phylogenetic trees are inferred from the non-redundant sequences and the clustered isolates are placed on a clade with the cluster representative sequence. The method was benchmarked and found to be accurate in grouping outbreak strains together, while discriminating from non-outbreak strains.The pipeline was applied in Evergreen Online, which processes publicly available sequencing data from foodborne bacterial pathogens on a daily basis, updating the phylogenetic trees as needed. It has so far placed more than 100,000 isolates into phylogenies, and has been able to keep up with the daily release of data. The trees are continuously published on https://cge.cbs.dtu.dk/services/Evergreen
Link Your Sites (LYS) Scripts: Automated search of protein structures and mapping of sites under positive selection detected by PAML
Authors: Moreta Lys Sanz , da Fonseca Rute R. 
Published: February 2019

ABSTRACTThe visualization of the molecular context of an amino acid mutation in a protein structure is crucial for the assessment of its functional impact and to understand its evolutionary implications. Currently, searches for fast evolving amino acid positions using codon substitution models like those implemented in PAML [1] are done in almost complete proteomes, generating large numbers of candidate proteins that require individual structural analyses. Here we present two python wrapper scripts as the package Link Your Sites (LYS). The first one i) mines the RCSB database [10] using the blast alignment tool to find the best matching homologous sequences, ii) fetches their domain positions by using Prosites [3,8,9], iii) parses the output of PAML extracting the positional information of fast-evolving sites and transform them into the coordinate system of the protein structure, iv) outputs a file per gene with the positions correlations to its homologous sequence. The second script uses the output of the first one to generate the protein’s graphical assessment. LYS can therefore generate figures to be used in publication highlighting the positively selected sites mapped on regions that are known to have functional relevance and/or be used to reduce the number of targets that will be further analyzed by providing a list of those for which structural information can be retrieved.MotivationAutomatizing the search for protein structures to assess the functional impact of sites found to be under positive selection by codeml, implemented in PAML [1]. Building publication-quality figures highlighting the sites on a protein structure model that are within and outside functional domains. reduces the workload associated with selecting proteins for which a functional assessment of the impact of mutations can be done using a protein structure. This is especially relevant when analyzing almost complete proteomes which is the case of large comparative genomic studies.SoftwareLYS scripts are executed in the command line. They automatically search for homologous proteins at the RSCB database [10], determine the functional domain locations and correlate the positions pointed by the M8 model [1], and output a data frame that can be used as the input by PyMOL [7] to generate a visualization of the results.AvailabilityLYS is easy to install and implement and they are available at https://github.com/LysSanzMoreta/LYSAutomaticSearch
Cranial anatomy of the predatory actinopterygianBrazilichthys macrognathusfrom the Permian (Cisuralian) Pedra de Fogo Formation, Parnaíba Basin, Brazil
Authors: Figueroa Rodrigo T. , Friedman Matt , Gallo Valéria 
Published: February 2019

ABSTRACTBrazilichthys macrognathusis the only named actinopterygian from the Permain (Cisuralian) Pedra de Fogo Formation of northeastern Brazil, where it is represented by a single three-dimensionally preserved but incompletely described skull of unclear systematic placement. We used X-ray computed microtomography (μ-CT) to better document its anatomy and phylogenetic affinities. μ-CT reveals parts of the internal skeleton. We correct errors in original description, including the number of infraorbital bones and the misidentification of the dermosphenotic as sclerotic ossifications. These reinterpretations of external anatomy are joined by new data on internal structure, including the palate, parasphenoid, and branchial and hyoid arches. A maximum parsimony analysis of anatomical data resolvesBrazilichthysas a stem actinopterygian, crownward of all Devonian species. This placement is supported by the absence of a dermosphenotic posterior ramus and the presence of opercular process of the hyomandibula. A similar placement is suggested by a Bayesian analysis of this same dataset, although relationships throughout the tree are less resolved. Our results reject previous interpretations ofBrazilichthysas a relative of Birgeriidae, a Triassic group consistently placed within the actinopterygian crown. AlthoughAcrolepisis too poorly known to be included in our analysis, we also reject a close relationship between this taxon andBrazilichthys, as their only shared similarities appear to be broadly distributed among early actinopterygians.
Sex biased expression and co-expression networks in development, using the hymenopteran Nasonia vitripennis
Authors: Rago Alfredo , Werren John (Jack) H , Colbourne John K 
Published: February 2019

ABSTRACTSexual dimorphism requires gene expression regulation in developing organisms. Differential expression, alternative splicing and transcript-transcript interactions all contribute to developmental differences between the sexes. However, few studies have described how these processes change across developmental stages, or how they interact to form co-expression networks. We compare the dynamics of all three regulatory processes in the sexual development of the model parasitoid wasp Nasonia vitripennis, a system that permits genome wide analysis of sex bias from early embryos to adults. We find relatively little sex-bias in embryos and larvae at the whole-gene level, but several sub-networks show sex-biased transcript-transcript interactions in early developmental stages. These provide new candidates for hymenopteran sex determination, including histone modification genes. In contrast, sex-bias in pupae and adults is driven by whole-gene differential expression. We observe sex-biased splicing consistently across development, but mostly in genes that are already biased at the whole-gene level. Finally, we discover that sex-biased networks are enriched by genes specific to the Nasonia clade, and that those genes possess the topological properties of key regulators. These findings suggest that regulators in sex-biased networks evolve more rapidly than regulators of other developmental networks.
Sulfur-oxidizing symbionts without canonical genes for autotrophic CO2fixation
Authors: Seah Brandon K. B. , Antony Chakkiath Paul , Huettel Bruno , Zarzycki Jan , Borzyskowski Lennart Schada von , Erb Tobias J. , Kouris Angela , Kleiner Manuel , Liebeke Manuel , Dubilier Nicole , Gruber-Vodicka Harald R. 
Published: February 2019

AbstractSince the discovery of symbioses between sulfur-oxidizing (thiotrophic) bacteria and invertebrates at hydrothermal vents over 40 years ago, it has been assumed that autotrophic fixation of CO2by the symbionts drives these nutritional associations. In this study, we investigatedCandidatusKentron, the clade of symbionts hosted byKentrophoros, a diverse genus of ciliates which are found in marine coastal sediments around the world. Despite being the main food source for their hosts, Kentron lack the key canonical genes for any of the known pathways for autotrophic fixation, and have a carbon stable isotope fingerprint unlike other thiotrophic symbionts from similar habitats. Our genomic and transcriptomic analyses instead found metabolic features consistent with growth on organic carbon, especially organic and amino acids, for which they have abundant uptake transporters. All known thiotrophic symbionts have converged on using reduced sulfur to generate energy lithotrophically, but they are diverse in their carbon sources. Some clades are obligate autotrophs, while many are mixotrophs that can supplement autotrophic carbon fixation with heterotrophic capabilities similar to those in Kentron. We have shown that Kentron are the only thiotrophic symbionts that appear to be entirely heterotrophic, unlike all other thiotrophic symbionts studied to date, which possess either the Calvin-Benson-Bassham or reverse tricarboxylic acid cycles for autotrophy.Significance StatementMany animals and protists depend on symbiotic sulfur-oxidizing bacteria as their main food source. These bacteria use energy from oxidizing inorganic sulfur compounds to make biomass autotrophically from CO2, serving as primary producers for their hosts. Here we describe apparently non-autotrophic sulfur symbionts called Kentron, associated with marine ciliates. They lack genes for known autotrophic pathways, and have a carbon stable isotope fingerprint heavier than other symbionts from similar habitats. Instead they have the potential to oxidize sulfur to fuel the uptake of organic compounds for heterotrophic growth, a metabolic mode called chemolithoheterotrophy that is not found in other symbioses. Although several symbionts have heterotrophic features to supplement primary production, in Kentron they appear to supplant it entirely.
Intraspecific Variation in Microsatellite Mutation Profiles in Daphnia magna
Authors: Ho Eddie K. H. , Macrae Fenner , Latta Leigh C. , Benner Maia J. , Sun Cheng , Ebert Dieter , Schaack Sarah 
Published: February 2019

AbstractMicrosatellite loci (tandem repeats of short nucleotide motifs) are highly abundant in eukaryotic genomes and are often used as genetic markers because they can exhibit variation both within and between populations. Although widely recognized for their mutability and utility, the mutation rates of microsatellites have only been empirically estimated in a few species and have rarely been compared across genotypes and populations and intraspecific differences in overall microsatellite content have rarely been explored. To investigate the accumulation of microsatellite DNA over long-and short-time periods, we quantified the abundance and genome-wide mutation rates in whole-genome sequences of 47 mutation accumulation (MA) lines and 12 non-MA lines derived from six different genotypes of the crustacean Daphnia magna collected from three populations (Finland, Germany, and Israel). Each genotype possessed a distinctive microsatellite profile and clustered according to their population of origin. During the period of mutation accumulation, we observed very high microsatellite mutation rates (a net change of −0.19 to 0.33 per copy per generation), which surpass rates reported from a closely-related congener, D. pulex, by an order of magnitude. Rates vary between microsatellite motifs and among genotypes, with those starting with high microsatellite content exhibiting greater losses and those with low microsatellite content exhibiting greater gains. Our results show that microsatellite mutation rates depend both on characteristics of the microsatellites and the genomic background. These context-dependent mutation dynamics may, in conjunction with other evolutionary forces that may differ among populations, explain the differential accumulation of repeat content in the genome over long time periods.
Deciphering the Genetics of Major End-Use Quality Traits in Wheat
Authors: Naraghi Sepehr Mohajeri , Simsek Senay , Kumar Ajay , Rabbi S.M. Hisam Al , Alamri Mohammed S. , Elias Elias M. , Mergoum Mohamed 
Published: February 2019

AbstractImproving the end-use quality traits is one of the primary objectives in wheat breeding programs. In the current study, a population of 127 recombinant inbred lines (RILs) derived from a cross between Glenn (PI-639273) and Traverse (PI-642780) was developed and used to identify quantitative trait loci (QTL) for 16 end-use quality traits in wheat. The phenotyping of these 16 traits was performed in nine environments in North Dakota, USA. The genotyping for the RIL population was conducted using the wheat Illumina iSelect 90K SNP assay. A high-density genetic linkage map consisting of 7,963 SNP markers identified a total of 76 additive QTL (A-QTL) and 73 digenic epistatic QTL (DE-QTL) associated with these traits. Overall, 12 stable major A-QTL and three stable DE-QTL were identified for these traits, suggesting that both A-QTL and DE-QTL played an important role in controlling end-use quality traits in wheat. The most significant A-QTL (AQ.MMLPT.ndsu.1B) was detected on chromosome 1B for mixograph middle line peak time. TheAQ.MMLPT.ndsu.1BA-QTL was located very close to the position of the Glu-B1 gene encoding for a subunit of high molecular weight glutenin and explained up to 24.43% of phenotypic variation for mixograph MID line peak time. A total of 23 co-localized QTL loci were detected, suggesting the possibility of the simultaneous improvement of the end-use quality traits through selection procedures in wheat breeding programs. Overall, the information provided in this study could be used in marker-assisted selection to increase selection efficiency and to improve the end-use quality in wheat.
Characterization of prevalence and health consequences of uniparental disomy in four million individuals from the general population
Authors: Nakka Priyanka , Smith Samuel Pattillo , O’Donnell-Luria Anne H. , McManus Kimberly F. ,   23andMe Research Team, Mountain Joanna L. , Ramachandran Sohini , Sathirapongsasuti J. Fah 
Published: February 2019

SummaryMeiotic nondisjunction and resulting aneuploidy can lead to severe health consequences in humans. Aneuploidy rescue can restore euploidy but may result in uniparental disomy (UPD), the inheritance of both homologs of a chromosome from one parent with no representative copy from the other. Current understanding of UPD is limited to ~3,300 cases for which UPD was associated with clinical presentation due to imprinting disorders or recessive diseases. Thus, the prevalence of UPD and its phenotypic consequences in the general population are unknown. We searched for instances of UPD in over four million consented research participants from the personal genetics company 23andMe, Inc., and 431,094 UK Biobank participants. Using computationally detected DNA segments identical-by-descent (IBD) and runs of homozygosity (ROH), we identified 675 instances of UPD across both databases. Here we present the first characterization of UPD prevalence in the general population, a machine-learning framework to detect UPD using ROH, and a novel association between autism and UPD of chromosome 22.
Integrating Biomedical Research and Electronic Health Records to Create Knowledge Based Biologically Meaningful Machine Readable Embeddings
Authors: Nelson Charlotte A. , Butte Atul J. , Baranzini Sergio E. 
Published: February 2019

ABSTRACTIn order to advance precision medicine, detailed clinical features ought to be described in a way that leverages current knowledge. Although data collected from biomedical research is expanding at an almost exponential rate, our ability to transform that information into patient care has not kept at pace. A major barrier preventing this transformation is that multi-dimensional data collection and analysis is usually carried out without much understanding of the underlying knowledge structure. In an effort to bridge this gap, Electronic Health Records (EHRs) of individual patients were connected to a heterogeneous knowledge network called Scalable Precision Medicine Oriented Knowledge Engine (SPOKE). Then an unsupervised machine-learning algorithm was used to create Propagated SPOKE Entry Vectors (PSEVs) that encode the importance of each SPOKE node for any code in the EHRs. We argue that these results, alongside the natural integration of PSEVs into any EHR machine-learning platform, provide a key step toward precision medicine.
Fingerprinting Adiposity and Metabolic Function in the Brains of Overweight and Obese Humans
Authors: Farruggia Michael C. , Van Kooten Maria J. , Burke Mary V. , Scheinost Dustin , Todd Constable R. , Small Dana M. 
Published: February 2019

AbstractThe brain plays a central role in the pathophysiology of obesity. Connectome-based Predictive Modeling (CPM) is a newly developed, data-driven approach that exploits whole-brain functional connectivity to predict a behavior or trait that varies across individuals. We used CPM to determine whether brain “fingerprints” evoked during milkshake consumption could be isolated for common measures of adiposity in 67 overweight and obese adults. We found that a CPM could be identified for waist circumference, but not percent body fat or BMI, the most frequently used measures to assess brain correlates of obesity. In an exploratory analysis, we were also able to derive a largely distinct CPM predicting fasting blood insulin. These findings demonstrate that brain network patterns are more tightly coupled to waist circumference than BMI or percent body fat and that adiposity and glucose tolerance are associated with distinct maps, pointing to dissociable central pathophysiological phenotypes for obesity and diabetes.
Immunization with recombinant enolase ofSporothrixspp (rSsEno) confers effective protection against sporotrichosis in mice
Authors: Fuentes Deivys Leandro Portuondo , Dores-Silva Paulo Roberto , Ferreira Lucas Souza , Téllez-Martínez Damiana , Marcos Caroline Maria , de Aguiar Loesch Maria Luiza , Quimbayo Fanny Guzmán , Borges Júlio César , Batista-Duharte Alexander , Carlos Iracilda Zeppone 
Published: February 2019

AbstractIn recent years, research has focused on the immunoreactive components of theS. schenckiicell wall that can be relevant targets for preventive and therapeutic vaccines against sporotrichosis, an emergent worldwide mycosis. In previous studies, we identified a 47-kDa enolase as an immunodominant antigen in mice vaccinated with purified fungal wall proteins and adjuvants. In this study, the immunolocalization of this immunogen in the cell wall ofS. schenckiiandS. brasiliensisis shown for the first time. In addition, a recombinant enolase ofSporothrixspp (rSsEno) was studied with the adjuvant Montanide Pet-GelA (PGA) as a vaccine candidate. The rSsEno was produced with high purity. In addition, mice immunized with rSsEno plus PGA showed increased antibody titers against enolase and increased median survival time comparedto nonimmunized or rSsEno-immunized mice. Enolase immunization induced a predominant T-helper-1 (Th1) cytokine pattern in splenic cells after in vitro stimulation with rSsEno. Elevated production of interferon-γ (IFN-γ) and interleukin-2 (IL-2) was observed with other cytokines involved in the innate immune defense, such as TNF-alpha, IL-6, and IL-4, which are necessary for antibody production. These results suggest that we should continue testing this antigen as a potential vaccine candidate against sporotrichosis.