bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of sequencing depth on the inferred taxonomic composition and AMR gene content of metagenomic samples
Authors: Gweon H. Soon , Shaw Liam P. , Swann Jeremy , Maio Nicola De , AbuOun Manal , Hubbard Alasdair T. M. , Bowes Mike J. , Bailey Mark J. , Peto Tim E. A. , Hoosdally Sarah J. , Walker A. Sarah , Sebra Robert P. , Crook Derrick W. , Anjum Muna , Read Daniel S. , Stoesser Nicole ,   on behalf of the REHAB consortium
Published: April 2019

ABSTRACTBackgroundShotgun metagenomics is increasingly used to characterise microbial communities, particularly for the investigation of antimicrobial resistance (AMR) in different animal and environmental contexts. There are many different approaches for inferring the taxonomic composition and AMR gene content of complex community samples from shotgun metagenomic data, but there has been little work establishing the optimum sequencing depth, data processing and analysis methods for these samples. In this study we used shotgun metagenomics and sequencing of cultured isolates from the same samples to address these issues. We sampled three potential environmental AMR gene reservoirs (pig caeca, river sediment, effluent) and sequenced samples with shotgun metagenomics at high depth (∼200 million reads per sample). Alongside this, we cultured single-colony isolates ofEnterobacteriaceaefrom the same samples and used hybrid sequencing (short- and long-reads) to create high-quality assemblies for comparison to the metagenomic data. To automate data processing, we developed an open-source software pipeline, ‘ResPipe’.ResultsTaxonomic profiling was much more stable to sequencing depth than AMR gene content. 1 million reads per sample was sufficient to achieve <1% dissimilarity to the full taxonomic composition. However, at least 80 million reads per sample were required to recover the full richness of different AMR gene families present in the sample, and additional allelic diversity of AMR genes was still being discovered in effluent at 200 million reads per sample. Normalising the number of reads mapping to AMR genes using gene length and an exogenous spike ofThermus thermophilusDNA substantially changed the estimated gene abundance distributions. While the majority of genomic content from cultured isolates from effluent was recoverable using shotgun metagenomics, this was not the case for pig caeca or river sediment.ConclusionsSequencing depth and profiling method can critically affect the profiling of polymicrobial animal and environmental samples with shotgun metagenomics. Both sequencing of cultured isolates and shotgun metagenomics can recover substantial diversity that is not identified using the other methods. Particular consideration is required when inferring AMR gene content or presence by mapping metagenomic reads to a database. ResPipe, the open-source software pipeline we have developed, is freely available (https://gitlab.com/hsgweon/ResPipe).
Is mechanical receptor ligand dissociation driven by unfolding or unbinding?
Authors: Milles Lukas F. , Gaub Hermann E. 
Published: April 2019

ABSTRACTMechanical force can play a pivotal role in biological systems. Single Molecule Force Spectroscopy, is a powerful tool to probe the mechanics of proteins and their binding partners. Yet, it remains unclear how complex dissociation of a protein-protein interaction under mechanical forces occurs. Are receptor and ligand unbinding, or are they unfolding? We utilize an approach wherein receptor and ligand are expressed as a single molecule fused by a long flexible linker. Force is applied to the complex via an ultrastable handle. Consequently, the events during and following complex dissociation can be monitored. We investigate two high-affinity systems: The cohesin-dockerin type I interaction in which we find that a binding partner unfolds upon complex dissociation, and a colicin-immunity protein complex in which both proteins unfold completely upon unbinding. Mechanical receptor ligand dissociation thus can encompass unfolding of one or both binding partners.
Population receptive fields of human primary visual cortex organised as DC-balanced bandpass filters
Authors: Kristensen Daniel Gramm , Sandberg Kristian 
Published: April 2019

AbstractThe response to visual stimulation of population receptive fields (pRF) in the human visual cortex can be accurately modelled with a Difference of Gaussians model, yet many aspects of their organisation remain poorly understood. Here, we examined the theoretical underpinnings of this model and argue that the DC-balanced Difference of Gaussians (DoG) holds a number of advantages over a DC-biased DoG. Through functional magnetic resonance imaging (fMRI) pRF mapping, we compared performance of DC-balanced and DC-biased models in human primary visual cortex and found that when model complexity is taken into account, the DC-balanced model is preferred. Finally, we present evidence indicating that the BOLD signal DC-offset contains information related to the processing of visual stimuli. Taken together, the results indicate that V1 neurons are at least frequently organised in the exact constellation that allows them to function as bandpass-filters, which allows for the separation of stimulus contrast and luminance. We further speculate that if the DoG models stimulus contrast, the DC-offset may reflect stimulus luminance. These findings suggest that it may be possible to separate contrast and luminance processing in fMRI experiments and this could lead to new insights on the haemodynamic response.
Non-uniform Crowding Enhances Transport: Relevance to Biological Environments
Authors: Collins Matthew , Mohajerani Farzad , Ghosh Subhadip , Guha Rajarshi , Lee Tae-Hee , Butler Peter J. , Sen Ayusman , Velegol Darrell 
Published: April 2019

AbstractThe cellular cytoplasm is crowded with macromolecules and other species that occupy up to 40% of the available volume. Previous studies have reported that for high crowder molecule concentrations, colloidal tracer particles have a dampened diffusion due to the higher solution viscosity. However, these studies employed uniform distributions of crowder molecules. We report a scenario, previously unexplored experimentally, of increased tracer transport driven by a non-uniform concentration of crowder macromolecules. In gradients of polymeric crowder, tracer particles undergo transport several times higher than that of their bulk diffusion rate. The direction of the transport is toward regions of lower crowder concentration. Mechanistically, hard-sphere interactions and the resulting volume exclusion between the tracer and crowder increases the effective diffusion by inducing a convective motion of tracers. Strikingly, soft deformable particles show even greater enhancement in transport in crowder gradients compared to similarly sized hard particles. We propose a model that supports the data and quantifies a “diffusiophoretic buoyancy force” when a tracer is in a gradient of crowder concentration. Overall, this demonstration of enhanced transport in non-uniform distributions of crowder is anticipated to clarify aspects of multi-component intracellular transport.
Predicting the Frequency of Drug Side effects
Authors: Galeano Diego , Paccanaro Alberto 
Published: April 2019

AbstractDrug side effects are a leading cause of morbidity and mortality. Currently, the frequency of drug side effects is determined experimentally during human clinical trials through placebo-controlled studies. Here we present a novel framework to computationally predict the frequency of drug side effects. Our algorithm is based on learning a latent variable model for drugs and side effects by matrix decomposition. Extensive evaluations on held out test sets show that the frequency class is predicted with 67.8% to 94% accuracy in the neighborhood of the correct class. Evaluations on prospective data confirm the commonly held hypothesis that most post-marketing side effects are very rare in the population, with occurrences of less than 1 in a 10,000. Importantly, our model provides explanations of the biology underlying drug side effect relationships. We show that the drug latent representations in our model are related to distinct anatomical drug activities and that the similarity between these representations are predictive of the drug clinical activity as well as drug targets.One summary sentencenovel explainable machine learning algorithm predicts the frequency of drug side effects in the population
Septins Coordinate with Microtubules and Actin to Initiate Cell Morphogenesis
Authors: Bogorodskaya Diana , Ligon Lee A. 
Published: April 2019

AbstractMany organs are formed by a process of branching morphogenesis, which begins with the formation of cytoplasmic extensions from the basal surface of polarized cells in an epithelial sheet. To study this process, we used a system of polarized epithelial spheroids, which emit cytoplasmic extensions in response to treatment with hepatocyte growth factor. We found that these extensions contain both actin and microtubules, but also septins, which are localized to microtubule bundles and appear to be important in maintaining microtubule organization. We found that these extensions are highly dynamic and form at a non-linear rate. We also demonstrated that the coordinated activity of microtubules, actin, and septins is necessary for the formation and dynamic behavior of extensions. Each cytoskeletal system plays a district role in this process, with microtubules enabling persistent growth of the extensions, actin enabling extension dynamics, and septins organizing microtubules in the extensions and supporting the extension formation. Together, our data offer insights into the dynamics of early morphogenic extensions and the distinct, but coordinated, roles of cytoskeleton in early morphogenesis.
Exploring Structural Aspects of the Human Golgi Matrix Protein GRASP55 in Solution
Authors: Thirupathi Reddy S. , Santos Mendes Luis Felipe , Fontana Natalia Aparecida , Costa-Filho Antonio José 
Published: April 2019

AbstractIn mammalian cells, the Golgi apparatus is a central hub for intracellular trafficking, sorting and post-translational modifications of proteins and lipids. The Golgi reassembly and stacking proteins (GRASPs) are somehow involved in the Golgi stacking, which is significant for the proper function of the Golgi apparatus, and also in unconventional protein secretion. However, the structural details on how GRASPs accomplish those tasks are still elusive. In this context, we have explored the biochemical and biophysical properties of the human full-length GRASP55 in solution. Sequence-based analyses and circular dichroism spectroscopy suggest that GRASP55 presents multiple intrinsically disordered sites, although keeping considerable contents of secondary structure. Size exclusion chromatography coupled with multiple-angle light scattering (SEC-MALS) studies show that GRASP55 are monomers in solution. Urea denaturation of GRASP55 suggests that the transition to the unfolded state is a cooperative process. Differential scanning calorimetry (DSC) analysis displays two endothermic transitions for GRASP55, indicating the existence of an intermediate state prior to unfolding. Thioflavin T fluorescence shows that GRASP55 can form protein aggregates/fibrils at the intermediate state. Transmission electron microscopy and fluorescence lifetime imaging microscopy prove that GRASP55 forms large amorphous aggregates but not amyloid-like fibrils in the intermediate state. The significance of these results could be helpful in discussing the proper function of human GRASP55 in the Golgi organization as well as unconventional secretion of proteins.
High-throughput single nucleotide polymorphism (SNP) discovery and validation through whole-genome resequencing of hundreds of individuals in Nile tilapia (Oreochromis niloticus)
Authors: Yáñez J.M. , Yoshida G. , Barria A. , Palma-Véjares R. , Travisany D. , Díaz D. , Cáceres G. , Cádiz M.I. , López M.E. , Lhorente J.P. , Jedlicki A. , Soto J. , Salas D. , Maass A. 
Published: April 2019

ABSTRACTNile Tilapia (Oreochromis niloticus) is the second most important farmed fish in the world and a sustainable source of protein for human consumption. Several genetic improvement programs have been established for this species in the world and so far, they are mainly based on conventional selection using genealogical and phenotypic information to estimate the genetic merit of breeders and make selection decisions. Genome-wide information can be exploited to efficiently incorporate traits that are difficult to measure in the breeding goal. Thus, SNPs are required to investigate phenotype–genotype associations and determine the genomic basis of economically important traits. We performedde novoSNP discovery in three different populations of farmed tilapias. A total of 29.9 million non-redundant SNPs were identified through Illumina (HiSeq 2500) whole-genome resequencing of 326 individual samples. After applying several filtering steps including removing SNP based on genotype and site quality, presence of Mendelian errors, and non unique position in the genome, a total of high quality 50,000 SNP were selected for validation purposes. These SNPs were highly informative in the three populations analyzed showing between 43,869 (94%) and 46,139 (99%) SNP in HWE; 37,843 (76%) and 45,171(90%) SNP with a MAF higher than 0.05 and; 43,450 (87%) and 46,570 (93%) SNPs with a MAF higher than 0.01. The final list of 50K SNPs will be very useful for the dissection of economically relevant traits, enhancing breeding programs through genomic selection as well as supporting genetic studies in farmed populations Nile tilapia using dense genome-wide information.
DNA epigenetic marks are linked to reproductive aberrations in amphipods
Authors: Gorokhova Elena , Martella Giulia , Motwani Nisha H. , Tretyakova Natalia Y. , Sundelin Brita , Motwani Hitesh V. 
Published: April 2019

ABSTRACTLinking exposure to environmental contaminants with diseases is crucial for proposing preventive and regulatory actions. Upon exposure to anthropogenic chemicals, covalent modifications on the genome can drive developmental and reproductive disorders in wild populations, with subsequent effects on the population persistence. Hence, screening of chemical modifications on DNA can be used to provide information on the probability of such disorders in populations of concern. Using a high-resolution mass spectrometry methodology, we identified DNA nucleoside adducts in gravid females of the Baltic amphipodsMonoporeia affinis, and linked the adduct profiles to the frequency of embryo malformations in the broods. Twenty-three putative nucleoside adducts were detected in the females and their embryos, and eight modifications were structurally identified using high-resolution accurate mass data. To identify which adducts were significantly associated with embryo malformations, partial least squares regression (PLSR) modelling was applied. The PLSR model yielded three adducts as the key predictors: methylation at two different positions of the DNA (5-methyl-2’-deoxycytidine and N6-methyl-2’-deoxyadenosine) representing epigenetic marks, and a structurally unidentified nucleoside adduct. These adducts predicted the elevated frequency of the malformations with a high classification accuracy (84%). To the best of our knowledge, this is the first application of DNA adductomics for identification of contaminant-induced malformations in field-collected animals. The method can be adapted for a broad range of species and evolve as a new omics tool in environmental health assessment.
A comprehensive genome-scale model forRhodosporidium toruloidesIFO0880 accounting for functional genomics and phenotypic data
Authors: Dinh Hoang V. , Suthers Patrick F. , Chan Siu Hung Joshua , Shen Yihui , Xiao Tianxia , Deewan Anshu , Jagtap Sujit Sadashiv , Rabinowitz Joshua D. , Rao Christopher V. , Zhao Huimin , Maranas Costas D. 
Published: April 2019

AbstractBackgroundRhodosporidium toruloidesis a basidiomycetes yeast that can accumulate large amount of lipids and natively produce carotenoids. To better assess this non-model yeast’s metabolic capabilities, we reconstruct a genome-scale model ofR. toruloidesIFO0880’s metabolic network (iRhto1108) using recent functional genomics and phenotypic data in literature or generated herein.ResultsThe modeliRhto1108 accounts for 2,203 reactions, 1,985 metabolites and 1,108 genes. In this work, we integrate and supplement the current knowledge with in-house generated biomass composition and experimental measurements pertaining to the organism’s metabolic capabilities. Phenotype-genotype relationship predictions were improved through manual curation of gene-protein-reaction rules for 543 reactions and validations with gene essentiality data leading to correct recapitulations of 84.5% of gene essentiality data (sensitivity of 94.3% and specificity of 53.8%). Organism-specific macromolecular composition and ATP maintenance requirements were experimentally measured for two separate growth conditions: (i) carbon and (ii) nitrogen limitations. Overall,iRhto1108 reproducedR. toruloides’s utilization capabilities for 18 alternate substrates, matched measured wild-type growth yield, and recapitulated the viability of 772 out of 819 deletion mutants. As a demonstration to the model’s fidelity in guiding engineering interventions, the OptForce procedure was applied oniRhto1108 for the overproduction of triacylglycerol. Suggested interventions recapitulated many of the previously successfully implemented genetic modifications and put forth a few new ones.ConclusioniRhto1108 offers a highly curated model for a non-model yeast supported by multiple layers of experimental data that can be used to inform genetic interventions.
STELAR: A statistically consistent coalescent-based species tree estimation method by maximizing triplet consistency
Authors: Islam Mazharul , Sarker Kowshika , Das Trisha , Reaz Rezwana , Bayzid Md. Shamsuzzoha 
Published: April 2019

AbstractBackgroundSpecies tree estimation is frequently based on phylogenomic approaches that use multiple genes from throughout the genome. However, estimating a species tree from a collection of gene trees can be complicated due to the presence of gene tree incongruence resulting from incomplete lineage sorting (ILS), which is modelled by the multi-species coalescent process. Maximum likelihood and Bayesian MCMC methods can potentially result in accurate trees, but they do not scale well to large datasets.ResultsWe present STELAR (Species Tree Estimation by maximizing tripLet AgReement), a new fast and highly accurate statistically consistent coalescent-based method for estimating species trees from a collection of gene trees. We formalized the constrained triplet consensus (CTC) problem and showed that the solution to the CTC problem is a statistically consistent estimate of the species tree under the multi-species coalescent (MSC) model. STELAR is an efficient dynamic programming based solution to the CTC problem which is highly accurate and scalable. We evaluated the accuracy of STELAR in comparison with SuperTriplets, which is an alternate fast and highly accurate triplet-based supertree method, and with MP-EST and ASTRAL – two of the most popular and accurate coalescent-based methods. Experimental results suggest that STELAR matches the accuracy of ASTRAL and improves on MP-EST and SuperTriplets.ConclusionsTheoretical and empirical results (on both simulated and real biological datasets) suggest that STELAR is a valuable technique for species tree estimation from gene tree distributions.
A Human Tissue-Specific Transcriptomic Analysis Reveals that Ageing Hinders Cancer and Boosts Cellular Senescence
Authors: Chatsirisupachai Kasit , Palmer Daniel , Ferreira Susana , de Magalhães João Pedro 
Published: April 2019

AbstractAgeing is the biggest risk factor for cancer, but the mechanisms linking these two processes remain unclear. We compared genes differentially expressed with age and genes differentially expressed in cancer among nine human tissues. In most tissues, ageing and cancer gene expression surprisingly changed in the opposite direction. These overlapping gene sets were related to several processes, mainly cell cycle and the immune system. Moreover, cellular senescence signatures derived from a meta-analysis changed in the same direction as ageing and in the opposite direction of cancer signatures. Therefore, transcriptomic changes in ageing and cellular senescence might relate to a decrease in cell proliferation, while cancer transcriptomic changes shift towards an increase in cell division. Our results highlight the complex relationship between ageing, cancer and cellular senescence and suggest that in most human tissues ageing processes and senescence act in tandem while being detrimental to cancer. Our work challenges the traditional view concerning the relationship between cancer and ageing and suggests that ageing processes may hinder cancer development.
Single subunit degradation of WIZ, a lenalidomide- and pomalidomide-dependent substrate of E3 ubiquitin ligase CRL4CRBN
Authors: Yu Helen H. , Reitsma Justin M. , Sweredoski Mike J. , Moradian Annie , Hess Sonja , Deshaies Raymond J. 
Published: April 2019

AbstractImmunomodulators (IMiDs) are an effective class of drugs used to treat blood cancers. IMiDs are believed to work by recruiting protein targets containing a β-hairpin motif for ubiquitination by E3 ubiquitin ligase complexes composed of cereblon (CRBN), Cullin-4a (CUL4a), DNA Damage Binding protein-1 (DDB1), and Ring Box-1 (RBX1). The ubiquitinated protein is subsequently degraded by the proteasome. By characterizing the repertoire of proteins that show an increased physical association with CRBN after IMiD treatment, we identified a novel IMiD substrate, Widely Interspaced Zinc Finger Motifs (WIZ). WIZ contains a C2H2 zinc finger domain, like several other substrates that were previously characterized. We demonstrate that IMiDs stabilize physical association of WIZ with CRBN, deplete WIZ steady state protein levels in a way that is dependent on E3 ligase activity, and enhance the rate of its degradation. Notably, proteins that assemble with WIZ are co-recruited to CRBN by IMiDs but are not degraded, illustrating the potential of targeted protein degradation to eliminate individual subunits of a protein complex. These findings suggest that systematic characterization of the full repertoire of proteins that are targeted for degradation by IMiD compounds will be required to better understand their biological effects.SynopsisProteolysis Targeting Chimeras (PROTACs) can be used to precisely target a subunit of a transcriptional complex for degradation in subpopulations of cells.