bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypically distinct human sequence is widespread in publicly archived microbial reads: an evaluation of methods for its detection
Authors: Bush Stephen J. , Connor Thomas R. , Peto Tim E. A. , Crook Derrick W. , Walker A. Sarah 
Published: December 2019

AbstractSequencing data from host-associated microbes can often be contaminated by the body of the investigator or research subject. Human DNA is typically removed from microbial reads either by subtractive alignment (dropping all reads that map to the human genome) or using a read classification tool to predict those of human origin, and then discarding them. To inform best practice guidelines, we benchmarked 8 alignment-based and 2 classification-based methods of human read detection using simulated data from 10 clinically prevalent bacteria and 3 viruses, into which contaminating human reads had been added.While the majority of methods successfully detected > 99% of the human reads, they were distinguishable by variance. The most precise methods, with negligible variance, were Bowtie2 and SNAP, both of which misclassified few, if any, bacterial reads (and no viral reads) as human. While correctly detecting a similar number of human reads, methods based on taxonomic classification, such as Kraken2 and Centrifuge, often misclassified bacterial reads as human, the extent of which was species-specific. Among the most sensitive methods of human read detection was BWA, although this also made the greatest number of false positive classifications. Across all methods, the set of human reads not identified as such, although often representing < 0.1% of the total reads, were non-randomly distributed along the human genome with many originating from the repeat-rich sex chromosomes.For viral reads and longer (> 300bp) bacterial reads, the highest performing approaches were classification-based, using Kraken2 or Centrifuge. For shorter (150-300bp) bacterial reads, combining multiple methods of human read detection maximised the recovery of human reads from contaminated short read datasets without being compromised by false positives. The highest-performing approach with shorter bacterial reads was a two-stage classification using Bowtie2 followed by SNAP. Using this approach, we re-examined 11,577 publicly archived bacterial readsets for hitherto undetected human contamination. We were able to extract a sufficient number of reads to call known human SNPs, including those with clinical significance, in 6% of the samples. These results show that phenotypically-distinct human sequence is widespread in publicly-archived (and nominally pure) bacterial datasets.
Protective microbe enhances colonisation of a novel host species by modifying immune gene expression
Authors: Ford Suzanne A. , King Kayla C. 
Published: December 2019

AbstractMicrobes that protect against infection inhabit hosts across the tree of life. It is unclear whether many protective microbes use or reduce the need for a host immune response, or how the immune system reacts when these microbes newly encounter a host species naturally and as part of a biocontrol strategy. We sequenced the transcriptome of a host (Caenorhabditis elegans) following its interaction with a non-native bacterium (Enterococcus faecalis) that has protective traits against the pathogen, Staphylococcus aureus. We show that microbe-mediated protection caused the differential expression of 1,557 genes, including the upregulation of many immune gene families conserved across the animal kingdom (e.g. lysozymes and c-type lectins). We found that this modulation of the host’s immune response was beneficial for both the protective microbe and the host. Given E. faecalis’ increased ability to resist lysozyme activity compared to S. aureus, our results indicate that the protective microbe could more easily invade and protect infected hosts by upregulating lysozyme genes. These results suggest that a protective microbe can exploit the host immune system even when introduced into a novel species. Microbes that protect via the host immune response in this way should favour continued investment into host immunity and avoid the evolution of host dependence.Author summaryOrganisms can be protected from infectious disease by the microbes they house. It is unclear, however, whether protective microbes affect the host immune response to infection, particularly in the early stages of symbiosis. In this study, we investigated the role of the host immune system in a novel protective interaction. We examined gene expression in a nematode after colonisation by a non-native microbe capable of suppressing the pathogen Staphylococcus aureus. The protective microbe altered the host immune response to infection in a way that it could exploit. By causing the host to increase the production of antimicrobials to which it itself is relatively resistant, the protective microbe was better able to colonise and defend infected hosts. These results indicate that protective microbes introduced into new host species can take advantage of the host immune system. Such a mechanism at the beginning of a protective symbiosis, formed either naturally or as part of a biocontrol strategy, could ensure continued investment in host-based defences over evolutionary time.
Sterols as dietary markers forDrosophila melanogaster
Authors: Knittelfelder Oskar , Prince Elodie , Sales Susanne , Fritzsche Eric , Wöhner Thomas , Brankatschk Marko , Shevchenko Andrej 
Published: December 2019

AbstractDuring cold acclimation fruit flies switch their feeding from yeast to plant food, however there are no robust markers to monitor it in the wild.Drosophila melanogasteris a sterol auxotroph and relies on dietary sterols to produce lipid membranes, lipoproteins and molting hormones. We employed shotgun lipidomics to quantify eight major food sterols in total extracts of heads, female and male genital tracts of adult flies. We found that their sterol composition is dynamic and reflective of flies diet in an organ-specific manner. Season-dependent changes observed in the organs of wild-living flies suggested that the molar ratio between yeast (ergosterol, zymosterol) and plant (sitosterol, stigmasterol) sterols is a quantifiable, generic and unequivocal marker of their feeding behavior, including cold acclimation. It provides technically simpler and more contrast readout compared to the full lipidome analysis and is suitable for ecological and environmental population-based studies.
Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice
Authors: Abato Jamie E. , Moftah Mahira , Cron Greg O. , Smith Patrice D. , Jadavji Nafisa M. 
Published: December 2019

AbstractObjectiveElevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C➔T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr+/− mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury.MethodsIn the present study, three-month-old male Mthfr+/− and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected.ResultsMthfr+/− animals used their non-impaired forepaw more during to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr+/− mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide dismutase 2 (SOD2).ConclusionsOur results suggest that Mthfr+/− mice are more vulnerable to PT-induced stroke damage through regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.
Further evidence of increased human Herpesvirus in Alzheimer’s disease
Authors: Readhead Ben , Haure-Mirande Jean-Vianney , Ehrlich Michelle E. , Gandy Sam , Dudley Joel T. 
Published: December 2019

AbstractThe recent coordination of scientific and political efforts within the field of Alzheimer’s disease (AD) research coupled with the rapid evolution of molecular profiling technologies has enabled the generation of unprecedented repositories of biological sequence data available for investigation by the scientific community. Next-generation sequences (NGS) represent complex readouts of cellular transcriptomic and genomic states, and hold the potential to illuminate disease biology via unexpected applications of collected data. We recently reported a multiomic study of the Alzheimer’s associated brain virome, leveraging NGS data to understand the potential relevance of viral activity to AD. We observed increased abundance of human herpesvirus 6A (HHV-6A), HHV-7, and herpes simplex virus 1 (HSV-1) genomes in banked postmortem brains from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. Although these findings might be of general interest to the field, such analyses present novel methodological challenges that have not been well characterized. The viral abundances that we detected were generally quite low, and, in many samples, no virome was detected. We sought to understand whether such sparsity might be associated with the spurious detection of differential abundance. Herein, we employ a simulation approach, which indicates that sparsity in abundance actually biases against the detection of significant differences between AD and control subjects. We also report new results based on previously unpublished whole genome sequences that show increases in both abundance and prevalence of HHV-6A in AD, consistent with our previously reported results. These findings, as well as reports from many other groups employing a variety of approaches, support the dedication of a coordinated effort toward a comprehensive characterization of the microbiome of the brain affected by AD. Such studies should advance our understanding of the potential clinical relevance of these observations.
Genome-wide Association Study of Pediatric Obsessive-Compulsive Traits: Shared Genetic Risk between Traits and Disorder
Authors: Burton Christie L. , Lemire Mathieu , Xiao Bowei , Corfield Elizabeth C. , Erdman Lauren , Bralten Janita , Poelmans Geert , Yu Dongmei , Shaheen S-M , Goodale Tara ,   OCD Working Group of the Psychiatric Genomics Consortium, Soreni Noam , Hanna Gregory L. , Fitzgerald Kate D. , Rosenberg David , Nestadt Gerry , Paterson Andrew D. , Strug Lisa , Schachar Russell J. , Crosbie Jennifer , Arnold Paul D. 
Published: December 2019

AbstractObjectiveTo identify genetic variants associated with obsessive-compulsive (OC) traits and test for sharing of genetic risks between OC traits and obsessive-compulsive disorder (OCD).MethodsWe conducted a genome-wide association analysis of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of three OCD case-controls samples (cases=3384, controls=8363). Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses.ResultsA locus tagged by rs7856850 in an intron ofPTPRD(protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p=2.48×10−8). The rs7856850 locus was also associated with OCD in a meta-analysis of three independent OCD case/control genome-wide datasets (p=0.0069). Polygenic risk scores derived from OC traits were significantly associated with OCD in a sample of childhood-onset OCD and vice versa (p’s<0.01). OC traits were highly but not significantly genetically correlated with OCD (rg=0.83,p=0.07).ConclusionsWe report the first validated genome-wide significant variant for OC traits. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the importance of the type of measure used to measure traits as well as the feasibility and power of using trait-based approaches in community samples for genetic discovery.
Multi-Model and Network Inference Based on Ensemble Estimates: Avoiding the Madness of Crowds
Authors: Stumpf Michael P.H. 
Published: December 2019

AbstractRecent progress in theoretical systems biology, applied mathematics and computational statistics allows us to compare quantitatively the performance of different candidate models at describing a particular biological system. Model selection has been applied with great success to problems where a small number — typically less than 10 — of models are compared, but recently studies have started to consider thousands and even millions of candidate models. Often, however, we are left with sets of models that are compatible with the data, and then we can use ensembles of models to make predictions. These ensembles can have very desirable characteristics, but as I show here are not guaranteed to improve on individual estimators or predictors. I will show in the cases of model selection and network inference when we can trust ensembles, and when we should be cautious. The analyses suggests that the careful construction of an ensemble – choosing good predictors – is of paramount importance, more than had perhaps been realised before: merely adding different methods does not suffice. The success of ensemble network inference methods is also shown to rest on their ability to suppress false-positive results. A Jupyter notebook which allows carrying out an assessment of ensemble estimators is provided.
Multiversal SpaceTime (MSpaceTime) Not Neural Network as Source of Intelligence in Generalized Quantum Mechanics, Extended General Relativity, Darwin Dynamics for Artificial Super Intelligence Synthesis
Authors: Zhang Yang 
Published: December 2019

AbstractFrom Synthesis perspective, whether Logic Synthesis, Physical Synthesis, Chemical Synthesis, or Biological Synthesis, Physical Geometry such as Universal Geometry and Quantum Geometry, and Biological Geometry like Conformal Geometry supported by Tensors and Manifolds, are the outcome of physical laws and biological laws in modeling non-linear physical and biological dynamics as opposed to traditional partial differential/difference equation way. We discover that Multiversal SpaceTime instead of Neural Network, governing physical and biological world at macroscopic and microscopic level, is the ultimate source of intelligence. With that we propose Multiversal Synthesis-based Artificial Design Automation (ADA), a bio-physical inspired model based on Multiverse in Darwin Dynamics, Generalized Quantum Mechanics, and Extended General Relativity, for Artificial Super Intelligence (ASI) implementation. Based on Schrodinger Equation of Quantum Mechanics, we generalize the 4-Dimensional Hilbert Space based Discrete Quantum SpaceTime to N-Dimensional (1 ≪N<M, with M is limited by Planck Length) Hilbert Space based Discrete MSpaceTime as part of MSpaceTime, in modeling both Micro-Environment Intelligence and Micro-Agent Intelligence of ASI; likewise based on Einstein Equations of General Relativity, we make a T-Symmetry extension first, and then extend the 4-Dimensional Pseudo-Riemannian Manifold based Continuous Curved SpaceTime as part of MSpaceTime to N-Dimensional (1 ≪N< ∞) Pseudo-Riemannian Manifold based Continuous MSpaceTime extension, in modeling both Macro-Environment Intelligence and Macro-Agent Intelligence of ASI. Our discovery only solves the black box puzzle of AI, but also paves the way in achieving ASI through ADA. Of course, our Multiverse Endeavor will never stop from there.
Network Inference from Multi-omic Data Uncovers Dynamic Transcriptional Regulation Modules in Pathogenic Fungus Fusarium graminearum
Authors: Guo Li , Ji Mengjie , Ye Kai 
Published: December 2019

ABSTRACTThe filamentous fungus Fusarium graminearum causes devastating crop disease and produces harmful mycotoxins worldwide. Understanding the complex F. graminearum transcriptional regulatory networks (TRNs) is vital for effective disease management. Reconstructing F. graminearum dynamic TRNs, an NP-hard problem, remains unsolved using commonly adopted reductionist or co-expression based approaches. Multi-omic data such as fungal genomic, transcriptomic data and phenomic data are vital to but so far have been largely isolated and untapped for unraveling phenotype-specific TRNs. Here for the first time, we harnessed these resources to infer global TRNs for F. graminearum using a Bayesian network based algorithm, “module networks”. The inferred TRNs contain 49 regulatory modules that show condition-specific gene regulation. Through a robust validation based on prior biological knowledge including functional annotations and TF binding site enrichment, our network prediction displayed high accuracy and concordance with existing knowledge, highlighted by its accurate capture of the well-known trichothecene gene cluster. In addition, we developed a new computational method to calculate the associations between modules and phenotypes, and discovered subnetworks responsible for fungal virulence, sexual reproduction and mycotoxin production. Finally, we found a clear compartmentalization of TRN modules in core and lineage-specific genomic regions in F. graminearum, reflecting the evolution of the TRNs in fungal speciation. This system-level reconstruction of filamentous fungal TRNs provides novel insights into the intricate networks of gene regulation that underlie key processes in F. graminearum pathobiology and offers promise for the development of improved disease control strategies.
Optogenetic control of Neisseria meningitidis Cas9 genome editing using an engineered, light-switchable anti-CRISPR protein
Authors: Hoffmann Mareike D. , Mathony Jan , Upmeier zu Belzen Julius , Harteveld Zander , Stengl Christina , Correia Bruno E. , Eils Roland , Niopek Dominik 
Published: December 2019

ABSTRACTOptogenetic control of CRISPR-Cas9 systems has significantly improved our ability to perform genome perturbations in living cells with high precision in time and space. As new Cas orthologues with advantageous properties are rapidly being discovered and engineered, the need for straightforward strategies to control their activity via exogenous stimuli persists. The Cas9 from Neisseria meningitidis (Nme) is a particularly small and target-specific Cas9 orthologue, and thus of high interest for in vivo genome editing applications.Here, we report the first optogenetic tool to control NmeCas9 activity in mammalian cells via an engineered, light-dependent anti-CRISPR (Acr) protein. Building on our previous Acr engineering work, we created hybrids between the NmeCas9 inhibitor AcrIIC3 and the LOV2 blue light sensory domain from Avena sativa. Two AcrIIC3-LOV2 hybrids from our collection potently blocked NmeCas9 activity in the dark, while permitting robust genome editing at various endogenous loci upon blue light irradiation. Structural analysis revealed that, within these hybrids, the LOV2 domain is located in striking proximity to the Cas9 binding surface. Together, our work demonstrates optogenetic regulation of a type II-C CRISPR effector and might suggest a new route for the design of optogenetic Acrs.
Building a better biofilm - formation of in vivo-like biofilm structures by Pseudomonas aeruginosa in a porcine model of cystic fibrosis lung infection
Authors: Harrington Niamh E. , Sweeney Esther , Harrison Freya 
Published: December 2019

AbstractPseudomonas aeruginosa biofilm infections in the cystic fibrosis (CF) lung are highly resistant to current antimicrobial treatments and are associated with increased mortality rates. The existing models for such infections are not able to reliably mimic the clinical biofilms observed. We aimed to further optimise an ex vivo pig lung (EVPL) model for P. aeruginosa CF lung infection that can be used to increase understanding of chronic CF biofilm infection. The EVPL model will facilitate discovery of novel infection prevention methods and treatments, and enhanced exploration of biofilm architecture. We investigated purine metabolism and biofilm formation in the model using transposon insertion mutants in P. aeruginosa PA14 for key genes: purD, gacA and pelA. Our results demonstrate that EVPL recapitulates a key aspect of in vivo P. aeruginosa infection metabolism, and that the pathogen forms a biofilm with a clinically realistic structure not seen in other in vitro studies. Two pathways known to be required for in vivo biofilm infection - the Gac regulatory pathway and production of the Pel exopolysaccharide - are essential to the formation of this mature, structured biofilm on EVPL tissue. We propose the high-throughput EVPL model as a validated biofilm platform to bridge the gap between in vitro and CF lung infection.
The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M2receptor subtype
Authors: Español Alejandro J. , Salem Agustina , Di Bari María , Cristofaro Ilaria , Sanchez Yamila , Tata Ada M. , Sales María E. 
Published: December 2019

AbstractTriple negative tumors are more aggressive than other breast cancer subtypes and there is a lack of specific therapeutic targets on them. Since muscarinic receptors have been linked to tumor progression, we investigated the effect of metronomic therapy employing a traditional anti-cancer drug, paclitaxel plus muscarinic agonists at low doses on this type of tumor. We observed that MDA-MB231 tumor cells express muscarinic receptors, while they are absent in the non-tumorigenic MCF-10A cell line, which was used as control. The addition of carbachol or arecaidine propargyl ester, a non-selective or a selective subtype 2 muscarinic (M2) receptor agonist respectively, plus paclitaxel reduces cell viability involving a down-regulation in the expression of ATP “binding cassette” G2 drug transporter and epidermal growth factor receptor. We also detected an inhibition of tumor cell migration and anti-angiogenic effects produced by those drug combinationsin vitroandin vivo(in NUDE mice) respectively. Our findings provide substantial evidence about M2receptors as therapeutic target for the treatment of triple negative tumors.