bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain solute transport is more rapid in periarterial than perivenous spaces
Authors: Vinje Vegard , Bakker Erik NTP , Rognes Marie E 
Published: March 2021

AbstractBackgroundPerivascular fluid flow, of cerebrospinal or interstitial fluid in spaces surrounding brain blood vessels, is recognized as a key component underlying brain transport and clearance. An important open question is how and to what extent differences in vessel type or geometry affect perivascular fluid flow and transport.MethodsUsing computational modelling in both idealized and image-based geometries, we study and compare fluid flow and solute transport in pial (surface) periarterial and perivenous spaces.ResultsOur findings demonstrate that differences in geometry between arterial and venous pial perivascular spaces (PVSs) lead to higher net CSF flow, more rapid tracer transport and earlier arrival times of injected tracers in periarterial spaces compared to perivenous spaces.ConclusionsThese findings can explain the experimentally observed rapid appearance of tracers around arteries, and the delayed appearance around veins without the need of a circulation through the parenchyma, but rather by direct transport along the PVSs.
The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells
Authors: Ajouaou Yousra , Azouz Abdulkader , Taquin Anaelle , Denanglaire Sebastien , Hussein Hind , Krayem Mohammad , Andris Fabienne , Moser Muriel , Goriely Stanislas , Leo Oberdan 
Published: March 2021

AbstractThe oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTregmice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing a Th1-like effector phenotype. Concomitantly, the expression of innate-type cytokines such asIl1b,Il12a,Il12bandTnfawas found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTregmice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs did not efficiently control inflammatory response in vivo, in particular those characterized by IFN-γ production. Further analysis revealed that Treg dysregulation was largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTregmice), but not in PHD2-HIF1α (PHD2-HIF1αΔTregmice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs identified the STAT1 pathway as a target of the PHD2-HIF2α axis in regulatory T cell phenotype and in vivo function.
A comparison of rotation-based scores for gene set analysis
Authors: Caballe Mestres Adria , Berenguer Llergo Antonio , Stephan-Otto Attolini Camille 
Published: March 2021

AbstractGene-wise differential expression is usually the first major step in the statistical analysis of high-throughput data obtained from tech-niques such as microarrays or RNA-sequencing. The analysis at gene level is often complemented by the screening of the data in a broader biological context that considers as unit of analysis meaningful groups of genes that may have functions in certain biological processes.Among the vast number of publications about gene set analysis, the rotation test for gene set analysis, also referred by roast, is a general sample randomization approach that maintains the integrity of the intra-gene set correlation structure in defining the null distribution of the test.In this work we compare the performance of several enrichment score functions using such rotational approach for hypothesis testing. We find that computationally intensive measures based on Kolmogorov-Smirnov statistics fail to improve the rates of simpler measures of GSA like mean and maxmean scores. We also show the importance of ac-counting for the gene linear dependence structure of the testing set, which it is linked to the loss of effective signature size. In this regard, weighted statistics are introduced with the aim of maximizing the ef-fective signature size. These are found to out-power other usual scores in some simulations scenarios. The average of absolute values is found to be the most powerful score using both simulated and benchmarking data.All tools are available in theroastgsaR package.
A comparison of approaches to scaffolding multiple regions along the 16S rRNA gene for improved resolution
Authors: Debelius Justine W , Robeson Michael , Hugerth Luisa W. , Boulund Fredrik , Ye Weimin , Engstrand Lars 
Published: March 2021

AbstractMotivationFull length, high resolution 16s rRNA marker gene sequencing has been challenging historically. Short amplicons provide high accuracy reads with widely available equipment, at the cost of taxonomic resolution. One recent proposal has been to reconstruct multiple amplicons along the full-length marker gene, however no barcode-free computationally tractable approach for this is available. To address this gap, we present Sidle (SMURF Implementation Done to acceLerate Efficiency), an implementation of the Short MUltiple Reads Framework algorithm with a novel tree building approach to reconstruct rRNA genes from individually amplified regions.ResultsUsing simulated and real data, we compared Sidle to two other approaches of leveraging multiple gene region data. We found that Sidle had the least bias in non-phylogenetic alpha diversity, feature-based measures of beta diversity, and the reconstruction of individual clades. With a curated database, Sidle also provided the most precise species-level resolution.Availability and ImplementationSidle is available under a BSD 3 license from https://github.com/jwdebelius/q2-sidle
Application of an integrated computational antibody engineering platform to design SARS-CoV-2 neutralizers
Authors: Riahi Saleh , Lee Jae Hyeon , Wei Shuai , Cost Robert , Masiero Alessandro , Prades Catherine , Olfati-Saber Reza , Wendt Maria , Park Anna , Qiu Yu , Zhou Yanfeng 
Published: March 2021

AbstractAs the COVID-19 pandemic continues to spread, hundreds of new initiatives including studies on existing medicines are running to fight the disease. To deliver a potentially immediate and lasting treatment to current and emerging SARS-CoV-2 variants, new collaborations and ways of sharing are required to create as many paths forward as possible. Here we leverage our expertise in computational antibody engineering to rationally design/optimize three previously reported SARS-CoV neutralizing antibodies and share our proposal towards anti-SARS-CoV-2 biologics therapeutics. SARS-CoV neutralizing antibodies, m396, 80R, and CR-3022 were chosen as templates due to their diversified epitopes and confirmed neutralization potency against SARS. Structures of variable fragment (Fv) in complex with receptor binding domain (RBD) from SARS-CoV or SARS-CoV2 were subjected to our established in silico antibody engineering platform to improve their binding affinity to SARS-CoV2 and developability profiles. The selected top mutations were ensembled into a focused library for each antibody for further screening. In addition, we convert the selected binders with different epitopes into the trispecific format, aiming to increase potency and to prevent mutational escape. Lastly, to avoid antibody induced virus activation or enhancement, we applied NNAS and DQ mutations to the Fc region to eliminate effector functions and extend half-life.
Shining a light on Laurentian Great Lakes cisco (Coregonus artedi): how ice coverage may impact embryonic development
Authors: Stewart Taylor R. , Vinson Mark R. , Stockwell Jason D. 
Published: March 2021

AbstractChanges in winter conditions, such as decreased ice coverage and duration, have been observed in the Laurentian Great Lakes for more than 20 years. Such changes have been hypothesized to be linked to lowCoregonusspp. survival to age-1 as most cisco (Coregonus artedi) populations are autumn spawners whose embryos incubate under ice throughout the winter. The quantity of light during winter is regulated by ice coverage, and light affects embryo survival and development in some teleosts. We experimentally evaluated how cisco embryos from lakes Superior and Ontario respond to three light treatments that represented day-light intensity under 0-10, 40-60, and 90-100% ice coverage. Embryonic response measures included two developmental factors (embryo survival and incubation period) and two morphological traits (length-at-hatch and yolk-sac volume). Embryo survival was highest at the medium light treatment and decreased at high and low treatments for both populations, suggesting cisco may be adapted to withstand some light exposure from inter-annual variability in ice coverage. Light intensity had no overall effect on length of incubation. Increasing light intensity decreased length-at-hatch in Lake Superior but had no effect in Lake Ontario. Yolk-sac volume was positively correlated with increasing light in Lake Superior and negatively correlated in Lake Ontario. Contrasting responses in embryo development between lakes suggests differences in populations’ response to light is flexible. Our results provide a step towards better understanding the high variability observed in coregonine recruitment and may help predict what the future of this species may look like under current climate trends.
Root carbon interaction with soil minerals is dynamic, leaving a legacy of microbially-derived residues
Authors: Neurath Rachel A. , Pett-Ridge Jennifer , Chu-Jacoby Ilexis , Herman Donald , Whitman Thea , Nico Peter , Lipton Andrew S. , Kyle Jennifer , Tfaily Malak M. , Thompson Alison , Firestone Mary K. 
Published: March 2021

1.ABSTRACTMinerals preserve the oldest most persistent soil carbon, and mineral characteristics appear to play a critical role in the formation of soil organic matter (SOM) associations. To test the hypothesis that carbon source and soil microorganisms also influence mineral-SOM associations, we incubated permeable minerals bags in soil microcosms with and without plants, in a13CO2labeling chamber. Mineral bags contained quartz, ferrihydrite, kaolinite, or native soil minerals isolated via density separation. Using13C-NMR, FTICR-MS, and lipidomics, we traced plant-derived carbon onto minerals harvested from microcosms at three plant growth stages, characterizing total carbon,13C enrichment, and SOM chemistry. While C accumulation was rapid and mineral-dependent, the accumulated amount was not significantly affected by the presence of plant roots. However, the rhizosphere did shape the chemistry of mineral-associated SOM. Minerals incubated in the rhizosphere were associated with a more diverse array of compounds with different C functional groups (carbonyl, aromatics, carbohydrates, lipids) than minerals incubated in a bulk soil control. These diverse rhizosphere-derived compounds may represent a “transient fraction” of mineral SOM, rapidly exchanging with mineral surfaces. Our results also suggest that many of the lipids which persist on minerals are microbially-derived with a large fraction of fungal lipids.SynopsisThis study explores the interaction of rhizosphere carbon, minerals, and microbial influence on the fate of soil carbon.TOC
Multiple origins of nematode-Wolbachiasymbiosis in supergroup F and convergent loss of bacterioferritin in filarialWolbachia
Authors: Sinha Amit , Li Zhiru , Poole Catherine B. , Ettwiller Laurence , Lima Nathália F. , Ferreira Marcelo U. , Fombad Fanny F. , Wanji Samuel , Carlow Clotilde K. S. 
Published: March 2021

AbstractThe intracellular endosymbiotic proteobacteriaWolbachiahave evolved across the phyla nematoda and arthropoda. InWolbachiaphylogeny, supergroup F is the only clade known so far with members from both arthropod and filarial nematode hosts and therefore can provide unique insights into their evolution and biology. In this study, 4 new supergroup FWolbachiagenomes have been assembled using a metagenomic assembly and binning approach,wMoz andwMpe from the human filarial parasitesMansonella ozzardiandMansonella perstans, andwOcae andwMoviF from the blue mason beeOsmia caerulescensand the sheep kedMelophagus ovinusrespectively. A comprehensive phylogenomic analysis revealed two independent origins of filarialWolbachiain supergroup F, most likely from ancestral arthropod hosts. The analysis also reveals that the switch from arthropod to filarial host is accompanied by a convergent pseudogenization and loss of the bacterioferritin gene, a phenomenon found to be shared by all filarialWolbachia, even those outside supergroup F. These observations indicate that differences in heme metabolism might be a key feature distinguishing filarial and arthropodWolbachia. The new genomes provide a valuable resource for further studies on symbiosis, evolution, and the discovery of new antibiotics to treat mansonellosis.Significance statementWolbachiaare bacterial endosymbionts of medically important parasitic filarial nematodes and arthropods. The evolutionary history and biological roles ofWolbachiain these different hosts are not well understood. The supergroup F inWolbachiaphylogeny harbors members from both filarial and arthropod hosts, providing an unparalleled opportunity for genomic comparisons to uncover distinguishing characteristics. This study provides new genomes from filarial and arthropodWolbachiafrom this unique supergroup. Their phylogenomic analysis reveals multiple, independent transfers ofWolbachiafrom arthropod to filariae. Remarkably, these transfers were associated with a convergent loss of the bacterioferritin gene, a key regulator of heme metabolism. Heme supplementation is considered a critical component ofWolbachia- filaria symbiosis. We demonstrate bacterioferritin loss is a novel feature exclusive to filarialWolbachia.
Crotamine as a vehicle for non-viral gene delivery for Pompe disease
Authors: Martiniuk Frank , Mack Adra , Martiniuk Justin , Karpel Richard , Meinke Peter , Schoser Benedikt , Wu Feng , Tchou-Wong Kam-Meng 
Published: March 2021

AbstractGenetic deficiency of lysosomal acid alpha glucosidase or acid maltase (GAA) results in Pompe disease (PD), encompassing at least five clinical subtypes of varying severity. The current approved enzyme replacement therapy (ERT) for PD is via IV infusion every 2 weeks of a recombinant human GAA (rhGAA) secreted by Chinese hamster ovary (CHO) cells (alglucosidase alfa/Myozyme, Sanofi/Genzyme). Although alglucosidase alfa has proven to be efficient in rescuing cardiac abnormalities and extending the life span of the infantile form, the response in skeletal muscle is variable. ERT usually begins when the patients are symptomatic and secondary problems are already present which are compounded by low alglucosidase alfa uptake, transient nature (every 2 weeks with a rapid return to defect levels), variable glycogen reduction, autophagic accumulation, immune response and high cost. A consensus at a recent US Acid Maltase Deficiency (AMD) conference suggested that a multi-pronged approach including gene therapy, diet, exercise, etc. must be evaluated for a successful treatment of PD. Compared to replication defective viruses, non-viral gene transfer offers fewer safety concerns and, if recent studies are validated, has a wider range of cells. In order for gene therapy (GT) to succeed, the gene of interest must be delivered into the affected cell and expressed to overcome the inherited deficiency. Cell penetrating peptides (CPPs) enter eukaryotic cells through an energy-independent mechanism and efficiently carry biologically active and therapeutic molecules into cells and localize in the cytoplasm or nucleus. CPPs are usually covalently linked to the cargo, including peptides and DNA. Crotamine (Cro) from the South American rattlesnake-Crotalus durrissus terrificusvenom, can bind electrostatically to plasmid DNA to deliver into cells, including muscle. We have assembled a bacterial expression vector for Cro and purified the recombinant Cro (rCro). Transient transfection in AMD fibroblasts andex vivoin whole blood from an adult Pompe patient with rCro complexed with the pcDNA3 xhGAAcDNA demonstrated increased GAA activity. In GAA knockout (KO) mice receiving a single injection of rCro complexed to pcDNA3 xhGAAcDNA intraperitoneally (IP), we found increased GAA activity in tissues after 48 hr. After 8 treatments-IP over 55 days, we found increased vertical hang-time activity, reduced glycogen deposition, increased GAA activity/hGAAplasmid in tissues and minimal immune-reaction to rCro. A subsequent study of 5 administrations every 2 to 3 weeks showed reverse of the clinical phenotypes by running wheel activity, Rotarod, grip-strength meter, open field mobility and T-maze. Tissue culture experiments in PD fibroblast, lymphoid and skeletal muscle cell lines showed increased GAA activity after rCro transient gene delivery.
The SARS-CoV-2 replication-transcription complex is a priority target for broad-spectrum pan-coronavirus drugs
Authors: Yazdani Setayesh , De Maio Nicola , Ding Yining , Shahani Vijay , Goldman Nick , Schapira Matthieu 
Published: March 2021

ABSTRACTIn the absence of effective treatment, COVID-19 is likely to remain a global disease burden. Compounding this threat is the near certainty that novel coronaviruses with pandemic potential will emerge in years to come. Pan-coronavirus drugs – agents active against both SARS-CoV-2 and other coronaviruses – would address both threats. A strategy to develop such broad-spectrum inhibitors is to pharmacologically target binding sites on SARS-CoV-2 proteins that are highly conserved in other known coronaviruses, the assumption being that any selective pressure to keep a site conserved across past viruses will apply to future ones. Here, we systematically mapped druggable binding pockets on the experimental structure of fifteen SARS-CoV-2 proteins and analyzed their variation across twenty-seven α- and β-coronaviruses and across thousands of SARS-CoV-2 samples from COVID-19 patients. We find that the two most conserved druggable sites are a pocket overlapping the RNA binding site of the helicase nsp13, and the catalytic site of the RNA-dependent RNA polymerase nsp12, both components of the viral replication-transcription complex. We present the data on a public web portal (https://www.thesgc.org/SARSCoV2_pocketome/) where users can interactively navigate individual protein structures and view the genetic variability of drug binding pockets in 3D.
fMRIflows: a consortium of fully automatic univariate and multivariate fMRI processing pipelines
Authors: Notter Michael P. , Herholz Peer , Da Costa Sandra , Gulban Omer F. , Isik Ayse Ilkay , Gaglianese Anna , Murray Micah M. 
Published: March 2021

AbstractHow functional MRI (fMRI) data are analyzed depends on the researcher and the toolbox used. It is not uncommon that the processing pipeline is rewritten for each new dataset. Consequently, code transparency, quality control and objective analysis pipelines are important for improving reproducibility in neuroimaging studies. Toolboxes, such as Nipype and fMRIPrep, have documented the need for and interest in automated pre-processing analysis pipelines. Recent developments in data-driven models combined with high-resolution neuroimaging datasets have strengthened the need not only for a standardized preprocessing workflow but also for a reliable and comparable statistical pipeline. Here, we introduce fMRIflows: a consortium of fully automatic neuroimaging pipelines for fMRI analysis, which performs standard preprocessing, as well as 1st- and 2nd-level univariate and multivariate analyses. In addition to the standardized pre-processing pipelines, fMRIflows provides flexible temporal and spatial filtering to account for datasets with increasingly high temporal resolution and to help appropriately prepare data for advanced machine learning analyses, improving signal decoding accuracy and reliability. This paperfirstdescribes fMRIflows’ structure and functionality,thenexplains its infrastructure and access, andlastlyvalidates the toolbox by comparing it to other neuroimaging processing pipelines such as fMRIPrep, FSL and SPM. This validation was performed on three datasets with varying temporal sampling and acquisition parameters to prove its flexibility and robustness. fMRIflows is a fully automatic fMRI processing pipeline that uniquely offers univariate and multivariate single-subject and group analyses as well as pre-processing.
Genetic analysis of coronary artery disease using tree-based automated machine learning informed by biology-based feature selection
Authors: Manduchi Elisabetta , Le Trang T. , Fu Weixuan , Moore Jason H. 
Published: March 2021

AbstractMachine Learning (ML) approaches are increasingly being used in biomedical applications. Important challenges of ML include choosing the right algorithm and tuning the parameters for optimal performance. Automated ML (AutoML) methods, such as Tree-based Pipeline Optimization Tool (TPOT), have been developed to take some of the guesswork out of ML thus making this technology available to users from more diverse backgrounds. The goals of this study were to assess applicability of TPOT to genomics and to identify combinations of single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD), with a focus on genes with high likelihood of being good CAD drug targets. We leveraged public functional genomic resources to group SNPs into biologically meaningful sets to be selected by TPOT. We applied this strategy to data from the UK Biobank, detecting a strikingly recurrent signal stemming from a group of 28 SNPs. Importance analysis of these uncovered functional relevance of the top SNPs to genes whose association with CAD is supported in the literature and other resources. Furthermore, we employed game-theory based metrics to study SNP contributions to individual level TPOT predictions and discover distinct clusters of well-predicted CAD cases. The latter indicates a promising approach towards precision medicine.