bluuebunny/crossref_metadata_2025_split huggingface dataset:
An 8 Dipole Transceive and 24 Loop Receive Array for Non-Human Primate Head Imaging at 10.5T
Authors: Lagore Russell L. , Moeller Steen , Zimmermann Jan , DelaBarre Lance , Radder Jerahmie , Grant Andrea , Ugurbil Kamil , Yacoub Essa , Harel Noam , Adriany Gregor 
Published: August 2020

AbstractA 32-channel RF coil was developed for brain imaging of anesthetized non-human primates (Rhesus Macaque) at 10.5 tesla. The coil is composed of an 8-channel dipole transmit/receive array, close-fitting 16-channel loop receive array headcap, and 8-channel loop receive array lower insert.The transceiver dipole array is composed of eight end-loaded dipole elements self-resonant at the 10.5 tesla proton Larmor frequency. These dipole elements were arranged on a plastic cylindrical former which was split in two to allow for convenient animal positioning. Nested into the bottom of the dipole array former is located an 8-channel loop receive array which contains 5×10 cm2square loops arranged in two rows of four loops. Arranged in a close-fitting plastic headcap is located a high-density 16-channel loop receive array. This array is composed of 14 round loops 37 mm in diameter and two partially detachable, irregularly shaped loops that encircle the ears. Imaging experiments were performed on anesthetized non-human primates on a 10.5 tesla MRI system equipped with body gradients with a 60 cm open bore.The coil enabled submillimeter (0.58 mm isotropic) high resolution anatomical and functional imaging as well as tractography of fasciculated axonal bundles. The combination of a close-fitting loop receive array and dipole transceiver array allowed for a higher channel count receiver and consequent higher SNR and parallel imaging gains. Parallel imaging performance supports high resolution fMRI and dMRI with a factor of three reduction in sampling. The transceive array elements during reception contributed approximately one quarter of SNR in the lower half of the brain which was farthest from the close-fitting headcap receive array.
Secondary analysis of transcriptomes of SARS-CoV-2 infection models to characterize COVID-19
Authors: Ghandikota Sudhir , Sharma Mihika , Jegga Anil G. 
Published: August 2020

ABSTRACTKnowledge about the molecular mechanisms driving COVID-19 pathophysiology and outcomes is still limited. To learn more about COVID-19 pathophysiology we performed secondary analyses of transcriptomic data from twoin vitro(Calu-3 and Vero E6 cells) and onein vivo(Ad5-hACE2-sensitized mice) models of SARS-CoV-2 infection. We found 1467 conserved differentially expressed host genes (differentially expressed in at least two of the three model system transcriptomes compared) in SARS-CoV-2 infection. To find potential genetic factors associated with COVID-19, we analyzed these conserved differentially expressed genes using known human genotype-phenotype associations. Genome-wide association study enrichment analysis showed evidence of enrichment for GWA loci associated with platelet functions, blood pressure, body mass index, respiratory functions, and neurodegenerative and neuropsychiatric diseases, among others. Since human protein complexes are known to be directly related to viral infection, we combined and analyzed the conserved transcriptomic signature with SARS-CoV-2-host protein-protein interaction data and found more than 150 gene clusters. Of these, 29 clusters (with 5 or more genes in each cluster) had at least one gene encoding protein that interacts with SARS-CoV-2 proteome. These clusters were enriched for different cell types in lung including epithelial, endothelial, and immune cell types suggesting their pathophysiological relevancy to COVID-19. Finally, pathway analysis on the conserved differentially expressed genes and gene clusters showed alterations in several pathways and biological processes that could enable in understanding or hypothesizing molecular signatures inducing pathophysiological changes, risks, or sequelae of COVID-19.
Capturing non-local through-bond effects in molecular mechanics force fields I: Fragmenting molecules for quantum chemical torsion scans [Article v1.1]
Authors: Stern Chaya D , Bayly Christopher I , Smith Daniel G A , Fass Josh , Wang Lee-Ping , Mobley David L , Chodera John D 
Published: August 2020

AbstractAccurate molecular mechanics force fields for small molecules are essential for predicting protein-ligand binding affinities in drug discovery and understanding the biophysics of biomolecular systems. Torsion potentials derived from quantum chemical (QC) calculations are critical for determining the conformational distributions of small molecules, but are computationally expensive and scale poorly with molecular size. To reduce computational cost and avoid the complications of distal through-space intramolecular interactions, molecules are generally fragmented into smaller entities to carry out QC torsion scans. However, torsion potentials, particularly for conjugated bonds, can be strongly affected by through-bond chemistry distal to the torsion it-self. Poor fragmentation schemes have the potential to significantly disrupt electronic properties in the region around the torsion by removing important, distal chemistries, leading to poor representation of the parent molecule’s chemical environment and the resulting torsion energy profile. Here we show that a rapidly computable quantity, the fractional Wiberg bond order (WBO), is a sensitive reporter on whether the chemical environment around a torsion has been disrupted. We show that the WBO can be used as a surrogate to assess the robustness of fragmentation schemes and identify conjugated bond sets. We use this concept to construct a validation set by exhaustively fragmenting a set of druglike organic molecules and examine their corresponding WBO distributions derived from accessible conformations that can be used to evaluate fragmentation schemes. To illustrate the utility of the WBO in assessing fragmentation schemes that preserve the chemical environment, we propose a new fragmentation scheme that uses rapidly-computable AM1 WBOs, which are available essentially for free as part of standard AM1-BCC partial charge assignment. This approach can simultaneously maximize the chemical equivalency of the fragment and the substructure in the larger molecule while minimizing fragment size to accelerate QC torsion potential computation for small molecules and reducing undesired through-space steric interactions.
Regulation of Decay Accelerating Factor primes human germinal center B cells for phagocytosis
Authors: Dernstedt Andy , Leidig Jana , Holm Anna , Mjösberg Jenny , Ahlm Clas , Henriksson Johan , Hultdin Magnus , Forsell Mattias NE 
Published: August 2020

AbstractGerminal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAFloB cells. Consistent with this, a majority of light and dark zone GC B cells were DAFloand susceptible to complement-dependent phagocytosis, as compared with DAFhiGC B cells. We could also show that the DAFhiGC B cell subset had increased expression of the plasma cell marker Blimp-1. DAF expression was also modulated during B cell hematopoiesis in the human bone marrow. Collectively, our results reveal a novel role of DAF to pre-prime activated human B cells for phagocytosis prior to apoptosis.
Immune modulatory effects of probioticStreptococcus thermophiluson human monocytes
Authors: Dargahi Narges , Johnson Joshua , Apostolopoulos Vasso 
Published: August 2020

ABSTRACTIngesting probiotics contributes to the development of a healthy microflora in the gastrointestinal tract with established benefits to human health. Some of these beneficial effects may be through modulating of the immune system and probiotics have become more common in the treatment of many inflammatory and immune disorders. We demonstrate a range of immune modulating effects ofStreptococcus thermophilusby human monocytes, including, decreased mRNA expression of IL-1R, IL-18, IFNγR1, IFNαR1, CCL2, CCR5, TLR-1, TLR-2, TLR-4, TLR-5, TLR-6, TLR-8, CD14, CD86, CD4, ITGAM, LYZ, TYK2, IFNR1, IRAK-1, NOD2, MYD88, ITGAM, SLC11A1, and, increased expression of IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-23, IFNγ, TNFα, CSF-2. Routine administration ofStreptococcus thermophilusin fermented dairy products, and their consumption may be beneficial to the treatment/management of inflammatory and autoimmune diseases.
A dual mechanism of enhancer activation by FOXA pioneer factors induces endodermal organ fates
Authors: Geusz Ryan J. , Wang Allen , Lam Dieter K. , Vinckier Nicholas K. , Alysandratos Konstantinos-Dionysios , Roberts David A. , Wang Jinzhao , Kefalopoulou Samy , Qiu Yunjiang , Chiou Joshua , Gaulton Kyle J. , Ren Bing , Kotton Darrel N. , Sander Maike 
Published: August 2020

SUMMARYFOXA pioneer transcription factors (TFs) displace nucleosomes and prime chromatin across enhancers of different endodermal organs in multipotent precursors before lineage induction. Here, we examined patterns and mechanisms of FOXA target site engagement using human pluripotent stem cell models of endodermal organ development. Unexpectedly, we find that only a subset of pancreatic, hepatic, and alveolar enhancers are FOXA-primed, whereas the majority are unprimed and engage FOXA only upon lineage induction. Analysis of sequence architecture revealed more abundant and stronger FOXA motifs at primed than unprimed enhancers and enrichment for lineage-specific TF motifs at unprimed enhancers. We show that FOXA recruitment to unprimed enhancers specifically depends on lineage-specific TFs, suggesting that regulatory DNA sequence logic governs temporal FOXA recruitment. Our findings suggest that FOXA-mediated enhancer priming broadly facilitates initiation of organ lineage programs, while secondary FOXA recruitment by lineage-specific TFs to the majority of enhancers confers organ specificity to gene expression.
Role of channels in the oxygen permeability of red blood cells
Authors: Zhao Pan , Geyer R. Ryan , Salameh Ahlam I. , Wass Amanda B. , Taki Sara , Huffman Dale E. , Meyerson Howard J , Gros Gerolf , Occhipinti Rossana , Moss Fraser J. , Boron Walter F. 
Published: August 2020

AbstractMany have believed that oxygen (O2) crosses red blood cell (RBC) membranes by dissolving in lipids that offer no resistance to diffusion. However, using stopped-flow (SF) analyses of hemoglobin (Hb) absorbance spectra during O2off-loading from mouse RBCs, we now report that most O2traverses membrane-protein channels. Two agents excluded from the RBC interior markedly slow O2off-loading: p-chloromercuribenzenesulfonate (pCMBS) reduces inferred membrane O2permeability (PMembrane) by ∼82%, and 4,4’-diisothiocyanatostilbene-2,2’-disulfonate (DIDS), by ∼56%. Because neither likely produces these effects via membrane lipids, we examined RBCs from mice genetically deficient in aquaporin-1 (AQP1), the Rh complex (i.e., rhesus proteins RhAG + mRh), or both. The double knockout (dKO) reducesPMembraneby ∼55%, and pCMBS+dKO, by ∼91%. Proteomic analyses of RBC membranes, flow cytometry, hematology, and mathematical simulations rule out explanations involving other membrane proteins, RBC geometry, or extracellular unconvected fluid (EUF). By identifying the first two O2channels and pointing to the existence of other O2channel(s), all of which could be subject to physiological regulation and pharmacological intervention, our work represents a paradigm shift for O2handling.
Two bi-functional cytochrome P450 CYP72 enzymes from olive (Olea europaea) catalyze the oxidative C-C bond cleavage in the biosynthesis of secoxy-iridoids - flavor and quality determinants in olive oil
Authors: Rodríguez-López Carlos E. , Hong Benke , Paetz Christian , Nakamura Yoko , Koudounas Konstantinos , Passeri Valentina , Baldoni Luciana , Alagna Fiammetta , Calderini Ornella , O’Connor Sarah E. 
Published: August 2020

SummaryOlive (Olea europaea) is an important crop in Europe, with high cultural, economic, and nutritional significance. Olive oil flavor and quality depend on phenolic secoiridoids, but the biosynthetic pathway of these iridoids remains largely uncharacterized.We discovered two novel, bi-functional cytochrome P450 enzymes, catalysing the rare oxidative C-C bond cleavage of 7-epi-loganin to produce oleoside methyl ester (OeOMES) and secoxyloganin (OeSXS), both through a ketologanin intermediary. Although these enzymes are homologous to the previously reportedCatharanthus roseusSecologanin Synthase (CrSLS), the substrate and product profiles differ.Biochemical assays provided mechanistic insights into the two-step OeOMES and CrSLS reactions. Model-guided mutations of OeOMES changed the product profile in a predictable manner, revealing insights into the molecular basis for this change in product specificity.Our results suggest that, in contrast to published hypotheses,in plantaproduction of secoxy-iridoids is secologanin independent. Notably, sequence data of cultivated and wild olives, points to a relation between domestication and OeOMES expression. Thus, the discovery of this key biosynthetic gene suggests a link between domestication and secondary metabolism, and could potentially be used as a genetic marker to guide next-generation breeding programs.
An integrative approach points to membrane composition as a key factor inE. colipersistence
Authors: Cañas-Duarte SJ , Perez-Lopez MI , Herrfurth C , Sun Lei , Contreras LM , Feussner I , Leidy C , Riaño-Pachón DM , Restrepo S , Pedraza JM 
Published: August 2020

SummaryIn spite of its medical importance, the genetic mechanisms of bacterial persistence, particularly spontaneous (type II) persistence, remain largely unknown. We use an integrative approach, combining mutant genome analysis, transcriptomics and lipid membrane composition analysis, to elucidate said mechanisms. In particular, we analyzed the genome of the high persistence mutantE. coliDS1 (hipQ), to identify candidate mutations responsible for the high persistence phenotype. Contrary to a recent study, we find no mutation in ydcI. We compared the expression of spontaneous persistent and growing cells using RNAseq, and find that the activation of stress response mechanisms is likely less important in spontaneous persistence than recent reports suggest. It also indicated that modifications in the cell membrane could play an important role. This hypothesis was then validated by the analysis of the fatty acid composition of persister cells of both types, which have markedly different saturation from growing cells and between each other. Taken together, our results indicate that changing membrane composition might be a key process in persistence.HighlightsRNAseq analysis of spontaneous persistence shows no evidence of stress responseIdentification of candidate SNPs for hipQ phenotype, excludes ydcIMembrane fatty acid composition is involved in both types of bacterial persistence
Two-step multi-omics modelling of drug sensitivity in cancer cell lines to identify driving mechanisms
Authors: Kusch Nina , Schuppert Andreas 
Published: August 2020

AbstractDrug sensitivity prediction models for human cancer cell lines constitute important tools in identifying potential driving factors of responsiveness in a pre-clinical setting. Integrating information derived from a range of heterogeneous data is crucial, but remains non-trivial, as differences in data structures may hinder fitting algorithms from assigning adequate weights to complementary information that is contained in distinct omics data. In order to counteract this effect that tends to lead to just one data type dominating supposedly multi-omics models, we developed a novel tool that enables users to train single-omics models separately in a first step and to integrate them into a multi-omics model in a second step. Extensive ablation studies are performed in order to facilitate an in-depth evaluation of the respective contributions of singular data types and of combinations thereof, effectively identifying redundancies and interdependencies between them. Moreover, the integration of the single-omics models is realized by a range of distinct classification algorithms, thus allowing for a performance comparison. Sets of molecular events and tissue types found to be related to significant shifts in drug sensitivity are returned to facilitate a comprehensive and straightforward analysis of potential drivers of drug responsiveness. Our two-step approach yields sets of actual multi-omics pan-cancer classification models that are highly predictive for a majority of drugs in the GDSC data base. In the context of targeted drugs with particular modes of action, its predictive performances compare favourably to those of classification models that incorporate multi-omics data in a simple one-step approach. Additionally, case studies demonstrate that it succeeds both in correctly identifying known key drivers of specific drug compounds as well as in providing sets of potential candidates for additional driving factors of drug sensitivity.
A Transferable Deep Learning Approach to Fast Screen Potent Antiviral Drugs against SARS-CoV-2
Authors: Wang Shiwei , Sun Qi , Xu Youjun , Pei Jianfeng , Lai Luhua 
Published: August 2020

AbstractThe COVID-19 pandemic calls for rapid development of effective treatments. Although various drug repurpose approaches have been used to screen the FDA-approved drugs and drug candidates in clinical phases against SARS-CoV-2, the coronavirus that causes this disease, no magic bullets have been found until now. We used directed message passing neural network to first build a broad-spectrum anti-beta-coronavirus compound prediction model, which gave satisfactory predictions on newly reported active compounds against SARS-CoV-2. Then we applied transfer learning to fine-tune the model with the recently reported anti-SARS-CoV-2 compounds. The fine-tuned model was applied to screen a large compound library with 4.9 million drug-like molecules from ZINC15 database and recommended a list of potential anti-SARS-CoV-2 compounds for further experimental testing. As a proof-of-concept, we experimentally tested 7 high-scored compounds that also demonstrated good binding strength in docking study against the 3C-like protease of SARS-CoV-2 and found one novel compound that inhibited the enzyme with an IC50of 37.0 μM. Our model is highly efficient and can be used to screen large compound databases with billions or more compounds to accelerate the drug discovery process for the treatment of COVID-19.
Sequence analysis of Indian SARS-CoV-2 isolates shows a stronger interaction of mutated receptor binding domain with ACE2 receptor
Authors: Dash Pujarini , Turuk Jyotirmayee , Behera Santosh Ku. , Palo Subrata Ku. , Raghav Sunil K. , Ghosh Arup , Sabat Jyotsnamayee , Rath Sonalika , Subhadra Subhra , Bhattacharya Debadutta , Kanungo Srikant , Kshatri Jayasingh , Mishra Bijaya kumar , Dash Saroj , Mahapatra Namita , Parida Ajay , Pati Sanghamitra 
Published: August 2020

AbstractSARS-CoV-2 is a RNA Coronavirus responsible for the pandemic of the Severe Acute Respiratory Syndrome (COVID-19). It has affected the whole world including Odisha, a state in eastern India. Many people migrated in the state from different countries as well as states during this SARS-CoV-2 pandemic. As per the protocol laid by ICMR and Health & Family welfare of India, all the suspected cases were tested for SARS-CoV-2 infection. The aim of this study was to analyze the RNA binding domain (RBD) sequence of spike protein from the isolates collected from the throat swab samples of COVID-19 positive cases and further to assess the RBD affinity with ACE2 of different species including human.Whole genome sequencing for 35 clinical SARS-CoV-2 isolates from COVID-19 positive patients was performed using ARTIC amplicon based sequencing. Sequence analysis and phylogenetic analysis was carried out for the Spike and RBD region of all isolates. The interaction between the RBD and ACE2 receptor of five different species was also analysed.Except three isolates, spike region of 32 isolates showed one/multiple alterations in nucleotide bases in comparison to the Wuhan reference strain. One of the identified mutation at 1204 (Ref A, RMRC 22 C) in the RBD of spike protein was identified which depicted a stronger binding affinity with human ACE2 receptor compared to the wild type RBD. Furthermore, RBDs of all the Indian isolates are capable of binding to ACE2 of human, bat, hamster and pangolin.As mutated RBD showed stronger interaction with human ACE2, it could potentially result in higher infectivity. The study shows that RBDs of all the studied isolates have binding affinity for all the five species, which suggests that the virus can infect a wide variety of animals which could also act as natural reservoir for SARS-CoV-2.
Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting its Protein-Protein Interactions
Authors: Bobone Sara , Pannone Luca , Biondi Barbara , Solman Maja , Flex Elisabetta , Canale Viviana , Calligari Paolo , Faveri Chiara De , Gandini Tommaso , Quercioli Andrea , Torini Giuseppe , Venditti Martina , Lauri Antonella , Fasano Giulia , Hoeksma Jelmer , Santucci Valerio , Cattani Giada , Bocedi Alessio , Carpentieri Giovanna , Tirelli Valentina , Sanchez Massimo , Peggion Cristina , Formaggio Fernando , Hertog Jeroen den , Martinelli Simone , Bocchinfuso Gianfranco , Tartaglia Marco , Stella Lorenzo 
Published: August 2020

AbstractWe developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in multiple signaling pathways and a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective on disease-associated SHP2 mutants. Based on the consideration that pathogenic lesions cause signaling hyperactivation due to increased SHP2 association with cognate proteins, we developed peptide-based molecules with low nM affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation and an affinity for pathogenic variants of SHP2 up to 20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool to investigate the role of protein-protein interactions in the function of SHP2.
Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2
Authors: Ghahremanpour Mohammad M. , Tirado-Rives Julian , Deshmukh Maya , Ippolito Joseph A. , Zhang Chun-Hui , de Vaca Israel Cabeza , Liosi Maria-Elena , Anderson Karen S. , Jorgensen William L. 
Published: August 2020

AbstractA consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (Mpro) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with Mpro, 17 were chosen for evaluation in a kinetic assay for Mproinhibition. Remarkably 14 of the compounds at 100-μM concentration were found to reduce the enzymatic activity and 5 provided IC50values below 40 μM: manidipine (4.8 μM), boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM), and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1’, and P2 pockets of Mpro. Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.