bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep learning-based classification of resting-state fMRI independent-component analysis
Authors: Nozais Victor , Boutinaud Philippe , Verrecchia Violaine , Gueye Marie-Fateye , Hervé Pierre Yves , Tzourio Christophe , Mazoyer Bernard , Joliot Marc 
Published: July 2020

AbstractFunctional connectivity analyses of fMRI data have shown that the activity of the brain at rest is spatially organized into resting-state networks (RSNs). RSNs appear as groups of anatomically distant but functionally tightly connected brain regions. Inter-RSN intrinsic connectivity analyses may provide an optimal spatial level of integration to analyze the variability of the functional connectome. Here we propose a deep learning approach to enable the automated classification of individual independent-component (IC) decompositions into a set of predefined RSNs. Two databases were used in this work, BIL&GIN and MRi-Share, with 427 and 1811 participants, respectively. We trained a multilayer perceptron (MLP) to classify each IC as one of 45 RSNs, using the IC classification of 282 participants in BIL&GIN for training and a 5-dimensional parameter grid search for hyperparameter optimization. It reached an accuracy of 92%. Predictions for the remaining individuals in BIL&GIN were tested against the original classification and demonstrated good spatial overlap between the cortical RSNs. As a first application, we created an RSN atlas based on MRi-Share. This atlas defined a brain parcellation in 29 RSNs covering 96% of the gray matter. Second, we proposed an individualbased analysis of the subdivision of the default-mode network into 4 networks. Minimal overlap between RSNs was found except in the angular gyrus and potentially in theprecuneus. We thus provide the community with an individual IC classifier that can be used to analyze one dataset or to statistically compare different datasets for RSN spatial definitions.
Spatial Transcriptomics Inferred from Pathology Whole-Slide Images Links Tumor Heterogeneity to Survival in Breast and Lung Cancer
Authors: Levy-Jurgenson Alona , Tekpli Xavier , Kristensen Vessela N. , Yakhini Zohar 
Published: July 2020

AbstractDigital analysis of pathology whole-slide images is fast becoming a game changer in cancer diagnosis and treatment. Specifically, deep learning methods have shown great potential to support pathology analysis, with recent studies identifying molecular traits that were not previously recognized on pathology H&E whole-slide images. Simultaneous to these developments, it is becoming increasingly evident that tumor heterogeneity is an important determinant of cancer prognosis and susceptibility to treatment, and should therefore play a role in the evolving practices of matching treatment protocols to patients. State of the art diagnostic procedures, however, do not provide automated methods for characterizing and/or quantifying tumor heterogeneity, certainly not in a spatial context. Further, existing methods for analyzing pathology whole-slide images from bulk measurements require many training samples and complex pipelines. Our work addresses these two challenges. First, we train deep learning models to spatially resolve bulk mRNA and miRNA expression levels on pathology whole-slide images (WSIs). Our models reach up to 0.95 AUC on held-out test sets from two cancer cohorts using a simple training pipeline and a small number of training samples. Using the inferred gene expression levels, we further develop a method to spatially characterize tumor heterogeneity. Specifically, we produce tumor molecular cartographies and heterogeneity maps of WSIs and formulate a heterogeneity index (HTI) that quantifies the level of heterogeneity within these maps. Applying our methods to breast and lung cancer slides, we show a significant statistical link between heterogeneity and survival. Our methods potentially open a new and accessible approach to investigating tumor heterogeneity and other spatial molecular properties and their link to clinical characteristics, including treatment susceptibility and survival.
Cis-regulatory evolution spotlights species differences in the adaptive potential of gene expression plasticity
Authors: He F. , Steige K. A. , Kovacova V. , Göbel U. , Bouzid M. , Keightley P. D. , Beyer A. , de Meaux J. 
Published: July 2020

AbstractPhenotypic plasticity is the variation in phenotype that a single genotype can produce in different environments and, as such, is an important component of individual fitness. However, whether the effect of new mutations, and hence evolution, depends on the direction of plasticity remains controversial. Here, we identify the cis-acting modifications that have reshaped gene expression in response to dehydration stress in three Arabidopsis species. Our study shows that the direction of effects of most cis-regulatory variants differentiating the response betweenA. thalianaand the sister speciesA. lyrataandA. halleridepends on the direction of pre-existing plasticity in gene expression. A comparison of the rate of cis-acting variant accumulation in each lineage indicates that the selective forces driving adaptive evolution in gene expression favors regulatory changes that magnify the stress response inA. lyrata.The evolutionary constraints measured on the amino-acid sequence of these genes support this interpretation. In contrast, regulatory changes that mitigate the plastic response to stress evolved more frequently inA. halleri. Our results demonstrate that pre-existing plasticity can be a stepping stone for adaptation, but its selective remodeling differs between lineages.
The condensation of HP1-α/Swi6 imparts nuclear stiffness
Authors: Williams Jessica F. , Surovtsev Ivan V. , Schreiner Sarah M. , Chen Ziyuan , Raiymbek Gulzhan , Nguyen Hang , Hu Yan , Biteen Julie S. , Mochrie Simon G.J. , Ragunathan Kaushik , King Megan C. 
Published: July 2020

SUMMARYThe condensation of proteins and nucleic acids underlies the formation of membraneless organelles, which have emerged as major drivers of cellular organization. It remains largely unexplored, however, whether these condensates can impart mechanical function(s) to the cell. The heterochromatin protein HP1-α (Swi6 inS. pombe) crosslinks histone H3K9 methylated nucleosomes and has been proposed to undergo condensation to drive the liquid-like clustering of heterochromatin domains. Here we leverage the genetically tractableS. pombemodel and a separation-of-function Swi6 allele to elucidate a mechanical function imparted by its condensation. Using a combination of single-molecule imaging, force spectroscopy on individual nuclei, and high-resolution live-cell imaging, we show that Swi6 is critical for nuclear resistance to external force. Strikingly, it is this condensed yet dynamic pool of Swi6, rather than the chromatin-bound molecules, that is essential to imparting mechanical stiffness. Our findings suggest that Swi6 condensates embedded in the chromatin meshwork establish the emergent mechanical behavior of the nucleus as a whole, revealing that biomolecular condensation can influence organelle and cell mechanics.
Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike
Authors: Derking Ronald , Allen Joel D. , Cottrell Christopher A. , Sliepen Kwinten , Seabright Gemma E. , Lee Wen-Hsin , Rantalainen Kimmo , Antanasijevic Aleksandar , Copps Jeffrey , Yasmeen Anila , van der Woude Patricia , de Taeye Steven W. , van den Kerkhof Tom L.G.M. , Klasse P.J. , Ozorowski Gabriel , van Gils Marit J. , Moore John P. , Ward Andrew B. , Crispin Max , Sanders Rogier W. 
Published: July 2020

SummaryThe HIV-1 envelope glycoprotein (Env) trimer is decorated withN-linked glycans, which are attached to asparagine residues in the amino acid sequon NxT/S by oligosaccharyltransferases (OST). Artificial glycan “holes” exist when a PNGS is under-occupied on recombinant Env-based vaccines, but not on their viral counterpart. Native-like SOSIP trimers, including clinical candidates, have these artificial holes in the glycan shield that induce strain-specific neutralizing antibodies (NAbs) or non-NAbs. To increase PNGS occupancy, eliminate artificial glycan holes, and mimic the glycosylation of native BG505 Env, we replaced all 12 NxS sequons on the BG505 SOSIP trimer with NxT, thereby increasing the affinity of the sequons for OST. All PNGS, except N133 and N160, were nearly fully occupied on the modified trimer. Occupancy of the N133 site could be increased by changing N133 to NxS, while occupancy of the N160 site could be restored by reverting the nearby N156 sequon to NxS. Hence, OST affinity can influence glycan occupancy when two PNGS are in close proximity. Increasing glycan occupancy should reduce off-target immune responses to artificial glycan holes on vaccine antigens.
Acetylcholine regulates pulmonary inflammation and facilitates the transition from active immunity to tissue repair during respiratory viral infection
Authors: Horkowitz Alexander P. , Schwartz Ashley V. , Alvarez Carlos A. , Herrera Edgar B. , Thoman Marilyn L. , Chatfield Dale A. , Osborn Kent G. , Feuer Ralph , George Uduak Z. , Phillips Joy A. 
Published: July 2020

ABSTRACTInflammatory control is critical to recovery from respiratory viral infection. Acetylcholine (ACh) secreted from non-neuronal sources, including lymphocytes, plays an important, albeit underappreciated, role in regulating immune-mediated inflammation. This study was designed to explore the role of ACh in acute viral infection and recovery. Using the murine model of influenza A, cholinergic status in the lungs and airway was examined over the course of infection and recovery. The results showed that airway ACh remained constant through the early stage of infection and increased during the peak of the acquired immune response. As the concentration of ACh increased, cholinergic lymphocytes appeared in the airway and lungs. Cholinergic capacity was found primarily in CD4 T cells, but also in B cells and CD8 T cells. The cholinergic CD4+ T cells bound to influenza-specific tetramers at the same frequency as their conventional (i.e., non-cholinergic) counterparts. In addition, they were retained in the lungs throughout the recovery phase and could still be detected in the resident memory regions of the lung up to two months after infection. Histologically, cholinergic lymphocytes were found in direct physical contact with activated macrophages throughout the lung. When ACh production was inhibited, mice exhibited increased tissue inflammation, altered lung architecture, and delayed recovery. Together, these findings point to a previously unrecognized role for ACh in the transition from active immunity to recovery and pulmonary repair following respiratory viral infection.
A fast numerical method for oxygen supply in tissue with complex blood vessel network
Authors: Lu Yuankai , Hu Dan , Ying Wenjun 
Published: July 2020

AbstractOxygen field evaluation is important in modeling and simulation of many important physiological processes of animals, such as angiogenesis. However, numerical simulation of the oxygen field in animal tissue is usually limited by the unusual coupling of different mechanisms, the nonlinearity of the model, and the complex geometry of refined blood vessel networks. In this work, a fast numerical method is designed for the simulation of oxygen supply in tissue with a large-scale complex vessel network. This method employs an implicit finite-difference scheme to compute the oxygen field. By virtue of an oxygen source distribution technique from vessel center lines to mesh points and a corresponding post-processing technique that eliminate the local numerical error induced by source distribution, square mesh with relatively large mesh sizes can be applied while sufficient numerical accuracy is maintained. The new method has computational complexity which is slightly higher than linear with respect to the number of mesh points and has a convergence order which is slightly lower than second order with respect to the mesh size. As an example, the oxygen field of a tissue irrigated by a blood vessel network with more than four thousand blood vessels can be accurately computed within one minute with our new method. The new method will definitely promote further researches based on evaluation of oxygen field, such as modeling of angiogenesis and pathogenesis of many cardiovascular diseases.
Penicillium purpurogenumexerts antitumor effects and ameliorates inflammations in Erlich mice model
Authors: Teles Amanda Mara , Pontes Leticia Prince Pereira , Guimarães Sulayne Janayna Araujo , de Araújo Butarelli Ana Luiza , Silva Gabriel Xavier , do Nascimento Flavia Raquel Fernandes , de Barros Bezerra Geusa Felipa , Tellis Carla Junqueira Moragas , da Costa Rui Miguel Gil , da Silva Marcos Antonio Custódio Neto , Almeida-Souza Fernando , de Azevedo-Santos Ana Paula Silva , Nascimento Maria do Desterro Soares Brandao 
Published: July 2020

ABSTRACTBackgroundThe bioactive metabolites production contributes to the resistance of fungi towards adverse environmental conditions. Some metabolites often have interesting health-promoting activities. This study addressed the anti-tumoural properties ofPenicillium purpurogenumisolated from a polluted lagoon in Northeastern Brazil.MethodsThe extract obtained from the polished environment strainP. purpurogenumwas fermented, filtered, concentrated and lyophilized, giving rise to the Ethyl Acetate Extracellular Extract (EAE). The metabolites of the extracellular extract ofP. purpurogenumwere studied using direct infusion mass spectrometry. The solid Ehrlic tumor model was used to evaluate the extract antitumor activity. Female Swiss mice were divided in groups (n=10/group) as follow: Negative control (CTL-) treated with phosphate buffered solution; Positive Control (CTL+) treated with cyclophosphamide (25mg/mL); Extracts treatment at doses 4, 20 and 100mg/Kg; Animals without tumor or treatment (Sham); and animals without tumor treated with intermediate dose (EAE20). All treatments were performed intraperitoneally, daily during 15 days. After, the animals were eutanized and the tumor, lymphoid organs and serum were used for immunological, histological and biochemical parameters evaluation.ResultsThe extract was rich in meroterpenoids. All doses of the extract significantly reduced tumor size compared to CLT- and were associated with 100% survival. Histologically, the 20 and 100mg/kg doses reduced tumour-associated inflammation and tumour necrosis. The extract also reduced cellular infiltration of lymphoid organs and circulating TNF-α levels when compared with CLT-. The extract did not induce weight loss and renal or hepatic toxic changes.ConclusionsThese results indicate thatP. purpurogenumfrom a polluted marine environment produce hybrid natural products of the terpenoid pathway that exhibits immunomodulatory and antitumor propertiesin vivo. Thus, fungal fermentation is a biotechnological approach for the production of antitumour agents.
Hydrophobicity drives receptor-mediated uptake of heat-processed proteins by THP-1 macrophages and dendritic cells, but not cytokine responses
Authors: Deng Ying , Govers Coen , Teodorowicz Malgorzata , Liobyte Ieva , De Simone Ilaria , Hettinga Kasper , Wichers Harry J. 
Published: July 2020

AbstractImpact of processing on immunogenicity of food proteins has clearly been demonstrated, but the underlying mechanisms are still unclear. In our previous study, the uptake of the cow’s milk protein β-lactoglobulin (BLG) by THP-1 macrophages varied after applying different processing methods and was positively correlated with hydrophobicity and aggregation. Here we applied the same 3 processing methods: wet heating (60 °C) and low- or high-temperature (50 °C or 130 °C, respectively) dry heating in absence or presence of reducing sugars (i.e. glucose, lactose or galacto-oligosaccharide) to lysozyme and thyroglobulin, which have different pI or molecular weight compared to BLG, respectively. Uptake of the soluble fraction was tested in two types of, genetically homogeneous, antigen-presenting cells (macrophages and dendritic cells derived from THP-1 monocytes). This revealed a strong correlation between the uptake of the different protein samples by macrophages and dendritic cells, and confirmed the key role of hydrophobicity, over aggregation, in determining the uptake. Several uptake routes were shown to contribute to the uptake of BLG by macrophages. However, cytokine responses following exposure of macrophages to BLG samples were not related to the levels of uptake. Heat-treatment-mediated increases in uptake did thus not induce a response in our read-out systems. Together, our results demonstrate that heat-treatment-induced increased hydrophobicity is the prime driving factor in uptake, but not in cytokine production, by THP-1 macrophages.
Contact with the CsrA core is required for allosteric inhibition by FliW inBacillus subtilis
Authors: Oshiro Reid T. , Kearns Daniel B. 
Published: July 2020

AbstractThe RNA-binding protein CsrA is a post-transcriptional regulator that is encoded in genomes throughout the bacterial phylogeny. In the gamma-proteobacteria, the activity of CsrA is inhibited by small RNAs that competitively sequester CsrA binding. In contrast, the firmicuteBacillus subtilisencodes a protein inhibitor of CsrA called FliW, that non-competitively inhibits CsrA activity but the precise mechanism of antagonism is unclear. Here we take an unbiased genetic approach to identify residues of FliW important for CsrA inhibition that fall into two distinct spatial and functional classes. Most loss-of-function alleles mutated FliW residues that surround the critical regulatory CsrA residue N55 and abolished CsrA interaction. Two loss-of-function alleles however mutated FliW residues near the CsrA core dimerization domain and maintained interaction with CsrA. One of these two alleles reversed charge at what appeared to be a salt bridge with the CsrA core region, charge reversal of the CsrA partner residue phenocopied the FliW allele, and charge reversal of both residues simultaneously restored antagonism. We propose a model in which initial interaction between FliW and CsrA is necessary but not sufficient for antagonism which also requires salt bridge formation with, and deformation of, the CsrA core domain to allosterically abolish RNA binding activity.SummaryCsrA is a small dimeric protein that binds RNA and is one of the few known examples of transcript-specific translational regulators in bacteria. A protein called FliW binds to and antagonizes CsrA; despite having a high-resolution three-dimensional structure of the FliW-CsrA complex, the mechanism of non-competitive inhibition remains unresolved. Here we identify FliW residues required for antagonism and we find that the residues make a linear connection in the complex from initial binding interaction with CsrA to a critical salt bridge near the core of the CsrA dimer. We propose that the salt bridge represents an allosteric contact that distorts the CsrA core to prevent RNA binding.
Exploring metal resistance genes and mechanisms in copper enriched metal ore metagenome
Authors: Forouzan Esmaeil , Karkhane Ali Asghar , Yakhchali Bagher 
Published: July 2020

AbstractHeavy metal pollution is a major global health challenge. In order to develop bioremediation solution for decontamination of environment from heavy metals one appropriate step is to investigate heavy metal resistance strategies used by microbial communities in the metal contaminated environments. The aim of the present study was to understand detailed mechanisms by which long time heavy metal (HM) exposed microbial community use to cope with excess of HMs. We exploited the Illumina high throughput metagenomic approach to examine taxonomical and functional diversity of copper enriched soil metagenome. Three enriched metagenomes were compared against 94 metagenomes derived from non-contaminated soils. Taxonomic composition analysis showed that phylogenetic profile of metal contaminated soils were enriched withγ-Proteobacteria. Comparison of functional profile of the two group reveled significant difference with potential role in HM resistance (HMR). Enriched SEED categories were “Membrane Transport”, “Cell Wall and Capsule”, “Stress Response”, “Iron acquisition and metabolism” and “virulence and defense mechanisms”. Raw metagenomic reads were assembled into scaffolds and predicted Open Reading Frames (ORFs) were searched against metal resistance gene database (BacMet). Based on enriched genes and gene categories and search of known HMR genes we concluded the microbial community cope with HM using at least 10 different mechanisms. Copper resistance genes were more abundant in the metagenome relative to other metals and pumping metals out of the cell were more abundant relative to other HMR mechanism. Results of the present study could be very helpful in understanding of HMR mechanism used by microbial communities.
Length of Mucin-Like Domains Enhance Cell-Ebola Virus Adhesion by Increasing Binding Probability
Authors: Cui X. , Lapinski N. , Zhang X. , Jagota A. 
Published: July 2020

AbstractThe Ebola virus (EBOV) hijacks normal physiological processes by apoptotic mimicry in order to be taken up by the cell it infects. The initial adhesion of the virus to the cell is based on the interaction between T-cell immunoglobulin and mucin domain protein, TIM, on the cell-surface and phosphatidylserine (PS) on the viral outer surface. Therefore, it is important to understand the interaction between EBOV/PS and TIM, with selective blocking of the interaction as a potential therapy. Recent experimental studies have shown that for TIM-dependent EBOV entry, a Mucin-like Domain (MLD) with a length of at least 120 amino acids is required, possibly due to the increase of area of the PS-coated surface sampled. We examine this hypothesis by modeling the process of TIM-PS adhesion using a coarse-grained molecular model. We find that the strength of bound PS−TIM pairs is essentially independent of TIM length. TIMs with longer MLDs have higher average binding strengths because of an increase in the probability of binding between EBOV and TIM proteins. Similarly, we find that for larger persistence length (less flexible) the average binding force decreases, again because of a reduction in the probability of binding.Statement of SignificanceThis work studies the mechanism of TIM-dependent adhesion of the Ebola virus to a cell. Through coarse grained modeling we show that longer TIM stalks adhere more easily as they can sample a larger area, thus offering a mechanistic interpretation of an experimental finding. Better mechanistic understanding can lead to therapeutic ideas for blocking adhesion.