bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potent Bacterial Vaccines Require FcγRIIB-mediated Pathogen Capture by Liver Sinusoidal Endothelium
Authors: Wang Juanjuan , An Haoran , Ding Ming , Liu Yanhong , Wang Shaomeng , Jin Qian , Dong Haodi , Tian Xianbin , Liu Jiankai , Zhang Jingfei , Zhu Tao , Li Junqiang , Shao Zhujun , Briles David E. , Zheng Haifa , Zhang Linqi , Zhang Jing-Ren 
Published: July 2022

ABSTRACTCertain vaccines are more effective than others against microbial infections, but the molecular mechanisms separating the two types of vaccines are largely undefined. Here, by comparing two vaccines ofStreptococcus pneumoniaewith identical antigens but different efficacies (pneumococcal conjugate vaccine – PCV13 and pneumococcal polysaccharide vaccine – PPV23), we reveal that superior vaccine protection against blood-borne bacteria is primarily achieved by activating pathogen capture of the sinusoidal endothelial cells (ECs) in the liver. Consistent with its superior protection in humans, PCV13 confers a more potent protection than PPV23 against pneumococcal infection in mice.In vivoreal-time imaging and genetic mutagenesis revealed that PCV13 activates both liver ECs and resident macrophages Kupffer cells (KCs) to capture IgG-coated bacteria via IgG Fc gamma receptor (FcγR). In particular, the FcγRIIB-mediated capture by ECs is responsible for PCV13-induced superior protection. In contrast, PPV23 only activates KCs (but not ECs) to achieve a less effective pathogen capture and protection through complement receptor-mediated recognition of IgM- and C3-coated bacteria. These liver-based vaccine protection mechanisms are also found with the vaccines ofNeisseria meningitidisandKlebsiella pneumoniae, another two important invasive human pathogens. Our findings have uncovered a novel EC- and FcγRIIB-mediated mechanism in the liver for more efficacious vaccine protection. These findings can serve asin vivofunctional readouts to evaluate vaccine efficacy and guide the future vaccine development.One Sentence SummaryVaccine efficacy is defined by FcγRIIB-mediated capture of antibody-coated bacteria via liver sinusoidal endothelial cells.
Mammalian Pumilio Proteins Control Cellular Morphology, Migration, and Adhesion
Authors: Sternburg Erin L. , Lillibridge Jordan J. , Phandthong Rattapol , Karginov Fedor V. 
Published: July 2022

AbstractPumilio proteins are RNA-binding proteins that control mRNA translation and stability by binding to the 3’ UTR of target mRNAs. Mammals have two canonical Pumilio proteins, PUM1 and PUM2, which are known to act in many biological processes, including embryonic development, neurogenesis, cell cycle regulation and genomic stability. Here, we characterized a new role of both PUM1 and PUM2 in regulating cell morphology, migration, and adhesion in T-REx-293 cells, in addition to previously known defects in growth rate. Gene ontology analysis of differentially expressed genes in PDKO cells for both cellular component and biological process showed enrichment in categories related to adhesion and migration. PDKO cells had a collective cell migration rate significantly lower than that of WT cells and displayed changes in actin morphology. In addition, during growth, PDKO cells aggregated into clusters (clumps) due to an inability to escape cell-cell contacts. Addition of extracellular matrix (Matrigel) alleviated the clumping phenotype. Collagen IV (ColIV), a major component of Matrigel, was shown to be the driving force in allowing PDKO cells to monolayer appropriately, however, ColIV protein levels remained unperturbed in PDKO cells. This study characterizes a novel cellular phenotype associated with cellular morphology, migration, and adhesion which can aid in developing better models for PUM function in both developmental processes and disease.
Glucocorticoid signaling mediates CD8+ T cell memory differentiation
Authors: Tehseen Azeez , Kumar Dhaneshwar , Sarkar Roman , Singh Sudhakar , Dubey Abhishek , Sehrawat Sharvan 
Published: July 2022

AbstractWe provide evidence on the TRM potentiation by glucocorticoids in stimulated CD8+ T cells. Signaling via glucocorticoid receptor reciprocally regulated short-lived effector cells and memory precursor effector cells. Influenza A virus infected mice treated transiently with dexamethasone preferentially generated multipotent TRM cells that efficiently responded to the subsequent infection. Compromised memory following abrogation of glucocorticoid signaling further confirmed their role in memory potentiation. Transcriptomic and biochemical analysis of dexamethasone treated cells revealed a metabolic switch to oxidative phosphorylation via an engagement of AMPK signaling due to reduced glucose uptake. These cells exhibited an accumulation of phosphorylated STAT3 and STAT5 to drive memory differentiation. Therefore, glucocorticoids mediate tissue homing memory T cell differentiation.One-Sentence SummaryGlucocorticoid signaling in responding CD8+ T cells promotes memory differentiation
OpenGenomeBrowser: A versatile, dataset-independent and scalable web platform for genome data management and comparative genomics
Authors: Roder Thomas , Oberhänsli Simone , Shani Noam , Bruggmann Rémy 
Published: July 2022

AbstractOpenGenomeBrowser is a self-hostable open-source platform that manages access to genomic data and drastically simplifies comparative genomics analyses. It enables users to interactively generate phylogenetic trees, compare gene loci, browse biochemical pathways, perform gene trait matching, create dot plots, execute BLAST searches, and access the data. It features a flexible user management system, and its modular folder structure enables the organization of genomic data and metadata, and to automate analyses. We tested OpenGenomeBrowser with bacterial, archaeal and yeast genomes. The largest instance currently contains over 1,400 bacterial genomes. Source code, documentation, tutorials and a demo server are available at opengenomebrowser.github.io.
A Newly Identified Class of Protein Misfolding in All-atom Folding Simulations Consistent with Limited Proteolysis Mass Spectrometry
Authors: Vu Quyen V. , Sitarik Ian , Jiang Yang , Yadav Divya , Sharma Piyoosh , Fried Stephen D. , Li Mai Suan , O’Brien Edward P. 
Published: July 2022

AbstractSeveral mechanisms intrinsic to a protein’s primary structure are known to cause monomeric protein misfolding. Coarse-grained simulations, in which multiple atoms are represented by a single interaction site, have predicted a novel mechanism of misfolding exists involving off-pathway, non-covalent lasso entanglements, which are distinct from protein knots and slip knots. These misfolded states can be long-lived kinetic traps, and in some cases are structurally similar to the native state according to those simulations. Here, we examine whether such misfolded states occur in long-time-scale, physics-based all-atom simulations of protein folding. We find they do indeed form, estimate they can persist for weeks, and some have characteristics similar to the native state. Digestion patterns from Limited Proteolysis Mass Spectrometry are consistent with the presence of changes in entanglement in these proteins. These results indicate monomeric proteins can exhibit subpopulations of misfolded, self-entangled states that can explain long-timescale changes in protein structure and functionin vivo.One-Sentence SummaryEntangled misfolded states form in physics-based all-atom simulations of protein folding and have characteristics similar to the native state.
CRI-SPA – a mating based CRISPR-Cas9 assisted method for high-throughput genetic modification of yeast strain libraries
Authors: Olsson Helén , Cachera Paul , Coumou Hilde , Jensen Mads L. , Sánchez Benjamín J. , Strucko Tomas , van den Broek Marcel , Daran Jean-Marc , Jensen Michael K. , Sonnenschein Nikolaus , Lisby Michael , Mortensen Uffe H. 
Published: July 2022

AbstractBiological functions are orchestrated by intricate networks of interacting genetic elements. Predicting the interaction landscape remains a challenge for systems biology and the identification of phenotypic maximas would be of great benefit to synthetic biology. Thus, new research tools allowing simple and rapid mapping of sequence to function are required to forward these research fields. Here, we describe CRI-SPA, a method allowing the transfer of a chromosomal genetic feature from a donor strain to arrayed strains in large libraries of Saccharomyces cerevisiae. CRI-SPA is based on mating, CRISPR-Cas9-induced gene conversion and Selective Ploidy Ablation and is executed within a week. We demonstrate the power of CRI-SPA by transferring four genes responsible for the production of betaxanthin, a yellow biosensor for the morphine precursor L-DOPA, into each strain of the yeast knock-out collection (≈4800 strains), providing a genome-wide overview of the genetic requirements for betaxanthin production. CRI-SPA is fast, highly reproducible, can be massively parallelized with automation and does not require selection for the transferred genetic feature.
FastCAR: Fast Correction for Ambient RNA to facilitate differential gene expression analysis in single-cell RNA-sequencing datasets
Authors: Berg Marijn , Petoukhov Ilya , van den Ende Inge , Meyer Kerstin B. , Guryev Victor , Vonk Judith M. , Carpaij Orestes , Banchero Martin , Hendriks Rudi W. , van den Berge Maarten , Nawijn Martijn C. 
Published: July 2022

AbstractCell type-specific differential gene expression analyses based on single-cell transcriptome datasets are sensitive to the presence of cell-free mRNA in the droplets containing single cells. This so-called ambient RNA contamination may differ between samples obtained from patients and healthy controls. Current ambient RNA correction methods were not developed specifically for single-cell differential gene expression (sc-DGE) analyses and might therefore not sufficiently correct for ambient RNA-derived signals. Here, we show that ambient RNA levels are highly sample-specific. We found that without ambient RNA correction, sc-DGE analyses erroneously identify transcripts originating from ambient RNA as cell type-specific disease-associated genes. We therefore developed a computationally lean and intuitive correction method, Fast Correction for Ambient RNA (FastCAR), optimized for sc-DGE analysis of scRNA-Seq datasets generated by droplet-based methods including the 10XGenomics Chromium platform. FastCAR uses the profile of transcripts observed in libraries that likely represent empty droplets to determine the level of ambient RNA in each individual sample, and then corrects for these ambient RNA gene expression values. FastCAR can be applied as part of the data pre-processing and QC in sc-DGE workflows comparing scRNA-Seq data in a health versus disease experimental design. We compared FastCAR with two methods previously developed to remove ambient RNA, SoupX and CellBender. All three methods identified additional genes in sc-DGE analyses that were not identified in the absence of ambient RNA correction. However, we show that FastCAR performs better at correcting gene expression values attributed to ambient RNA, resulting in a lower frequency of false-positive observations. Moreover, the use of FastCAR in a sc-DGE workflow increases the cell-type specificity of sc-DGE analyses across disease conditions.
Exploring the in-situ evolution of Nitrofurantoin resistance in clinically derived Uropathogenic Escherichia coli isolates
Authors: Vallée Maxime , Harding Chris , Hall Judith , Aldridge Phillip D , Tan Aaron 
Published: July 2022

AbstractBACKGROUNDNitrofurantoin has been re-introduced as a first-choice antibiotic to treat uncomplicated acute urinary tract infections in England and Wales. Its mode of action involves initial reduction by nitroreductases, to generate electrophilic intermediates that inhibit protein and nucleic acid synthesis. Highly effective against common uropathogens such as Escherichia coli, its use is accompanied by a low incidence (<10%) of antimicrobial resistance. Resistance to Nitrofurantoin is predominantly via the acquisition of loss-of-function, step-wise mutations in the nitroreductase genes nfsA and nfsB.OBJECTIVETo explore the in situ evolution of NitR, longitudinal uropathogenic E. coli isolates recovered from two rUTI patients.RESULTSGrowth rate analysis identified a 2-10% slower doubling time for Nitrofurantoin resistant strains, but statistically, these data suggested there was no fitness advantage of evolved strains over their sensitive predecessor (ANOVA P-value = 0.13). Genetic manipulation of E. coli to mimic nitrofurantoin resistance evolution, again confirmed no fitness advantages (ANOVA P-value = 0.22). Rather, further analysis argued that a first-step mutant gained a selective advantage, at sub-MIC (4-8 mg/L) nitrofurantoin concentrations.CONCLUSIONCorrelation of these findings to Nitrofurantoin pharmacokinetic data suggests that the low incidence of E. coli NitR, within the community, is driven by urine-based nitrofurantoin concentrations that selectively inhibit the growth of E. coli strains carrying the key first-step loss-of-function mutation.
Deep Multimodal Graph-Based Network for Survival Prediction from Highly Multiplexed Images and Patient Variables
Authors: Fu Xiaohang , Patrick Ellis , Yang Jean Y. H. , Feng David Dagan , Kim Jinman 
Published: July 2022

AbstractThe spatial architecture of the tumour microenvironment and phenotypic heterogeneity of tumour cells have been shown to be associated with cancer prognosis and clinical outcomes, including survival. Recent advances in highly multiplexed imaging, including imaging mass cytometry (IMC), capture spatially resolved, high-dimensional maps that quantify dozens of disease-relevant biomarkers at single-cell resolution, that contain potential to inform patient-specific prognosis. However, existing automated methods for predicting survival typically do not leverage spatial phenotype information captured at the single-cell level, and current methods tend to focus on a single modality, such as patient variables (PVs). There is no end-to-end method designed to leverage the rich information in whole IMC images and all marker channels, and aggregate this information with PVs in a complementary manner to predict survival with enhanced accuracy. We introduce a deep multimodal graph-based network (DMGN) that integrates entire IMC images and multiple PVs for end-to-end survival prediction of breast cancer. We propose a multimodal graph-based module that considers relationships between spatial phenotype information in all image regions and all PVs, and scales each region–PV pair based on its relevance to survival. We propose another module to automatically generate embeddings specialised for each PV to enhance multimodal aggregation. We show that our modules are consistently effective at improving survival prediction performance using two public datasets, and that DMGN can be applied to an independent validation dataset across the same antigens but different antibody clones. Our DMGN outperformed state-of-the-art methods at survival prediction.
Formulation of FMD vaccine in Naloxone/Alum mixture: A potency study
Authors: Alemalhoda Danasadat , Ajamian Farzam , Khorasani Akbar , Haghighat Setareh , Amreie Mona Mahdavi , Sarkeshikzadeh Moghadas Fatemeh Sadat , Asgarhalvaei Fatemeh , Kalantari Alireza , Mahdavi Mehdi 
Published: July 2022

AbstractBackgroundCurrent Foot-and-Mouth disease (FMD) vaccines are commonly formulated in the alum adjuvant. Several studies showed that this form of vaccine, although able to control the infection, lacks the ability to eradicate the infection completely.ObjectivesIn this study, the FMD vaccine was formulated in a naloxone/alum mixture as an adjuvant, and its potency was compared with the alum-formulated vaccine.MethodsExperimental Balb/c mice were immunized with a commercial vaccine or naloxone/alum-based vaccine two times, subcutaneously at two-week intervals. Lymphocyte proliferation was assessed using BrdU, and IL-4, IFN-γ, and TNF-α cytokines, specific total IgG as well as IgG1/IgG2a were evaluated by ELISA. In addition, the gene expression profiles of IL-12, IL-17, and IFN-γ cytokines were determined by real-time PCR.ResultsResults showed that mice immunized with the FMD vaccine formulated with the naloxone/alum mixture exhibited a tiny increase in the production of IFN-γ and TNF-α cytokines compared to the routine vaccine. However, mice immunized with the FMD vaccine formulated with the naloxone/alum mixture revealed a significant increase in the expression of IL-12, IL-17, and IFN-γ cytokines compared to those immunized with the routine vaccine. In addition, the novel formulation led to increased production of specific total IgG in comparison with the routine vaccine.ConclusionsOur findings suggest that naloxone formulated in the FMD vaccine could improve cellular and humoral immune responses. However, the effect of this formulation on the efficacy of vaccine is remained to be clarified in future studies.
Slow integrin-dependent migration organizes networks of tissue-resident mast cells
Authors: Bambach Sarah K. , Kaltenbach Lukas , Aizarani Nadim , Martzloff Paloma , Gavrilov Alina , Glaser Katharina M. , Thünauer Roland , Mihlan Michael , Stecher Manuel , Thiriot Aude , Wienert Stephan , von Andrian Ulrich , Schmidt-Supprian Marc , Nerlov Claus , Klauschen Frederick , Roers Axel , Bajénoff Marc , Grün Dominic , Lämmermann Tim 
Published: July 2022

SUMMARYMany leukocytes use fast and flexible amoeboid migration strategies to move autonomously throughout tissues. Here, we show that the movement of mast cells (MCs), leukocytes with important roles during allergies and anaphylaxis, fundamentally differs from this rapid adhesion-free leukocyte migration. We identify a crucial role for integrin-dependent adhesion in controlling slow MC movement, which shapes the positioning and network-like tissue distribution of this long-lived immune cell type. In contrast to other immune and non-immune cells, MCs cannot compensate for the lack of integrin function by switching to another migration mode. Single-cell RNA-sequencing revealed a special role for integrins in defining a mature MC phenotype in the periarteriolar tissue space where several stromal cell types provide an anatomical niche rich in Kit ligand, the major MC growth and survival factor. Collectively, this study highlights substrate-dependent haptokinesis as an important mechanism for MC network formation and the tissue organization of resident immune cells.
Growth anisotropy of the extracellular matrix drives mechanics in a developing organ
Authors: Harmansa Stefan , Erlich Alexander , Eloy Christophe , Zurlo Giuseppe , Lecuit Thomas 
Published: July 2022

AbstractThe final size and shape of organs results from volume expansion by growth and shape changes by contractility. Complex morphologies arise from differences in growth rate between tissues. We address here how differential growth drives epithelial thickening and doming during the morphogenesis of the growing Drosophila wing imaginal disc. We report that 3D morphology results from elastic deformation due to differential growth between the epithelial cell layer and its enveloping extracellular matrix (ECM). Furthermore, the ECM envelope exhibits differential growth anisotropy (i.e. anisotropic expansion in 3D), growing in-plane on one side, but out of plane on the other side. The elasticity, anisotropy and morphogenesis is fully captured by a mechanical bilayer model. Moreover, differential expression of the Matrix metalloproteinase MMP2 controls growth anisotropy of the two ECM layers. This study shows that the ECM is a controllable mechanical constraint whose intrinsic growth anisotropy directs tissue morphogenesis in a developing organ.
Adipocyte-secreted IL-6 sensitizes macrophages to IL-4 signaling
Authors: Luan Danny , Dadpey Benyamin , Zaid Jessica , Bridge-Comer Pania E. , DeLuca Julia H. , Xia Wenmin , Castle Joshua , Reilly Shannon M. 
Published: July 2022

AbstractComplex bidirectional crosstalk between adipocytes and adipose tissue immune cells plays an important role in regulating adipose function, inflammation, and insulin responsiveness. Adipocytes secrete the pleiotropic cytokine IL-6 in response to both inflammatory and catabolic stimuli. Previous studies suggest that IL-6 secretion from adipocytes in obesity may promote adipose tissue inflammation. Here we investigated catabolic stimulation of adipocyte IL-6 secretion and its impact on adipose tissue immune cells. In obesity, catecholamine resistance reduces cAMP-driven adipocyte IL-6 secretion in response to catabolic signals. By restoring adipocyte catecholamine sensitivity in obese adipocytes, amlexanox stimulates adipocyte-specific IL-6 secretion. Here we report that in this context, adipocyte secreted IL-6 activates local macrophage STAT3 to promoteIl4raexpression, thereby sensitizing them to IL-4 signaling, and promoting an anti-inflammatory gene expression pattern. Supporting a paracrine adipocyte to macrophage mechanism, these effects could be recapitulated using adipocyte conditioned media to pretreat bone marrow derived macrophages prior to polarization with IL-4. The effects of IL-6 signaling in the adipose tissue are complex and context specific. These results suggest that cAMP driven IL-6 secretion from adipocytes sensitizes adipose tissue macrophages to IL-4 signaling.
DEFECTIVELY ORGANIZED TRIBUTARIES 5is not required for leaf venation patterning inArabidopsis thaliana
Authors: Vlad Daniela , Langdale Jane A. 
Published: July 2022

ABSTRACTThe search for genetic regulators of leaf venation patterning started over thirty years ago, primarily focussed on mutant screens in the eudicotyledonArabidopsis thaliana. Developmental perturbations in either cotyledons or true leaves led to the identification of transcription factors required to elaborate the characteristic reticulated vein network. An ortholog of one of these, the C2H2 Zn finger protein DEFECTIVELY ORGANIZED TRIBUTARIES 5 (AtDOT5), was recently identified through transcriptomics as a candidate regulator of parallel venation in maize leaves. To elucidate howAtDOT5orthologs regulate vein patterning, we generated three independent loss of function mutations by gene editing in Arabidopsis. Surprisingly, none of them exhibited any obvious phenotypic perturbations. To reconcile our findings with earlier reports, we re-evaluated the originalAtdot5-1andAtdot5-2alleles. By genome sequencing, we show that reported mutations at theAtdot5-1locus are actually polymorphisms between Landsbergerectaand Columbia ecotypes, and that other mutations present in the background most likely cause the pleiotropic mutant phenotype observed. We further show that a T-DNA insertion in theAtdot5-2locus has no impact on leaf venation patterns when segregated from other T-DNA insertions present in the original line. We thus conclude thatAtDOT5plays no role in leaf venation patterning in Arabidopsis.Significance statementAn understanding of gene function is often derived on the basis of loss of function mutant phenotypes and thus correct identification of mutated loci is crucial. Through gene editing we reveal previous mis-identification of a causative mutation that led to inappropriate functional assignation for theDEFECTIVELY ORGANIZED TRIBUTARIES 5 geneinArabidopsis thaliana.