bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gαq modulates the energy metabolism of osteoclasts
Authors: Chakraborty S. , Handrick B. , Yu D. , Bode K. , Hafner A. , Schenz J. , Schaack D. , Uhle F. , Tachibana T. , Kamitani S. , Vogl T. , Kubatzky K.F. 
Published: April 2022

SummaryThe bacterial protein toxin Pasteurella multocida toxin (PMT) mediates RANKL-independent osteoclast differentiation. Although these osteoclasts are small, their resorptive activity is high and destroys the nasal turbinate bones of pigs. Analysis of the proteome of classical and toxin-derived osteoclasts showed that PMT induces the upregulation of metabolic pathways. This includes strong glycolytic activity, increased expression of GLUT1 and upregulation of the mTOR pathway. As OxPhos components are also expressed more efficiently, cells display increased mitochondrial respiration. We found that the heterotrimeric G protein Gαq plays a central role in this hypermetabolic cell activation. Gαq triggers mitochondrial relocalisation of pSerSTAT3 and an increase in OPA1 expression. Overexpression of Gαq in Hoxb8 cells mimicked this hypermetabolic phenotype and resulted in higher glycolytic and mitochondrial activity as well as increased bone resorptive activity. Rheumatoid arthritis patients show an increase in Gnaq expression especially in the synovial fluid, suggesting that Gαq is a target of pathophysiological relevance.
Different factors drive community assembly of rare and common ectomycorrhizal fungi
Authors: van Galen Laura G. , Orlovich David A. , Lord Janice M. , Bohorquez Julia , Nilsen Andy R. , Summerfield Tina C. , Larcombe Matthew J. 
Published: April 2022

1.AbstractUnderstanding what drives community assembly processes and how communities respond to environmental gradients are fundamental goals in community ecology. Ectomycorrhizal fungi support major forest systems across the globe, but the diversity, distribution and environmental controls affecting ectomycorrhizal community composition are unknown in many regions, particularly in the southern hemisphere. Here we investigate the assembly of ectomycorrhizal fungal communities based on eDNA samples from 81 Nothofagus forests across New Zealand’s South Island. We apply zeta diversity analysis and multi-site generalised dissimilarity modelling (MS-GDM) to investigate assembly patterns and quantify the effects of 43 biotic and environmental variables on community turnover. The zeta diversity MS-GDM framework differentiates between the environmental factors driving turnover of rare and common species, so provides a more complete picture of community dynamics than traditional beta diversity analyses. Results showed that community assembly was dominated by deterministic rather than stochastic processes. Soil variables were important drivers across the full range of rare, intermediate and common species. Ground cover variables, forest patch size and rainfall had greater effects on turnover of rare species, whereas temperature variables and host tree size had greater effects on common species turnover. Applying these methods for the first time to fungi demonstrates that there are distinct differences in the ecological processes affecting different aspects of the ectomycorrhizal community, which has important implications for understanding the functional effects of community responses to environmental change.
Multiple lines of evidence indicate survival of the Ivory-billed Woodpecker in Louisiana
Authors: Latta Steven C. , Michaels Mark A. , Scheifler Don , Michot Thomas C. , Shrum Peggy L. , Johnson Patricia , Tischendorf Jay , Weeks Michael , Trochet John , Ford Bob 
Published: April 2022

AbstractThe history of decline of the Ivory-billed Woodpecker is long, complex, and controversial. The last widely accepted sighting of this species in continental North America was 1944. Reports of Ivory-billed Woodpeckers have continued, yet in 2021 the U.S. Fish and Wildlife Service proposed declaring the species extinct. We draw on 10 years of search effort, and provide trail camera photos and drone videos suggesting the consistent presence of Ivory-billed Woodpeckers at our study site. Data indicate repeated re-use of foraging sites and core habitat. We offer insights into behaviors of the Ivory-billed Woodpecker that contribute to difficulty in finding this species. We discuss results with regard to the value of accumulated evidence, and what repeated observations may indicate for continued survival of this iconic species.
Transcription factors organize into functional groups on the linear genome and in 3D chromatin
Authors: Vadnala Rakesh Netha , Hannenhalli Sridhar , Narlikar Leelavati , Siddharthan Rahul 
Published: April 2022

AbstractTranscription factors (TFs) and their binding sites have evolved to interact cooperatively or competitively with each other. Here we examine in detail, across multiple cell lines, such cooperation or competition among TFs both in sequential and spatial proximity (using chromatin conformation capture assays) on one hand, and based on both in vivo binding as well as TF binding motifs on the other. We ascertain significantly co-occurring (“attractive”) or avoiding (“repulsive”) TF pairs using robust randomized models that retain the essential characteristics of the experimental data. Across human cell lines TFs organize into two groups, with intra-group attraction and inter-group repulsion. This is true for both sequential and spatial proximity, as well as for both in vivo binding and motifs. Attractive TF pairs exhibit significantly more physical interactions suggesting an underlying mechanism. The two TF groups differ significantly in their genomic and network properties, as well in their function—while one group regulates housekeeping function, the other potentially regulates lineage-specific functions, that are disrupted in cancer. We also show that weaker binding sites tend to occur in spatially interacting regions of the genome. Our results suggest a complex pattern of spatial cooperativity of TFs that has evolved along with the genome to support housekeeping and lineage-specific functions.
The Delta variant SARS-CoV-2 spike protein uniquely promotes aggregation of pseudotyped viral particles
Authors: Petersen Jennifer D. , Lu Jianming , Fitzgerald Wendy , Zhou Fei , Blank Paul S. , Matthies Doreen , Zimmerberg Joshua 
Published: April 2022

AbstractIndividuals infected with the SARS-CoV-2 Delta variant, lineage B.1.617.2, exhibit faster initial infection with a higher viral load than prior variants, and pseudotyped particles bearing the SARS-CoV-2 Delta variant spike protein induce a faster initial infection rate of target cells compared to those bearing other SARS-CoV-2 variant spikes. Here, we show that pseudotyped particles bearing the Delta variant spike form unique aggregates, as evidenced by negative stain and cryogenic electron microscopy (EM), flow cytometry, and nanoparticle tracking analysis. Viral particles pseudotyped with other SARS-CoV-2 spike variants do not show aggregation by any of these criteria. The contribution to infection kinetics of the Delta spike’s unique property to aggregate is discussed with respect to recent evidence for collective infection by other viruses. Irrespective of this intriguing possibility, spike-dependent aggregation is a new functional parameter of spike-expressing viral particles to evaluate in future spike protein variants.
TLR2 axis on peripheral blood mononuclear cells regulates inflammatory responses to circulating, non-infectious immature dengue virus particles
Authors: Aguilar-Briseño José A. , Pereira Lennon Ramos , van der Laan Marleen , Pauzuolis Mindaugas , ter Ellen Bram M. , Upasani Vinit , Moser Jill , de Souza Ferreira Luís Carlos , Smit Jolanda M. , Rodenhuis-Zybert Izabela A. 
Published: April 2022

AbstractSevere dengue virus (DENV) infection is characterized by exacerbated inflammatory responses that lead to endothelial dysfunction and plasma leakage. We have recently demonstrated that Toll-like receptor 2 (TLR2) on blood monocytes senses DENV infection leading to endothelial activation. Here, we report that non-infectious immature DENV particles, which are released in large numbers by DENV-infected cells, drive endothelial activation via the TLR2 axis. We show that fully immature DENV particles induce a rapid, within 6 hours post-infection, inflammatory response in PBMCs. Furthermore, pharmacological blocking of TLR2/TLR6/CD14 and/or NF-kB prior to exposure of PBMCs to immature DENV reduces the initial production of inter alia TNF-α and IL-1β by monocytes and prevents endothelial activation. However, prolonged TLR2 block induces TNF-α production and leads to exacerbated endothelial activation, indicating that TLR2-mediated responses play an important role not only in the initiation but also the resolution of inflammation. Altogether, these data indicate that the maturation status of the virus has the potential to influence the kinetics and extent of inflammatory responses during DENV infection.Author SummarySevere dengue virus (DENV) infection is characterized by endothelial dysfunction leading to vascular permeability and plasma leakage. This is thought to be mediated by the exacerbated production of inflammatory mediators from cells of the innate immune system. We have previously demonstrated that Toll-like receptor 2 (TLR2), a pattern recognition receptor present on the surface of human monocytes, can sense DENV infection leading to the activation of the endothelium. Importantly, a large proportion of DENV particles is immature and are not readily infectious. Here we aimed to elucidate if and how these non-infectious immature DENV particles contribute to systemic inflammation. We evaluated if monocytes sense immature DENV and found that sensing of immature DENV induced early inflammatory responses in PBMCs. Pharmacological inhibition of TLR2/TLR6/CD14 and/or NF-κB prior to exposure to immature DENV demonstrates that this is the pathway leading to the early production inflammatory mediators and endothelial activation. However, prolonged inhibition of TLR2 induced the production of TNF-α and the subsequent activation of the endothelium, suggesting that TLR2-mediated responses play an important tole during both, initiation and resolution of inflammation. We propose that the maturation status of DENV in the human host can influence the extent and kinetics of the inflammatory responses during DENV infection.
Tissue-Specific Transcriptome Responses to Fusarium Head Blight and Fusarium Root Rot
Authors: Haidoulis J F. , Nicholson P. 
Published: April 2022

AbstractFusarium head blight (FHB) and Fusarium root rot (FRR) are important diseases of small-grained cereals caused by Fusarium species. While host response to FHB has been subject to extensive study, very little is known about response to FRR and the transcriptome responses of FHB and FRR have not been thoroughly compared. Brachypodium distachyon (Bd) is an effective model for investigating host responses to both FHB and FRR. In this study the transcriptome response of Bd to F. graminearum (Fg) infection of heads and roots was investigated. An RNA-seq analysis was performed on both Bd FHB and FRR during the early infection. Additionally, an RNA-seq analysis was performed on in vitro samples of Fg for comparison with Fg gene expression in planta. Differential gene expression and gene-list enrichment analyses were used to compare FHB and FRR transcriptome responses in both Bd and Fg. Differential expression of selected genes was confirmed using RT-qPCR. Most genes associated with receptor signalling, cell-wall modification, oxidative stress metabolism, and cytokinin and auxin biosynthesis and signalling genes were generally upregulated in FHB or were downregulated in FRR. In contrast, Bd genes involved in jasmonic acid and ethylene biosynthesis and signalling, and antimicrobial production were similarly differentially expressed in both tissues in response to infection. A transcriptome analysis of predicted Fg effectors with the same infected material revealed elevated expression of both core tissue- independent genes including cell-wall degradation enzymes and the gene cluster for DON production but also several tissue-dependent genes including those for aurofusarin production and cutin degradation. This evidence suggests that Fg modulates its transcriptome to different tissues of the same host.
Restoration of high-sensitivity patterned vision in motion with an engineered light-gated G protein-coupled receptor
Authors: Holt Amy , Berry Michael H. , Lo Jamie , Donthamsetti Prashant , Visel Meike , Broichhagen Johannes , Flannery John G. , Isacoff Ehud Y. 
Published: April 2022

AbstractInherited retinal degenerations (IRDs) result in blindness due to apoptotic cell death of rods and cones, but spare other retinal neurons, providing a potential that delivery of a light-activated signaling protein to surviving neurons may restore vision. We previously demonstrated that aspects of vision could be restored by introduction into surviving cells of a G protein-coupled receptor for glutamate (mGluR) bearing a tethered photoswitchable agonist. However, this system, containing one photoswitchable agonist per glutamate binding site, yielded low sensitivity, responding only to visual stimuli at the intensity of bright outdoor light, similar to channelrhodopsins. To increase sensitivity, we designed a multi-branched photoswitch, bearing four light-activatable glutamates for each glutamate binding site. When tethered to a modified mGluR2 expressed in retinal ganglion cells via intravitreal AAV gene delivery, this photoswitch boosted sensitivity by ~100-fold compared to the unbranched (single photo-ligand) photoswitch. This improvement in sensitivity enabled an IRD mouse model (rd1) to perform visually-guided object recognition under incidental room light and pattern recognition using standard LCD computer displays. The restored line pattern differentiation approached the acuity reported for normal mouse vision. Pattern recognition functioned as well as wildtype vision with line patterns moving at speeds of up to 36°/s. In summary, this two-component chemical-optogenetic approach combines high sensitivity and high acuity with superior motion vision, and, unlike optogenetic gene therapy, can be adjusted for dose, upgraded, as new photoswitches are developed, and discontinued at will.
SARS-CoV-2 and its variants, but not Omicron, induces thymic atrophy and impaired T cell development
Authors: Rizvi Zaigham Abbas , Sadhu Srikanth , Dandotiya Jyotsna , Binyka Akshay , Sharma Puja , Singh Virendra , Das Vinayaka , Khatri Ritika , Kumar Rajesh , Samal Sweety , Kalia Manjula , Awasthi Amit 
Published: April 2022

AbstractPathogenic infections cause thymic atrophy, perturb thymic-T cell development and alter immunological response. Previous studies reported dysregulated T cell function and lymphopenia in coronavirus disease-19 (COVID-19) patients. However, immune-pathological changes, in the thymus, post severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have not been elucidated. Here, we report SARS-CoV-2 infects thymocytes, depletes CD4+CD8+ (double positive; DP) T cell population associated with an increased apoptosis of thymocytes, which leads to severe thymic atrophy in K18-hACE2-Tg mice. CD44+CD25-T cells were found to be enriched in infected thymus, indicating an early arrest in the T cell developmental pathway. Further, Interferon gamma (IFN-γ) was crucial for thymic atrophy, as anti-IFN-γ antibody neutralization rescued the loss of thymic involution. Therapeutic use of remdesivir (prototype anti-viral drug) was also able to rescue thymic atrophy. While Omicron variant of SARS-CoV2 caused marginal thymic atrophy, delta variant of SARS-CoV-2 exhibited most profound thymic atrophy characterized by severely depleted DP T cells. Recently characterized broadly SARS-CoV-2 neutralizing monoclonal antibody P4A2 was able to rescue thymic atrophy and restore thymic developmental pathway of T cells. Together, we provide the first report of SARS-CoV-2 associated thymic atrophy resulting from impaired T cell developmental pathway and also explains dysregulated T cell function in COVID-19.
Organisation of gene programs revealed by unsupervised analysis of diverse gene-trait associations
Authors: Mizikovsky Dalia , Sanchez Marina Naval , Nefzger Christian M. , Partida Gabriel Cuellar , Palpant Nathan J. 
Published: April 2022

ABSTRACTGenome wide association studies provide statistical measures of gene-trait associations that reveal how genetic variation influences phenotypes. This study develops an unsupervised dimensionality reduction method called UnTANGLeD (Unsupervised Trait Analysis of Networks from Gene Level Data) which organises 16,849 genes into discrete gene programs by measuring the statistical association between genetic variants and 1,393 diverse complex traits. UnTANGLeD reveals 173 gene clusters enriched for protein-protein interactions and highly distinct biological processes governing development, signalling, disease, and homeostasis. We identify diverse gene networks with robust interactions but not associated with known biological processes. Analysis of independent disease traits shows that UnTANGLeD gene clusters are conserved across all complex traits, providing a simple and powerful framework to predict novel gene candidates and programs influencing orthogonal disease phenotypes. Collectively, this study demonstrates that gene programs co-ordinately orchestrating cell functions can be identified without reliance on prior knowledge, providing a method for use in functional annotation, hypothesis generation, machine learning and prediction algorithms, and the interpretation of diverse genomic data.
Expression Analysis, Molecular Characterization and Prognostic Evaluation on TMED4 and TMED9 Gene Expression in Glioma
Authors: Ullah Md. Asad , Tabassum Tahani , Farzana Maisha , Moin Abu Tayab , Zohora Umme Salma , Rahman Mohammad Shahedur 
Published: April 2022

AbstractHere, we utilized a database mining approach to unfold the prognostic and therapeutic potentials of Transmembrane EmP24 Trafficking Protein 4 (TMED4) and 9 (TMED) coding gene expressions in glioma. Both the genes were found to be overexpressed at the mRNA and protein level in low grade glioma (LGG) and glioblastoma multiforme (GBM) tissues including different glioma cell lines. Significant increase in the expression level of these genes with advancing glioma patients’ age, glioma grades and histological subtypes was observed. Differential and distinct promoter and coding sequence methylation pattern of TMED4 and TMED9 was observed in LGG and GBM tissues that may aid in methylation-sensitive diagnosis of glioma patients. The presence of multiple heterozygous genetic alterations (frequency: 0.4-1.1%) in those genes unveiled their potentials in high-throughput screening of glioma patients. The overexpression of TMED4 and TMED9 genes was associated with poor overall survival (OS) of LGG and GBM patients (HR:>1.6). Association of the expression levels of these genes with different immune cell infiltration levels i.e., B cell and T cell and modulators like CD274 and IL10RB was observed providing assurance in TMED-based diagnostic measure and therapeutic intervention discovery. Furthermore, functional enrichment analysis of the neighbor genes of TMED4 and TMED9 revealed that they are involved in metal ion binding, focal adhesion of cells and protein processing, and the deregulation of these activities are associated with gliomagenesis. Altogether, this study suggests that TMED4 and TMED9 are potential prognostic and therapeutic targets for glioma. However, further laboratory research is warranted.
Ultra-high-throughput microbial single-cell whole genome sequencing for genome-resolved metagenomics
Authors: Li Jie , Zhang Rong , Li Ting , Shi Qingyuan , Song Zhangyue , Jiang Lichun , Shi Yunfeng , Ma Conghui , Liang Xue , Zhang Jingwei , Liu Yifan 
Published: April 2022

AbstractMicrobes exist widely in nature. However, less than 1% of the species of microorganisms have been discovered so far, and more than 99% of microorganisms still remain unknown, which is called microbial dark matter. Unravelling microbial dark matter is not only helpful for exploring the unknown microbial world, but also of great significance for human health research. Ever since a long time ago, due to technical limitations, the microbiome, to a great extent, is still a black box. The traditional population-based metagenomic analysis tools are without single microbial resolution and they are stretched when studying rare and unknown microbial species. Here, we use high-throughput microdroplet technology to achieve the whole genome amplification of microbial single-cell genomes in pico-litter sized microdroplets, and develop subsequent library preparation steps such as indexing of the genome, to achieve the development of ultra-high-throughput microbial single-cell whole genome sequencing for genome-resolved metagenomics, aiming to provide a powerful new weapon for exploring microbial dark matter and other microbiological studies.
Oncogenic metabolic rewiring independent of proliferative control in human mammary epithelial cells
Authors: Dong Wentao , Keibler Mark A. , Moon Sun Jin , Cho Patricia , Liu Nian , Berrios Christian J. , Kelleher Joanne K. , Sikes Hadley D. , Iliopoulos Othon , Coloff Jonathan L. , Vander Heiden Matthew G. , Stephanopoulos Gregory 
Published: April 2022

SummaryThe use of isotopic tracers and metabolic flux analysis (MFA) has unveiled a number of metabolic pathways differentially activated in cancer cells. To support efforts to design effective metabolic therapies for cancer, we sought to distinguish metabolic behavior in cancer versus normal cells growing at the same rate. To this end, we performed13C-isotope tracing and MFA in human mammary epithelial cells (HMECs) harboring different combinations of oncogenes. By introducing a new quantity termed metabolic flux intensity, defined as pathway flux divided by specific growth rate, we showed that metabolism is dually controlled by proliferation and oncogenotypes.13C-MFA further revealed that oxidative pentose phosphate pathway (oxPPP), malate dehydrogenase (MDH) and isocitrate dehydrogenase (IDH) were most enhanced in cancerous HMECs. Drug targeting of these pathways selectively reduced growth in the tumorigenic HMEC line. Our study provides direct evidence that metabolism of cancer cells is different than that of normal proliferating cells.