bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome mining as a biotechnological tool for the discovery of novel biosynthetic genes in lichens
Authors: Singh Garima , Dal Grande Francesco , Schmitt Imke 
Published: May 2022

AbstractThe ever-increasing demand for novel drugs highlights the need for bioprospecting unexplored taxa for their biosynthetic potential. Lichen-forming fungi (LFF) are a rich source of natural products but their implementation in pharmaceutical industry is limited, mostly because the genes corresponding to a majority of their natural products is unknown. Furthermore, it is not known to what extent these genes encode structurally novel molecules. Advance in next-generation sequencing technologies has expanded the range of organisms that could be exploited for their biosynthetic potential. In this study, we mine the genomes of nine lichen-forming fungal species of the genus Umbilicaria for biosynthetic genes, and categorize the BGCs as “associated product structurally known”, and “associated product putatively novel”. We found that about 25-30% of the biosynthetic genes are divergent when compared to the global database of BGCs comprising of 1,200,000 characterized biosynthetic genes from planta, bacteria and fungi. Out of 217 total BGCs, 43 were only distantly related to known BGCs, suggesting they encode structurally and functionally unknown natural products. Clusters encoding the putatively novel metabolic diversity comprise PKSs (30), NRPSs (12) and terpenes (1). Our study emphasizes the utility of genomic data in bioprospecting microorganisms for their biosynthetic potential and in advancing the industrial application of unexplored taxa. We highlight the untapped structural metabolic diversity encoded in the lichenized fungal genomes. To the best of our knowledge, this is the first investigation identifying genes coding for NPs with potentially novel therapeutic properties in LFF.
Bi-axial orientation could explain range expansion in a migratory songbird
Authors: Wynn Joe , Fandos Guillermo , Delmore Kira , Van Doren Benjamin M. , Fransson Thord , Liedvogel Miriam 
Published: May 2022

AbstractThe likelihood of a new migratory route evolving is a function of the associated fitness payoff, and the probability that the route arises in the first place. Cross-breeding studies suggest that young birds migrate in a direction intermediate between their parents, though this would seemingly not explain how highly divergent migratory trajectories arise in apparently sympatric populations. It has been suggested that diametrically opposed ‘reverse’ migratory trajectories might be surprisingly common, and if such routes were heritable it follows that they could underlie the rapid evolution of divergent migratory trajectories. Here, we used Eurasian blackcap (Sylvia atricapilla; ‘blackcap’) ringing recoveries and geolocator trajectories to investigate whether a recently-evolved northwards autumn migratory route could be explained by the reversal of each individual’s expected southwards migratory direction. We found that northwards migrants were recovered closer to the sites specified by a precise axis reversal than would be expected by chance, consistent with the rapid evolution of new migratory routes via bi-axial variation in orientation. We suggest that the surprisingly high probability of axis reversal might allow birds to expand their wintering ranges rapidly, and hence propose that understanding how direction is encoded is crucial when characterising the genetic basis of migratory direction and how this relates to route evolution.
Multivariate Analysis of PET Pharmacokinetic Parameters
Authors: Matheson Granville J. , Ogden R. Todd 
Published: May 2022

AbstractPurposeIn positron emission tomography (PET) quantification, multiple pharmacokinetic parameters are typically estimated from each time activity curve. Conventionally, all but the parameter of interest are discarded before performing subsequent statistical analysis. However, we assert that these discarded parameters also contain relevant information which can be exploited to improve the precision and power of statistical analyses on the parameter of interest. Properly taking this into account can thereby draw more informative conclusions without collecting more data.MethodsBy applying a hierarchical multifactor multivariate Bayesian approach, all estimated parameters from all regions can be analysed at once. We refer to this method as PuMBA (Parameters undergoing Multivariate Bayesian Analysis). We simulated patientcontrol studies with different radioligands, varying sample sizes and measurement error to explore its performance, comparing the precision, statistical power, false positive rate and bias of estimated group differences relative to univariate analysis methods.ResultsWe show that PuMBA improves the statistical power for all examined applications relative to univariate methods without increasing the false positive rate. PuMBA improves the precision of effect size estimation, and reduces the variation of these estimates between simulated samples. Furthermore, we show that PuMBA yields performance improvements even in the presence of substantial measurement error. Remarkably, owing to its ability to leverage information shared between pharmacokinetic parameters, PuMBA even shows greater power than conventional univariate analysis of the true binding values from which the parameters were simulated. Across all applications, PuMBA exhibited a small degree of bias in the estimated outcomes, however this was small relative to the variation in estimated outcomes between simulated datasets.ConclusionPuMBA improves the precision and power of statistical analysis of PET data without requiring the collection of additional measurements. This makes it possible to study new research questions in both new and previously collected data. PuMBA therefore holds great promise for the field of PET imaging.
The radio-protective effects of (-)- Epigallocatechin-3-gallate (EGCG): regulating macrophage function in radiation-induced intestinal injury
Authors: Gu Jia , Tang Zhibing , Li Jiaxin , Cui Yilin , Liu Shanghai , Guo Qing , Chen Yuzhong , Lv Sichen , Zhao Lin , Xu Jiaying 
Published: May 2022

AbstractAccidental and medical radiation exposure may cause radiation-induced intestinal injury (RIII), a catastrophic disease requiring efficient therapies. (-)-Epigallocatechin-3-gallate (EGCG), a major constituent of green tea, has been shown to have potent biological activity as well as strong anti-inflammation effects. Here, we demonstrate that EGCG treatment not only protects mice against total body irradiation (TBI)-induced toxicity and weight loss but also alleviates whole abdominal irradiation (WAI)-induced intestinal injury. EGCG promotes proliferation and survival of intestinal stem cells, inhibits radiation-induced apoptosis and inflammation. At the same time, EGCG preserves the composition of the gut microbiota in WAI mice. In vitro, we demonstrate that EGCG regulates the release of radiation-induced inflammatory factors by inhibiting inflammatory pathways such as toll-like receptor signaling pathway in peritoneal macrophages. Mechanistically, the radioprotective effect of EGCG was likely attributable to its preservation on macrophages and the colonized gut microbiota composition, thus relieving the intestinal inflammation. EGCG provides a novel strategy to mitigate RIII and improve the prognosis of patients after radiotherapy.
Plasma miRNA-214 is a predictive candidate biomarker of progression speed in patients with ALS
Authors: Noh Min-Young , Kwon Min-Soo , Oh Ki-Wook , Nahm Minyeop , Park Jinseok , Kim Young-Eun , Jin Hee Kyung , Bae Jae-sung , Ki Chang-Seok , Kim Seung Hyun 
Published: May 2022

ABSTRACTThis study was designed to develop and validate a reliable biomarker to predict the progression speed reflecting immune function of amyotrophic lateral sclerosis (ALS). After establishing the induced microglia model (iMGs) derived from peripheral blood monocytes, comparative studies to find factors related to phagocytic differences between iMGs of patients with rapidly progressive ALS [ALS(R)-iMGs, n = 15] and those of patients with slowly progressive ALS [ALS(S)-iMGs, n = 14] were conducted in the discovery cohort. To validate discovered candidate and whether it could be used as a reliable biomarker predicting the progression speed of ALS, we recruited 132 patients with ALS and 30 age-matched healthy controls as the validation cohort. ALS(R)-iMGs showed impaired phagocytic function. Transcriptomic analysis revealed that the perturbed phagocytosis in ALS(R)-iMGs was related to the decreased expression of NCKAP1 (NCK-associated protein 1) and NCKAP1 overexpression rescued the impaired phagocytic function. miRNA-214-3p targeting NCKAP1 in ALS-iMGs was correlated with progression speed in the discovery cohort. The validation cohort revealed that plasma miRNA-214-3p levels were significantly increased in ALS patients (p < 0.0001, AUC = 0.839), correlated with disease progression speed (p = 0.0005), and distinguished the rapidly progressive subgroup (Q1) from the slowly progressive (Q4, p = 0.029), respectively. Plasma miRNA-214-3p can predict the progression speed in ALS. Plasma miRNA-214-3p could be used as a simple and easily accessible biomarker for predicting the future progression speed related to phagocytic dysfunction in ALS patients.
Cyclic nucleotide-induced superhelical structure activates a bacterial TIR immune effector
Authors: Hogrel Gaëlle , Guild Abbie , Graham Shirley , Rickman Hannah , Grüschow Sabine , Bertrand Quentin , Spagnolo Laura , White Malcolm F 
Published: May 2022

ABSTRACTCyclic nucleotide signalling is a key component of anti-viral defence in all domains of life, from bacteria to humans. Viral detection activates a nucleotide cyclase to generate a second messenger, resulting in activation of effector proteins. This is exemplified by the metazoan cGAS-STING innate immunity pathway1, which originated in bacteria2. These defence systems require a sensor domain such as STING or SAVED to bind the cyclic nucleotide, coupled with an effector domain that causes cell death when activated by destroying essential biomolecules3. One example is the TIR (Toll/interleukin-1 receptor) domain, which degrades the essential cofactor NAD+when activated in response to pathogen invasion in plants and bacteria2,4,5or during nerve cell programmed death6. Here, we show that a bacterial anti-viral defence system generates a cyclic tri-adenylate (cA3) signal which binds to a TIR-SAVED effector, acting as the “glue” to allow assembly of an extended superhelical solenoid structure. Adjacent TIR subunits interact to organise and complete a composite active site, allowing NAD+degradation. Our study illuminates a striking example of large-scale molecular assembly controlled by cyclic nucleotides and reveals key details of the mechanism of TIR enzyme activation.
High-resolution mass spectrometry reveals environmentally relevant uptake, elimination, and metabolic alterations following early embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish
Authors: Kossack Michelle E. , Manz Katherine E. , Martin Nathan R. , Pennell Kurt D. , Plavicki Jessica 
Published: May 2022

ABSTRACTDioxin and dioxin-like compounds are ubiquitous environmental contaminants that induce toxicity by binding to the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. The zebrafish model has been used to define the developmental toxicity observed following exposure to exogenous AHR ligands such as the potent agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD). While the model has successfully identified cellular targets of TCDD and molecular mechanisms mediating TCDD-induced phenotypes, fundamental information such as the body burden produced by standard exposure paradigms is still unknown. We performed targeted gas chromatography (GC) high-resolution mass spectrometry (HRMS) in tandem with non-targeted liquid chromatography (LC) HRMS to quantify TCDD uptake, model the elimination dynamics of TCDD, and determine how TCDD exposure affects the zebrafish metabolome. We found that 10 ppb, 1 ppb, and 50 ppt waterborne exposures during early embryogenesis produced environmentally relevant body burden of TCDD: 38 ± 4.34, 26.6 ± 1.2, and 8.53 ± 0.341 pg/embryo, respectively, at 24 hours post fertilization. In addition, we discovered that TCDD exposure was associated with the dysregulation of several metabolic pathways that are critical for brain development and function including glutamate metabolism, chondroitin sulfate biosynthesis, and tyrosine metabolism pathways. Together, these data demonstrate that existing exposure paradigms produce environmentally relevant body burdens of TCDD in zebrafish and provide insight into the biochemical pathways impacted by toxicant-induced AHR activation.HIGHLIGHTSHistorical TCDD exposure paradigms produce environmentally relevant body burdens in zebrafish embryos.TCDD elimination for high doses can be modeled using an exponential regression.Exposure to TCDD alters metabolic pathways that are essential for brain development and function.GRAPHICAL ABSTRACT
SARS-CoV-2 Omicron subvariants evolved to promote further escape from MHC-I recognition
Authors: Moriyama Miyu , Lucas Carolina , Monteiro Valter Silva ,   Yale SARS-CoV-2 Genomic Surveillance Initiative, Iwasaki Akiko 
Published: May 2022

AbstractSARS-CoV-2 variants of concern (VOCs) possess mutations that confer resistance to neutralizing antibodies within the Spike protein and are associated with breakthrough infection and reinfection. By contrast, less is known about the escape from CD8+T cell-mediated immunity by VOC. Here, we demonstrated that all SARS-CoV-2 VOCs possess the ability to suppress MHC I expression. We identified several viral genes that contribute to the suppression of MHC I expression. Notably, MHC-I upregulation was strongly inhibited after SARS-CoV-2 infectionin vivo. While earlier VOCs possess similar capacity as the ancestral strain to suppress MHC I, Omicron subvariants exhibit a greater ability to suppress surface MHC-I expressions. Collectively, our data suggest that, in addition to escape from neutralizing antibodies, the success of Omicron subvariants to cause breakthrough infection and reinfection may in part be due to its optimized evasion from T cell recognition.SignificanceNumerous pathogenic viruses have developed strategies to evade host CD8+T cell-mediated clearance. Here, we demonstrated that SARS-CoV-2 encodes multiple viral factors that can modulate MHC-I expression in the host cells. We found that MHC-I upregulation was strongly suppressed during SARS-CoV-2 infectionin vivo. Notably, the Omicron subvariants showed an enhanced ability to suppress MHC-I compared to the original strain and the earlier SARS-CoV-2 variants of concern (VOCs). Our results point to the inherently strong ability of SARS-CoV-2 to hinder MHC-I expression and demonstrated that Omicron subvariants have evolved an even more optimized capacity to evade CD8 T cell recognition.
A Proximity-Dependent Biosensor System for Visualizing Cell-Cell Interactions Induced by Therapeutic Antibodies
Authors: Tang Yu , Cao Yanguang 
Published: May 2022

AbstractBackground and PurposeDespite the promising results of therapeutic antibodies in engaging the immune system to eliminate malignant cells, many aspects of the complex interplay between immune cells and cancer cells during antibody therapy remain incompletely understood. This study aimed to develop a biosensor system that can evaluate direct cell-cell contact and interactions between immune effector and target cells induced by therapeutic antibodies in physiologically relevant environments.Experimental ApproachThe system uses two structural complementary luciferase units (SmBit and LgBit) expressed on the respective membranes of immune effector and target cells. Upon cell-cell contact, the two subunits form active NanoLuc, generating a luminescent signal, allowing for real-time monitoring of cell-cell interactions and quantitatively assessing the pharmacological effects of therapeutic antibodies.Key ResultsWe optimized the system to ensure selectivity by adjusting the spacer lengths between two luciferase units to minimize interference from nonspecific intercellular contact. The system was able to quantitatively and longitudinally monitor cell-cell interactions between NK and target cells induced by rituximab and between T and target cells induced by blinatumomab in a three-dimensional cell culture system. The observation that NK cells exhibited faster interactions with target cells compared to T cells is intriguing and suggests potential differences in the mechanisms or kinetics of cell-cell interactions between different types of effector cells and tumor cells.Conclusions and ImplicationsThe biosensor system has the potential for broad applications to optimize antibody pharmacology and efficacy in various therapeutic areas through a deeper understanding of antibody-mediated cell-cell interactions.What is already knownTherapeutic antibodies can activate the immune system to elicit cytotoxicity through inducing cell-cell interactions between immune and tumor cells.Approaches for longitudinally evaluating cell-cell interaction induced by therapeutic antibodies remain limited.What does this study addThis study develops a biosensor system for detecting cell-cell interactions induced by therapeutic antibodies in a longitudinal manner.The system is able to monitor cell-cell interactions between NK and target cells, as well as between T and target cells, in a three-dimensional cell culture system.What is the clinical significanceThe biosensor system has the potential for broad applications in the field of antibody pharmacology by providing a deeper understanding of antibody-mediated cell-cell interactions and their dynamics.
Polaramycin B, and not physical interaction, is the signal that rewires fungal metabolism in the Streptomyces – Aspergillus interaction
Authors: Berger Harald , Bacher Markus , Labuda Roman , Eppel Isabel Maria , Bayer Florentina , Sulyok Michael , Gasparotto Erika , Zehetbauer Franz , Doppler Maria , Gratzl Hannes , Strauss Joseph 
Published: May 2022

AbstractCo-culturing the bacterium Streptomyces rapamycinicus and the ascomycete Aspergillus nidulans has previously been shown to trigger the production of orsellinic acid (ORS) and its derivates in the fungal cells. Based on these studies it was assumed that direct physical contact is a prerequisite for the metabolic reaction that involves a fungal amino acid starvation response and activating chromatin modifications at the biosynthetic gene cluster (BGC). Here we show that not physical contact, but a guanidine containing macrolide, named polaramycin B, triggers the response. The substance is produced constitutively by the bacterium and provokes the production of ORS above a certain concentration. In addition, several other secondary metabolites were induced by polaramycin B. Our genome-wide transcriptome analysis showed that polaramycin B treatment causes down-regulation of fungal genes necessary for membrane stability, general metabolism and growth. A compensatory genetic response can be observed in the fungus that included up-regulation of BGCs and genes necessary for ribosome biogenesis, translation and membrane stability. Our work discovered a novel chemical communication, in which the antifungal bacterial metabolite polaramycin B leads to the production of antibacterial defence chemicals and to the up-regulation of genes necessary to compensate for the cellular damage caused by polaramycin B.
Curation of BIDS (CuBIDS): a workflow and software package for streamlining reproducible curation of large BIDS datasets
Authors: Covitz Sydney , Tapera Tinashe M. , Adebimpe Azeez , Alexander-Bloch Aaron , Bertolero Maxwell A. , Feczko Eric , Franco Alexandre R. , Gur Raquel E. , Gur Ruben C. , Hendrickson Timothy , Houghton Audrey , Mehta Kahini , Murtha Kristin , Perrone Anders J. , Robert-Fitzgerald Tim , Schabdach Jenna M. , Shinohara Russell T , Vogel Jacob W. , Zhao Chenying , Fair Damien A. , Milham Michael P. , Cieslak Matthew , Satterthwaite Theodore D. 
Published: May 2022

ABSTRACTThe Brain Imaging Data Structure (BIDS) is a specification accompanied by a software ecosystem that was designed to create reproducible and automated workflows for processing neuroimaging data. BIDS Apps flexibly build workflows based on the metadata detected in a dataset. However, even BIDS valid metadata can include incorrect values or omissions that result in inconsistent processing across sessions. Additionally, in large-scale, heterogeneous neuroimaging datasets, hidden variability in metadata is difficult to detect and classify. To address these challenges, we created a Python-based software package titled “Curation of BIDS” (CuBIDS), which provides an intuitive workflow that helps users validate and manage the curation of their neuroimaging datasets. CuBIDS includes a robust implementation of BIDS validation that scales to large samples and incorporates DataLad––a version control software package for data––to ensure reproducibility and provenance tracking throughout the entire curation process. CuBIDS provides tools to help users perform quality control on their images’ metadata and identify unique combinations of imaging parameters. Users can then execute BIDS Apps on a subset of participants that represent the full range of acquisition parameters that are present, accelerating pipeline testing on large datasets.HIGHLIGHTSCuBIDS is a workflow and software package for curating BIDS data.CuBIDS summarizes the heterogeneity in a BIDS dataset.CuBIDS prepares BIDS data for successful preprocessing pipeline runs.CuBIDS helps users perform metadata-based quality control.