bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymer-directed inhibition of reversible to irreversible attachment prevents Pseudomonas aeruginosa biofilm formation
Authors: Carabelli Alessandro M. , Dubern Jean-Frédéric , Papangeli Maria , Farthing Nicola E. , Sanni Olutoba , Heeb Stephan , Hook Andrew L. , Alexander Morgan R. , Williams Paul 
Published: January 2022

AbstractNon-toxic, biocompatible materials that inhibit bacterial biofilm formation on implanted medical devices and so prevent infection are urgently required. Weakly amphiphilic acrylate polymers with rigid hydrocarbon pendant groups resist bacterial biofilm formation in vitro and in vivo but the biological mechanism involved is not known. By comparing biofilm formation on polymers with the same acrylate backbone but with different pendant groups, we show that poly(ethylene glycol dicyclopentenyl ether acrylate; pEGdPEA) but not neopentyl glycol propoxylate diacrylate (pNGPDA) inhibited the transition from reversible to irreversible attachment. By using single-cell tracking algorithms and controlled flow microscopy we observed that fewer Pseudomonas aeruginosa PAO1 cells accumulated on pEGdPEA compared with pNGPDA. Bacteria reaching the pEGdPEA surface exhibited shorter residence times and greater asymmetric division with more cells departing from the surface post-cell division, characteristic of reversible attachment. Migrating cells on pEGdPEA deposited fewer exopolysaccharide trails and were unable top adhere strongly. Discrimination between the polymers required type IV pili and flagella. On pEGdPEA, the lack of accumulation of cyclic diguanylate or expression of sadB were consistent with the failure to transit from reversible to irreversible attachment. Constitutive expression of sadB increased surface adhesion sufficient to enable P. aeruginosa to form biofilms in a Mot flagellar stator dependent manner. These findings were extendable to other biofilm resistant acrylates highlighting their unique ability to inhibit reversible to irreversible attachment as a mechanism for preventing biofilm-associated infections.SignificanceBacteria readily attach to surfaces forming biofilms. These are commonly associated with medical device-associated infections and highly refractory to antibiotics. Biocompatible, weakly amphiphilic acrylate polymers with large hydrophobic pendant groups that inhibit biofilm formation and can prevent such infections have been described. However, the biological mechanism involved is not understood. By comparing a biofilm-inhibiting with a biofilm-supporting acrylate, we showed that Pseudomonas aeruginosa PAO1 cells responded differentially to the two polymers and were unable to accumulate and adhere strongly, activate cyclic diguanylate signalling or transit from reversible to irreversible attachment on the inhibitory polymer. Constitutive expression of sadB increased surface adhesion sufficient to enable P. aeruginosa to form biofilms in a flagellar stator dependent manner overcoming the biofilm inhibitory properties of the polymer.
Toxoflavin secreted byPseudomonas alcaliphilainhibits growth ofLegionella pneumophilaand its hostVermamoeba vermiformis
Authors: Faucher Sebastien P. , Matthews Sara , Nickzad Arvin , Vounba Passoret , Shetty Deeksha , Bédard Émilie , Prévost Michele , Déziel Eric , Paranjape Kiran 
Published: January 2022

ABSTRACTLegionella pneumophilais a natural inhabitant of water systems. From there, it can be transmitted to humans by aerosolization resulting in severe pneumonia. Most large outbreaks are caused by cooling towers contaminated withL. pneumophila. The resident microbiota of the cooling tower is a key determinant for the colonization and growth ofL. pneumophila. The genusPseudomonascorrelates negatively with the presence ofL. pneumophila, but it is not clear which species is responsible. Therefore, we identified thePseudomonasspecies inhabiting 14 cooling towers using aPseudomonas-specific 16S rRNA amplicon sequencing strategy. Cooling towers free ofL. pneumophilacontained a high relative abundance of members from thePseudomonas alcaliphila/oleovoransphylogenetic cluster.In vitro,P. alcaliphilaJCM 10630 inhibited the growth ofL. pneumophilaon agar plates. Analysis of theP. alcaliphilagenome revealed the presence of a genes cluster predicted to produce toxoflavin.L. pneumophilagrowth was inhibited by pure toxoflavin and by extract fromP. alcaliphilaculture found to contain toxoflavin by LC-ESI-MS. In addition, toxoflavin inhibits growth ofVermameoba vermiformis, a host cell ofL. pneumophila. Our study indicates thatP. alcaliphilamay be important to restrict growth ofL. pneumophilain water systems through the production of toxoflavin. A sufficiently high concentration is likely not achieved in the bulk water but might have a local inhibitory effect such as in biofilm.
NOX4 inhibition promotes the remodeling of dystrophic muscle
Authors: Hammers David W. 
Published: January 2022

ABSTRACTThe muscular dystrophies (MDs) are genetic muscle diseases that result in progressive muscle degeneration followed by the fibrotic replacement of affected muscles as regenerative processes fail. Therapeutics that specifically address the fibrosis and failed regeneration associated with MDs represent a major unmet clinical need for MD patients, particularly those with advanced stage disease progression. The current study investigates targeting NAD(P)H oxidase (NOX) 4 as a potential strategy to reduce fibrosis and promote regeneration in disease-burdened muscle that models Duchenne muscular dystrophy (DMD). NOX4 is elevated in the muscles of dystrophic mice and DMD patients, localizing primarily to interstitial cells located between muscle fibers. Genetic and pharmacological targeting of NOX4 significantly reduces fibrosis in dystrophic respiratory and limb muscles. Mechanistically, NOX4 targeting decreases the number of fibrosis-depositing cells (myofibroblasts) and restores the number of muscle-specific stem cells (satellite cells) to their physiological niche, thereby, rejuvenating muscle regeneration. Furthermore, acute inhibition of NOX4 is sufficient to induce apoptotic clearing of myofibroblasts within dystrophic muscle. These data indicate that targeting NOX4 is an effective strategy to promote the beneficial remodeling of disease-burdened muscle representative of DMD and, potentially, other MDs and muscle pathologies.SIGNIFICANCE STATEMENTMuscular dystrophies are progressive muscle diseases. Therapeutics capable of combating the severe fibrosis that replaces functional muscle in these devastating diseases is a major unmet clinical need, particularly for the treatment of older patients. The current work reveals that targeting NOX4 in dystrophic muscle promotes the beneficial remodeling of disease-burdened musculature. This is achieved by the removal of disease-causing cells, known as myofibroblasts, which results in reduced muscle fibrosis and rejuvenation of muscle regeneration. NOX4-targeting strategies, therefore, represent remodeling therapeutics capable of improving muscle disease caused by muscular dystrophy, and, likely, other muscle pathologies.
Transcriptome-based phylogeny of the semi-aquatic bugs (Hemiptera: Heteroptera: Gerromorpha) reveals patterns of lineage expansion in a series of new adaptive zones
Authors: Armisén David , Viala Séverine , da Rocha Silva Cordeiro Isabelle , Crumière Antonin Jean Johan , Hendaoui Elisa , Le Bouquin Augustin , Duchemin Wandrille , Santos Emilia , Toubiana William , Vargas-Lowman Aidamalia , Floriano Carla Fernanda Burguez , Polhemus Dan A. , Wang Yan-hui , Rowe Locke , Moreira Felipe Ferraz Figueiredo , Khila Abderrahman 
Published: January 2022

AbstractKey innovations enable access to new adaptive zones and are often linked to increased species diversification. As such, they have attracted much attention, yet their concrete consequences on the subsequent evolutionary trajectory and diversification of the bearing lineages remain unclear. The monophyletic group of water striders and relatives (Hemiptera: Heteroptera: Gerromorpha) represent a group of insects that transited to live on the water-air interface and diversified to occupy ponds, puddles, streams, mangroves and even oceans. This lineage offers an excellent model to study the patterns and processes underlying species diversification following the conquest of new adaptive zones. However, such studies require a reliable and comprehensive phylogeny of the infraorder. Based on whole transcriptomic datasets of 97 species and fossil records, we reconstructed a new phylogeny of the Gerromorpha that resolved inconsistencies and uncovered strong support for previously unknown relationships between some important taxa. We then used this phylogeny to reconstruct the ancestral state of a set of adaptations associated with water surface invasion (fluid locomotion, dispersal and transition to saline waters) and sexual dimorphism. Our results uncovered important patterns and dynamics of phenotypic evolution revealing how the initial event of water surface invasion enabled multiple subsequent transitions to new adaptive zones, representing distinct niches of water surfaces, and further diversification of the group. This phylogeny and the associated transcriptomic datasets constitute highly valuable resources, making Gerromorpha an attractive model lineage to study phenotypic evolution.
The Cryo-EM Structures of two Amphibian Antimicrobial Cross-β Amyloid Fibrils
Authors: Bücker Robert , Seuring Carolin , Cazey Cornelia , Veith Katharina , García-Alai Maria , Grünewald Kay , Landau Meytal 
Published: January 2022

AbstractThe amyloid-antimicrobial link hypothesis is based on antimicrobial properties found in human amyloids involved in neurodegenerative and systemic diseases, along with amyloidal structural properties found in antimicrobial peptides (AMPs) across kingdoms of life. Supporting this hypothesis, we here determined the fibril structure of two AMPs from amphibians, uperin 3.5 and aurein 3.3, by cryogenic electron microscopy (cryo-EM), revealing amyloid cross-β fibrils of mated β-sheets at atomic resolution. Uperin 3.5 displayed substantial polymorphism with a protofilament of two mated β-sheets. The determined structure was a polymorph showing a 3-blade symmetrical propeller of nine peptides per fibril layer including tight β-sheet interfaces. This cross-β cryo-EM structure complements the cross-α fibril conformation previously determined by a crystal structure, substantiating a secondary structure switch mechanism of uperin 3.5. The aurein 3.3 arrangement consisted of six peptides per fibril layer, all showing kinked β-sheets allowing a rounded compactness of the fibril. The kinked β-sheets are similar to LARKS (Low-complexity, Amyloid-like, Reversible, Kinked segments) found in human functional amyloids. The amyloidal properties of antimicrobial peptides shed light on a mechanism of regulation of animicrobial activity involving self-assembly and fibril morphological variations. Moreover, the known endurance of amyloid structures can provide a template for the design of sturdy antimicrobials.
OptiDiff: structural variation detection from single optical mapping reads
Authors: Akdel Mehmet , de Ridder Dick 
Published: January 2022

AbstractDetecting structural variation (SV) in eukaryotic genomes is of broad interest due to its often dramatic phenotypic effects, but remains a major, costly challenge based on DNA sequencing data. A cost-effective alternative in detecting large-scale SV has become available with advances in optical mapping technology. However, the algorithmic approaches to identifying SVs from optical mapping data are limited. Here, we propose a novel, open-source SV detection tool, OptiDiff, which employs a single molecule based approach to detect and classify homozygous and heterozygous SVs at coverages as low as 20x, showing better performance than the state of the art.
Visual threats reduce blood-feeding and trigger escape responses in Aedes aegypti mosquitoes
Authors: Wynne Nicole E. , Chandrasegaran Karthikeyan , Fryzlewicz Lauren , Vinauger Clément 
Published: January 2022

AbstractThe diurnal mosquitoes Aedes aegypti are vectors of several arboviruses, including dengue, yellow fever, and Zika viruses. To find a host to feed on, they rely on the sophisticated integration of olfactory, visual, thermal, and gustatory cues reluctantly emitted by the hosts. If detected by their target, this latter may display defensive behaviors that mosquitoes need to be able to detect and escape. In humans, a typical response is a swat of the hand, which generates both mechanical and visual perturbations aimed at a mosquito. While the neuro-sensory mechanisms underlying the approach to the host have been the focus of numerous studies, the cues used by mosquitoes to detect and identify a potential threat remain largely understudied. In particular, the role of vision in mediating mosquitoes’ ability to escape defensive hosts has yet to be analyzed. Here, we used programmable visual displays to generate expanding objects sharing characteristics with the visual component of an approaching hand and quantified the behavioral response of female mosquitoes. Results show that Ae. aegypti is capable of using visual information to decide whether to feed on an artificial host mimic. Stimulations delivered in a LED flight arena further reveal that landed females Ae. aegypti display a stereotypical escape strategy by taking off at an angle that is a function of the distance and direction of stimulus introduction. Altogether, this study demonstrates mosquitoes can use isolated visual cues to detect and avoid a potential threat.Summary StatementIn isolation, visual stimuli programmed to mimic a human swat prevent mosquitoes from blood-feeding by triggering take-offs and escape responses.
Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases
Authors: Zhao Huiling , Rasheed Humaria , Nøst Therese Haugdahl , Cho Yoonsu , Liu Yi , Bhatta Laxmi , Bhattacharya Arjun ,   Global Biobank Meta-analysis Initiative, Hemani Gibran , Smith George Davey , Brumpton Ben Michael , Zhou Wei , Neale Benjamin M. , Gaunt Tom R. , Zheng Jie 
Published: January 2022

AbstractProteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans, but limited data has made identification of causal proteins in other ancestries challenging. Here we present a multi-ancestry proteome-wide MR analysis pipeline based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the causal effects of 1,545 proteins on eight complex diseases in up to 32,658 individuals of African ancestries and 1.22 million individuals of European ancestries. We identified 45 and seven protein-disease pairs with MR and genetic colocalization evidence in the two ancestries respectively. 15 protein-disease pairs showed evidence of differential effects between males and females. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence of an effect in both ancestries, seven pairs with European-specific effects and seven with African-specific effects. Integrating these MR signals with observational and clinical trial evidence, we were able to evaluate the efficacy of one existing drug, identify seven drug repurposing opportunities and predict seven novel effects of proteins on diseases. Our results highlight the value of proteome-wide MR in informing the generalisability of drug targets across ancestries and illustrate the value of multi-cohort and biobank meta-analysis of genetic data for drug development.Graphical abstractNotation: genome-wide association study (GWAS); Mendelian randomization (MR); primary open-angle glaucoma (POAG); idiopathic pulmonary fibrosis (IPF); chronic obstructive pulmonary disease (COPD); heart failure (HF), venous thromboembolism (VTE). European ancestry (EUR); African ancestry (AFR)*For the seven protein-disease associations, one association passed FDR threshold of 0.05 in proteome-wide MR, six additional associations passed FDR of 0.05 in the multi-ancestry comparison analysis.HighlightsA multi-ancestry proteome-wide Mendelian randomization (MR) analysis of 1,545 proteins on eight diseases in more than 1.26 million individuals from a disease GWAS meta-analysis of 19 biobanks.We find evidence for putative causal effects in 45 protein-disease pairs in European ancestry and seven protein-disease pairs in African ancestry, with 15 pairs showing sex specific effects.We identify evidence of causality for two protein-disease pairs that are common to both African and European ancestries, seven pairs with European-specific effects and seven pairs with African-specific effects.Triangulating with clinical trial and observational evidence prioritizes seven new targets, seven drug repurposing opportunities and one existing drug target that generalise to African ancestry.
BML-257, a small molecule that protects against drug induced liver injury in zebrafish
Authors: Jagtap Urmila , Basu Sandeep , Lokhande Lavanya , Bharti Nikhil , Sachidanandan Chetana 
Published: January 2022

AbstractThe use of many essential drugs is restricted due to their deleterious effects on the liver. Molecules that can prevent or protect the liver from drug induced liver injury (DILI) would be valuable in such situations. We used hepatocyte-specific expression of bacterial nitroreductase in zebrafish to cause temporally controlled liver damage. This transgenic line was used to run a whole organism based chemical screen in zebrafish larvae. In this screen we identified BML-257, a potent small molecule AKT inhibitor, that protected the liver against metronidazole-induced liver injury. BML-257 also showed potent prophylactic and pro-regenerative activity in this liver damage model. BML-257 also showed remarkable protective action in two independent toxicological models of liver injury caused by acetaminophen and Isoniazid. This suggests that BML-257 may have the potential to protect against multiple kinds of drug induced liver injury.
Estradiol mediates stress-susceptibility in the male brain
Authors: Georgiou Polymnia , Mou Ta-Chung M. , Potter Liam E. , An Xiaoxian , Zanos Panos , Patton Michael S. , Pultorak Katherine J. , Clark Sarah M. , Ngyuyen Vien , Powels Chris F. , Prokai-Tatrai Katalin , Merchenthaler Istvan , Prokai Laszlo , McCarthy Margaret M. , Mathur Brian N. , Gould Todd D. 
Published: January 2022

AbstractIn susceptible populations, stress is a major risk factor for the development of mental disorders, including depression. Estradiol, often considered a female hormone, is distributed in the male brain via aromatization of testosterone. The role of estrogen receptors (ERs) in male stress susceptibility and depression is not well understood. We found that absence of ERβ is associated with susceptibility to stress in male mice and that activity of ERβ-projecting neurons from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal mice subjected to stress, while activation of this circuit reverses stress-induced maladaptive behaviors. We identified that absence of estradiol, but not testosterone per se, underlies stress susceptibility and that brain-selective delivery of estradiol prevents the development of depression-related behaviors. Our findings provide evidence for an estrogen-based mechanism underlying stress susceptibility and offer an unexpected therapeutic strategy for treating depression in males.
A neural-mechanistic hybrid approach improving the predictive power of genome-scale metabolic models
Authors: Faure Léon , Mollet Bastien , Liebermeister Wolfram , Faulon Jean-Loup 
Published: January 2022

AbstractConstraint-based metabolic models have been used for decades to predict the phenotype of microorganisms in different environments. However, quantitative predictions are limited unless labor-intensive measurements of media uptake fluxes are performed. We show how hybrid neural-mechanistic models can serve as an architecture for machine learning providing a way to improve phenotype predictions. We illustrate our hybrid models with growth rate predictions ofEscherichia coliandPseudomonas putidagrown in different media and with phenotype predictions of gene knocked-outEscherichia colimutants. Our neural-mechanistic models systematically outperform constraint-based models and require training set sizes orders of magnitude smaller than classical machine learning methods. Our hybrid approach opens a doorway to enhancing constraint-based modeling: instead of constraining mechanistic models with additional experimental measurements, our hybrid models grasp the power of machine learning while fulfilling mechanistic constrains, thus saving time and resources in typical systems biology or biological engineering projects.
Pericentriolar matrix integrity relies on cenexin and Polo-Like Kinase (PLK)1
Authors: Aljiboury Abrar , Mujcic Amra , Curtis Erin , Cammerino Thomas , Magny Denise , Lan Yiling , Bates Michael , Freshour Judy , Ahmed-Braimeh Yasir H. , Hehnly Heidi 
Published: January 2022

SUMMARYPolo-Like-Kinase (PLK) 1 activity is associated with maintaining the functional and physical properties of the centrosome’s pericentriolar matrix (PCM). In this study, we use a multimodal approach of human cells (HeLa) and zebrafish embryos in parallel to phylogenic analysis to test the role of a PLK1 binding protein, cenexin, in regulating the PCM. Our studies identify that cenexin is required for tempering microtubule nucleation and that a conserved C-terminal PLK1 binding site between humans and zebrafish is needed for PCM maintenance through mediating PLK1-dependent substrate phosphorylation events. PCM architecture in cenexin-depleted zebrafish embryos was rescued with wild-type human cenexin, but not with a C-terminal cenexin mutant (S796A) deficient in PLK1 binding. We propose a model where cenexin’s C-terminus acts in a conserved manner in eukaryotes, excluding nematodes and arthropods, to anchor PLK1 moderating its potential to phosphorylate PCM substrates required for PCM maintenance and function.
LinkExplorer: Predicting, explaining and exploring links in large biomedical knowledge graphs
Authors: Ott Simon , Barbosa-Silva Adriano , Samwald Matthias 
Published: January 2022

AbstractSummaryMachine learning algorithms for link prediction can be valuable tools for hypothesis generation. However, many current algorithms are black boxes or lack good user interfaces that could facilitate insight into why predictions are made. We present LinkExplorer, a software suite for predicting, explaining and exploring links in large biomedical knowledge graphs. LinkExplorer integrates our novel, rule-based link prediction engine SAFRAN, which was recently shown to outcompete other explainable algorithms and established black box algorithms. Here, we demonstrate highly competitive evaluation results of our algorithm on multiple large biomedical knowledge graphs, and release a web interface that allows for interactive and intuitive exploration of predicted links and their explanations.Availability and ImplementationA publicly hosted instance, source code and further documentation can be found athttps://github.com/OpenBioLink/Explorer.Contactmatthias.samwald@meduniwien.ac.atSupplementary informationSupplementary data are available atBioinformaticsonline.