bluuebunny/crossref_metadata_2025_split huggingface dataset:
Episomal virus maintenance enables bacterial population recovery from infection and virus-bacterial coexistence
Authors: Sanchez-Martinez Rodrigo , Arani Akash , Krupovic Mart , Weitz Joshua S. , Santos Fernando , Anton Josefa 
Published: July 2024

ABSTRACTHypersaline environments harbor the highest concentrations of virus-like particles (VLPs) reported for aquatic ecosystems. The substantial densities of both microbial populations and VLPs challenge traditional explanations of top-down control exerted by viruses. At close to saturation salinities, prokaryotic populations are dominated byArchaeaand the bacterial cladeSalinibacter. In this work we examine the episomal maintenance of a virus within aSalinibacter ruberhost. We found that infected cultures ofSal. ruberM1 developed a population-level resistance and underwent systematic and reproducible recovery post infection that was counter-intuitively dependent on the multiplicity of infection (MOI), where higher MOI led to better host outcomes. Furthermore, we developed a nonlinear population dynamics model that successfully reproduced the qualitative features of the recovery. This suggests that the maintenance of the virus episomally, often referred to as pseudolysogeny, and lysis inhibition allow for host-virus co-existence under high MOI infections. Our results emphasize the ecological importance of exploring a spectrum of viral infection strategies beyond the conventional binary of lysis or lysogeny.
A survey of ADP-ribosyltransferase families in the pathogenicLegionella
Authors: Krysińska Marianna , Gradowski Marcin , Baranowski Bartosz , Pawłowski Krzysztof , Dudkiewicz Małgorzata 
Published: July 2024

AbstractBackgroundADP-ribosyltransferases (ARTs) are a superfamily of enzymes implicated in various cellular processes, including pathogenic mechanisms. TheLegionellagenus, known for causing Legionnaires’ disease, possesses diverse ART-like effectors. This study explores the proteomes of 41Legionellaspecies to bioinformatically identify and characterise novel ART-like families, providing insights into their potential roles in pathogenesis and host interactions.MethodsWe conducted a comprehensive bioinformatic survey of 41Legionellaspecies to identify proteins with significant sequence or structural similarity to known ARTs. Sensitive sequence searches were performed to detect candidate ART-like families. Subsequent validation, including structure prediction of such families, was achieved using artificial intelligence-driven tools, such as AlphaFold. Comparative analyses were performed to assess sequence and structural similarities between the novel ART-like families and known ARTs.ResultsOur analysis identified 63 proteins with convincing similarity to ARTs, organised into 39 ART-like families, including 26 novel families. Key findings include:DUF2971 family: exhibits sequence similarity to DarT toxins and other DNA-acting ARTs.DUF4291 family: the largest newly identified family shows structural and sequence similarity to the diphtheria toxin, suggesting the ability to modify proteins.Most members of the novel ART families are predicted effectors. Although experimental validation of the predicted ART effector functions is necessary, the novel ART-like families identified present promising targets for understandingLegionellapathogenicity and developing therapeutic strategies. We publish a complete catalogue of our results in the astARTe database:http://bioinfo.sggw.edu.pl/astarte/.
Water availability determines plant regeneration fates
Authors: Kareem Abdul , van Wüllen Anna K. , Zhang Ai , Walckiers Gabriel , Fasth Ellen , Melnyk Charles W. 
Published: July 2024

AbstractWounding and hormones serve as diverse triggers for regeneration in animals and plants but how organisms determine regeneration outcomes remains largely unknown. Here, we demonstrated that wounded Arabidopsis tissues regenerate two distinct fates, wound-induced callus or de novo root formation, that are driven by antagonizing molecular pathways related to cambium and root development. We discovered that local water availability dictated these regeneration outcomes in Arabidopsis and tomato, with high water triggering root fate and low water initiating callus fate. Moreover, distinct spatial distributions of auxin response maxima were critical for fate progression and water availability regulated these auxin maxima through the hormones ethylene and jasmonic acid. We propose that water availability determines environmental control of regeneration plasticity with applied potential for improving regeneration in agriculture.
In silicoPK predictions in Drug Discovery: Benchmarking of Strategies to Integrate Machine Learning with Empiric and Mechanistic PK modelling
Authors: Walter Moritz , Aljayyoussi Ghaith , Gerner Bettina , Rapp Hermann , Tautermann Christofer S. , Balazki Pavel , Skalic Miha , Borghardt Jens M. , Humbeck Lina 
Published: July 2024

ABSTRACTA successful drug needs to combine several properties including high potency and good pharmacokinetic (PK) properties to sustain efficacious plasma concentration over time. To estimate required doses for preclinical animal efficacy models or for the clinics,in vivoPK studies need to be conducted. While the prediction of ADME properties of compounds using Machine Learning (ML) models based on chemical structures is well established in drug discovery, the prediction of complete plasma concentration-time profiles has only recently gained attention. In this study, we systematically compare various approaches that integrate ML models with mechanistic PK models to predict PK profiles in rats after i.v. administration prior to synthesis. More specifically, we compare a standard noncompartmental analysis (NCA) based approach (prediction of CL and Vss), a pure ML approach (non-mechanistic PK description), a compartmental modeling approach, and a physiologically based pharmacokinetic (PBPK) approach. Our study based on internal preclinical data shows that the latter three approaches yield PK profile predictions of comparable accuracy (evaluated as geometric mean fold errors for each profile) across a large test set (>1000 small molecules). In summary, we demonstrate the improved ability to prioritize drug candidates with desirable PK properties prior to synthesis with ML predictions.
Circulating mucosal-like IgA responses associate with severity of Puumala orthohantavirus-caused hemorrhagic fever with renal syndrome
Authors: Cabrera Luz E. , Buckner Cienna , Martinez Veronica , Mäki Sanna , Vapalahti Olli , Vaheri Antti , Hepojoki Jussi , Tietäväinen Johanna , Mäkelä Satu , Mustonen Jukka , Strandin Tomas 
Published: July 2024

AbstractOld World Orthohantaviruses cause hemorhagic fever with renal syndrome (HFRS) characterized by increased vascular permeability and acute kidney injury (AKI). Despite the systemic nature of the disease, the virus enters humans through inhalation and therefore initially encounters the immunoglobulin class A (IgA) dominated mucosal immune system. Herein, we characterized systemic IgA responses and their potential relationship to the mucosal immune activation by examining blood samples obtained from patients hospitalized due to acute Puumala orthohantavirus infection. Our findings reveal increased frequencies of IgA-expressing circulating mucosal-associated B1 cells and plasmablasts, as well as elevated levels of polyreactive, polymeric, virus-specific and secretory IgA in the acute stage of the disease. Importantly, the levels of circulating virus-specific and secretory IgA associated with the severity of AKI. Furthermore, circulating polymeric IgA displayed enhanced effector functions by forming stable complexes with the IgA receptor CD89 and induced pro-inflammatory neutrophil responses. These results suggest that, while an efficient mucosal immune response is likely to be crucial for infection clearance, an excessive mucosal immune activation may contribute to HFRS disease progression.
Senescent cell clearance ameliorates temporal lobe epilepsy and associated spatial memory deficits in mice
Authors: Khan Tahiyana , McFall David J. , Hussain Abbas I. , Frayser Logan A. , Casilli Timothy P. , Steck Meaghan C. , Sanchez-Brualla Irene , Kuehn Noah M. , Cho Michelle , Barnes Jacqueline A. , Harris Brent T. , Vicini Stefano , Forcelli Patrick A. 
Published: July 2024

AbstractCurrent therapies for the epilepsies only treat the symptoms, but do not prevent epileptogenesis (the process in which epilepsy develops). Many cellular responses during epileptogenesis are also common hallmarks ofcellular senescence, which halts proliferation of damaged cells. Clearing senescent cells (SCs) restores function in several age-associated and neurodegenerative disease models. It is unknown whether SC accumulation contributes to epileptogenesis and associated cognitive impairments. To address this question, we used a mouse model of temporal lobe epilepsy (TLE) and characterized the senescence phenotype throughout epileptogenesis. SCs accumulated 2 weeks after SE and were predominantly microglia. We ablated SCs and reduced (and in some cases prevented) the emergence of spontaneous seizures and normalized cognitive function in mice. Suggesting that this is a translationally-relevant target we also found SC accumulation in resected hippocampi from patients with TLE. These findings indicate that SC ablation after an epileptogenic insult is a potential anti-epileptogenic therapy.
The reducing end of cell wall oligosaccharides is critical for DAMP activity inArabidopsis thalianaand can be exploited by oligosaccharide oxidases in the scavenging of phenolic radicals
Authors: Giovannoni Moira , Scortica Anna , Scafati Valentina , Piccirilli Emilia , Sorio Daniela , Benedetti Manuel , Mattei Benedetta 
Published: July 2024

SummaryThe enzymatic hydrolysis of cell wall polysaccharides results in the production of oligosaccharides with nature of damage-associated molecular patterns (DAMPs) that are perceived by plants as danger signals.In vitro, the oxidation of oligogalacturonides and cellodextrins by plant FAD-dependent oligosaccharide-oxidases (OSOXs) suppresses their elicitor activity, suggesting a protective role of OSOXs against a prolonged activation of defense responses potentially deleterious for plant health. However, OSOXs are also produced by phytopathogens and saprotrophs, complicating the understanding of their role in plant-microbe interactions.The oxidation catalyzed by specific fungal OSOXs also converts the elicitor-active cello-tetraose and xylo-tetraose into elicitor-inactive forms, indicating that the oxidation state of cell wall oligosaccharides is crucial for their DAMP function, irrespective of whether the OSOX originates from fungi or plants.Certain OSOXs can transfer the electrons from the reducing end of these oligosaccharides to phenolic radicals instead of molecular O2, highlighting an unexpected sub-functionalization of these enzymes.The activity of OSOXs may be crucial for a thorough understanding of cell wall metabolism since these enzymes can redirect the reducing power from sugars to phenolic components of the plant cell wall, an insight with relevant implications for both plant physiology and green technologies.
Understanding the Transfer and Persistence of Antimicrobial Resistance in Aquaculture Using a Model Teleost Gut System
Authors: Barcan Alexandru Stefan , Humble Joseph , Kasaragod Sandeep , Sajib Mohammad Saiful Islam , Barcan Rares Andrei , McGinnity Philip , Welch Timothy J. , Robertson Brendan , Vamanu Emanuel , Bacigalupo Antonella , Llewellyn Martin Stephen , Samsing Francisca 
Published: July 2024

AbstractThe development, progression, and dissemination of antimicrobial resistance (AMR) is determined by interlinked human, animal, and environmental drivers, posing severe risks to human health. Conjugative plasmid transfer drives the rapid dissemination of AMR among bacteria. Besides antibiotic judicious use and implementation of antibiotic stewardship programs, mitigating antibiotic resistance spread requires an understanding of the dynamics of AMR transfer among microbial communities, as well as the role of various microbial taxa as potential reservoirs that promote long term AMR persistence. Here, we employed Hi-C, a high-throughput, culture-free technique, combined with qPCR, to monitor carriage and transfer of a multidrug-resistant plasmid within an Atlantic salmon in vitro gut model during florfenicol treatment, a benzenesulfonyl antibiotic widely deployed in fin-fish aquaculture. Microbial communities from the pyloric ceaca of three healthy adult farmed salmon were inoculated into three bioreactors developed for the SalmoSim gut system. The model system was then inoculated with anEscherichia colistrain ATCC 25922 carrying plasmid pM07-1 and treated with florfenicol at a concentration of 150 mg/L fish feed media for five days prior to a washout/recovery phase. Hi-C and metagenomic sequencing identified numerous transfer events, including to gram-negative and gram-positive taxa and, crucially, continuing transfer and persistence of the plasmid once florfenicol treatment had been withdrawn. Our findings highlight the role of commensal teleost gut flora as a reservoir for AMR, and our system provides a model to study how different treatment regimes and interventions may be deployed to mitigate AMR persistence.
Insights into Therapeutic Discovery Through the Kelch Domain Structure of Keap1 at Ambient Temperature
Authors: Yilmaz Merve , Sever Belgin , Kutlu Yigit , Gul Mehmet , Okuducu Ceren , Tavli Serra , Otsuka Masami , Fujita Mikako , Haliloglu Turkan , Ciftci Halilibrahim , DeMirci Hasan 
Published: July 2024

AbstractTheKelch-like-ECH associated protein 1(Keap1) is a part of the E3-ubiquitin ligase complex that binds toNuclear factor erythroid 2-related factor 2(Nrf2) protein and facilitates its degradation by the eukaryotic 26S proteasome. The Kelch domain of Keap1 includes six repeated structural signature motifs, approximately 45–55 amino acid residues in length. Each Kelch repeat contains highly conserved residues and is known to form one blade of beta-propeller structure. Here, we report the dimeric Kelch domain of Keap1 determined at 3.0 Å resolution at the Turkish Light Source‘Turkish DeLight’ at ambient temperature. Our structure provides new structural dynamics information of the dimeric Keap1 Kelch domain at ambient temperature. It displays potential conformational changes of Keap1 residues, particularly at the Dimethyl fumarate (DMF) and Nrf2 binding regions, due to observed temperature shifts. Supported by the Gaussian Network Model (GNM) analysis, the dynamics of the Kelch domain revealed that the allosteric behavior of DMF binding residues is fully established in the ambient temperature structure. We also performed complementary molecular docking studies using our ambient temperature structure for numerous compounds acting as electrophilic irreversible indirect or non-covalent direct inhibitors of the Keap1/Nrf2 complex. Our data suggest that our previously reported novel compound, a hybrid ofL-carnosine andL-histidyl hydrazide (CNN), revealed the most favorable scoring functions and prominent interactions with critical Keap1 residues. Collectively, ourin silicoandin crystalloresults suggest a new potential lead compound for Keap1 inhibition. Additionally, understanding the dimeric form of the Keap1 Kelch domain and conformational changes around the DMF and Nrf2 binding sites at ambient temperature is critical for understanding Keap1-Nrf2 interaction dynamics.
Method and timing of rhizobacteria inoculation to plant roots alters success and strength of aphid suppression
Authors: Blenkinsopp Sophie , Henderson Milo , Zytynska Sharon E 
Published: July 2024

AbstractInsect pests cause substantial yield losses globally, necessitating novel pest control approaches beyond chemical pesticides. Rhizobacteria, beneficial root-associated bacteria, present a promising alternative by enhancing plant growth and defences against pests. This study explores the use of sodium alginate encapsulation for precise inoculation of two rhizobacteria,Acidovorax radicisandBacillus subtilis, to suppress aphid populations on barley (Hordeum vulgare). We optimized a method using 4mm diameter wet-matrix alginate beads for controlled bacterial delivery directly to plant roots. Two experiments evaluated the impact of inoculation methods and timing on aphid suppression. Results indicated that rhizobacteria inoculation via alginate beads at root emergence significantly reduced aphid reproductive output, outperforming seed soaking methods. This suggests that more consistent bacterial establishment and prolonged release from alginate beads enhances plant defence priming. Additionally, alginate bead inoculation demonstrated effective long-term bacterial viability following storage at 4° C for eight months, supporting potential field application. Our findings highlight the potential of alginate bead-encapsulated rhizobacteria for aphid suppression on barley, but emphasizing the need for precise inoculation timing and placement. This approach offers a robust method for empirical research and practical agricultural application, paving the way for sustainable pest management strategies. Future work should focus on optimizing formulations and understanding plant-microbe interactions to enhance field efficacy.
CHANGES IN MUSCLE QUALITY FOLLOWING SHORT-TERM RESISTANCE TRAINING IN OLDER ADULTS: A COMPARISON OF ECHO INTENSITY AND TEXTURE ANALYSIS
Authors: Knowles Kevan S. , Pagan Jason I. , Beausejour Jonathan P. , Mongold Scott J. , Anderson Abigail W. , Stout Jeffrey R. , Stock Matt S. 
Published: July 2024

ABSTRACTBackgroundSkeletal muscle echo intensity (EI) is associated with functional outcomes in older adults, but resistance training interventions have shown mixed results. Texture analysis has been proposed as a novel approach for assessing muscle quality, as it captures spatial relationships between pixels.PurposeTo examine changes in first-order (EI) and second-order (texture) features of muscle quality following lower-body resistance training in older adults.MethodsTwelve older adults (2 males, 10 females; mean ± SD age = 70 ± 5 years) completed 6 weeks of progressive resistance training, consisting of twice-weekly sessions at 85% of estimated 1RM. Pre- and post-intervention assessments included ultrasound imaging of the rectus femoris (RF) and vastus lateralis (VL), 5-repetition maximum (5RM) leg extension strength, and maximal voluntary isometric contraction (MVIC) force. Ultrasound images were analyzed for EI and texture features using gray-level co-occurrence matrix (GLCM) analysis.ResultsLarge improvements were observed in 5RM leg extension strength (p< 0.001,d= 2.09), MVIC force (p= 0.006,d= 0.969), and RF EI (uncorrected:p= 0.003,d= 0.727; corrected:p= 0.012,d= 0.864). No significant changes were observed in muscle size, VL EI, or texture features for either muscle.ConclusionsShort-term resistance training improved strength and RF muscle quality as measured by EI. However, texture analysis features were not sensitive to changes following training. These findings suggest that traditional EI measures may be more appropriate than texture analysis for tracking changes in muscle quality following resistance training in older adults.NEW & NOTEWORTHYWe studied muscle quality changes after 6 weeks of resistance training in older adults, comparing traditional EI to texture analysis. Despite significant strength gains, only RF EI improved, with minimal changes in muscle size, VL EI, or texture parameters. Surprisingly, texture analysis was less sensitive than traditional EI in detecting muscle quality changes. Our results suggest that conventional EI measures may be more suitable for evaluating short-term adaptations to resistance training in older adults.
Muscarinic receptor activation preferentially inhibits rebound in vulnerable dopaminergic neurons
Authors: Beaver Megan L. , Evans Rebekah C. 
Published: July 2024

AbstractDopaminergic subpopulations of the substantia nigrapars compacta(SNc) differentially degenerate in Parkinson’s disease and are characterized by unique electrophysiological properties. The vulnerable population expresses a T-type calcium channel-mediated afterdepolarization (ADP) and shows rebound activity upon release from inhibition, whereas the resilient population does not have an ADP and is slower to fire after hyperpolarization. This rebound activity can trigger dopamine release in the striatum, an important component of basal ganglia function. Using whole-cell patch clamp electrophysiology onex vivoslices from adult mice of both sexes, we find that muscarinic activation with the non-selective muscarinic agonist Oxotremorine inhibits rebound activity more strongly in vulnerable vs resilient SNc neurons. Here, we show that this effect depends on the direct activation of muscarinic receptors on the SNc dopaminergic neurons. Through a series of pharmacological and transgenic knock-out experiments, we tested whether the muscarinic inhibition of rebound was mediated through the canonical rebound-related ion channels: T-type calcium channels, hyperpolarization-activated cation channels (HCN), and A-type potassium channels. We find that muscarinic receptor activation inhibits HCN-mediated current (Ih) in vulnerable SNc neurons, but that Ihactivity is not necessary for the muscarinic inhibition of rebound activity. Similarly, we find that Oxotremorine inhibits rebound activity independently of T-type calcium channels and A-type potassium channels. Together these findings reveal new principles governing acetylcholine and dopamine interactions, showing that muscarinic receptors directly affect SNc rebound activity in the midbrain at the somatodendritic level and differentially modify information processing in distinct SNc subpopulations.Significance StatementDopaminergic neurons in the substantia nigrapars compacta(SNc) can be divided into functional subpopulations with distinct basal ganglia connectivity and different degeneration patterns in Parkinson’s disease. We show that the vulnerable and resilient subpopulations of SNc dopaminergic neurons are differentially modulated by muscarinic receptor activation. Specifically, muscarinic receptor activation inhibits rebound activity more strongly in the vulnerable SNc neurons than in the resilient. We find that this inhibition occurs through a non-canonical rebound-related pathway and is not mediated through the channels best known for modulating rebound in midbrain dopaminergic neurons. These findings are important because they reveal novel acetylcholine-dopamine interactions that occur in the midbrain and affect information processing in distinct basal ganglia circuits.