bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatially-divergent metabolic impact of experimental toxoplasmosis: immunological and microbial correlates
Authors: Lesani Mahbobeh , Middleton Caitlyn E. , Feng Tzu-Yu , Arroyo Jan Carlos Urban , Casarez Eli , Ewald Sarah E. , McCall Laura-Isobel 
Published: January 2025

AbstractMaladaptive host metabolic responses to infection are emerging as major determinants of infectious disease pathogenesis. However, the factors regulating these metabolic changes within tissues remain poorly understood. In this study, we used toxoplasmosis, as a prototypical example of a disease regulated by strong type I immune responses, to assess the relative roles of local parasite burden, local tissue inflammation and the microbiome in shaping local tissue metabolism during acute and chronic infection. Toxoplasmosis is a zoonotic disease caused by the parasiteToxoplasma gondii. This protozoan infects the small intestine and then disseminates to nearly every organ in the acute stage of infection, before establishing chronic infection in the skeletal muscle, cardiac muscle and brain. We compared metabolism in eleven sampling sites in C57BL/6 mice during the acute and chronic stage ofT. gondiiinfection. Strikingly, significant metabolic changes were observed in the large intestine and colon during chronic infection, organs not associated withT. gondiipersistence. Overall, major spatial mismatches were observed between metabolic perturbation and local parasite burden for both disease stages. In contrast, a stronger association with indicators of type I immune responses was observed, indicating a tighter relationship between metabolic perturbation and local immunity, than with local parasite burden. In addition, we observed significant changes in microbiota composition with infection, and candidate microbial origins for multiple metabolites impacted by infection. These findings highlight the metabolic consequences of toxoplasmosis across different organs, and their regulators.ImportanceInflammation is a major driver of tissue perturbation. However, the signals driving these changes on a tissue-intrinsic and molecular level are poorly understood. This study evaluated tissue-specific metabolic perturbations across eleven sampling sites following systemic murine infection with the parasiteToxoplasma gondii. Results revealed relationships between differential metabolite enrichment and variables including inflammatory signals, pathogen burden and commensal microbial communities. These data will inform hypotheses about the signals driving specific metabolic adaptation in acute and chronic protozoan infection, with broader implications for infection and inflammation in general.
Global DNA signatures of temperature and nutrient limitation in prokaryotes
Authors: Antman Tomer , Lewin-Epstein Ohad , Yerushalmi Tamir , Broder Yonatan , Zeevi David 
Published: January 2025

AbstractMicroorganisms adapt to their environment through changes in both their genes and overall genome composition. However, identifying universal principles of genomic adaptation remains challenging because different environments present multiple, overlapping selective pressures. To overcome this challenge, we analyzed DNA composition patterns across diverse environments using machine learning. By examining tetranucleotide frequencies from 1,112 marine and soil metagenomic samples, we discovered that environmental temperature can be accurately predicted from DNA composition alone (R2=0.82). This temperature signal remained robust even when analyzing individual bacterial phyla and classes, suggesting a fundamental adaptive response. To examine this adaptation mechanism, we analyzed GC content relationships with temperature and found opposing relationships in different environments: positive correlations in soil but negative correlations in marine samples. We show that this inverse relationship in marine environments is driven by nutrient availability, as GC content increases with nutrient levels while nutrients decrease with temperature in marine ecosystems. Despite these contrasting GC patterns, we identified specific tetranucleotides composed of equal numbers of GC and AT bases (50% GC content) that showed consistent temperature correlations across all environments. These findings reveal a complex interplay between temperature adaptation and nutrient limitation in shaping microbial genomes.
Cytoneme-mediated signalling coordinates the development of glial cells and neurons in theDrosophilaeye
Authors: García-Arias Juan Manuel , Girón Gonzalo G. , Foronda David , Guerrero Isabel , Baonza Antonio 
Published: January 2025

SUMMARYEffective cell communication is essential for the development and maintenance of the nervous system, where neurons and glial cells must interact closely. While cytoneme-mediated signalling is well-documented in various biological contexts, its role in coordinating neuron-glia development remains poorly understood. In this study, we investigated the function of cytonemes in neuron-glia coordination using theDrosophilaeye imaginal disc as a model. This is a well-established system for examining the orchestrated development of glial and neuronal cells. Our results reveal that glial cells produce two distinct types of cytonemes based on their spatial orientation: one set extends toward nascent photoreceptors, while the other targets the morphogenetic furrow (MF). We have characterised the dynamics of glial cytonemes and demonstrated that disrupting these structures has a significant impact on glial cell migration and differentiation. This highlights the critical role of cytoneme-mediated signalling in regulating glial behaviour. Our findings also demonstrate that cytoneme function is essential for activating the Hedgehog (Hh) pathway in glial cells, with Hh ligand produced by photoreceptors. This pathway is necessary for glial differentiation, uncovering a previously unrecognised role for Hh signalling in this process. Overall, our results suggest that cytoneme-mediated Hh signalling is key to coordinating the development of both glial and neuronal populations.
Omics-based insights into human liver reveal GTPase-driven mechanisms of MASLD progression in obesity
Authors: Zhao Qing , De Nardo William , Wang Ruoyu , Zhong Yi , Keles Umur , Zhao Li Na , Tay Huiyi , Youhanna Sonia , Yan Mengchao , Xie Ye , Kim Youngrae , Lee Sungdong , Lim Rachel Liyu , Teo Guoshou , Narayanaswamy Pradeep , Burton Paul R. , Lauschke Volker M. , Choi Hyungwon , Watt Matthew J. , Kaldis Philipp 
Published: January 2025

AbstractMetabolic dysfunction-associated steatotic liver disease (MASLD) is generally asymptomatic in the early stages but, without appropriate intervention, it can progress to severe liver morbidities. To elucidate the molecular mechanisms of early development of MASLD, we performed transcriptomic analysis on liver biopsies and metabolomic analysis on liver and plasma samples from 109 obese individuals with no liver pathology or early stages of MASLD. The liver metabolome is remodeled by the parenchymal accumulation of neutral lipids, whereas the plasma metabolome displayed little differences. The liver transcriptome revealed that the progression of steatosis and fibrosis is characterized by distinct gene expression signatures. While metabolic remodeling characterizes steatosis, global rewiring of gene expression underpins fibrosis progression. Importantly, GTPases and their regulators were identified as a novel signature for the transition from steatosis to fibrosis. GTPase genes and their regulators were associated with hepatic fibrosis grades and co-expressed with TGF-β signaling. We further verified the involvement of GTPase regulation in fibrogenesis in HSC-like LX-2 cells and a 3D liver spheroid model of primary human hepatocytes and non-parenchymal cells. Our study suggests that modulation of GTPase signaling is a potential therapeutic entry point for the treatment of early liver fibrosis in MASLD.Graphical abstractHighlightsLiver metabolome remodeling is marked by accumulation of neutral lipids and relative reduction of glycerophospholipids and sphingolipids. Changes in the plasma metabolome were poorly correlated with the changes in the liver metabolome in early-stage MASLD.Steatosis is closely linked to metabolic remodeling, whereas fibrosis progression is associated with global rewiring of gene expression.Over 200 genes were identified as progressive markers for fibrosis progression.GTPase signaling emerged as the top enriched pathway involved in the transition from non-fibrotic steatosis to the onset of fibrosis. The involvement of GTPase and its regulation in liver fibrogenesis was validated in a 3D spheroid MASH model. Pharmacological-mediated GTPase inhibition hindered collagen production in HSC-like LX-2 cells.
Spinal Cord Ultrasound Stimulation Modulates Corticospinal Excitability
Authors: Hou Lin , Lei Yuming 
Published: January 2025

AbstractBackgroundLow-intensity focused ultrasound (LIFU) offers superior tissue penetration and enables precise neuromodulation of cortical and subcortical circuits. However, its effects on neural activity in the human spinal cord remain largely unexplored.ObjectiveTo investigate the effects of LIFU on spinal cord neuromodulation under varying conditions of intensity (spatial-peak pulse-average intensity, ISPPA), duty cycle (DC), and pulse repetition frequency (PRF).MethodsThirty-six healthy human volunteers participated in the study. A 500 kHz ultrasound transducer with a focal depth exceeding 100 mm was used to target the C8 spinal cord. Transcranial magnetic stimulation (TMS) was applied to the primary motor cortex (M1) hotspot corresponding to the first dorsal interosseous (FDI) muscle, innervated by the C8 nerve. A 500 ms-duration LIFU was delivered to the C8 spinal cord 400 ms prior to single-pulse TMS over the FDI hotspot. Spinal cord ultrasound stimulation (SCUS) was administered with varying acoustic parameters: intensities (ISPPA: 2.5 and 10 W/cm²), DCs (10% and 30%), and PRFs (500 and 1000 Hz). Changes in corticospinal excitability were assessed by comparing TMS-elicited motor-evoked potentials (MEPs) between active and sham SCUS conditions.ResultsSCUS with an ISPPAof 10 W/cm², a DC of 30%, and a PRF of 1000 Hz significantly reduced MEP amplitudes compared to sham stimulation. However, at the high intensity (ISPPAof 10 W/cm²), varying the DC between 10% and 30% did not affect MEP amplitudes. Additionally, while a PRF of 1000 Hz decreased MEP amplitudes at 10 W/cm², a PRF of 500 Hz did not produce significant changes.ConclusionsThe results indicate that ultrasound stimulation of the spinal cord can suppress corticospinal drive to muscles, especially when utilizing high intensity and high PRF parameters. This suggests that ultrasound stimulation may provide a novel method for modulating human spinal neural activity.
A reference-quality NLRome for the hexaploid sweetpotato and diploid wild relatives
Authors: Parada-Rojas C. H. , Childs K. L. , Fernández de Soto M. , Salcedo A. , Pecota K. , Yencho G. C. , Almeyda C. , Kitavi M. , Buell C. R. , Conant G. C. , Baltzegar D. , Quesada-Ocampo L. M. 
Published: January 2025

ABSTRACTBreeding for sweetpotato (Ipomea batatas) resistance requires accelerating our understanding genomic of sources of resistance. Nucleotide-binding domain leucine-rich repeat receptors (NLRs) proteins represent a key component of the plant immune system that mediate plant immune responses. We cataloged the NLR diversity in 32 hexaploid sweetpotato genotypes and three diploid wild relatives using resistance gene enrichment sequencing (RenSeq) to capture and sequence full NLRs. A custom designed NLR bait-library enriched NLR genes with an average 97% target capture rate. We employed a curated database of cloned and functionally characterized NLRs to assign sequenced sweetpotato NLRs to canonical phylogenetic clades. We identified between 800 to 1,200 complete NLRs, highlighting the expanded diversity of coiled-coil NLRs (CNLs) across all genotypes. NLRs among sweetpotato genotypes exhibited large conservation across genotypes. Phylogenetic distance between 6X (hexaploid) and 2X (diploid) genotypes revealed that a small repertoire ofI. batatasCNLs diverged from the sweetpotato wild relatives. Finally, we obtained chromosome coordinates in hexaploid (Beauregard) and diploid (Ipomoea trifida) genomes and recorded clustering of NLRs on chromosomes arms. Our study provides a catalog of NLR genes that can be used to accelerate breeding and increase our understanding of evolutionary dynamics of sweetpotato NLRs.
A prime editing strategy to rewrite the γ-globin promoters and reactivate fetal hemoglobin for sickle cell disease
Authors: Chalumeau Anne , Dames Maria Bou , Antoniou Panagiotis , Loganathan Priyanka , Mombled Margaux , Corre Guillaume , Peterka Martin , Amendola Mario , Giovannangeli Carine , Maresca Marcello , Miccio Annarita , Brusson Mégane 
Published: January 2025

AbstractFetal hemoglobin (HbF) reactivation is a promising therapy for β-hemoglobinopathies. We developed a prime editing strategy that introduces multiple mutations in the fetal γ-globin promoters of patients’ hematopoietic stem/progenitor cells (HSPCs), boosting HbF expression and offering alternative therapeutic perspectives.
Commonly used non-antibiotic medications promote mutation frequency and antimicrobial resistance inEscherichia coli
Authors: Chen Hanbiao , Sapula Sylvia A. , Turnidge John , Venter Henrietta 
Published: January 2025

AbstractAntimicrobial resistance (AMR) poses a global threat to public health. The excessive use of antibiotics significantly contributed to the rise of resistance. Recent evidence suggests that non-antibiotic medications (NAMs) also play a role in antimicrobial resistance development, although this aspect remains less explored and understood. This issue is particularly relevant in residential aged care facilities (RACFs) where both NAMs and antibiotics are frequently used, and AMR is prevalent. We investigated the propensity of NAMs that are commonly used in RACFs and contribute to polypharmacy including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and diclofenac, acetaminophen (antipyretic), metformin (glucose-lowering medication), atorvastatin (lipid-lowering agent), tramadol (opioid analgesic), temazepam (hypnotic), and pseudoephedrine (sympathomimetic) to promote bacterial antibiotic resistance by increasing the acquisition of mutations.Escherichia coliwas exposed to different NAMs at their gut concentration, combined with ciprofloxacin and the mutation frequency was determined. Additionally, we explored the simultaneous effect of two NAMs as a starting point for studying polypharmacy.Ibuprofen and acetaminophen significantly increased mutation frequency, and conferred high levels of ciprofloxacin resistance, especially whenE. coliwas exposed to two NAMs. Whole genome sequencing revealed that these changes correlated with mutations in DNA gyrase GyrA, the multiple antibiotic resistance regulator, MarR, and the drug efflux pump expression suppressor, AcrR. Consequently, an increase in transcription of theacrAgene from the AcrAB-TolC drug efflux pump was observed. The combination of two NAMs increased the mutation rate. These multiple mutations caused the higher levels of ciprofloxacin resistance that were observed.Given the risk of polypharmacy to induce AMR, and the results observed in this study, the assessment NAMs in their ability to promote bacterial resistance warrants special attention in future studies into prescribing practices.
Prolyl isomerase FKBP12 reduces axon growth and negatively regulates microtubule polymerization by inhibiting CRMP2A
Authors: Weissova Romana , Sabo Jan , Chafai Djamel Eddine , Ziak Jakub , Buran Peter , Bodakuntla Satish , Janke Carsten , Lansky Zdenek , Balastik Martin 
Published: January 2025

AbstractProlyl isomerases are enzymes catalyzing conformational change of the peptide bond between proline and the preceding amino acid, regulating the function and stability of their substrates. We have previously identified CRMP2A - the longer isoform of a microtubule-associated protein Collapsin response mediator protein 2 - as a substrate of the phospho-specific prolyl isomerase Pin1. CRMP2A is negatively regulated and destabilized by CDK5 phosphorylation in the distal axons and growth cones. Pin1 specifically binds to phosphorylated CRMP2A and stabilizes it by inducing conformational changes. However, the conformational regulation of unphosphorylated CRMP2 remains unknown. Here, we show that the prolyl isomerase FKBP12 specifically binds to unphosphorylated CRMP2A and regulates its activity. Usingin vitromicrotubule polymerization assays we demonstrate that CRMP2A promotes microtubule growth and that this function is inhibited by FKBP12. Next, using GFP-EB3 microtubule plus-end tracking assay, we demonstrate that FKBP12 inhibits CRMP2A-mediated microtubule polymerization also in cells. Furthermore, we show that FKBP12 co-localizes with unphosphorylated CRMP2A in growth cones and that expression of FKBP12 reduces axon growth in microfluidic chambers, while FKBP12 knockdown enhances it. Together, we demonstrate that FKBP12 is a negative regulator of microtubule dynamics and axon growth. Moreover, we show that two prolyl isomerases can differentially (positively or negatively) regulate activity of a common substrate depending on its phosphorylation. This provides an additional layer of phosphorylation-dependent or -independent control of protein activity, microtubule dynamics, and neuronal growth. Given the broad substrate specificity of FKBP12 and Pin1, this regulatory mechanism likely contributes to the modulation of diverse proteins and cellular processes in the nervous system and beyond.
MDL-001: An Oral, Safe, and Well-Tolerated Broad-Spectrum Inhibitor of Viral Polymerases
Authors: Woods Virgil , Umansky Tyler , Russell Sean M , McGovern Briana L , Rosales Romel , Rodriguez M Luis , van Bakel Harm , Sordillo Emilia Mia , Simon Viviana , García-Sastre Adolfo , White Kris M , Brubaker William F , Smith Davey , Haders Daniel 
Published: January 2025

ABSTRACTThe death toll and financial stress posed by the recent COVID-19 pandemic have highlighted the pressing need to develop safe and effective, broad-spectrum inhibitors to treat viral infections. To accelerate the antiviral drug discovery process, we developed GALILEO™, a computational platform that interfaces with a customizable bioinformatics pipeline with a geometric deep learning algorithm we named ChemPrint™ for in silico drug screening. Combining these algorithms with a large chemical repositioning library, we discovered MDL-001, which interacts with the Thumb pocket 1 subdomain of multiple single-stranded RNA viruses. For MDL-001, we demonstrate potent in vitro activity against a broad spectrum of pathogenic viruses, and we demonstrate potent in vivo efficacy in a mouse model of SARS-CoV-2 infection. In clinical trials, orally administered MDL-001 has been shown to be safe and well tolerated. These data underline both the effectiveness of the GALILEO™ platform for drug discovery and the promise of MDL-001 as a novel broad-spectrum antiviral clinical candidate.
Characterization of auditory responsive neurons in the mouse superior colliculus to naturalistic sounds
Authors: Si Yufei , Ito Shinya , Litke Alan M. , Feldheim David A. 
Published: January 2025

AbstractLocating the source of a specific sound in a complex environment and determining its saliency is critical for survival. The superior colliculus (SC), a sensorimotor midbrain structure, plays an important role in sound localization and has been shown to have a topographic map of the auditory space in a range of species. In mice, previous studies using broadband white noise stimuli found that neurons use high-frequency monaural spectral cues and interaural level differences (ILDs) to compute spatially restricted receptive fields (RFs), and that these RFs are organized topographically along the azimuth. However, in a naturalistic environment, the auditory stimuli that an animal encounters may have rich spectral components; however, these sound sources can still be localized efficiently. It remains unknown whether and how the SC neurons respond to naturalistic sounds and, in turn, compute a spatially restricted RF. Here, we show results from large-scale in vivo physiological recordings of SC neurons in response to white noise, naturalistic ultrasonic pup calls and chirps. We find that mouse SC auditory neurons respond to pup calls with distinct temporal patterns and a spatial preference predominantly at ∼60 degrees in contralateral azimuth. In addition, we categorized auditory SC neurons based on their spectrotemporal receptive field patterns and demonstrated that there are at least 4 distinct subtypes of auditory responsive SC neurons.Significance StatementThe superior colliculus (SC) receives visual and auditory information that is used to localize objects. While the organization and composition of visually responsive SC neurons is well described, much less is known about the types and response properties of auditory SC neurons. Here, we presented white noise, ultrasonic mouse pup calls, and chirp stimuli to mice while recording from SC neurons. Analysis of neuronal responses defines 4 distinct classes of auditory neurons. We also show that while auditory neurons respond to naturalistic stimuli, these responses mainly occur when presented from the side but not the front of the animal. These results lead to the hypothesis that mice use different strategies to localize sound depending on the spectral composition of the source.
Strand-swapping in the LolA-like protein GerS promotes the allosteric activation of a bacterial amidase inClostridioides difficile
Authors: Bouchier Jacob M. , Shen Aimee 
Published: January 2025

AbstractGerS is a key lipoprotein regulator ofClostridioides difficilespore germination that shares structural, but not sequence, similarity to LolA in Gram-negative bacteria. GerS and LolA have vastly different biological roles: LolA functions in the trafficking of lipoproteins across the periplasmic space to the outer membrane of Gram-negative bacteria, while GerS allosterically activates the germination-specific amidase CwlD in endospore-forming Gram-positive bacteria. Here, we explore the diversity of LolA-like proteins across bacteria and reveal that GerS homodimer formation is a conserved feature of Peptostreptococcaceae family orthologs. Since dimerization ofC. difficileGerS occurs via strand-swapping, we sought to investigate the functional importance of its strand swap by identifying mutations that alter the GerS dimer:monomer equilibrium. Our analyses reveal that GerSK71Rand GerSN74Lsubstitutions in the strand-swap hinge of GerS stabilize the homodimer, while a GerST72Psubstitution promotes monomer formation. Conversely, substituting the highly conserved proline at the equivalent site in LolA for threonine converts LolA from a monomer to a homodimer. Since our data indicate that destabilizing the GerS dimer impairs both GerS:CwlD bindingin vitroand CwlD function inC. difficile, strand-swapped dimer formation in LolA-like proteins enhances their affinity for their binding partners. These data are consistent with analyses of equivalent LolA mutants inE. coliand thus provide new insight into the evolution and specialization of this intriguing group of proteins across the bacterial domain.