bluuebunny/crossref_metadata_2025_split huggingface dataset:
DEAD box RNA helicase 5 is a new pro-viral host factor for Sindbis virus infection
Authors: Messmer Mélanie , Pierson Louison , Pasquier Charline , Djordjevic Nikola , Chicher Johana , Hammann Philippe , Pfeffer Sébastien , Girardi Erika 
Published: September 2023

AbstractBackgroundRNA helicases are emerging as key factors regulating host-virus interactions. The DEAD-box ATP-dependent RNA helicase DDX5, which plays an important role in many aspects of cellular RNA biology, was also found to either promote or inhibit viral replication upon infection with several RNA viruses. Here, our aim is to examine the impact of DDX5 on Sindbis virus (SINV) infection.MethodsWe analysed the interaction between DDX5 and the viral RNA using imaging and RNA-immunoprecipitation approaches. The interactome of DDX5 in mock- and SINV-infected cells was determined by mass spectrometry. We validated the interaction with DDX17 and the viral capsid by co-immunoprecipitation in the presence or absence of an RNase treatment. We determined the subcellular localization of DDX5, its cofactor DDX17 and the viral capsid protein by co-immunofluorescence. Finally, we investigated the impact of DDX5 depletion and overexpression on SINV infection at the viral protein, RNA and infectious particle accumulation level. The contribution of DDX17 was also tested by knockdown experiments.ResultsIn this study we demonstrate that DDX5 interacts with the SINV RNA during infection. Furthermore, the proteomic analysis of the DDX5 interactome in mock and SINV-infected HCT116 cells identified new cellular and viral partners and confirmed the interaction between DDX5 and DDX17. Both DDX5 and DDX17 re-localize from the nucleus to the cytoplasm upon SINV infection and interact with the viral capsid protein. We also show that DDX5 depletion negatively impacts the viral replication cycle, while its overexpression has a pro-viral effect. Finally, we observed that DDX17 depletion reduces SINV infection, an effect which is even more pronounced in a DDX5-depleted background, suggesting a synergistic pro-viral effect of the DDX5 and DDX17 proteins on SINV.ConclusionsThese results not only shed light on DDX5 as a novel and important host factor to the SINV life cycle, but also expand our understanding of the roles played by DDX5 and DDX17 as regulators of viral infections.
Multiple Intermediates in the Detergent-Induced Fusion of Lipid Vesicles
Authors: Dresser Lara G. , Kunstmann-Olsen Casper , Conteduca Donato , Hofmair Christopher M. , Smith Nathan , Clark Laura , Johnson Steven , Penedo J. Carlos , Leake Mark C. , Quinn Steven D. 
Published: September 2023

AbstractDetergent-induced vesicle interactions, critical for applications including virus inactivation, varies according to the detergent type and membrane composition, but the underlying mechanistic details remain underexplored. Here, we use a lipid mixing assay based on Förster resonance energy transfer (FRET), and single-vesicle characterization approaches to identify that sub-micron sized vesicles are induced to fuse by the non-ionic detergent Triton-X 100. We demonstrate that the process is a multi-step mechanism, characterized by discrete values of FRET efficiency between membrane-embedded fluorophores, and involves permeabilization, vesicle docking, hemi-fusion and full lipid mixing at sub-solubilizing detergent concentrations. We also dissect the kinetics of vesicle fusion to surface-tethered vesicles using a label-free quartz-crystal microbalance with dissipation monitoring approach, opening a platform for biotechnology applications. The presented strategies provide mechanistic insight into the dynamics of vesicle fusion and have implications for applications including drug delivery and sensor development where transport and manipulation of encapsulated cargo is essential.
Phenformin’s impact on lifespan inC. elegansis resilient to environmental factors that inhibit metformin-induced longevity downstream ofskn-1/Nrf and AMP-activated protein kinase
Authors: Li Sainan , Ahsan Fasih , Zhou Yifei , Yerevanian Armen , Soukas Alexander A. 
Published: September 2023

AbstractDespite being principally prescribed to treat type 2 diabetes, biguanides, especially metformin and phenformin, have been shown to extend lifespan and healthspan in preclinical models, and to reduce the impact of aging-associated diseases such as cancer. While there have been conflicting results in studies involving rodents and humans, consistent evidence from laboratories worldwide, including our own, indicates metformin and phenformin’s ability to significantly extend lifespan inC. elegans. However, the pro-longevity effect of metformin can vary depending on environmental conditions. Specifically, the choice of agar from different manufacturers or batches influences metformin’s ability to extend lifespan inC. elegans. We traced ability of certain agar batches to interfere with metformin-prompted lifespan extension to the presence of a factor that acts directly in the worm, independently of the bacterial food source, that prevents longevity promoting effects downstream of longevity effectorsskn-1and AMPK. In contrast, phenformin prompts robust lifespan extension in the face of environmental changes and exhibits broad positive effects in aging across genetically diverseCaenorhabditisspecies where the impact of metformin is highly variable. Thus metformin effects in aging are impacted by heretofore unappreciated environmental factors. Phenformin may represent a more robust agent with which to understand the longevity promoting mechanisms downstream of biguanides.
Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models
Authors: Dumont Beth L. , Gatti Daniel , Ballinger Mallory A. , Lin Dana , Phifer-Rixey Megan , Sheehan Michael J. , Suzuki Taichi A. , Wooldridge Lydia K. , Opoku Frempong Hilda , Churchill Gary , Lutz Cathleen , Rosenthal Nadia , White Jacqueline K. , Nachman Michael W. 
Published: September 2023

ABSTRACTThe laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for a century. However, laboratory mice capture a narrow subset of the genetic variation found in wild mouse populations. This consideration inherently restricts the scope of potential discovery in laboratory models and narrows the pool of potentially identified phenotype-associated variants and pathways. Wild mouse populations are reservoirs of predicted functional and disease-associated alleles, but the sparsity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently imported, sequenced, and phenotyped a set of 11 wild-derived inbred strains developed from wild-caughtMus musculus domesticus. Each of these “Nachman strains” immortalizes a unique wild haplotype sampled from five environmentally diverse locations across North and South America: Saratoga Springs, New York, USA; Gainesville, Florida, USA; Manaus, Brazil; Tucson, Arizona, USA; and Edmonton, Alberta, Canada. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the mouse reference assembly, with 42.5% of variants in the Nachman strain genomes absent from classical inbred mouse strains. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels alone. Taken together, our work introduces a novel wild-derived inbred mouse strain resource that will enable new discoveries in basic and preclinical research. These strains are currently available through The Jackson Laboratory Repository under laboratory codeNachJ.
Pateamine A mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs
Authors: Saito Hironori , Handa Yuma , Chen Mingming , Schneider-Poetsch Tilman , Shichino Yuichi , Takahashi Mari , Romo Daniel , Yoshida Minoru , Fürstner Alois , Ito Takuhiro , Fukuzawa Kaori , Iwasaki Shintaro 
Published: September 2023

AbstractSmall-molecule compounds that elicit mRNA-selective translation repression have attracted interest due to their potential for expansion of druggable space. However, only limited examples have been reported to date. Here, we show that pateamine A (PatA) represses translation in an mRNA-selective manner by clamping eIF4A, a DEAD-box RNA-binding protein, on GNG motifs. Through a systematic comparison of multiple eIF4A inhibitors by ribosome profiling, we found that PatA has unique mRNA selectivity in translation repression. Unbiased Bind-n-Seq revealed that PatA-targeted eIF4A exhibits a sequence preference for GNG motifs in an ATP-independent manner. This unusual RNA binding sterically hinders scanning by 40S ribosomes.In silicosimulation, combination of classical molecular dynamics simulation and quantum chemical calculation, and the subsequent development of an inactive PatA derivative revealed that the positive charge of the tertiary amine on the trienyl arm induces G selectivity. Moreover, we identified DDX3, another DEAD-box protein, as an alternative target of PatA, showing the same effect as on eIF4A. Our results provide an example of the sequence-selective anchoring of RNA-binding proteins and mRNA-selective inhibition of protein synthesis by small-molecule compounds.
Comparative transcriptomics of Venus flytrap (Dionaea muscipula) across stages of prey capture and digestion
Authors: Rentsch Jeremy D. , Blanco Summer Rose , Leebens-Mack James H. 
Published: September 2023

AbstractThe Venus flytrap,Dionaea muscipula, is perhaps the world’s best-known botanical carnivore. The act of prey capture and digestion along with its rapidly closing, charismatic traps make this species a compelling model for studying the evolution and fundamental biology of carnivorous plants. There is a growing body of research on the genome, transcriptome, and digestome ofDionaea muscipula, but surprisingly limited information on changes in trap transcript abundance over time since feeding. Here we present the results of a comparative transcriptomics project exploring the transcriptomic changes across seven timepoints in a 72-hour time series of prey digestion and three timepoints directly comparing triggered traps with and without prey items. We document a dynamic response to prey capture including changes in abundance of transcripts with Gene Ontology (GO) annotations related to digestion and nutrient uptake. Comparisons of traps with and without prey documented 174 significantly differentially expressed genes at 1 hour after triggering and 151 genes with significantly different abundances at 24 hours. Approximately 50% of annotated protein-coding genes in Venus flytrap genome exhibit change (10041 of 21135) in transcript abundance following prey capture. Whereas peak abundance for most of these genes was observed within 3 hours, an expression cluster of 3009 genes exhibited continuously increasing abundance over the 72-hour sampling period, and transcript for these genes with GO annotation terms including both catabolism and nutrient transport may continue to accumulate beyond 72 hours.
Spatiotemporal properties of common semantic categories for words and pictures
Authors: Bezsudnova Yulia , Quinn Andrew J. , Jensen Ole 
Published: September 2023

AbstractThe timing of semantic processing during object recognition in the brain is a topic of ongoing discussion. One way of addressing this question is by applying multivariate pattern analysis (MVPA) to human electrophysiological responses to object images of different semantic categories. However, while MVPA can reveal whether neuronal activity patterns are distinct for different stimulus categories, concerns remain on whether low-level visual features also contribute to the classification results. To circumvent this issue, we applied a cross-decoding approach to magnetoencephalography (MEG) data from stimuli from two different modalities: images and their corresponding written words. We employed items for three categories and presented them in a randomized order. We show that If the classifier is trained on words, pictures are classified between 150 - 430 ms from after stimulus onset, and when training on pictures, words are classified between 225 - 430 ms. The topographical map identified using a searchlight approach for cross-modal activation in both directions showed left lateralization confirming the involvement of linguistics representations. These results point to semantic activation of pictorial stimuli occurring at ≈150 ms whereas for words the semantic activation occurs at ≈230 ms.
Phage-induced efflux down-regulation boosts antibiotic efficacy
Authors: Kraus Samuel , Łapińska Urszula , Chawla Krina , Baker Evan , Attrill Erin L , O’Neill Paul , Farbos Audrey , Jeffries Aaron , Galyov Edouard E. , Korbsrisate Sunee , Barnes Kay B. , Harding Sarah V , Tsaneva-Atanasova Krasimira , Blaskovich Mark A T , Pagliara Stefano 
Published: September 2023

SummaryThe interactions between a virus and its host vary in space and time and are affected by the presence of molecules that alter the physiology of either the host or the virus. Determining the molecular mechanisms underpinning these interactions is paramount for predicting the fate of bacterial and phage populations and for designing rational phage-antibiotic therapies. We study the interactions between stationary phaseBurkholderia thailandensisand the phage ΦBp-AMP1. Although heterogeneous genetic resistance to phage rapidly emerges inB. thailandensis, the presence of phage enhances the efficacy of three major antibiotic classes, the quinolones, the beta-lactams and the tetracyclines, but antagonizes tetrahydrofolate synthesis inhibitors. We discovered that enhanced antibiotic efficacy is underpinned by reduced antibiotic efflux in the presence of phage. This new phage-antibiotic therapy allows for eradication of stationary phase bacteria, whilst requiring reduced antibiotic concentrations, which is crucial for treating infections in sites where it is difficult to achieve high antibiotic concentrations.
The gene expression signature of electrical stimulation in the human brain
Authors: Chatterjee Snehajyoti , Vanrobaeys Yann , Gleason Annie I , Park Brian J. , Heiney Shane A. , Rhone Ariane E. , Nourski Kirill V. , Langmack Lucy , Basu Budhaditya , Mukherjee Utsav , Kovach Christopher K. , Kocsis Zsuzsanna , Kikuchi Yukiko , Ayala Yaneri A. , Petkov Christopher I. , Hefti Marco M. , Bahl Ethan , Michaelson Jacob J , Kawasaki Hiroto , Oya Hiroyuki , Howard Matthew A. , Nickl-Jockschat Thomas , Lin Li-Chun , Abel Ted 
Published: September 2023

AbstractDirect electrical stimulation has been used for decades as a gold standard clinical tool to map cognitive function in neurosurgery patients1–8. However, the molecular impact of electrical stimulation in the human brain is unknown. Here, using state-of-the-art transcriptomic and epigenomic sequencing techniques, we define the molecular changes in bulk tissue and at the single-cell level in the human cerebral cortex following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Direct electrical stimulation surprisingly had a robust and consistent impact on the expression of genes related to microglia-specific cytokine activity, an effect that was replicated in mice. Using a newly developed deep learning computational tool, we further demonstrate cell type-specific molecular activation, which underscores the effects of electrical stimulation on gene expression in microglia. Taken together, this work challenges the notion that the immediate impact of electrical stimulation commonly used in the clinic has a primary effect on neuronal gene expression and reveals that microglia robustly respond to electrical stimulation, thus enabling these non-neuronal cells to sculpt and shape the activity of neuronal circuits in the human brain.
MolPhase: An Advanced Phase Separation Predictor and an Investigation of Phytobacterial Effector in Plant
Authors: Liang Qiyu , Peng Nana , Xie Yi , Kumar Nivedita , Gao Weibo , Miao Yansong 
Published: September 2023

AbstractWe introduce MolPhase (http://molphase.sbs.ntu.edu.sg/), an advanced protein phase separation (PS) prediction algorithm that improves accuracy and reliability by utilizing diverse physicochemical features and extensive experimental datasets. MolPhase applies a user-friendly interface to compare distinct biophysical features side-by-side along protein sequences. By additional comparison with structural predictions, MolPhase enables efficient predictions of new phase-separating proteins and guides hypothesis generation and experimental design. Key contributing factors underlying MolPhase include pi-pi interaction, disorder, and prion-like domain. As an example, MolPhase finds that phytobacterial type III effectors (T3Es) are highly prone to homotypic PS, which was experimentally validatedin vitrobiochemically andin vivoin plants, mimicking their injection and accumulation in the host during microbial infection. In addition, the phase-separation of T3Es were evolved bothin vivoandin vitro, suggesting their determinative scaffolding function, though there is a difference in material properties, implying a difference in homotypic and heterotypic macromolecular condensation. Robust integration of MolPhase’s effective prediction and experimental validation exhibit the potential to evaluate and explore how biomolecule PS functions in biological systems.
Theoretical Considerations and Empirical Predictions of the Pharmaco- and Population Dynamics of Heteroresistance
Authors: Levin Bruce R. , Berryhill Brandon A. , Gil-Gil Teresa , Manuel Joshua A. , Smith Andrew P. , Choby Jacob E. , Andersson Dan I. , Weiss David S. , Baquero Fernando 
Published: September 2023

AbstractAntibiotics are considered one of the most important contributions to clinical medicine in the last 100 years. Due to the use and overuse of these drugs, there have been increasing frequencies of infections with resistant pathogens. One form of resistance, heteroresistance, is particularly problematic; pathogens appear sensitive to a drug by common susceptibility tests. However, upon exposure to the antibiotic, resistance rapidly ascends, and treatment fails. To quantitatively explore the processes contributing to the emergence and ascent of resistance during treatment and the waning of resistance following cessation of treatment, we develop two distinct mathematical and computer-simulations models of heteroresistance. In our analysis of the properties of these models, we consider the factors that determine the response to antibiotic-mediated selection. In one model, heteroresistance is progressive, with each resistant state sequentially generating a higher resistance level. In the other model, heteroresistance is non-progressive, with a susceptible population directly generating populations with different resistance levels. The conditions where resistance will ascend in the progressive model are narrower than those of the non-progressive model. The rates of reversion from the resistant to the sensitive states are critically dependent on the transition rates and the fitness cost of resistance. Our results demonstrate that the standard test used to identify heteroresistance is insufficient. The predictions of our models are consistent with empirical results. Our results demand a reevaluation of the definition and criteria employed to identify heteroresistance. We recommend the definition of heteroresistance should include a consideration of the rate of return to susceptibility.Significance StatementThis mathematical modeling and computer-simulation study quantitatively explores two broadly different, previously undescribed, classes of heteroresistance. In our analysis of the properties of these models, we consider the response of heteroresistant populations to antibiotic exposure, focusing on the conditions where heteroresistance could lead to clinical treatment failure. We also provide novel consideration to the rate of reversion from a resistant to sensitive state. Our analysis illustrates the need to include the reversion rate from resistant to sensitive in the definition of heteroresistance and questions the sufficiency of the method currently used to identify heteroresistance.
Functional copy number variation inSQUALENE EPOXIDASE-LIKEgenes affects photosystem II efficiency in Arabidopsis
Authors: van Bezouw Roel F.H.M. , Nguyen Thu-Phuong , Hoang Nam V. , Vincenzi Elena , van Velthoven Rosanne , Zhang Hui , Gao Yanrong , Zhang Wenyan , Jacobi Renze , de Snoo Bastiaan , Marquez Francisca Reyes , Catalá Livia Vazquez , Iqbal Muhammad , Jansen Stan , Mumm Roland , Harbinson Jeremy , Keurentjes Joost J.B. , Aarts Mark G.M. 
Published: September 2023

ABSTRACTIn this study, we found a single quantitative trait locus for photosystem II efficiency (ΦPSII) in the Arabidopsis Ler-0 x Col-0 recombinant inbred line population. This locus on chromosome 5 is caused by genetic variation in a cluster of tandemly repeatedSQUALENE EPOXIDASE-LIKE(SQE-like) genes, with unknown function. We show the QTL is caused by variation in theSQE5,SQE6andSQE7genes affecting ΦPSIIin a dose-dependent manner, due to a combination of functional copies. Col-0 carries only one functional copy,SQE5, while Ler-0 carries functional copies ofSQE6and SQE7. Overexpression of a functional copy ofSQE6enhances ΦPSIIto exceed that of the Ler-0 parent in Arabidopsis, but does not affect ΦPSIIin tobacco. Phylogenetic analysis of theSQEandSQE-likesin 135 plant species revealed that theSQE-likes are evolutionary confined to two sister families, the Cleomaceae and Brassicaceae, and diversified independently. The tandem cluster of fourSQE-likegenes in Arabidopsis is likely the result of two recent gene duplication events, one generatingSQE5fromSQE4, the next one generatingSQE6andSQE7fromSQE5. The involvement ofSQE-likegenes in photosynthesis will open up new avenues to determine the function of these novel genes.
The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity
Authors: Mamar Hasan , Fajka-Boja Roberta , Mórocz Mónika , Jurado Eva Pinto , Zentout Siham , Mihuț Alexandra , Kopasz Anna Georgina , Mérey Mihály , Smith Rebecca , Haracska Lajos , Huet Sébastien , Timinszky Gyula 
Published: September 2023

ABSTRACTThe clinical success of PARP1/2 inhibitors prompts the expansion of their applicability beyond homologous recombination deficiency. Here, we demonstrate that the loss of the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes cells to PARP inhibitors. We show that the sensitivity of POLE4 knockouts is not due to a compromised response to DNA damage or homologous recombination deficiency. Instead, POLE4 deletion generates replication stress with the accumulation of single-stranded DNA gaps upon PARP inhibitor treatment. In POLE4 knockouts, replication stress leads to elevated DNA-PK signaling revealing a role of POLE4 in regulating DNA-PK activation. Moreover, POLE4 knockouts show synergistic sensitivity to the co-inhibition of ATR and PARP. Finally, POLE4 loss enhances the sensitivity of BRCA1-deficient cells to PARP inhibitors and counteracts acquired resistance consecutive to restoration of homologous recombination. Altogether, our findings establish POLE4 as a promising target to improve PARP inhibitor driven therapies and hamper acquired PARP inhibitor resistance.