bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monkeypox virus quadrivalent mRNA vaccine induces antibody responses and cellular immunity and protects mice against Vaccinia virus
Authors: Sang Ye , Zhang Zhen , Liu Fan , Lu Haitao , Yu Changxiao , Sun Huisheng , Long Jinrong , Cao Yiming , Mai Jierui , Wang Xin , Fang Jiaxin , Wang Youchun , Huang Weijin , Yang Jing , Wang Shengqi 
Published: November 2022

AbstractThere is an urgent need for efficient and safe vaccines against the monkeypox virus (MPXV) in response to the rapidly spreading monkeypox epidemic. In the age of COVID-19, mRNA vaccines have been highly successful and emerged as platforms enabling rapid development and large-scale preparation. Here, we have developed two MPXV quadrivalent mRNA vaccines, named mRNA-A-LNP and mRNA-B-LNP, based on two IMVs (A29L and M1R) and two EEVs (A35R and B6R). By administering mRNA-A-LNP and mRNA-B-LNP intramuscularly twice, mice have induced MPXV-specific IgG antibodies and potent Vaccinia virus (VACV)-specific neutralizing antibodies. Additionally, it elicited durable MPXV-specific killer memory T-cell immunity as well as memory B-cell immunity in mice. Furthermore, the passive transfer of sera from mRNA-A-LNP and mRNA-B-LNP-immunized mice protected nude mice against the VACV challenge. In addition, two doses of mRNA-A-LNP and mRNA-B-LNP were also protective against the VACV challenge in mice. Overall, our results demonstrated that mRNA-A-LNP and mRNA-B-LNP appear to be safe and effective vaccine candidates against monkeypox epidemics, as well as against outbreaks caused by other orthopoxviruses, including the smallpox virus.
Identification of differential polypharmacology between the PARP inhibitor rucaparib and its major metabolite
Authors: Hu Huabin , Serra Carme , Llebaria Amadeu , Antolin Albert A. 
Published: November 2022

AbstractThe (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery and development. However, some drug metabolites can reach high plasma concentrations and display relevant in vivo activity, which can be distinct from its parent drug. Here, we use computational and experimental methods to comprehensively characterise the kinase polypharmacology of M324, the major metabolite of the FDA-approved PARP inhibitor rucaparib. We experimentally demonstrate that M324 displays a distinct in vitro kinome profile from its parent drug, characterized by potent in vitro inhibition of GSK3A and PLK2 at clinically-relevant concentrations. These confirmed kinase activities of M324 could have potential implications for the efficacy and safety of rucaparib and therefore warrant further clinical investigation. The study reported here highlights the importance of thoroughly characterizing the activity of significant drug metabolites to better understanding drug responses in the clinic and maximally exploit the current drug arsenal in personalized and precision medicine.
NAT10, an RNA acetyl cytidine transferase restrains ferroptosis in cancer cells by maintaining SLC7A11 RNA stability
Authors: Dalhat Mahmood Hassan , Choudhry Hani , Khan Mohammad Imran 
Published: November 2022

AbstractRecently, we reported that N-acetyltransferase 10 (NAT10) regulates fatty acid metabolism through ac4C-dependent RNA modification of key genes in cancer cells. During this work, we noticed ferroptosis as one of the most negatively enriched pathways among other pathways in NAT10 depleted cancer cells. In the current work, we explored the possibility of whether NAT10 acts as an epitrancriptomic regulator of ferroptosis pathway in cancer cells. Global ac4C levels and expression of NAT10 with other ferroptosis-related genes were assessed via dotblot and RT-qPCR respectively. Flow cytometry and biochemical analysis were used to assess oxidative stress and ferroptosis features. The ac4C mediated mRNA stability was conducted RIP-PCR and mRNA stability assay. Metabolites were profiled using LC-MS/MS. Our results showed significant downregulation in expression of essential genes related to ferroptosis namelySLC7A11, GCLC, MAP1LC3A, andSLC39A8in NAT10 depleted cancer cells. Further, we noticed a reduction in cystine uptake and reduced GSH levels along with elevated ROS, and lipid peroxidation levels in NAT10 depleted cells. Consistently, overproduction of oxPLs as well as increased mitochondrial depolarization and decreased activities of antioxidant enzymes support the notion of ferroptosis induction in NAT10 depleted cancer cells. Mechanistically, reduced ac4C level shortens the half-life ofGCLCandSLC7A11mRNA, resulting in low levels of intracellular cystine and reduced GSH, failing to detoxify ROS leading to increased cellular oxPLs which facilitates ferroptosis induction. Collectively, our findings suggest that NAT10 restrains ferroptosis by stabilizing the SLC7A11 mRNA transcripts to avoid oxidative stress that induces oxidation of phospholipids to initiate ferroptosis.
MuVEH and mitoMuVEH improve discovery of genetic variation from single cells
Authors: Ransom Monica R. , Engel Krysta L. , Stevens Brett M. , Jordan Craig T. , Gillen Austin E. 
Published: November 2022

AbstractUnderstanding the genetic underpinnings and clonal structure of malignancies at single-cell resolution is critical to accurately predicting drug response and understanding mechanisms of drug resistance and disease evolution in heterogeneous populations of cells. Here, we introduce an accessible, multiplexable, targeted mutation enrichment approach and end-to-end analysis pipeline called MuVEH (Multiplexed Variant Enrichment by Hybridization) that increases the resolution of variant detection in scRNA-seq analysis. When applied specifically to the mitochondrial chromosome (“mitoMuVEH”), this technique can also be used to reconstruct and trace clonal relationships between individual cells. We applied both approaches to two pairs of primary bone marrow specimens from acute myelogenous leukemia (AML) patients collected at diagnosis and after relapse following Venetoclax+Azacitidine (Ven/Aza) therapy. Used together, MuVEH and mitoMuVEH reveal clonal evolution and changing mutational burden in response to treatment at single-cell resolution in these patients. Ultimately, these approaches have the potential to extract additional biological insights from precious patient samples and provide insight into the contributions clonality and genotype have during disease progression.
A singleVerticillium dahliaeeffector determines pathogenicity on tomato by targeting auxin response factors
Authors: Li Jinling , Faino Luigi , Fiorin Gabriel L. , Bashyal Sagar , Schaveling Arno , van den Berg Grardy C.M. , Seidl Michael F. , Thomma Bart P.H.J. 
Published: November 2022

SUMMARYVerticillium dahliaeis a xylem-invading fungal pathogen that causes devastating vascular wilt diseases on hundreds of plant hosts, including tomato (Solanum lycopersicum). Although individualV. dahliaestrains are typically characterized by their broad host range, differential pathogenicity occurs on nearly all hosts. Currently, the molecular basis underlying such pathogenicity differences remains unknown. We used comparative genomics to identify a single effector gene that specifically occurs in tomato-pathogenicV. dahliaestrains and is expressed during tomato colonization. Functional analyses showed that this Tom1 effector governs pathogenicity on tomato, asTom1deletion prohibited tomato colonization, while introduction ofTom1into non-pathogenicV. dahliaeor into saprophytic sister speciesV. tricorpusandV. nubilumresulted in disease. Through proteomics-based approaches, auxin response factors (ARFs) were identified asin plantatargets of Tom1. Intriguingly, repression ofSlARF2aexpression by virus-induced gene silencing fully impairedV. dahliaecolonization of tomato, solidifying its role as susceptibility target.Collectively, our findings indicate that a single effector, Tom1, mediates pathogenicity ofV. dahliaeon tomato by targeting auxin response factors.
Pump it up: bioelectric stimulation controls tissue shape and size
Authors: Shim Gawoon , Breinyn Isaac B. , Martínez-Calvo Alejandro , Sameeksha  , Cohen Daniel J. 
Published: November 2022

AbstractEpithelial tissues sheath many organs, separating ‘outside’ from ‘inside’ and exquisitely regulating ion and water transport electromechanically to maintain homeostatic balance and tissue hydrostatic pressure. While it is increasingly clear that the ionic microenvironment and external electric stimuli can affect epithelial function and behavior, the coupling between electrical perturbation and tissue form remain unclear. We investigated this by combining electrical stimulation with three-dimensional epithelial tissues with hollow ‘lumens’—both kidney cysts and complex intestinal stem cell organoids. Our core finding is that physiological strength electrical stimulation of order 1-3 V/cm (with both direct and alternating currents) can drive powerful and rapid inflation of hollow tissues through a process we call ‘electro-inflation’, inducing up to a threefold increase in tissue volume and striking asymmetries in tissue form. Electro-inflation is primarily driven by field-induced ion crowding on the outer surface of the hollow tissue that creates an ion gradient across the epithelial shell, which drives increased ionic flux mediated by ion channels/transporters and subsequent osmotic water flow into the lumen. This influx generates hydrostatic pressure, and inflation results from a competition between this pressure and cell cytoskeletal tension. We validated these interpretations with computational models connecting ion crowding around tissues to tissue mechanics. Electrically stimulated cysts and organoids also exhibited pronounced asymmetry, where the epithelial shell thickened on the cathode-facing side and thinned on the anode-facing side of the tissue. We discovered that this process is the result of 3D electrotaxis–directed migration of cells in an electric field–causing a redistribution of cells around the shell. The ability of electrical cues to dramatically regulate tissue size and shape highlight the key role of the electrical micro-environment and the potential offered by manipulating these signals.
A Novel Approach to Topological Network Analysis for the Identification of Metrics and Signatures in Non-Small Cell Lung Cancer
Authors: Wu Isabella , Wang Xin 
Published: November 2022

ABSTRACTNon-small cell lung cancer (NSCLC), the primary histological form of lung cancer, accounts for about 25% - the highest - of all cancer deaths. As NSCLC is often undetected until symptoms appear in the late stages, it is imperative to discover more effective tumor-associated biomarkers for early diagnosis. Topological data analysis is one of the most powerful methodologies applicable to biological networks. However, current studies fail to consider the biological significance of their quantitative methods and utilize popular scoring metrics without verification, leading to low performance. To extract meaningful insights from genomic data, it is essential to understand the relationship between geometric correlations and biological function mechanisms. Through bioinformatics and network analyses, we propose a novel composite selection index, the C-Index, that best captures significant pathways and interactions in gene networks to identify biomarkers with the highest efficiency and accuracy. Furthermore, we establish a 4-gene biomarker signature that serves as a promising therapeutic target for NSCLC and personalized medicine. We designed a Cascading machine learning model to validate both the C-Index and the biomarkers discovered. The methodology proposed for finding top metrics can be applied to effectively select biomarkers and early diagnose many diseases, revolutionizing the approach to topological network research for all cancers.
Not all pathways are the same – unique adaptations to submerged environments emerge from comparative seagrass genomics
Authors: Bayer Philipp E , Fraser Matthew W. , Martin Belinda C. , Petereit Jakob , Severn-Ellis Anita A. , Sinclair Elizabeth A. , Batley Jacqueline , Kendrick Gary A. , Edwards David 
Published: November 2022

AbstractSeagrasses are an ecologically important group of plants that have returned to the sea from terrestrial ancestors on at least three occasions (Cymodoceaceae, Posidoniaceae, Zosteraceae). Seagrass-specific genomic adaptations to marine life are known from the Zosteraceae. However, independent lineages may have devised different solutions to life underwater. Here, we present two new genome assemblies from endemic Australian seagrasses,Amphibolis antarctica(Cymodoceaceae) andPosidonia australis(Posidoniaceae). We found large differences in genome size betweenAmphibolisandPosidoniadriven by repeat expansion inPosidonia. We show that parts of ethylene pathways known to be lost in Zosteraceae are partially retained in older seagrass lineages (Cymodoceaeceae and Posidoniaceae). We describe adaptations within salinity, disease resistance, cell wall, and photosynthesis-related pathways not shared with other seagrasses. These findings provide insight into the impact of recolonising marine environments on formerly terrestrial plant genomes, with some adaptations previously thought to be universal to marine living not having occurred inA. antarcticaandP. australis.
The synergistic anti-Warburg efficacy of temozolomide, metformin and epigallocatechin gallate in glioblastoma
Authors: Kuduvalli Shreyas S. , Precilla Daisy S , Biswas Indrani , Anitha T. S 
Published: November 2022

AbstractBackgroundAn important hallmark of glioblastoma aggressiveness is its altered metabolism of glucose. This metabolic shift wherein the tumor cells employ aerobic glycolysis regardless of oxygen availability via reprogramming of mitochondrial oxidative phosphorylation is known as the Warburg effect. Previous literatures have linked this metabolic reprograming to tumor progression glioblastoma cell proliferation making it a key target for targeted drug therapy.ObjectiveTo evaluate the anti-Warburg efficacies of the triple-drug combination of temozolomide, metformin and epigallocatechin gallate in preclinical glioblastoma models.MethodologyBased on this lacuna, the current study aimed to explore the therapeutic efficacy of the triple-drug combination of temozolomide, metformin and epigallocatechin gallate in attenuating Warburg effect and glucose uptake in glioblastoma bothin vitroandin vivo.ResultsOur results showed that the triple-drug combination had significantly reduced glucose uptake and reversed the Warburg effect in glioblastoma cells and in the xenograft-induced glioma rat model.ConclusionThus, the triple-drug combination would serve as an effective therapeutic regime to hamper glioblastoma progression via altering glucose metabolism and improve the overall prognosis in patient setting.
Functional promiscuity of small multidrug resistance transporters fromStaphylococcus aureus,Pseudomonas aeruginosa, andFrancisella tularensis
Authors: Spreacker Peyton J. , Porter Colin J. , Wegrzynowicz Andrea , Beeninga Will F. , Demas Sydnye , Powers Emma N. , Henzler-Wildman Katherine A. 
Published: November 2022

ABSTRACTSmall multidrug resistance (SMR) transporters efflux toxic substrates from bacterial cells and were recently divided into two subfamilies: specific toxic metabolite transporters and promiscuous drug exporters. These drug exporters are thought to function similarly to EmrE, the model system for this subfamily of SMR transporters. Studies of EmrE homologs indicate that they are able to confer resistance to EmrE substrates inE. coliand in their native organisms. Recent work from our lab showed that functional EmrE can confer resistance or susceptibilityin vivodepending on the drug substrate. Here, we test whether this functional promiscuity of EmrE extends to SMR transporters from three additional human or animal pathogens: SAsmr fromStaphylococcus aureus, PAsmr fromPseudomonas aeruginosa, and FTsmr fromFrancisella tularensis. We find that these SMR homologs can confer either resistance or susceptibility to different toxic substrates inE. coli. This demonstrates that the ability of a single transporter to lead to opposite biological outcomes when transporting different substrates is a general property of the promiscuous multidrug transporters in the SMR family. It also suggests the potential for novel antibiotic development targeting these transporters with small molecules that trigger susceptibility. Such a strategy does not require that the target be the primary mode for antibiotic resistance because the goal is not simple inhibition of activity, but rather activation of an alternative transport function that is detrimental to bacteria.
Holistic monitoring of freshwater and terrestrial vertebrates by camera trapping and environmental DNA
Authors: Rubæk Holm Anne Marie , Knudsen Steen Wilhelm , Månsson Malene , Pedersen Ditte Elmgreen , Nordfoss Pauli Holm , Johansson Daniel Klingberg , Gramsbergen Marthe , Havmøller Rasmus Worsøe , Sigsgaard Eva Egelyng , Thomsen Philip Francis , Olsen Morten Tange , Møller Peter Rask 
Published: November 2022

AbstractThe anthropogenic impact on the world’s ecosystems is severe and the need for non-invasive, cost-effective tools for monitoring and understanding those impacts are therefore urgent. Here we combine two such methods in a comprehensive multi-year study; camera trapping (CT) and analysis of environmental DNA (eDNA), in river marginal zones of a temperate, wetland Nature Park in Denmark. CT was performed from 2015 to 2019 for a total of 8,778 camera trap days and yielded 24,376 animal observations. The CT observations covered 87 taxa, of which 78 were identified to species level, and 73 were wild native species. For eDNA metabarcoding, a total of 114 freshwater samples were collected from eight sites in all four seasons from 2017 to 2018. The eDNA results yielded a total detection of 80 taxa, of which 74 were identified to species level, and 65 were wild native species. While the number of taxa detected with the two methods were comparable, the species overlap was only 20 %. In combination, CT and eDNA monitoring thus yielded a total of 115 wild species (20 fishes, four amphibians, one snake, 23 mammals and 67 birds), representing half of the species found via conventional surveys over the last ca. 20 years (83% of fishes, 68 % of mammals, 67 % of amphibians, 41 % of birds and 20 % of reptiles). Our study demonstrates that a holistic approach combining two non-invasive methods, CT and eDNA metabarcoding, has great potential as a cost-effective biomonitoring tool for vertebrates.
Prophage regulation ofShewanella fidelis3313 motility and biofilm formation: implications for gut colonization dynamics inCiona robusta
Authors: Natarajan Ojas , Gibboney Susanne L. , Young Morgan N. , Lim Shen Jean , Nguyen Felicia , Pluta Natalia , Atkinson Celine G.F. , Liberti Assunta , Kees Eric D. , Leigh Brittany A. , Breitbart Mya , Gralnick Jeffrey A. , Dishaw Larry J. 
Published: November 2022

AbstractLysogens, bacteria that contain viruses (prophages) integrated into their genomes, are abundant in the gut of animals. Prophages often influence bacterial traits; however, the influence of prophages on the gut microbiota-host immune axis in animals remains poorly understood.Here, we investigate the influence of the prophage SfPat onShewanella fidelis3313, a persistent member of the gut microbiome of the model marine tunicate,Ciona robusta. Establishment of a SfPat deletion mutant (ΔSfPat) reveals the influence of this prophage on bacterial physiologyin vitroand during colonization of theCionagut.In vitro, deletion of SfPat reducesS. fidelis3313 motility and swimming while increasing biofilm formation. To understand thein vivoimpact of these prophage-induced changes in bacterial traits, we exposed metamorphic stage 4Cionajuveniles to wildtype (WT) and ΔSfPat strains. During colonization, ΔSfPat localizes to distinct areas of the gut compared to the WT strain. We tested the differential expression of various regulators of cyclic-di-GMP, a secondary signaling molecule known to mediate biofilm formation and motility. The pdeB gene, which encodes a bacterial phosphodiesterase known to influence biofilm formation and motility by degrading cyclic-di-GMP, is upregulated in the WT strain but not in ΔSfPat when examinedin vivo. Expression of theCionagut immune effector, VCBP-C, is enhanced during colonization by ΔSfPat compared to the WT strain; however, VCBP-C binding to the WT strain does not promote the excision of SfPat in an SOS-dependent pathway. Our findings suggest that SfPat influences host perception of this important colonizing commensal and highlights the significance of investigating interkingdom dynamics between prophages, bacteria, and their animal hosts to better understand the gut microbiota-host immune axis.
miRNome profiling of lung cancer metastases revealed a key role for miRNA-PD-L1 axis in the modulation of chemotherapy response
Authors: Cuttano Roberto , Colangelo Tommaso , Guarize Juliana , Dama Elisa , Cocomazzi Maria Pia , Mazzarelli Francesco , Melocchi Valentina , Palumbo Orazio , Marino Elena , Belloni Elena , Montani Francesca , Vecchi Manuela , Barberis Massimo , Graziano Paolo , Pasquier Andrea , Sanz-Ortega Julian , Montuenga Luis M. , Carbonelli Cristiano , Spaggiari Lorenzo , Bianchi Fabrizio 
Published: November 2022

ABSTRACTLocally-advanced non–small-cell lung cancer (NSCLC) is frequent at diagnosis and requires multimodal treatment approaches. Neoadjuvant chemotherapy (NACT) followed by surgery is the treatment of choice for operable locally-advanced NSCLC (Stage IIIA). However, the majority of patients are NACT-resistant and shows persistent lymph nodal metastases (LNmets) and an adverse outcome. Therefore, the identification of mechanisms and biomarkers of NACT resistance is paramount for ameliorating prognosis of patients with Stage IIIA NSCLC. Here, we investigated the miRNome and transcriptome of chemo naïve LNmets collected from patients with Stage IIIA NSCLC (N=64). We found that a microRNA signature accurately predicts NACT response. Mechanistically, we discovered a miR-455-5p/PD-L1 regulatory axis which drives chemotherapy resistance, hallmarks metastases with active IFN-γresponse pathway (an inducer of PD-L1 expression), and impacts T cells viability and relative abundances in tumor-microenviroment (TME). Our data provides new biomarkers to predict NACT response and adds molecular insights relevant for improving the management of patients with locally-advanced NSCLC.
Tissue-specific overexpression of the double-stranded RNA transporter SID-1 limits lifespan inC. elegans
Authors: Camara Henrique , Vergani-Junior Carlos A. , Pinto Silas , Knittel Thiago L. , Salgueiro Willian G. , Tonon-da-Silva Guilherme , Ramirez Juliana , De-Souza Evandro A. , Mori Marcelo A. 
Published: November 2022

ABSTRACTIntertissue RNA transport has emerged as a novel signaling mechanism. InC. elegans, this is conferred by the systemic RNAi pathway, in which the limiting step is the cellular import of extracellular RNAs via SID-1. To better understand the physiological role of systemic RNAiin vivo, we modified the function of SID-1 through loss-of-function mutation and tissue-specific overexpression ofsid-1inC. elegans. We observed thatsid-1loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression ofsid-1in intestine, muscle, or neurons rendered worms short-lived. The effects of intestinalsid-1overexpression were reversed by silencing the components of the systemic RNAi pathwaysid-1, sid-2andsid-5, thus implicating RNA transport. Moreover, silencing the miRNA biogenesis proteinspash-1anddcr-1rendered the lifespan of worms with intestinalsid-1overexpression similar to controls. Lastly, we observed that the lifespan decrease produced by tissue-specificsid-1overexpression was dependent on the bacterial food source. Collectively, our data support the notion that systemic RNA signaling is tightly regulated, and unbalancing that process provokes a reduction in lifespan.