bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRIM25 inhibits Influenza A infection by destabilising its mRNA and is redundant for the RIG-I pathway
Authors: Choudhury Nila Roy , Heikel Gregory , Trus Ivan , Dos Santos Pinto Rute Maria , Trubitsyna Maryia , Gaunt Eleanor , Digard Paul , Michlewski Gracjan 
Published: September 2021

AbstractThe E3 ubiquitin ligase TRIM25 is a key factor in the innate immune response to RNA viruses. TRIM25 has been shown to play a role in the retinoic-acid-inducible gene-1 (RIG-I) pathway, which triggers expression of type 1 interferons upon viral infection. We and others have recently shown that TRIM25 is an RNA-binding protein, however not much is known about the RNA-binding roles of TRIM25 in the innate immune response to RNA viruses. Here, we demonstrate that influenza Avirus (IAV A/PR/8/34_NS1(R38K41A)) infection is inhibited by TRIM25. Surprisingly, host RNA-binding deficient mutant TRIM25ΔRBD and TRIM25ΔRING, which lack E3 ubiquitin ligase activity rescued IAV inhibition in TRIM25 knock-out cells. Furthermore, we show that in human cultured cells activation of the RIG-I/interferon type 1 pathway mediated by an IAV-derived 5’-triphosphate RNA does not require TRIM25 activity. Additionally, knocking out TRIM25 does not affect the activity of the IAV polymerase. We present new evidence that TRIM25 restricts IAV by directly binding to and destabilising its mRNAs. Finally, we show that direct tethering of TRIM25 to RNA is sufficient to downregulate the targeted RNA. In summary, our results uncover a novel mechanism that TRIM25 uses to inhibit IAV infection and regulate RNA metabolism.
Systemic and local immune response to intraocular AAV vector administration in non-human primates
Authors: Ail Divya , Ren Duohao , Brazhnikova Elena , Nouvel-Jaillard Céline , Bertin Stephane , Fisson Sylvain , Dalkara Deniz 
Published: September 2021

ABSTRACTThe positive clinical outcomes in adeno-associated virus (AAV)-mediated retinal gene therapy have often been attributed to the low immunogenicity of AAVs along with the immune-privilege of the eye. However, several recent preclinical studies and clinical trials have shown potential for inflammatory responses to AAV mediated gene therapy. Our current understanding of the factors contributing to intraocular inflammation such as the existence of serum antibodies against AAVs prior to injection and their contribution to increases in antibody levels post-injection is incomplete. The parameters that regulate the generation of new antibodies in response to the AAV capsid or transgene post-injection after intraocular administration are also insufficiently described. In this study we carried out a retrospective analysis of the pre-existing serum antibodies in correlation with changes in antibody levels after intraocular injections of AAV in non-human primates (NHPs). We analyzed NHP serums for the presence of both Binding Antibodies (BABs), as well as a subset of these called Neutralizing Antibodies (NABs) that impede AAV transduction upon binding. We observed significantly higher pre-existing serum BABs against AAV8 compared to other serotypes. We observed a dose-dependent increase in both BABs and NABs in the serums collected post-injection, irrespective of the serotype or the mode of injection. Lastly, we were able to demonstrate a co-relation between the serum BAB levels with clinical grading of inflammation and levels of transgene expression.
Amoxicillin-resistant Streptococcus pneumoniae can be resensitized by targeting the mevalonate pathway as indicated by sCRilecs-seq
Authors: Dewachter Liselot , Liu Xue , Dénéréaz Julien , de Bakker Vincent , Costa Charlotte , Baldry Mara , Sirard Jean-Claude , Veening Jan-Willem 
Published: September 2021

AbstractAntibiotic resistance in the important opportunistic human pathogen Streptococcus pneumoniae is on the rise. This is particularly problematic in the case of the β-lactam antibiotic amoxicillin, which is the first-line therapy. It is therefore crucial to uncover targets that would kill or resensitize amoxicillin-resistant pneumococci. To do so, we developed a genome-wide, single-cell based, gene silencing screen using CRISPR interference called sCRilecs-seq (subsets of CRISPR interference libraries extracted by fluorescence activated cell sorting coupled to next generation sequencing). Since amoxicillin affects growth and division, sCRilecs-seq was used to identify targets that are responsible for maintaining proper cell size. Our screen revealed that downregulation of the mevalonate pathway leads to extensive cell elongation. Further investigation into this phenotype indicates that it is caused by insufficient transport of cell wall precursors across the cell membrane due to a limitation in the production of undecaprenyl phosphate (Und-P), the lipid carrier responsible for this process. The data suggest that whereas peptidoglycan synthesis continues even with reduced Und-P levels, cell constriction is specifically halted. We successfully exploited this knowledge to create a combination treatment strategy where the FDA-approved drug clomiphene, an inhibitor of Und-P synthesis, is paired up with amoxicillin. Our results show that clomiphene potentiates the antimicrobial activity of amoxicillin and that combination therapy resensitizes amoxicillin-resistant S. pneumoniae. These findings could provide a starting point to develop a solution for the increasing amount of hard-to-treat amoxicillin-resistant pneumococcal infections.
Elicitation of potent SARS-CoV-2 neutralizing antibody responses through immunization using a versatile adenovirus-inspired multimerization platform
Authors: Chevillard C , Amen A , Besson S , Hannani D , Bally I , Dettling V , Gout E , Moreau CJ , Buisson M , Gallet S , Fenel D , Vassal-Stermann E , Schoehn G , Poignard P , Dagher MC , Fender P 
Published: September 2021

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has shown that vaccine preparedness is critical to anticipate a fast response to emergent pathogens with high infectivity. To rapidly reach herd immunity, an affordable, easy to store and versatile vaccine platform is thus desirable. We previously designed a non-infectious adenovirus-inspired nanoparticle (ADDomer), and in the present work, we efficiently decorated this original vaccine platform with glycosylated receptor binding domain (RBD) of SARS-CoV-2. Cryo-Electron Microscopy structure revealed that up to 60 copies of this antigenic domain were bound on a single ADDomer particle with the symmetrical arrangements of a dodecahedron. Mouse immunization with the RBD decorated particles showed as early as the first immunization a significant anti-coronavirus humoral response, which was boosted after a second immunization. Neutralization assays with spike pseudo-typed-virus demonstrated the elicitation of strong neutralization titers. Remarkably, the existence of pre-existing immunity against adenoviral-derived particles enhanced the humoral response against SARS-CoV-2. This plug and play vaccine platform revisits the way of using adenovirus to combat emergent pathogens while potentially taking advantage of the adenovirus pre-immunity.
Decoding the olfactory map: targeted transcriptomics link olfactory sensory neurons to glomeruli
Authors: Zhu Kevin W. , Burton Shawn D. , Nagai Maira H. , Silverman Justin D. , de March Claire A. , Wachowiak Matt , Matsunami Hiroaki 
Published: September 2021

ABSTRACTSensory processing in vertebrate olfactory systems is organized across olfactory bulb glomeruli, wherein axons of peripheral sensory neurons expressing the same olfactory receptor co-terminate to transmit receptor-specific activity to central neurons. Understanding how receptors map to glomeruli is therefore critical to understanding olfaction. High-throughput spatial transcriptomics is a rapidly advancing field, but low-abundance olfactory receptor expression within glomeruli has previously precluded high-throughput mapping of receptors to glomeruli. Here we combined spatial sectioning along the anteroposterior, dorsoventral, and mediolateral axes with target capture enrichment sequencing to overcome low-abundance target expression. This strategy allowed us to spatially map 86% of olfactory receptors across the olfactory bulb and uncover a relationship between OR sequence and glomerular position.ONE SENTENCE SUMMARYTargeted enrichment of olfactory receptor mRNA in olfactory bulb sections determines spatial positions for murine glomeruli.
Elucidation of the interactions between SARS-CoV-2 Spike protein and wild and mutant types of IFITM proteins by in silico methods
Authors: Giritlioglu Nazli Irmak , Kucuk Gizem Koprululu 
Published: September 2021

ABSTRACTCOVID-19 is a viral disease that has been a threat to the whole world since 2019. Although effective vaccines against the disease have been developed, there are still points to be clarified about the mechanism of SARS-CoV-2, which is the causative agent of COVID-19. In this study, we determined the binding energies and the bond types of complexes formed by open (6VYB) and closed (6VXX) forms of the Spike protein of SARS-CoV-2 and wild and mutant forms of IFITM1, IFITM2, and IFITM3 proteins using the molecular docking approach. First, all missense SNPs were found in the NCBI Single Nucleotide Polymorphism database (dbSNP) for IFITM1, IFITM2, and IFITM3 and analyzed with SIFT, PROVEAN, PolyPhen-2, SNAP2, Mutation Assessor, and PANTHER cSNP web-based tools to determine their pathogenicity. When at least four of these analysis tools showed that the SNP had a pathogenic effect on the protein product, this SNP was saved for further analysis. Delta delta G (DDG) and protein stability analysis for amino acid changes were performed in the web-based tools I-Mutant, MUpro, and SAAFEC-SEQ. The structural effect of amino acid change on the protein product was made using the HOPE web-based tool. HawkDock server was used for molecular docking and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and binding energies of all complexes were calculated. BIOVIA Discovery Studio program was utilized to visualize the complexes. Hydrogen bonds, salt bridges, and non-bonded contacts between Spike and IFITM protein chains in the complexes were detected with the PDBsum web-based tool. The best binding energy among the 6VYB-IFITM wild protein complexes belong to 6VYB-IFITM1 (-46.16 kcal/mol). Likewise, among the 6VXX-IFITM wild protein complexes, the most negative binding energy belongs to 6VXX-IFITM1 (-52.42 kcal/mol). An interesting result found in the study is the presence of hydrogen bonds between the cytoplasmic domain of the IFITM1 wild protein and the S2 domain of 6VYB. Among the Spike-IFITM mutant protein complexes, the best binding energy belongs to the 6VXX-IFITM2 N63S complex (-50.77 kcal/mol) and the worst binding energy belongs to the 6VXX-IFITM3 S50T complex (4.86 kcal/mol).The study suggests that IFITM1 protein may act as a receptor for SARS-CoV-2 Spike protein. Assays must be advanced from in silico to in vitro for the determination of the receptor-ligand interactions between IFITM proteins and SARS-CoV-2.
Disrupting the CmP signaling network unveils novel biomarkers for triple negative breast cancer in Caucasian American women
Authors: Abou-Fadel Johnathan , Bhalli Muaz , Grajeda Brian , Zhang Jun 
Published: September 2021

AbstractTriple-negative breast cancer (TNBC) constitutes ∼15 percent of all diagnosed invasive breast cancer cases with limited options for treatment since immunotherapies that target the ER, PR and HER2 receptors are ineffective. Progesterone (PRG) is capable of inducing its effects through either classic, non-classic, or combined responses by binding to classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Under PRG-induced actions, we previously demonstrated that the CSC (CCM signaling complex) can couple both nPRs and mPRs into a CmPn signaling network which plays an important role in nPR(+) breast cancer tumorigeneses. We recently defined the novel CmP signaling network in TNBC cells, which overlapped with our previously defined CmPn network in nPR(+) breast cancer cells. In this study, we were able to demonstrate alterations to key tumorigenesis pathways in Caucasian American Women (CAW)-TNBC cells, under mPRs-specific steroid actions. These results suggest that even though TNBC diagnoses in AAW are associated with more aggressive forms of the disease, and experience a higher mortality rate, TNBC in CAW share similar altered signaling pathways, under mPRs-specific steroid actions, demonstrating the overall aggressive nature of TNBCs, regardless of racial differences. Furthermore, in this report, we have identified 21 new CAW-TNBC specific candidate biomarkers that reinforce the definitive role of the CmP signaling network in TNBC tumorigenesis, initially identified in our previous studies with AAW-TNBCs. This new set of potential prognostic biomarkers may revolutionize molecular mechanisms and currently known concepts of tumorigenesis in CAW-TNBCs, leading to hopeful new therapeutic strategies.
Genetic and functional odorant receptor variation in the Homo lineage
Authors: de March Claire A. , Matsunami Hiroaki , Abe Masashi , Cobb Matthew , Hoover Kara C. 
Published: September 2021

AbstractUsing ancient DNA sequences, we explored the function of olfactory receptor genes in the genus Homo. Humans, Neandertals, and Denisovans independently adapted to a wide range of geographic environments and the odours produced by their food. Variations in their odorant receptor protein sequence and structure resulted in variation in detection and perception. Studying thirty olfactory receptor genes, we found our relatives showed highly conserved receptor structures, but Homo sapiens did not. Variants led to changes in sensitivity to some odors, but no change in specificity, indicating a common olfactory repertoire in our genus. Diversity of geographic adaptations in H. sapiens may have produced greater functional variation in our lineage, increasing our olfactory repertoire and expanding our adaptive capacity.One-Sentence SummaryUsing ancient DNA we studied the sense of smell in our extinct ancestors and in our relatives, Denisovans and Neanderthals
Decoding natural astrocyte rhythms: dynamic actin waves result from environmental sensing by primary rodent astrocytes
Authors: O’Neill Kate M. , Saracino Emanuela , Barile Barbara , Mennona Nicholas J. , Mola Maria Grazia , Pathak Spandan , Posati Tamara , Zamboni Roberto , Nicchia Grazia P. , Benfenati Valentina , Losert Wolfgang 
Published: September 2021

AbstractAstrocytes are key regulators of brain homeostasis, an important physiological process that includes but is not limited to buffering of extracellular K+, equilibrating osmotic gradients, regulating pH, uptake of neurotransmitters, and releasing growth factors – all of which are essential for proper cognitive function. While previous studies have revealed how specific molecular components of the astrocytic cytoskeleton affect the efficacy of these homeostatic processes, none have studied how homeostasis is linked to the excitable systems character of the cytoskeleton. As recently discovered, excitability of the actin cytoskeleton manifests in second-scale dynamic fluctuations and acts as a sensor of chemo-physical environmental cues. Here we find that homeostatic regulation may be more active than previously thought, involving the excitable dynamics of actin in certain subcellular regions, especially near the cell boundary. Our results further indicate that actin dynamics concentrates into “hotspot” regions that selectively respond to certain chemo-physical stimuli, specifically the homeostatic challenges of ion or water concentration increases. Substrate topography makes the actin dynamics of astrocytes weaker. Superresolution images demonstrate that surface topography is also associated with predominant perpendicular alignment of actin filaments near the cell boundary whereas flat substrates result in an actin cortex mainly parallel to the cell boundary. Additionally, co-culture with neurons increases both the probability of actin dynamics and the strength of hotspots. The excitable systems character of actin thus makes astrocytes direct participants in neural cell network dynamics.
Inference of disease-associated microbial gene modules based on metagenomic and metatranscriptomic data
Authors: Liu Zhaoqian , Wang Qi , Ma Anjun , Chung Dongjun , Zhao Jing , Ma Qin , Liu Bingqiang 
Published: September 2021

AbstractThe identification of disease-associated microbial characteristics is crucial for disease diagnosis and therapy. However, the heterogeneity, high dimensionality, and large amounts of microbial data present tremendous challenges for the discovery of key microbial features. In this paper, we present IDAM, a novel computational method for disease-associated gene module inference from metagenomic and metatranscriptomic data. This method integrates gene context conservation (uber-operon) and regulatory mechanisms (gene co-expression patterns) to explore gene modules associated with specific phenotypes using a mathematical graph model, without relying on prior meta-data. We applied IDAM to publicly available datasets from inflammatory bowel disease, melanoma, type 1 diabetes mellitus, and irritable bowel syndrome and demonstrated the superior performance of IDAM in disease-associated characteristics inference compared to popular tools. We also showed high reproducibility of the inferred gene modules of IDAM using independent cohorts with inflammatory bowel disease. We believe that IDAM can be a highly advantageous method for exploring disease-associated microbial characteristics. The source code of IDAM is freely available athttps://github.com/OSU-BMBL/IDAM.
Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery Against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques
Authors: Yu Jingyou , Collins Natalie D. , Mercado Noe B. , McMahan Katherine , Chandrashekar Abishek , Liu Jinyan , Anioke Tochi , Chang Aiquan , Giffin Victoria M. , Hope David L. , Sellers Daniel , Nampanya Felix , Gardner Sarah , Barrett Julia , Wan Huahua , Velasco Jason , Teow Elyse , Cook Anthony , Van Ry Alex , Pessaint Laurent , Andersen Hanne , Lewis Mark G. , Hofer Christian , Burke Donald S. , Barkei Erica K. , King Hannah A.D. , Subra Caroline , Bolton Diane , Modjarrad Kayvon , Michael Nelson L. , Barouch Dan H. 
Published: September 2021

AbstractLive oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Post-pyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that post-pyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques.ImportanceSARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations; however no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Here we report that oral administration of live SARS-CoV-2 in non-human primates may offer prophylactic benefits, but that formulation and route of administration will require further optimization.
Molecular basis of differential adventitious rooting competence in poplar genotypes
Authors: Ranjan Alok , Perrone Irene , Alallaq Sanaria , Singh Rajesh , Rigal Adeline , Brunoni Federica , Chitarra Walter , Guinet Frederic , Kohler Annegret , Martin Francis , Street Nathaniel , Bhalerao Rishikesh , Legué Valérie , Bellini Catherine 
Published: September 2021

AbstractRecalcitrant adventitious root (AR) development is a major hurdle in propagating commercially important woody plants. Although significant progress has been made to identify genes involved in subsequent steps of AR development, the molecular basis of differences in apparent recalcitrance to form AR between easy-to-root and difficult-to-root genotypes remains unknown.To address this, we generated cambium tissue-specific transcriptomic data from stem cuttings of hybrid aspen, T89 (difficult-to-root) and hybrid poplar OP42 (easy-to-root) and used transgenic approaches to verify the role of several transcription factors (TF) in the control of adventitious rooting.Increased peroxidase activity is positively correlated with better rooting. We found differentially expressed genes encoding Reactive Oxygen Species (ROS) scavenging proteins to be enriched in OP42 compared to T89. A higher number of differentially expressed TF in OP42 compared to T89 cambium cells was revealed by a more intense transcriptional reprograming in the former. PtMYC2, a potential negative regulator, was less expressed in OP42 compared to T89. Using transgenic approaches, we have demonstrated that PttARF17.1 and PttMYC2.1 negatively regulate adventitious rooting.Our results provide insights into the molecular basis of genotypic differences in AR and implicate differential expression of the master regulator MYC2 as a critical player in this process.
Mitoxantrone dihydrochloride, an FDA approved drug, binds with SARS-CoV-2 NSP1 C-terminal
Authors: Kumar Prateek , Bhardwaj Taniya , Giri Rajanish 
Published: September 2021

AbstractOne of the major virulence factors of SARS-CoV-2, NSP1, is a vital drug target due to its role in host immune evasion through multiple pathways. NSP1 protein is associated with inhibiting host mRNA translation by binding to the small subunit of ribosome through its C-terminal region. Previously, we have shown the structural dynamics of NSP1 C-terminal region (NSP1-CTR) in different physiological environments. So, it would be very interesting to investigate the druggable compounds that could bind with NSP1-CTR. Here, in this article, we have performed the different spectroscopic technique-based binding assays of an anticancer drug Mitoxantrone dihydrochloride (MTX) against the NSP1-CTR. We have also performed molecular docking followed by computational simulations with two different forcefields up to one microsecond. Overall, our results have suggested good binding between NSP1-CTR and MTX and may have implications in developing therapeutic strategies targeting NSP1 protein of SARS-CoV-2.