bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of cell death induction by the barley NLR immune receptor PBR1
Authors: Jaiswal Namrata , Myers Ariana , Weese Terri L. , Carter Morgan E. , Scofield Steven R. , Helm Matthew 
Published: January 2023

ABSTRACTThe barley (Hordeum vulgaresubsp.vulgare) disease resistance proteinAvrPphB Response 1(PBR1) mediates recognition of thePseudomonas syringaeeffector, AvrPphB. PBR1 belongs to the coiled-coil nucleotide-binding leucine-rich repeat (CNL) family. However, little is known about the molecular mechanisms that lead to PBR1-dependent cell death (hypersensitive reaction; HR) in response to AvrPphB. Here, we investigated PBR1 immune signaling afterAgrobacterium-mediated transient expression inNicotiana benthamiana. We found that co-expression of PBR1 with AvrPphB resulted in robust cell death, confirming previous observations that PBR1 is indeed the cognate NLR that recognizes AvrPphB. The N-terminal tagging of PBR1 with super Yellow Fluorescent Protein (sYFP) abolished PBR1-mediated cell death, demonstrating that an N-terminal epitope tag disrupts PBR1-mediated immune signaling. Furthermore, none of the individual protein domains or truncations of PBR1 induced a HR-like cell death response as strong as full-length PBR1 when co-expressed with AvrPphB, indicating that the individual domains and fragments of PBR1 are insufficient to trigger HR. Intriguingly, introducing the typically auto-activating D496V mutation within NB-ARC-containing fragments of PBR1 does not activate immune signaling revealing PBR1-mediated immune signaling requires cooperation of all domainsin cis. Using co-immunoprecipitation and split-luciferase assays, we also show full-length PBR1 self-associates in the absence of AvrPphB and such self-association is not dependent on a functional P-loop/Walker A motif. Collectively, these findings provide valuable insights into PBR1-mediated disease resistance and extends upon our understanding of NLR-mediated immune signaling.
PeruNPDB: The Peruvian Natural Products Database for in silico drug screening
Authors: Barazorda-Ccahuana Haruna Luz , Ranilla Lena Gálvez , Candia-Puma Mayron Antonio , Cárcamo-Rodriguez Eymi Gladys , Centeno-Lopez Angela Emperatriz , Del-Carpio Gonzalo Davila , Medina-Franco José L. , Chávez-Fumagalli Miguel Angel 
Published: January 2023

AbstractSince the number of drugs based on natural products (NPs) represents a large source of novel pharmacological entities, NPs have acquired significance in drug discovery. Peru is considered a megadiverse country with many endemic species of plants, terrestrial, and marine animals, and microorganisms. NPs databases have a major impact on drug discovery development. For this reason, several countries such as Mexico, Brazil, India, and China have initiatives to assemble and maintain NPs databases that are representative of their diversity and ethnopharmacological usage. We describe the assembly, curation, and full chemoinformatic evaluation of the content and coverage in chemical space, as well as the physicochemical attributes and chemical diversity of the initial version of the Peruvian Natural Products Database (PeruNPDB), which contains 280 compounds. Access to PeruNPDB is available for free (https://perunpdb.com.pe/). The PeruNPDB’s collection is intended to be used in a variety of tasks, such as virtual screening campaigns against various disease targets or biological endpoints. This emphasizes the significance of biodiversity protection both directly and indirectly on human health.
Serum protein N-glycome patterns reveal alterations associated with endometrial cancer and its phenotypes of differentiation
Authors: Zhang Zejian , Cao Zhen , Wang Jinhui , Li Zepeng , Wang Tao , Xiang Yang 
Published: January 2023

AbstractBackground and aimsAberrant N-glycosylation and its involvement in pathogenesis have been reported in endometrial cancer (EC). Nevertheless, the serum N-glycomic signature of EC remains unknown. Here, we investigated serum N-glycome patterns of EC to identify candidate biomarkers.Materials and methodsThis study enrolled 34 untreated EC patients and 34 matched healthy controls (HC) from Peking Union Medical College Hospital. State-of-the-art MS-based methods were employed for N-glycans profiling. Multivariate and univariate statistical analyses were used to identify discriminative N-glycans driving classification. Receiver operating characteristic analyses were performed to evaluate classification accuracy.ResultsEC patients displayed distinct differences in serum N-glycome and had abnormal high-mannose and hybrid-type N-glycans, fucosylation, galactosylation, and linkage□specific sialylation compared with HC. The glycan panel built with the four most discriminative and biologically important derived N-glycan traits could accurately identify EC (random forest model, the area under the curve [AUC]=0.993 [95%CI 0.955-1]). The performance was validated by two other models. Total hybrid-type N-glycans significantly associated with the differentiation types of EC could effectively stratify EC into well- or poorly-differentiated subgroups (AUC>0.8).ConclusionThis study to the best of our knowledge provides the initial evidence supporting the utility of serum N-glycomic signature as potential markers for the diagnosis and phenotyping of EC.
Cryo-EM reveals the mechanism of DNA compaction byMycobacterium smegmatisDps2
Authors: Garg Priyanka , Satheesh Thejas , Ganji Mahipal , Dutta Somnath 
Published: January 2023

AbstractDNA-binding protein under starvation (Dps), is a miniature ferritin complex which plays a vital role in protecting bacterial DNA during starvation for maintaining the integrity of bacteria from hostile conditions.Mycobacterium smegmatisis one such bacteria that express MsDps2, which binds DNA to protect it under oxidative and nutritional stress conditions. Several approaches, including cryo-electron tomography (Cryo-ET), were implemented to identify the structure of the Dps protein that is bound to DNA. However, none of the structures of the Dps-DNA complex was resolved to high resolution to be able to identify the DNA binding residues. In this study, we implemented various biochemical and biophysical studies to characterize the DNA protein interactions of Dps protein. We employed single-particle cryo-EM-based structural analysis of MsDps2-DNA and identify that the region close to N-terminal confers the DNA binding property. Based on cryo-EM data, we performed mutations of several arginine residues proximal to DNA binding region, which dramatically reduced the MsDps2-DNA interaction. In addition, we demonstrated the proposed model for DNA compaction during lattice formation. We also pinpointed arginine residues, which are responsible for DNA binding in lattice arrangement of MsDps2. We performed single-molecule imaging experiments of MsDps2-DNA interactions that corroborate well with our structural studies.
Deadenylation rate is not a major determinant of RNA degradation in yeast
Authors: Audebert Léna , Feuerbach Frank , Decourty Laurence , Namane Abdelkader , Permal Emmanuelle , Badis Gwenaël , Saveanu Cosmin 
Published: January 2023

AbstractGene expression and its regulation depend on mRNA degradation. In eukaryotes, degradation is controlled by deadenylation rates, since a short poly(A) tail is considered to be the signal that activates decapping and triggers mRNA degradation. In contrast to this view, we show that global stability of mRNAs can be explained by variations in decapping speed alone. Rapid decapping of unstable mRNAs, for example, allows little time for deadenylation, which explains their longer than average poly(A) tails. As predicted by modeling of RNA degradation kinetics, mRNA stabilization in the absence of decapping led to a decrease in the length of the poly(A) tail, while depletion of deadenylases only increased the tail length. Our results suggest that decapping activation dictates mRNA stability independent of the deadenylation speed.One-Sentence SummaryUnstable mRNAs are characterized by rapid 5’ cap removal, independent of a prior shortening of the poly(A) tail.
The emergence of goblet inflammatory or ITGB6hinasal progenitor cells determines age-associated SARS-CoV-2 pathogenesis
Authors: Woodall Maximillian , Cujba Ana-Maria , Worlock Kaylee B. , Case Katie-Marie , Masonou Tereza , Yoshida Masahiro , Polanski Krzysztof , Huang Ni , Lindeboom Rik G. H. , Mamanova Lira , Bolt Liam , Richardson Laura , Ellis Samuel , Palor Machaela , Burgoyne Thomas , Pinto Andreia , Moulding Dale , McHugh Timothy D. , Saleh Aarash , Kilich Eliz , Mehta Puja , O’Callaghan Chris , Zhou Jie , Barclay Wendy , Coppi Paolo De , Butler Colin R. , Vinette Heloise , Roy Sunando , Breuer Judith , Chambers Rachel C. , Heywood Wendy E. , Mills Kevin , Hynds Robert E. , Teichmann Sarah A. , Meyer Kerstin B. , Nikolić Marko Z. , Smith Claire M. 
Published: January 2023

AbstractChildren infected with SARS-CoV-2 rarely progress to respiratory failure, but the risk of mortality in infected people over 85 years of age remains high, despite vaccination and improving treatment options. Here, we take a comprehensive, multidisciplinary approach to investigate differences in the cellular landscape and function of paediatric (<11y), adult (30- 50y) and elderly (>70y) nasal epithelial cells experimentally infected with SARS-CoV-2. Our data reveal that nasal epithelial cell subtypes show different tropism to SARS-CoV-2, correlating with age, ACE2 and TMPRSS2 expression. Ciliated cells are a viral replication centre across all age groups, but a distinct goblet inflammatory subtype emerges in infected paediatric cultures, identifiable by high expression of interferon stimulated genes and truncated viral genomes. In contrast, infected elderly cultures show a proportional increase in ITGB6hiprogenitors, which facilitate viral spread and are associated with dysfunctional epithelial repair pathways.Graphical Abstract
The impact of modern admixture on archaic human ancestry in human populations
Authors: Witt Kelsey E. , Funk Alyssa , Fang Lesly Lopez , Huerta-Sanchez Emilia 
Published: January 2023

AbstractAdmixture, the genetic merging of parental populations resulting in mixed ancestry, has occurred frequently throughout the course of human history. Numerous admixture events have occurred between human populations across the world, as well as introgression between humans and archaic humans, Neanderthals and Denisovans. One example are genomes from populations in the Americas, as these are often mosaics of different ancestries due to recent admixture events as part of European colonization. In this study, we analyzed admixed populations from the Americas to assess whether the proportion and location of admixed segments due to recent admixture impact an individual’s archaic ancestry. We identified a positive correlation between non-African ancestry and archaic alleles, as well as a slight enrichment of Denisovan alleles in Indigenous American segments relative to European segments in admixed genomes. We also identify several genes as candidates for adaptive introgression, based on archaic alleles present at high frequency in admixed American populations but low frequency in East Asian populations. These results provide insights into how recent admixture events between modern humans redistributed archaic ancestry in admixed genomes.
Extraordinary Evasion of Neutralizing Antibody Response by Omicron XBB.1.5, CH.1.1 and CA.3.1 Variants
Authors: Qu Panke , Faraone Julia N. , Evans John P. , Zheng Yi-Min , Carlin Claire , Anghelina Mirela , Stevens Patrick , Fernandez Soledad , Jones Daniel , Panchal Ashish , Saif Linda J. , Oltz Eugene M. , Xu Kai , Gumina Richard J. , Liu Shan-Lu 
Published: January 2023

AbstractNewly emerging Omicron subvariants continue to emerge around the world, presenting potential challenges to current vaccination strategies. This study investigates the extent of neutralizing antibody escape by new subvariants XBB.1.5, CH.1.1, and CA.3.1, as well as their impacts on spike protein biology. Our results demonstrated a nearly complete escape of these variants from neutralizing antibodies stimulated by three doses of mRNA vaccine, but neutralization was rescued by a bivalent booster. However, CH.1.1 and CA.3.1 variants were highly resistant to both monovalent and bivalent mRNA vaccinations. We also assessed neutralization by sera from individuals infected during the BA.4/5 wave of infection and observed similar trends of immune escape. In these cohorts, XBB.1.5 did not exhibit enhanced neutralization resistance over the recently dominant BQ.1.1 variant. Notably, the spike proteins of XBB.1.5, CH.1.1, and CA.3.1 all exhibited increased fusogenicity compared to BA.2, correlating with enhanced S processing. Overall, our results support the administration of new bivalent mRNA vaccines, especially in fighting against newly emerged Omicron subvariants, as well as the need for continued surveillance of Omicron subvariants.
Ribosome rescue factor PELOTA modulates translation start site choice and protein isoform levels of transcription factor C/EBPα
Authors: Fernandez Samantha G. , Ferguson Lucas , Ingolia Nicholas T. 
Published: January 2023

AbstractTranslation initiation at alternative start sites can dynamically control the synthesis of two or more functionally distinct protein isoforms from a single mRNA. Alternate isoforms of the hematopoietic transcription factor CCAAT-enhancer binding proteinα(C/EBPα) produced from different start sites exert opposing effects during myeloid cell development. This alternative initiation depends on sequence features of theCEBPAtranscript, including a regulatory upstream open reading frame (uORF), but the molecular basis is not fully understood. Here we identifytrans-acting factors that affect C/EBPαisoform choice using a sensitive and quantitative two-color fluorescence reporter coupled with CRISPRi screening. Our screen uncovered a role for the ribosome rescue factor PELOTA (PELO) in promoting expression of the longer C/EBPαisoform, by directly removing inhibitory unrecycled ribosomes and through indirect effects mediated by the mechanistic target of rapamycin (mTOR) kinase. Our work provides further mechanistic insights into coupling between ribosome recycling and translation reinitiation in regulation of a key transcription factor, with implications for normal hematopoiesis and leukemiagenesis.
Synovial Monocytes Drive the Pathogenesis in Oligoarticular Juvenile Idiopathic Arthritis via IL-6/JAK/STAT Signalling and Cell-Cell Interactions
Authors: Schmidt Tobias , Dahlberg Alma , Berthold Elisabet , Król Petra , Arve-Butler Sabine , Rydén Emilia , Najibi Seyed Morteza , Mossberg Anki , Bengtsson Anders , Kahn Fredrik , Månsson Bengt , Kahn Robin 
Published: January 2023

AbstractObjectivesSynovial monocytes in oligoarticular juvenile idiopathic arthritis (oJIA) are polarized, but little is known of how they contribute to disease and attain their pathogenic features. The aim of this study was to investigate the role of monocytes in the pathogenesis of oJIA.MethodsThe function of synovial monocytes was analysed by several assays believed to reflect key pathogenic events, such as T-cell activation-, efferocytosis- and cytokine production assays through flow cytometry in untreated oJIA patients (n=33). The effect of synovial fluid on healthy monocytes was investigated through mass spectrometry, broad-spectrum phosphorylation assays and functional assays. Additional effects on monocytes were studied through co-cultures with primary fibroblast-like synoviocytes.ResultsThe results demonstrate that synovial monocytes display functional alterations, e.g., increased ability to induce T-cell activation, increased efferocytosis and resistance to cytokine production following activation with LPS.In vitro, synovial fluid induced regulatory features in healthy monocytes through an IL-6/JAK/STAT mechanism. The magnitude of synovial IL-6 driven activation in monocytes was reflected in circulating cytokine levels. An increased ability to induce T-cell activation and markers of antigen presentation could be induced by co-culture with fibroblast-like synoviocytes.ConclusionsSynovial monocytes in oJIA are functionally affected, drive chronic inflammation, and promote adaptive immune responses. This phenotype can be replicatedin vitrothrough a combination of synovial fluid (through IL-6/JAK/STAT) and cell-cell interactions. These data support a role of monocytes in the pathogenesis of oJIA and highlight a group of patients more likely to benefit from targeting the IL-6/JAK/STAT axis to restore synovial homeostasis.Key messagesWhat is already known on this topicMonocytes infiltrate the joint in oligoarticular juvenile idiopathic arthritis (JIA), where they display a pathogenic phenotype and signs of activationWhat this study addsThe results of this study demonstrate functional alterations of synovial monocytes in driving chronic inflammation in oligoarticular JIASynovial monocytes acquire their regulatory properties through the IL-6/JAK/STAT pathway in synovial fluid and their inflammatory properties through cell-cell interactionsIn patients with high IL-6/JAK/STAT involvement, this is reflected in elevated circulating cytokine levelsHow this study might affect research, practice or policyThis study describes the mechanisms controlling the function of synovial monocytes in oligoarticular JIA and identifies patients likely to respond to IL-6/JAK/STAT inhibition, which should be further explored to facilitate personalized medicine.
Aqueous Spice Extracts as Alternative Antimycotics to Control Highly Drug Resistant Extensive Biofilm Forming Clinical Isolates ofCandida albicans
Authors: Sadanandan Bindu , Vijayalakshmi Vaniyamparambath , Ashrit Priya , Babu U V , Kumar L M Sharath , Sampath V , Shetty Kalidas , Joglekar Amruta Purushottam , Awaknavar Rashmi 
Published: January 2023

AbstractCandida albicansforms biofilm by associating with biotic and abiotic surfaces. Biofilm formation byC. albicansis relevant and significant as the organisms residing within, gain resistance to conventional antimycotics and are therefore difficult to treat. This study targeted the potential of spice-based antimycotics to controlC. albicansbiofilms. Ten clinical isolates ofC. albicansalong with a standard culture MTCC-3017 (ATCC-90028) were screened for their biofilm-forming ability.C. albicansM-207 andC. albicansS-470 were identified as high biofilm formers by point inoculation on TSA medium as they formed a lawn within 16 h and exhibited resistance to fluconazole and caspofungin at 25 mcg and 8 mcg respectively. Aqueous and organic spice extracts were screened for their antimycotic activity againstC. albicansM-207 and S-470 by agar and disc diffusion and Zone of Inhibition was observed. Minimal Inhibitory Concentration was determined based on growth absorbance and cell viability measurements. The whole aqueous extract of garlic inhibited biofilms ofC. albicansM-207, whereas whole aqueous extracts of garlic, clove, and Indian gooseberry were effective in controllingC. albicansS-470 biofilm within 12 h of incubation. The presence of allicin, ellagic acid, and gallic acid as dominant compounds in the aqueous extracts of garlic, clove, and Indian gooseberry respectively was determined by High-Performance Thin Layer Chromatography and Liquid Chromatography-Mass Spectrometry. The morphology ofC. albicansbiofilm at different growth periods was also determined through bright field microscopy, phase contrast microscopy, and fluorescence microscopy. The results of this study indicated that the alternate approach in controlling high biofilm-forming, multi-drug resistant clinical isolates ofC. albicansM-207 and S-470 using whole aqueous extracts of garlic, clove, and Indian gooseberry is a safe, potential, and cost-effective one that can benefit the health care needs with additional effective therapeutics to treat biofilm infections.
Quorum sensing inhibits Type III-A CRISPR-Cas system activity through repressing positive regulators SarA and ArcR inStaphylococcus aureus
Authors: Li Yang , Tang Yuanyue , Li Xiaofei , Høyland-Kroghsbo Nina Molin , Ingmer Hanne , Jiao Xinan , Li Qiuchun 
Published: January 2023

ABSTRACTCRISPR-Cas is an adaptive immune system that protects prokaryotes from the invasion of foreign genetic elements. The components and immunity mechanisms of CRISPR-Cas have been extensively studied, but the regulation of this system inStaphylococciremains unclear. Here, we show that in theS. aureusType III-A CRISPR-Cas system, the Pcasof 300 bp located incas1displays as a critical regulatory node that initiates the transcription ofcasgene clusters. We discovered two transcriptional regulators, SarA and CRP-like ArcR, promote the expression and activity of the CRISPR-Cas system by directly binding to the novel promoter Pcas. Furthermore, we demonstrated that the cell-cell communication, known as quorum sensing (QS), inhibits the activity of CRISPR-Cas system by repressing the positive regulators SarA and ArcR. Bioinformatic analyses suggest that Pcasis conserved in many Type II and III CRISPR-Cas systems in Firmicutes. Our data reveal a new regulatory mechanism for QS-mediated repression of the Type III-A CRISPR-Cas system, which may allowS. aureusto acquire foreign genetic elements encoding antibiotic resistance or virulence factors specifically at high cell density.
Cell division tracing combined with single-cell transcriptomics reveals new cell types and differentiation paths in the regenerating mouse lung
Authors: Martins Leila R. , Sieverling Lina , Michelhans Michelle , Schiller Chiara , Erkut Cihan , Triana Sergio , Fröhling Stefan , Velten Lars , Glimm Hanno , Scholl Claudia 
Published: January 2023

ABSTRACTUnderstanding the molecular and cellular processes involved in lung epithelial regeneration may fuel the development of new therapeutic approaches for lung diseases. We combined new mouse models that allow diphtheria toxin (DTA)-mediated depletion of specific epithelial cell types and GFP-labeling of dividing cells with single-cell transcriptomics to characterize the regeneration of the distal lung. We uncovered new cell types, some of which likely represent epithelial precursors, propose goblet cells as progenitor cells, and provide evidence that adventitial fibroblasts act as supporting cells in epithelial regeneration. We also found that DTA-expressing cells can persist in the lung, express specific inflammatory factors, and resemble a previously undescribed population in the lungs of COVID-19 patients. Our study provides a comprehensive single-cell atlas of the distal lung that characterizes early transcriptional and cellular responses to defined epithelial injury, encompassing proliferation, differentiation, and cell-to-cell interactions.