bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disruption of the rice4-DEOXYOROBANCHOL HYDROXYLASEunravels specific functions of canonical strigolactones
Authors: Chen Guan-Ting Erica , Wang Jian You , Votta Cristina , Braguy Justine , Jamil Muhammad , Kirschner Gwendolyn K , Fiorilli Valentina , Berqdar Lamis , Balakrishna Aparna , Blilou Ikram , Lanfranco Luisa , Al-Babili Salim 
Published: April 2023

AbstractStrigolactones (SLs) regulate many developmental processes, including shoot-branching/tillering, and mediate rhizospheric interactions. SLs are structurally diverse, divided into a canonical and a non-canonical sub-family. To better understand the biological function of particular SLs, we generated CRISPR/Cas9 mutants disrupted inOsMAX1-1400orOsMAX1-1900, which encode cytochrome P450 enzymes (CYP711A clade) contributing to SL diversity. The disruption ofOsMAX1-1900did neither affect the SL pattern nor plant architecture, indicating a functional redundancy. In contrast, disruption of OsMAX1-1400 activity, a 4-deoxyorobanchol hydroxylase, led to a complete lack of orobanchol and an accumulation of its precursor 4-deoxyorobanchol (4DO), both of which are a canonical SLs common in different plant species, accompanied by higher levels of the non-canonical methyl 4-oxo-carlactonoate (4-oxo-MeCLA).Os1400mutants showed also shorter plant height, panicle and panicle base length, but did not exhibit a tillering phenotype. Hormone quantification and transcriptome analysis revealed elevated auxin levels and changes in the expression of auxin-related, as well as of SL biosynthetic genes. Interestingly, theOs900/1400double mutant lacking both orobanchol and 4DO did not show the observedOs1400architectural phenotypes, indicating that they are a result of 4DO accumulation. A comparison of the mycorrhization and Striga seed germinating activity ofOs900, Os900/1400, andOs1400loss-of-function mutants demonstrates that the germination activity positively correlates with 4DO content while disruptingOsMAX1-1400negatively impact mycorrhizal symbiosis. Taken together, our paper deciphers the biological function of canonical SLs in rice and depicts their particular contributions to establishing architecture and rhizospheric communications.
Sweet and sour synergy: exploring the antibacterial and antibiofilm activity of acetic acid and vinegar combined with medical-grade honeys
Authors: Harrison Freya , Blower Anisa , de Wolf Chris , Connelly Erin 
Published: April 2023

AbstractOxymel, a combination of honey and vinegar, has been used as a remedy for wounds and infections from antiquity to the present day. While honey is now clinically used to treat infected wounds, this use of a complex, raw natural product (NP) mixture is unusual in modern western medicine. Research into the antimicrobial activity of NPs more usually focusses on finding a single active compound. The acetic acid in vinegar is known to have antibacterial activity at low concentrations and is in clinical use to treat burn wound infections. Here, we investigated the potential for synergistic activity of different compounds present in a complex ingredient used in historical medicine (vinegar) and in an ingredient mixture (oxymel). We conducted a systematic review to investigate published evidence for antimicrobial effects of vinegars against human pathogenic bacteria and fungi. No published studies explicitly compared the activity of vinegar with that of a comparable concentration of acetic acid. We then characterised selected vinegars by high-performance liquid chromatography (HPLC) and assessed the antibacterial and antibiofilm activity of the vinegars and acetic acid, alone and in combination with medical-grade honeys, againstP. aeruginosaandS. aureus. We found that some vinegars have antibacterial activity that exceeds that predicted by their acetic acid content alone, but that this depends on the bacterial species being investigated and the growth conditions (media type, planktonic vs. biofilm). Pomegranate vinegars may be particularly interesting candidates for further study. We also conclude that there is potential for acetic acid, and some vinegars, to show synergistic antibiofilm activity with manuka honey.Data SummaryRaw quantitative data and R code for analyses are provided in the supplementary data (Document S1).
Identification of a novel MCR-1 variant displaying low level of co-resistance to β-lactam antibiotics that uncovers a potential novel antimicrobial peptide
Authors: Liang Lujie , Zhong Lan-Lan , Wang Lin , Zhou Dianrong , Li Yaxin , Li Jiachen , Chen Yong , Liang Wanfei , Wei Wenjing , Zhang Chenchen , Zhao Hui , Lyu Lingxuan , Stoesser Nicole , Doi Yohei , Paterson David L , Bai Fang , Feng Siyuan , Tian Guo-Bao 
Published: April 2023

AbstractThe emerging and global spread of a novel plasmid-mediated colistin resistance gene,mcr-1, threatens human health. It is accepted that MCR-1 affects bacterial fitness, and this fitness cost correlates with bacterial membrane lipid A perturbation. However, the detailed molecular mechanism remains unclear. Here, we screened out a novel MCR-1 variant, named M6, with a two-point mutation that rendered a low level of co-resistance to β-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe lipid A perturbation resulting in peptidoglycan layer remodelling and thus resulted in phenotypic co-resistance to β-lactams. Moreover, we found that a lipid A loading cavity is localized at the linker domain of MCR-1 and governs colistin resistance and bacterial membrane permeability, and the mutated pocket of M6 facilitates the binding affinity of lipid A. More importantly, synthetic peptides derived from M6 achieved broad-spectrum antimicrobial activity. These findings provide insights into a potential vulnerability that could be exploited in future antimicrobial drug design.
Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions
Authors: Tai Yi-Heng , Engels Daniel , Locatelli Giuseppe , Emmanouilidis Ioanna , Fecher Caroline , Theodorou Delphine , Müller Stephan A. , Licht-Mayer Simon , Kreutzfeldt Mario , Wagner Ingrid , Prudente de Mello Natalia , Gkotzamani Sofia-Natsouko , Trovo Laura , Kendirli Arek , Aljovic Almir , Breckwoldt Michael O. , Naumann Ronald , Bareyre Florence M. , Perocchi Fabiana , Mahad Don , Merkler Doron , Lichtenthaler Stefan F. , Kerschensteiner Martin , Misgeld Thomas 
Published: April 2023

ABSTRACTInflammation in the central nervous system (CNS) can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell type-specific mitochondrial proteomics within vivobiosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.
Multi-resolution deep learning characterizes tertiary lymphoid structures in solid tumors
Authors: van Rijthoven Mart , Obahor Simon , Pagliarulo Fabio , Broek Maries van den , Schraml Peter , Moch Holger , Laak Jeroen van der , Ciompi Francesco , Silina Karina 
Published: April 2023

AbstractTertiary lymphoid structures (TLSs) are dense accumulations of lym-phocytes in inflamed peripheral tissues, including cancer, and are associated with improved survival and response to immunotherapy in various solid tumors. Histological TLS quantification has been pro-posed as a novel predictive and prognostic biomarker, but lack of standardized methods of TLS characterization hampers assessment of TLS densities across different patients, diseases, and clinical centers. We introduce a novel approach based on HookNet-TLS, a multi-resolution deep learning model, for automated and unbiased TLS quantification and identification of germinal centers in routine hema-toxylin and eosin stained digital pathology slides. We developed a HookNet-TLS model using n=1019 manually annotated TCGA slides from clear cell renal cell carcinoma, muscle-invasive blad-der cancer, and lung squamous cell carcinoma. We show that HookNet-TLS automates TLS quantification with a human-level performance and demonstrates prognostic associations similar to visual assessment. We made HookNet-TLS publicly available to aid the adoption of objective TLS assessment in routine pathology.
Keystone pathobionts associated with colorectal cancer promote oncogenic reprograming
Authors: Jones Josh , Shi Qiaojuan , Nath Rahul R. , Brito Ilana L. 
Published: April 2023

AbstractFusobacterium nucleatum(Fn) and enterotoxigenicBacteroides fragilis(ETBF) are two pathobionts consistently enriched in the gut microbiomes of patients with colorectal cancer (CRC) compared to healthy counterparts and frequently observed for their direct association within tumors. Although several molecular mechanisms have been identified that directly link these organisms to features of CRC in specific cell types, their specific effects on the epithelium and local immune compartment are not well-understood. To fill this gap, we leveraged single-cell RNA sequencing (scRNA-seq) on wildtype mice and mouse model of CRC. We find that Fn and ETBF exacerbate cancer-like transcriptional phenotypes in transit-amplifying and mature enterocytes in a mouse model of CRC. We also observed increased T cells in the pathobiont-exposed mice, but these pathobiont-specific differences observed in wildtype mice were abrogated in the mouse model of CRC. Although there are similarities in the responses provoked by each organism, we find pathobiont-specific effects in Myc-signaling and fatty acid metabolism. These findings support a role for Fn and ETBF in potentiating tumorigenesis via the induction of a cancer stem cell-like transit-amplifying and enterocyte population and the disruption of CTL cytotoxic function.
Directed evolution of piperazic acid incorporation by a nonribosomal peptide synthetase
Authors: Stephan Philipp , Langley Chloe , Winkler Daniela , Basquin Jérôme , Caputi Lorenzo , O’Connor Sarah E. , Kries Hajo 
Published: April 2023

AbstractEngineering of biosynthetic enzymes is increasingly employed to synthesize structural analogues of antibiotics. Of special interest are non-ribosomal peptide synthetases (NRPSs) responsible for production of important antimicrobial peptides. Here, directed evolution of an adenylation domain of a Pro-specific NRPS module completely switched substrate specificity to the non-standard amino acid piperazic acid (Piz) bearing a labile N-N bond. This success was achieved by LC-MS/MS based screening of small, rationally designed mutant libraries and can presumably be replicated with a larger number of substrates and NRPS modules. The evolved NRPS produces a Piz-derived gramicidin S analog. Thus, we give new impetus to the too-early dismissed idea that widely accessible low-throughput methods can switch the specificity of NRPSs in a biosynthetically useful fashion.
Cell-free expressed membraneless organelles sequester RNA in synthetic cells
Authors: Robinson Abbey O , Lee Jessica , Cameron Anders , Keating Christine D , Adamala Katarzyna P. 
Published: April 2023

AbstractCompartments within living cells create specialized microenvironments, allowing for multiple reactions to be carried out simultaneously and efficiently. While some organelles are bound by a lipid bilayer, others are formed by liquid-liquid phase separation, such as P-granules and nucleoli. Synthetic minimal cells have been widely used to study many natural processes, including organelle formation. Here we describe a synthetic cell expressing RGG-GFP-RGG, a phase-separating protein derived from LAF-1 RGG domains, to form artificial membraneless organelles that can sequester RNA and reduce protein expression. We create complex microenvironments within synthetic cell cytoplasm and introduce a tool to modulate protein expression in synthetic cells. Engineering of compartments within synthetic cells furthers understanding of evolution and function of natural organelles, as well as it facilitates the creation of more complex and multifaceted synthetic life-like systems.
Noninvasive estimation of mean pulmonary artery pressure by CMR in under 2 minutes scan time
Authors: Abdula Goran , Ramos Joao G , Marlevi David , Fyrdahl Alexander , Engblom Henrik , Sörensson Peder , Giese Daniel , Jin Ning , Sigfridsson Andreas , Ugander Martin 
Published: April 2023

AbstractBackgroundNon-invasive estimation of mean pulmonary artery pressure (mPAP) by cardiovascular magnetic resonance (CMR) four-dimensional (4D) flow analysis has shown excellent agreement with invasive right heart catheterization. However, clinical application is limited by relatively long scan times.ObjectivesThe aim of this study was to evaluate the accuracy and time reduction of compressed sensing (CS) accelerated acquisition for mPAP estimation.MethodsPatients (n=51) referred for clinical CMR at 1.5T or 3T underwent imaging with both a prototype CS□accelerated and a non-CS-accelerated flow sequence acquiring time-resolved multiple 2D slice phase contrast three-directional velocity-encoded images covering the pulmonary artery. Prototype software was used for blinded analysis of pulmonary artery (PA) vortex duration to estimate mPAP as previously validated.ResultsCS-accelerated and non-CS-accelerated acquisition showed increased mPAP in 22/51 (43%) and 24/51 (47%) patients, respectively. Mean bias for estimating mPAP between the two methods was 0.1±1.9 mmHg and the intraclass correlation coefficient was 0.97 [95% confidence interval 0.94-0.98]. Effective scan time was lower for the CS-accelerated acquisition (1 min 55 sec ± 27 sec vs 9 min 6 sec ± 2 min 20 sec, p<0.001, 79% reduction).ConclusionsCS-accelerated CMR acquisition enables preserved accuracy for estimating mPAP compared to a non-CS-accelerated sequence, allowing for an average scan time of less than 2 minutes. CS-acceleration thereby increases the clinical utility of CMR 4D flow analysis to estimate mPAP.
At the head and heart of oxytocin’s stress-regulatory neural and cardiac effects: a chronic administration RCT in children with autism
Authors: Alaerts Kaat , Daniels Nicky , Moerkerke Matthijs , Evenepoel Margaux , Tang Tiffany , Van der Donck Stephanie , Chubar Viktoria , Claes Stephan , Steyaert Jean , Boets Bart , Prinsen Jellina 
Published: April 2023

AbstractIntranasal administration of oxytocin is increasingly explored as a new approach to facilitate social development and reduce disability associated with a diagnosis of autism spectrum disorder (ASD). In light of the growing number of trials, it is crucial to gain deeper insights into the neuroplastic changes that are induced from multiple-dose, chronic use of oxytocin, over a course of weeks. To date however, oxytocin’s chronic neuromodulatory impact in the pediatric brain remains unknown.Here, we present a double-blind, randomized, placebo-controlled pharmaco-neuroimaging trial examining the neural effects of a four-week intranasal oxytocin administration regime (12 IU, twice daily) in pre-pubertal school-aged children with ASD (8-12 years, 45 boys, 12 girls). Resting-state fMRI scanning and simultaneous, in-scanner heart rate measurements were assessed before, immediately after and four weeks after the nasal spray administration period.Four weeks of chronic oxytocin administration in children with ASD induced significant reductions in intrinsic functional connectivity between amygdala and orbitofrontal cortex, particularly at the four-week follow-up session, thereby replicating prior observations of neuromodulatory changes in the adult brain. Notably, the observed reductions in amygdala-orbitofrontal connectivity were associated with improved autonomic stress-regulation, indexed by increased high-frequency heart rate variability. Further, oxytocin’s neural and cardiac autonomic effects were significantly modulated by epigenetic modifications of the oxytocin receptor gene, indicating that oxytocin-induced stress-regulatory effects were more pronounced in children with reduced epigenetic methylation, and thus higher oxytocin receptor expression. Finally, whole-brain exploratory functional connectivity analyses also revealed an overall oxytocin-induced enhancing effect on amygdala coupling to regions of the salience network (insula, anterior cingulate cortex), likely reflective of oxytocin’s (social) salience effects.Together, these observations provide initial insights into the stress-regulatory neural and cardiac effects induced by chronic oxytocin administration in children with ASD, and point toward important epigenetic modulators that may explain inter-individual variations in oxytocin-induced responses.
PRADclass: Multi-pronged Gleason grade-informed computational strategy identifies consensus biomarker features of prostate adenocarcinoma that predict aggressive cancer
Authors: Balraj Alex Stanley , Muthamilselvan Sangeetha , Raja Rachanaa , Palaniappan Ashok 
Published: April 2023

ABSTRACTBackgroundProstate adenocarcinoma (PRAD) is the most common cancer in men worldwide, yet gaps in our knowledge persist with respect to molecular bases of PRAD progression and aggression. It is largely an indolent cancer, asymptomatic at early stage, and slow-growing in most cases, but aggressive prostate cancers cause significant morbidity and mortality within five years. Automated methods to type the aggressiveness of PRAD are necessary and urgent for informed treatment management.MethodsBased on TCGA transcriptomic data pertaining to PRAD and the associated clinical metadata, we used the grading guidelines of the International Society of Urological Pathology (ISUP), and converted the clinical information of a cancer sample to its Gleason grade. To model the distinction between aggressive prostate cancers (Gleason grade IV or V) and indolent prostate cancers (Gleason grade I or II), we performed: (i) Gleason-grade wise linear modeling, followed by five contrasts against controls and ten contrasts between grades; and (ii) Gleason-grade wise network modeling using weighted gene correlation network analysis (WGCNA). Consensus between the grade-salient genes from the statistical modeling and the trait-specific key genes from network modeling were used as features for learning a ternary classification: benign, indolent or aggressive malignancy.ResultsThe statistical modeling yielded 77 Gleason grade-salient genes, viz. ten genes in grade-1, two genes in grade-II, one gene in grade-III, 34 genes in grade-IV, and 30 genes in grade-V. Using the WGCNA method, we reconstructed grade-specific networks, and defined trait-specific key genes in grade-wise significant modules. Consensus analysis yielded two genes in Grade 1 (SLC43A1, PHGR1), 26 genes in Grade 4 (LOC100128675, PPP1R3C, NECAB1, UBXN10, SERPINA5, CLU, RASL12, DGKG, FHL1, NCAM1), and seven genes in Grade 5 (CBX2, DPYS, FAM72B, SHCBP1, TMEM132A, TPX2, UBE2C). PRADclass, a RandomForest model trained on these 35 consensus biomarkers, yielded 100% cross-validation accuracy on the ternary classification problem.ConclusionsConsensus of orthogonal computational strategies has yielded Gleason grade-specific biomarkers that are useful in pre-screening (cancer vs normal) as well as typing the aggressiveness of cancer. PRADclass has been deployed at:https://apalania.shinyapps.io/pradclass/for scientific and non-commercial use.
Plant Arbovirus Mobilizes a Vector Salivary Protein to Initiate Plant Infection
Authors: Zhao Jing , Yang Jie , Meng Xiangyi , Fang Rongxiang , Huo Yan , Zhang Lili 
Published: April 2023

AbstractPlant arboviruses rely heavily on insects’ feeding activities for successful transmission. Insect salivary proteins have been suggested to be essential for successful viral infection, but their exact mechanisms are largely unknown. In this study, we reveal that salivary factors fromLaodelphax striatellusare necessary for infection ofRice stripe virus(RSV) in plants. A salivary carbonic anhydrase (LssaCA) is identified as an essential factor in promoting RSV infection. LssaCA interacts with a rice thaumatin-like protein (OsTLP) that has endo-β-1,3-glucanase activity and can degrade callose in plants. RSV infection induces callose deposition, which can be reversed by LssaCA. Furthermore, LssaCA directly binds to the RSV nucleocapsid protein (NP) in salivary glands, and the LssaCA-RSV NP complex still binds OsTLP and further increases its glucanase activity. This study provides new insights into the tripartite virus-insect vector-plant interaction, which is relevant to many agriculturally important plant arboviruses whose transmission is facilitated by insect salivary proteins.