bluuebunny/crossref_metadata_2025_split huggingface dataset:
SATB2 organizes the 3D genome architecture of cognition in cortical neurons
Authors: Wahl Nico , Espeso-Gil Sergio , Chietera Paola , Laighneach Aodán , Morris Derek W. , Rajarajan Prashanth , Akbarian Schahram , Dechant Georg , Apostolova Galina 
Published: December 2022

SummarySATB2is genetically associated with human intelligence. Since SATB2 protein structure predicts a function in DNA looping, we analyzed the impact of SATB2 on 3D genome architecture and chromatin accessibility in cortical neurons. Our data reveal strong effects of SATB2 on chromatin looping between enhancers and promoters of neuronal activity-regulated genes, which closely correlate with gene expression. We furthermore identify SATB2-dependent alterations at all 3D genome architectural levels, including compartments, Topologically Associated Domains and Frequently Interacting Regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. The altered non-coding regions are enriched for common variants associated with educational attainment, intelligence and schizophrenia. Our data establish SATB2 as a 3D genome organizer, which operates both independently and in cooperation with CTCF to set up the chromatin landscape of pyramidal neurons for cognitive processes.
Directly and indirectly determinable rate constants in Michaelian enzyme-catalyzed reactions
Authors: Udema Ikechukwu Iloh 
Published: December 2022

AbstractBacked by kinetic schemes, attempts had been made to derive equations for the calculation of all zero-order first-order rate constants (ZOFORC) for the activation of the enzyme-substrate (ES) complex and its deactivation,k+2andk−2, respectively. The values of ZOFORC, including the kind for the dissociation of the enzyme-product complex (EP) to free enzyme (E) and product (P), are hardly reported. The methods of research were primarily Bernfeld and Lineweaver methods. The goal of the research was to determine ways for the utilization of experimental data for the determination of verifiable and quantifiable rate constants, with the following objectives: 1) To derive equations for the first order rate constants,k+2andk-2, for the activation of ES and its deactivation, respectively; 2) to quantify by calculation the first order rate constant for product release; 3) ultimately quantify the rate constants,k-2andk+2; and 4) to advise the reactor, process, chemical engineers,etc. in different industrial concerns on the usefulness ofk-2andk+2. The value of ZOFORC for the dissociation of EP to free E and P is 3.155 exp. (+5)/min; the values ofk+2andk-2are 3.513 exp. (+4) and 2.377 exp. (+8)/min, respectively. Ultimately, it is imperative for all stakeholder groups to devise means of controlling the enzymatic rate of catalysis by manipulating the magnitudes ofk+2andk-2in particular. The derived equations can be fitted to the experimentally generated and calculated data. A future research project should entail conducting the assay under optimum conditions so as to verify possible variations in the ZOFORC values when compared with values generated outside optimum conditions.
A Clinically Useful and Biologically Informative Genomic Classifier for Papillary Thyroid Cancer
Authors: Craig Steven , Stretch Cynthia , Farshidfar Farshad , Sheka Dropen , Alabi Nikolay , Siddiqui Ashar , Kopciuk Karen , Park Young Joo , Khalil Moosa , Khan Faisal , Harvey Adrian , Bathe Oliver F. 
Published: December 2022

SUMMARYClinical management of papillary thyroid cancer depends on estimations of prognosis. Standard care, which relies on prognostication based on clinicopathologic features, is inaccurate. We applied a machine learning algorithm (HighLifeR) to 502 cases annotated by The Cancer Genome Atlas Project to derive an accurate molecular prognostic classifier. Unsupervised analysis of the 82 genes that were most closely associated with recurrence after surgery enabled identification of three unique molecular subtypes. One subtype had a high recurrence rate, an immunosuppressed microenvironment, and enrichment of the EZH2-HOTAIR pathway. Two other unique molecular subtypes with a lower rate of recurrence were identified, including one subtype with a paucity of BRAFV600Emutations and a high rate of RAS mutations. The genomic risk classifier, in addition to tumor size and lymph node status, enabled effective prognostication that outperformed the American Thyroid Association clinical risk stratification. The genomic classifier we derived can potentially be applied preoperatively to direct clinical decision-making. Distinct biological features of molecular subtypes also have implications regarding sensitivity to radioactive iodine, EZH2 inhibitors, and immune checkpoint inhibitors.
Prenatal Carotenoid Supplementation with Lutein or Zeaxanthin Ameliorates Oxygen-Induced Retinopathy (OIR) inBco2-/-Macular Pigment Mice
Authors: Arunkumar Ranganathan , Li Binxing , Addo Emmanuel K. , Hartnett M. Elizabeth , Bernstein Paul S. 
Published: December 2022

AbstractPurposePremature infants at risk of retinopathy of prematurity (ROP) miss placental transfer of carotenoids, lutein (L) and zeaxanthin (Z), during the third trimester. We previously demonstrated that prenatal L and Z supplementation raises carotenoid levels in infants at birth in theLutein andZeaxanthin inPregnancy (L-ZIP) study (NCT03750968). Based on their antioxidant effects and bioavailability, we hypothesized that prenatal maternal supplementation with macular carotenoids would reduce risk of ROP. To test this hypothesis, we utilized “macular pigment mice” genetically engineered to take up L and Z into the retina in a model of oxygen-induced retinopathy (OIR).MethodsPregnantBco2-/-mice were divided into nine experimental subgroups based on the type of supplementation (L, Z, or placebo) and on maternal supplementation start date corresponding to the three trimesters of human fetal development (E0, E11, and P1). Pups and nursing mothers were exposed to 75% O2for 5 days (P7-12) and returned to room air for 5 days (P12-17). Pups were sacrificed at P12 and P17, and their retinas were analyzed for vaso-obliteration (VO) and intravitreal neovascularization (INV).ResultsPups of pregnant mice supplemented with L or Z had significant reductions in VO and INV areas compared to placebo. Prenatal carotenoid supplementation starting at E0 or E11 was significantly more protective against OIR than postnatal supplementation starting at P1.ConclusionPrenatal supplementation with L and Z was beneficial in a mouse OIR model. We recommend testing prenatal L and Z supplementation in future human clinical trials to prevent ROP.
SCellBOW: AI-Driven Tumor Risk Stratification from Single-Cell Transcriptomics Using Phenotype Algebra
Authors: Bhattacharya Namrata , Rockstroh Anja , Deshpande Sanket Suhas , Thomas Sam Koshy , Yadav Anunay , Goswami Chitrita , Chawla Smriti , Solomon Pierre , Fourgeux Cynthia , Ahuja Gaurav , Hollier Brett , Kumar Himanshu , Roquilly Antoine , Poschmann Jeremie , Lehman Melanie , Nelson Colleen C. , Sengupta Debarka 
Published: December 2022

ABSTRACTSingle-cell RNA-sequencing (scRNA-seq) coupled with robust computational analysis facilitates the characterization of phenotypic heterogeneity within tumors. Current scRNA-seq analysis pipelines are capable of identifying a myriad of malignant and non-malignant cell subtypes from single-cell profiling of tumors. However, given the extent of intra-tumoral heterogeneity, it is challenging to assess the risk associated with individual cell subpopulations, primarily due to the complexity of the cancer phenotype space and the lack of clinical annotations associated with tumor scRNA-seq studies. To this end, we introduce SCellBOW, a scRNA-seq analysis framework inspired by document embedding techniques from the domain of Natural Language Processing (NLP). SCellBOW is a novel computational approach that facilitates effective identification and high-quality visualization of single-cell subpopulations. We compared SCellBOW with existing best practice methods for its ability to precisely represent phenotypically divergent cell types across multiple scRNA-seq datasets, including our in-house generated human splenocyte and matched peripheral blood mononuclear cell (PBMC) dataset. For tumor cells, SCellBOW estimates the relative risk associated with each cluster and stratifies them based on their aggressiveness. This is achieved by simulating how the presence or absence of a specific cell subpopulation influences disease prognosis. Using SCellBOW, we identified a hitherto unknown and pervasive AR−/NElow(androgen-receptor-negative, neuroendocrine-low) malignant subpopulation in metastatic prostate cancer with conspicuously high aggressiveness. Overall, the risk-stratification capabilities of SCellBOW hold promise for formulating tailored therapeutic interventions by identifying clinically relevant tumor subpopulations and their impact on prognosis.
The effects of multifactorial stress combination on rice and maize
Authors: Sinha Ranjita , Peláez-Vico María Ángeles , Shostak Benjamin , Nguyen Thi Thao , Pascual Lidia S. , Zandalinas Sara I. , Joshi Trupti , Fritschi Felix B. , Mittler Ron 
Published: December 2022

ABSTRACTThe complexity of environmental factors affecting plants is gradually increasing due to global warming, an increase in the number and intensity of climate change-driven weather events, such as droughts, heat waves, and floods, and the accumulation of different pollutants. The impact of multiple stress conditions on plants was recently termed ‘multifactorial stress combination’ (MFSC) and defined as the occurrence of three or more stressors that impact plants simultaneously or sequentially. We recently reported that with the increased number and complexity of different stressors, the growth and survival ofArabidopsis thalianaseedlings declines; even if the level of each individual stress is low enough to have no significant effect on plants. This finding is alarming since it reveals that MFSCs of different low-level stressors could impact crops and cause a dramatic reduction in overall growth. However, whether MFSC would impact commercial crop cultivars has not been studied. Here, we reveal that a MFSC of 5 different low level abiotic stresses (salinity, heat, the herbicide paraquat, phosphorus deficiency, and the heavy metal cadmium), applied in an increasing level of complexity, has a significant negative impact on the growth and biomass of a commercial rice (Oryza sativa) cultivar and a maize (Zea mays) hybrid. We further report on the first proteomics analysis of MFSC in plants that identified over 300 proteins common to all 4- and 5-MFSCs. Taken together our findings reveal that the impacts of MFSC on two different crop species are severe, and that MFSC may significantly affect agricultural productivity.
Displacement of extracellular chloride by immobile anionic constituents of the brain’s extracellular matrix
Authors: Normoyle Kieran P , Lillis Kyle P , Egawa Kiyoshi , McNally Melanie A , Paulchakrabarti Mousumi , Coudhury Biswa P , Lau Lauren , Shiu Fu Hung , Staley Kevin J 
Published: December 2022

AbstractGABA is the primary inhibitory neurotransmitter. Membrane currents evoked by GABAAreceptor activation have uniquely small driving forces: their reversal potential (EGABA) is very close to the resting membrane potential. As a consequence, GABAAcurrents can flow in either direction, depending on both the membrane potential and the local intra and extracellular concentrations of the primary permeant ion, chloride (Cl). Local cytoplasmic Cl concentrations vary widely due to displacement of mobile Cl ions by relatively immobile anions. Here we use new reporters of extracellular chloride (Cl-o) to demonstrate that Cl is displaced in the extracellular space by high and spatially heterogenous concentrations of immobile anions including sulfated glycosaminoglycans (sGAGs). Cl-ovaries widely, and the mean Cl-ois only half the canonical concentration, i.e. the Cl concentration in the cerebrospinal fluid. These unexpectedly low and heterogenous Cl-odomains provide a mechanism to link the varied but highly stable distribution of sGAGs and other immobile anions in the brain’s extracellular space to neuronal signal processing via the effects on the amplitude and direction of GABAAtransmembrane Cl currents.Key Points SummaryExtracellular chloride concentrations in the brain were measured using a new chloride-sensitive organic fluorophore and two photon fluorescence lifetime imaging.In vivo, the extracellular chloride concentration was spatially heterogenous and only half of the CSF chloride concentrationStable displacement of extracellular chloride by immobile extracellular anions was responsible for the low extracellular chloride concentrationThe changes in extracellular chloride were of sufficient magnitude to alter the conductance and reversal potential of GABAAchloride currentsThe stability of the extracellular matrix, the impact of the component immobile anions including sulfated glycosaminoglycans on extracellular chloride concentrations, and the consequent effect on GABAAsignaling suggests a previously unappreciated mechanism for modulating GABAAsignaling.
Porcine cytomegalovirus detection by nanopore-based metagenomic sequencing in a Hungarian pig farm
Authors: Tóth Adrienn Gréta , Fiam Regina , Becsei Ágnes , Spisák Sándor , Csabai István , Makrai László , Reibling Tamás , Solymosi Norbert 
Published: December 2022

ABSTRACTThe rapid diagnosis of infectious diseases has an essential impact on their control, treatment and recovery. Oxford Nanopore Technologies (ONT) sequencing opens up a new dimension in applying clinical metagenomics. In a large-scale pig farm in Hungary, four fattening and one piglet nasal swab pooled samples were sequenced using ONT for metagenomic analysis. Long reads covering 53.69% of the porcine cytomegalovirus genome were obtained in the piglet sample. The 650 bp long read matching theglycoprotein Bgene of the virus is sequentially most similar to Japanese, Chinese and Spanish isolates.
Plant age-dependent dynamics of annatto pigment (bixin) biosynthesis inBixa orellanaL.
Authors: de Godoy Machado Kleiton Lima , Faria Daniele Vidal , Duarte Marcos Bruno Silva , Silva Lázara Aline Simões , dos Reis de Oliveira Tadeu , de Arruda Falcão Thais Castilho , Batista Diego Silva , Costa Marcio Gilberto Cardoso , Santa-Catarina Claudete , Silveira Vanildo , Romanel Elisson , Otoni Wagner Campos , Nogueira Fabio Tebaldi Silveira 
Published: December 2022

SummaryAge affects the production of secondary metabolites, but how developmental cues regulate secondary metabolism remains poorly understood. Annatto(Bixa orellanaL.) is a source of bixin, an apocarotenoid used in the world’s food industry worldwide. Understanding how age-dependent mechanisms control bixin biosynthesis is of great interest for plant biology and for pharmaceutical, cosmetic, and textile industries. Here, we used genetic and molecular tools to unravel the role of the annatto age regulated miRNA156 (miR156) targetedSQUAMOSA PROMOTER BINDING PROTEIN LIKE (BoSPL)genes in secondary metabolism. Low expression of severalBoSPLgenes in miR156 overexpressing annatto plants (OE::156) impacted leaf ontogeny, reducing bixin production and increasing abscisic acid (ABA) levels. Modulation ofBoCCD4;4andBoCCD1expression, key genes in lycopene cleavage, was associated with diverting the carbon flux from bixin to ABA, whereas upregulation oflycopene β cyclasegenes implies the xanthophyll biosynthetic pathway acted as a carbon sink in OE::156 plants. Proteomic analyses revealed low accumulation of most secondary metabolite-related enzymes in OE::156 plants, suggesting that miR156 targetedBoSPLsare required to activate several annatto secondary metabolic pathways. Our findings suggest that carbon flux inB. orellanaOE::156 leaves was redirected from bixin to ABA production, indicating an age-dependent leaf dynamics of bixin biosynthesis. Importantly, our study opened a new venue to future annatto breeding programs aiming to improve bixin output.
Analysis of the Toll and spaetzle genes involved in Toll pathway-dependent antimicrobial gene induction in the red flour beetle,Tribolium castaneum(Coleoptera: Tenebriodae)
Authors: Kato Daiki , Miura Ken , Yokoi Kakeru 
Published: December 2022

AbstractInsects rely only on their innate immune system to protect themselves from pathogens. Antimicrobial peptide (AMP) production is the main immune reaction in insects. InDrosophila melanogaster, the reaction is regulated mainly by the Toll and immune deficiency (IMD) pathways. Spaetzle proteins, activated by immune signals from upstream components, bind to Toll proteins, thus activating the Toll pathway, which in turn induces AMP genes. Previous studies have shown the difference immune ststems related to Toll and IMD pathways betweenD. melanogasterandTribolium castaneum. InT. castaneum, 9 Toll and 7 spaetzle genes have been identified. To extend our understanding of AMP production byT. castaneum, we conducted functional assays of Toll and spaetzle genes related to Toll pathway-dependent AMP gene expression inT. castaneumunder challenge with bacteria or budding yeast using RNA interference and qRT-PCR. The results revealed thatToll3andToll4double-knockdown andspz7knockdown strongly and moderately reduced the Toll pathway-dependent expression of AMP genes, respectively. Moreover,Toll3andToll4double-knockdown pupae more rapidly succumbed to entomopathogenic bacteria than the control pupae, butspz7knockdown pupae did not. The results suggest thatToll3 and Toll4play a large role in Toll pathway-dependent immune reactions, whereasspz7plays a small part.
Development of an antibody fused with an antimicrobial peptide targetingPseudomonas aeruginosa:a new approach to prevent and treat bacterial infections
Authors: Johnson Kenneth , Delaney James C. , Guillard Thomas , Reffuveille Fanny , Varin-Simon Jennifer , Li Kai , Wollacott Andrew , Frapy Eric , Mong Surin , Tissire Hamid , Viswanathan Karthik , Touti Faycal , Babcock Gregory J. , Shriver Zachary , Pentelute Bradley L. , Plante Obadiah , Skurnik David 
Published: December 2022

AbstractThe increase of emerging drug resistant Gram-negative bacterial infections is of global concern. In addition, there is growing recognition that compromising the microbiota, through the use of broad spectrum antibiotics, may affect patient health in the long term. Therefore, there is the need to develop new -cidal strategies to combat Gram-negative infections that would consider these specific issues. In this study, we report and characterize one such approach, the antibody-drug conjugates (ADCs) that combine (i) targeting a specific pathogenic organism through a monoclonal antibody with (ii) the high killing activity of antimicrobial peptides. We focused on a major pathogenic Gram-negative bacterium associated with antibacterial resistance:Pseudomonas aeruginosaand designed an ADC by fusing an antimicrobial peptide at the C-terminal end of the VHand/or VL-chain of a monoclonal antibody, VSX, that targets the core ofP. aeruginosalipopolysaccharide (LPS). This ADC demonstrated appropriately minimal levels of toxicity to mammalian cells and rapidly killsP. aeruginosastrains through several mechanisms while protecting mice fromP. aeruginosalung infection when administered therapeutically. Furthermore, we found that the ADC was synergistic with several classes of antibiotics. This approach described in this study may result in a widely useful strategy to target specific pathogenic microorganisms without augmenting further antibiotic resistance.Author SummaryThe increasing of emerging drug resistant bacterial infections is a worldwide issue and infections caused by antibiotic resistant Gram-negative pathogens are particularly concerning. In addition, there is now growing recognition that disruption of the microbiota, through the use of broad spectrum antibiotics, may affect patient health in the long term. Therefore, there is the need to develop new -cidal strategies to combat Gram-negative infections while preserving the microbiota and also avoid enhancement of antibiotic resistance. We report and characterize here one such approach by using a specific monoclonal antibody associated with the potent killing activity of antimicrobial peptides in the form of an antibody-drug conjugate (ADC). The selected pathogenic bacterium wasPseudomonas aeruginosa,that presents numerous markers for both innate and acquired antibiotic resistance. The ADC lacked significant cytotoxicity against mammalian cells and was shown to be effective bothin vitroandin vivoagainstP. aeruginosa.
Systematic characterization ofDrosophilaRhoGEF/GAP localizations uncovers regulators of mechanosensing and junction formation during epithelial cell division
Authors: di Pietro Florencia , Osswald Mariana , De las Heras José M , Cristo Ines , Gay Jesus Lopez- , Wang Zhimin , Pelletier Stéphane , Gaugué Isabelle , Leroy Adrien , Martin Charlotte , Morais-De-Sá Eurico , Bellaïche Yohanns 
Published: December 2022

SummaryCell proliferation is central to epithelial tissue development, repair and homeostasis. During cell division, small RhoGTPases control both actomyosin dynamics and cell-cell junction remodelling to faithfully segregate the duplicated genome while maintaining tissue polarity and integrity. To decipher the mechanisms of RhoGTPases spatiotemporal regulation during epithelial cell division, we generated a transgenic fluorescently tagged library forDrosophilaRho Guanine exchange factors (GEF) and GTPase activating proteins (GAP), and systematically characterized their endogenous distributions by time- lapse microscopy. Thereby, we unveiled candidate regulators of the interplay between actomyosin and junctional dynamics during epithelial cell division. Building on these findings, we uncovered that during cytokinesis, Cysts and RhoGEF4 play sequential roles in mechanosensing andde novojunction formation, respectively. We foresee that the RhoGEF/GAP library will be a key resource to understand the broad range of biological processes regulated by RhoGTPases.