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Overview of real-time VEGFA-targeted FME in Barrett’s esophagus. (a) Schematic overview and timeline of two NIR-FME approaches, i.e., intravenous administration and topical application. (b) Examples of results after intravenous administration of bevacizumab-800CW, and (c) results after topical application. The first row in Fig. 3c displays a lesion that was not visible during white light endoscopy but turned out to be adenocarcinoma. Previously published in Gut [13]

PMC9971088

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Process of the selection of cases of intravitreal anti-VEGF-associated renal adverse effects from the FAERS database. VEGF, vascular endothelial growth factor; FAERS, Food and Drug Administration’s Adverse Event Reporting System.

PMC9972674

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Time to event onset of renal adverse effects following intravitreal administration of anti-VEGF agents. VEGF, vascular endothelial growth factor.

PMC9972674

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117cc13f84b14e1bb21d1dae65bf80b5

Biophysical characterization of the interaction of indole-3-acetic acid (IAA) and indole-3-pyruvic acid (IPA) with AdmX and AdmX-LBD. (A) IAA and IPA compete for binding at AdmX-LBD. Shown are the results from isothermal titration calorimetry analysis of the binding of IAA and IPA to AdmX-LBD in the presence and absence of saturating concentrations of IPA and IAA, respectively. (Upper panel) Titration raw data for the injection of 6.4- to 9.6-μL aliquots of 1 mM IAA or IPA into 50 to 100 μM AdmX-LBD in the absence and presence of 2 mM IPA or IAA (present in both the injector syringe and sample cell). (Lower panel) Integrated, dilution heat-corrected and concentration-normalized peak areas fitted with the “One binding site” model of ORIGIN. (B) Sedimentation velocity analytical ultracentrifugation analysis of AdmX and AdmX-LBD in the absence and presence of IAA or IPA. Values correspond to experiments conducted at 10°C in the corresponding buffers for AdmX (50 mM KH2PO4-K2HPO4, 300 mM NaCl, 10% [vol/vol] glycerol, 2 mM β-mercaptoethanol [pH 7.0]) and AdmX-LBD (20 mM HEPES, 150 mM NaCl, 2 mM β-mercaptoethanol [pH 7.4]). (C) Effect of IAA and IPA binding on the thermal unfolding behavior of AdmX-LBD and AdmX. Differential scanning calorimetry thermograms are shown. LBD, ligand binding domain; DBD, DNA binding domain.

PMC9973260

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Three-dimensional structures of the AdmX-LBD in complex with IAA and IPA. Shown is a ribbon diagram of AdmX-LBD bound to IAA (A) and IPA (B) in which secondary structural elements are labeled. Each structure is shown in two different orientations, rotated by 90°. IAA and IPA are shown in the stick mode in cyan and green, respectively.

PMC9973260

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74b90ae3945247d2a68f9022e06ed2e0

Molecular detail of auxin recognition by AdmX-LBD. (A) Enlarged views of the ligand binding site of AdmX. The meshes represent the final |2Fo − Fc| electron density map contoured at the 1.0-σ level for the complexes of AdmX-LBD with IAA and IPA. (B) Amino acid residues involved in auxin binding. Dashed lines indicate hydrogen bonds with distances provided in angstroms, whereas hydrophobic interactions are shown as spoked arcs. The figures were produced using PYMOL and LIGPLOT+. In all cases, cartoons correspond to chains A of both structures.

PMC9973260

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Amino acid residues involved in auxin binding determined by molecular dynamics simulations. (A) Frequency of occurrence of hydrogen bonds, hydrophobic and ionic interactions, and water bridges throughout 500-ns molecular dynamics simulations of AdmX-LBD with IAA and IPA bound. (B) Hydrogen bonding dynamics of AdmX with IAA and IPA bound throughout 500-ns molecular dynamics simulations. Residues with interaction fraction less than 0.5% were omitted from the plot.

PMC9973260

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96546dda6b5043af8d74c4bbc9d58976

Structural changes in AdmX-LBD with IAA and IPA bound. (A and B) Topological organization of secondary structural elements of AdmX bounded to IAA (A) and IPA (B) as determined with DSSP (109). We observed how the small parallel β-sheets near the binding region of IAA (residues 189 to 191) are absent in the model with IPA, which on the other hand shows an α10-helix (residues 183 to 186) and the division of the long β-sheet number 7 (residues 244 to 262) in two fragments. (C) Superimposition of both structural models represented as ribbons and colored in red (α-helixes), pink (β-sheets), and blue (turns). New or modified secondary structure elements are shown in cartoon mode. For simplicity, only IAA is represented in stick mode. (D) Superposition of the AdmX-LBD homodimers with IAA (green) and IPA (blue) bound. Auxins are shown in space-filling mode.

PMC9973260

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d46f97de8e584cbb81c4daefba2d52bb

Protein sequence alignments and maximum likelihood tree from representative AdmX homologs. Residues Cys100, Glu213, and Cys215 are highlighted for purposes of comparison.

PMC9973260

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8880e474cd184165a003f24029cea7ef

Isothermal titration calorimetry studies of AdmX-LBD and site-directed mutants. (A and B) Microcalorimetric titrations with indole-3-acetic acid (A) and indole-3-pyruvic acid (B). Protein at 50 to 100 μM was titrated with 6.4- to 12.8-μL aliquots of 1 to 5 mM IAA and 1 to 3 mM IPA. (Upper panels) raw titration data. (Lower panels) integrated, dilution heat-corrected and concentration-normalized peak areas of the titration data fitted with the “One binding site” model of ORIGIN. The derived dissociation constants are shown in Table S1.

PMC9973260

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8ef1fec3043943809bc82fc9d43d5d26

Endocrine complications after hematopoietic stem cell transplantation (HSCT) for each organ and tissue affected. Pre- and post-transplant conditions that are considered as risk factors of endocrine sequelae are also displayed. Abbreviations. TBI, total body irradiation; GvHD, Graft versus Host DIsease. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

PMC9973314

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Examples of different histologic patterns of vaccine-associated myocarditis. (A) Lymphocytic myocarditis, the most common pattern reported in COVID-19 vaccination–associated myocarditis, is characterized by a dense mononuclear infiltrate and associated myocyte damage. (B) Healing myocarditis is more typically characterized by a loose and more mixed inflammatory infiltrate and with underlying damage already entering stages of repair (matrix formation). (C) Eosinophilic myocarditis, the pattern typically associated with other vaccinations, is characterized by a patchy infiltrate of eosinophils with relatively little cardiomyocyte damage. All images are hematoxylin and eosin (H&E)-stained slides, digital image capture (Leica DM2500 microscope, 200x original magnification with 10x Plan ocular and 20x FluorTar objective, OMAX 18MP camera, Toupview software, post-processing in GNU Image Manipulator Program 2.0); scale bar as indicated (100 μm).

PMC9973554

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Potential mechanisms of myocarditis following COVID-19 mRNA vaccination. Overview of the potential mechanisms of myocarditis related to mRNA-based COVID-19 vaccination. ACE, angiotensin-converting enzyme; Th1, helper T cell. Created with BioRender.com.

PMC9973554

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COVID-19 vaccine–associated myocarditis. Short-axis 1.5 T MRI images of a young adult man with myocarditis following mRNA COVID-19 vaccine administration demonstrating (A) subepicardial late gadolinium enhancement (LGE) at the basal to mid-inferior lateral wall (red arrows), with corresponding (B) hyperintensity on T2-weighted imaging (orange arrows), (C) abnormal high native T1 (1274 ms, maximum region of interest), and (D) abnormal high native T2 (65 ms, maximum region of interest).

PMC9973554

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ee45d9bc141b455192a5027681216017

Baseline and follow-up CMR in COVID-19 vaccine–associated myocarditis. Short-axis cardiac MRI images in a young adult man with myocarditis following the second dose of mRNA-1273. Baseline MRI at 1.5 T demonstrates subepicardial late gadolinium enhancement (LGE) at the basal inferior and inferolateral wall (red arrows) with corresponding high T2 signal in keeping with edema (yellow arrows), high regional native T1 (green arrows), and high regional T2 (blue arrows). Follow-up cardiac MRI performed 4 months later at 3 T demonstrates interval decrease in LGE extent (orange arrow) with resolution of edema and normalization of T1 and T2 values.

PMC9973554

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Structure of GRL0617 and HY-17542.

PMC9975351

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c7b49379e636464d8c193ab89d0367e5

QTOF mass spectra of GRL0617 and HY-17542, obtained in the ESI + mode. (A) MS spectrum of GRL0617, (B) MS/MS spectrum and fragmentation pattern of GRL0617, (C) MS spectrum of HY-17542, and (D) MS/MS spectrum and fragmentation pattern of HY-17542.

PMC9975351

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Metabolic stability of GRL0617 in HLMs. (A) 1 µM of GRL0617 was incubated in HLMs with NADPH, NADPH plus UDPGA, or UDPGA. (B) Formation of hydroxy metabolite, M1. 1 µM of GRL0617 was incubated in HLMs with NADPH, NADPH plus UDPGA. (C) Formation of desaturated metabolite, M3. 1 µM of GRL0617 was incubated in HLMs with NADPH, NADPH plus UDPGA. Each value represents the mean ± SD (n = 3). (D) Various concentrations (1, 3.3, 10, 25, and 50 µM) of GRL0617 were incubated in 0.1 M PPB (pH 7.4) with 1 mg/mL HLM and NADPH for 0, 5, 15, 30, 45, and 60 min. (E) For determination of M1 formation, various concentrations (1, 3.3, 10, 25, and 50 µM) of GRL0617 was incubated in HLMs with NADPH. (F) For determination of M3 formation, various concentrations (1, 3.3, 10, 25, and 50 µM) of GRL0617 were incubated in HLMs with NADPH. Data are presented as mean ± SD from three independent samples (n = 3). (G) Representative chromatogram of GRL0617 and its metabolites from QTOF MS analysis in HLMs with NADPH. (H) Representative chromatogram of GRL0617 and its metabolites from QTOF MS analysis in HLMs with NADPH plus UDPGA.

PMC9975351

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Metabolic stability of HY-17542 in HLMs. (A) 1 µM of HY-17542 was incubated with HLMs in the presence or absence of NADPH and incubated with recombinant CES 1 or CES2. (B) GRL0617 generation rates in incubations of HY-17542 with HLMs in the presence or absence of NADPH and with CES1 and CES2. (C) Formation of M1 in the incubation of 1 µM of HY-17542 in HLMs with NADPH. (D) Formation of M3 in the incubation of 1 µM of HY-17542 in HLMs with NADPH. Data are presented as mean ± SD from three independent samples (n = 3). (E) Representative chromatogram of GRL0617 and its metabolites in the presence of a NADPH-generating system from QTOF MS analysis.

PMC9975351

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37fb2e806e3a4881a603f62202921444

Metabolism of GRL0617 with recombinant human cytochrome P450 (CYP) enzymes. GRL0617 (1 μM) was incubated with 50 pmol/mL of each recombinant enzyme in the presence of a NADPH-generating system for 60 min. Control values were determined in a mock recombinant assay and the peak areas were compared with the control for (A) GRL0617 and its metabolites, including (B) M1, (C) M2, (D) M3, (E) M6, (F) M7, and (G) M8. Data are presented as mean ± SD from three independent samples (n = 3).

PMC9975351

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Effects of GRL0617 on the activities of (A) CYP1A2, (B) CYP2A6, (C) CYP2B6, (D) CYP2C8, (E) CYP2C9, (F) CYP219, (G) CYP2D6, (H) CYP2E1, (I) CYP3A4 (midazolam as a substrate), and (J) CYP3A4 (testosterone as a substrate) in pooled HLMs. Activity is expressed as the percentage of activity remaining as compared with a control sample containing no inhibitor (100%). Data are presented as mean ± SD from three independent samples (n = 3).

PMC9975351

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Proposed metabolic pathways of GRL0617 and HY-17542 in the liver.

PMC9975351

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a) t-SNE plots based on RDKit fingerprints for the three training data sets (gray dots) alongside the molecules in the tight (blue triangles) and loose (red squares) testing data sets. b) Violin plots showing the distributions of experimental log(S), molecular weight, and number of rotatable bonds for the compounds in the 3 training and 2 testing data sets.

PMC9976279

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Tanimoto similarity analysis comparing all data sets to the tight set (left) and the loose set (right).

PMC9976279

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A graph representing the chemical space. Each node is one molecule, and node sizes are proportional to the number of connections (We note some points are hidden due to overlapping nodes in the tighter cluster.). D5697 are blue, D2999 are green, D300 are red, tight are pink, and loose are cyan. The graph topology comes from connecting nodes with a Tanimoto similarity of 0.5 and higher and running annealing through the Networkx implementation of the Fruchterman-Reingold force-directed algorithm.48

PMC9976279

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RMSE values for predictions of the tight set from the second solubility challenge: a) machine learning models built using Mordred or RDKit descriptors and b) three graph based deep learning models. The dotted horizontal line indicates the RMSE of the best model for reference (NNM, RMSE = 0.85 log units).

PMC9976279

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RMSE values for validation compared to RMSE values for prediction of the tight set from the second solubility challenge: a) models built using Mordred descriptors, Weave models, and GraphConv models and b) models built using RDKit descriptors and DAG models.

PMC9976279

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Correlation plots of the predicted intrinsic solubility values vs experimentally determined solubility values for RFR (top), RFMOE (middle), and RFM (bottom), each predicting the tight (left) and loose (right) testing sets, using the D300 training set. The y = x line is plotted as a red dashed line, while the line of best fit is plotted as a solid blue line.

PMC9976279

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Correlation plots of the predicted intrinsic solubility values vs experimentally determined solubility values for RFM (top), NNM (middle), and Weave (bottom), each predicting the tight (left) and loose (right) testing sets, using the D2999 training set. The y = x line is plotted as a red dashed line, while the line of best fit is plotted as a solid blue line.

PMC9976279

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3fd157b1df724f77897497054411b9c7

Correlation plots of the predicted intrinsic solubility values vs experimentally determined solubility values for RFM (top), NNM (middle), and Weave (bottom), each predicting the tight (left) and loose (right) testing sets, using the D5697 training set. The y = x line is plotted as a red dashed line, while the line of best fit is plotted as a solid blue line.

PMC9976279

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Expression pattern and overall survival (OS) rates of CAPRIN1 in ESCA patients and cell lines. A Comparison of CAPRIN1 expression among EA, ESCC, and normal tissues based on data from the TCGA-ESCA cohort. B Immunohistochemical staining and quantification of Caprin-1 protein in ESCC tissues and adjacent normal tissues. C The protein expression level of Caprin-1 in 14 paired ESCC tissues was examined using Western blot. T, tumor; N, adjacent normal tissues. D CAPRIN1 mRNA expression levels in different ESCA cell lines and fibroblast cultured from esophageal squamous cell carcinoma tissue in the GEO cohort (GSE63941). E OS analysis according to the mRNA expression of CAPRIN1 in ESCC and EA F patients using a Kaplan–Meier plotter. G The ROC curve of CAPRIN1 for the diagnosis of patients with ESCA. * P < 0.05, ** P < 0.01, *** P < 0.001

PMC9976378

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Differentially expressed genes and gene set enrichment analysis (GSEA) with high and low CAPRIN1 expression groups. A The heat map of the top 25 genes positively (red) and negatively (blue) correlated with CAPRIN1 in the TCGA-ESCA database. B The top 20 hub genes screened in the PPI network using the cytoHubba module of Cytoscape (higher color represents stronger connectivity). C The most significantly enriched GO annotations and KEGG pathways D of CAPRIN1 in the GEO database (GSE69925) by GSEA

PMC9976378

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2f4fae0f53bd4fa6a4a86c069f937151

Down-regulation of Caprin-1 inhibited cell proliferation and induced apoptosis. A Western blot showing effective knockdown of Caprin-1 protein in two ESCA cell lines. B Immunofluorescence staining of Caprin-1 in Eca109 cells. C Colorimetric growth assay in Eca109 cells and KYSE150 cells transfected with Caprin-1 siRNAs or control oligos. D Representative images and quantification E of Edu positive rate in Eca109 cells. F Colony formation assay and quantification G in Eca109 cells and KYSE150 cells. H Flow cytometry analyses of cell apoptosis rate in Eca109 cells

PMC9976378

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2cc820d7f12941d9a30da65455cf6fa7

Knockdown of Caprin-1 inhibited glycolytic metabolism through the down-regulation of SLC2A1, HK2, HIF1A, MYC, NUP160, NUP133, and NUP155. A Gene-set enrichment analysis (GSEA) of the interrogated glycolysis signatures between the high and low CAPRIN1 groups in the database (GSE69925); NES, normalized enrichment score. B ECAR were measured in Eca109 cells 48 h after Caprin-1 knockdown using the Seahorse XF24 extracellular flux analyzer. C Lactate production was assessed in Eca109 cells after 48 h of siRNA transfection. D Correlation between CAPRIN1 and the top four leading-edge genes contributing to GSEA in the TCGA database. E Correlation between CAPRIN1 and glycolysis genes (HIF1A and MYC) in the TCGA database. F The protein expression level of HIF1α, c-Myc, and Caprin-1 in 7 paired ESCC tissues was examined using Western blot. T, tumor; N, adjacent normal tissues. G The expression patterns of HIF1α and c-Myc in Eca109 cells after silencing Caprin-1. H Changes in mRNA levels were detected by real time PCR after the Caprin-1 1# knockdown of Eca109 cells

PMC9976378

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High expression of Caprin-1 was correlated with high glycolytic activity based on metabolic parameters in 18F-FDG PET imaging. A Representative images of PET/CT imaging and immunohistochemical staining for Caprin-1 in ESCC patients with high SUVmax (left) and low SUVmax (right). B The TLG, MTV C, SUVmax D, and SUVmean E showed a linear correlation with the protein levels of Caprin-1 with correlation coefficients of 0.390, 0.216, 0.538, and 0.540 respectively. F The determination of the cutoff value of SUVmax, SUVmean, TLG, and MTV by the receiver operating characteristics (ROC) curve

PMC9976378

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Caprin-1 expression was significantly correlated with WTAP and METTL3 in ESCA. A Comparison of m6A related genes in TCGA-ESCA tumors with high or low CAPRIN1 expression. B Expression pattern of m6A writers in ESCA tumor tissue and normal tissues as shown in the TCGA database. C The co-expression of CAPRIN1 with METTL3 and WTAP in ESCA from the TCGA database. D The expression patterns of METTL3 and WTAP in Eca109 cells after silencing Caprin-1 were determined by qRT-PCR and Western blot assay E, F

PMC9976378

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Overexpression of METTL3 and WTAP rescued the cell proliferation phenotype induced by silencing Caprin-1. A The mRNA and proteins of METTL3 and WTAP in Eca109 cells upon Caprin-1 silencing or combined with METTL3 and WTAP overexpression. B The cell viability and lactate release C of Eca109 cells upon Caprin-1 silencing or combined with METTL3 and WTAP overexpression. D qRT-PCR analysis was applied in Eca109 cells using indicated PCR primers

PMC9976378

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The growth of ESCA xenografts is inhibited by silencing Caprin-1. A Representative images of transplanted tumors in nude mice injected with Eca109 cells. B Tumour growth curve of shCtrl and shCaprin-1 group (n = 5). C, D Western blot analysis of Caprin-1, METTL3, and WTAP expression in tumor tissues. E IHC analysis of Ki67 in xenografs. The histogram indicates the Ki67 positive cells. *P < 0.05, ***P < 0.001

PMC9976378

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“Disaster avoided: repairs on the Endeavour River.”© Stamp Design Royal Mail Group Ltd (2018).Image source: Collect GB Stamps <www.collectgbstamps.co.uk/explore/issues/?issue=22788#collectgbstamps-10>.

PMC9976635

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“View of Endeavour River, on the Coast of New Holland, where Captain Cook had the Ship laid on Shore.”Image cropped from: George William Anderson, A New, Authentic, and Complete Collection of Voyages round the World, Undertaken and Performed by Royal Authority (London: A. Hogg, 1800), plate ante p.65. Available as part of the Wellcome Collection, under Public Domain Mark: <https://wellcomecollection.org/works/mcsjmyz8>.

PMC9976635

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“Repairing of Capt. Cook’s Ship in Endeavour River (Cook’s First Voyage)” (etching, c.1780), PAD5990.© National Maritime Museum, Greenwich, London. <https://collections.rmg.co.uk/collections/objects/110141.html>.

PMC9976635

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Eighteenth-century British naval bases. These were not all simultaneously under British control, but were created and lost at different times.Blank base map source: <www.needpix.com/photo/81785/world-map-continent-country-geography-planet-earth-africa-asia>.

PMC9976635

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Matthew Flinders, General Chart of Terra Australis or Australia. Flinders, Voyage, Atlas, Plate I (note 54). Source: “Encounter 1802–2002,” State Library of South Australia, B 1298521 <https://encounter.collections.slsa.sa.gov.au/collection/B12985211_92.htm> [accessed 03/10/2020].

PMC9976635

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Matthew Flinders Memorial Statue at Euston Station (photograph by Sara Caputo).

PMC9976635

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Detail of the route of HMS Investigator.From Flinders, Voyage, Atlas, Plate I (note 54). Cropped from: “Encounter 1802–2002,” State Library of South Australia, B 1298521 <https://encounter.collections.slsa.sa.gov.au/collection/B12985211_92.htm> [accessed 06/12/2014].

PMC9976635

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51c0b3bb90134309a685ab8080a82d57

High-throughput cel-pri-miRNA cleavage assays. (A) Schematic diagram illustrating the layout of the high-throughput (HT) cel-pri-miRNA cleavage assay. (B) The graph shows that in the HT cleavage assays, 132 out of 137 cel-pri-miRNAs were identified in the control (uncleaved cel-pri-miRNA) sample. (C) The fraction of cleaved RNAs (F2 fragments) containing different overhang nt. (D) The global cleavage efficiency of cDrosha and cMP was estimated as the ratio of the products cleaved at all cleavage sites to the original substrate. (E) The cleavage site patterns of cel-pri-miRNAs. The upper panel shows the diagram of pri-miRNA and the cleavage sites (CL) at different positions. CL0 indicates the canonical cleavage sites of cel-pri-miRNAs annotated in MirGeneDB (37). CL1 to CL5 and CL-1 to CL-5 are the cleavage sites located 1–5 nt downstream and upstream of CL0, respectively, on the 5p-strand of cel-pri-miRNAs. The middle and lower panels show the cleavage accuracy scores of cel-pri-miRNAs by cDrosha (middle panel) and cMP (lower panel) at different cleavage sites. Each line indicates one cel-pri-miRNA. (F) The cleavage sites of cMP in cel-pri-mir-358 and cel-pri-mir-253. The blue circles indicate the major cleavage site (mCL), the cleavage site with the highest cleavage accuracy score. (G) The number of cel-pri-miRNAs containing mCLs, consistent with their annotated cleavage sites (CL0). (H) Cleavage patterns of representative cel-pri-miRNAs in each group in panel (G). The blue, green, and gray arrowheads indicate the major cleavage sites (mCL) of cDrosha, cMP, and CL0 annotated in MirGeneDB, respectively.

PMC9976908

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cDrosha measures ∼16 bp of the lower stem. (A) The schematic diagram shows that cDrosha measures the length of lower stems in cel-pri-miRNAs to determine its cleavage sites. (B) The number of cel-pri-miRNAs containing different distances between their mCLs of cDrosha and the basal junction (bJC). The pie chart shows the fraction of cel-pri-miRNAs containing the 15–17-bp mCL-bJC distance. 122/126 cel-pri-miRNAs cleaved by cDrosha were selected for this analysis. The remaining four cel-pri-miRNAs (cel-pri-mir-240, cel-pri-mir-4808, cel-pri-mir-84 and cel-pri-mir-246) were excluded as their CL0 was not located in their stems. (C, D) The average (C) cleavage accuracy and (D) efficiency scores of the CLs of cDrosha at different distances from the bJC. (E) Graph showing the percentage of pri-miRNAs containing different lengths of the lower stem in C. elegans and humans. 130/138 cel-pri-miRNAs and 491/508 hsa-pri-miRNAs were selected for this analysis. The remaining 8 cel-pri-miRNAs and 17 hsa-pri-miRNAs were excluded as they contained multiple-loop structures. (F, H, J) Diagrams and sequences of cel-pri-mir-244 (F), cel-pri-mir-61 (H), hsa-pri-mir-16-1 and hsa-pri-mir-342 (J). The inserted nt are red letters. The deleted nt are shown in the red dashed box. (G, I) Gels showing the results from the in vitro cleavage assays of cDrosha for cel-pri-mir-244, cel-pri-mir-61, and their variants. The F2 products of the cleavage assay in (I) were confirmed by sequencing (Supplementary Table S4). (K) Gel showing the results from the in vitro cleavage assays of cDrosha and hDROSHA for hsa-pri-mir-16-1 and hsa-pri-mir-342. In all panels of Figure 2, the blue and black arrowheads indicate the cleavage sites of cDrosha and hDROSHA, respectively. The gray arrowhead indicates the unproductive cleavage of cDrosha.

PMC9976908

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Pasha measures ∼25 bp of the upper stem. (A) The schematic diagram shows that Pasha measures the lengths of the upper stems in cel-pri-miRNAs and determines the cleavage sites of the cMP complex. (B) The fraction of cel-pri-miRNAs containing the different major cleavage sites (mCLs) between cDrosha and cMP, so-called inconsistent mCLs. (C) The number of cel-pri-miRNAs containing inconsistent mCLs at different distances to the apical junction (aJC). (D) The cleavage patterns of cDrosha and cMP in a representative cel-pri-miRNA, cel-pri-mir-1820. (E) Graph showing the percentage of pri-miRNAs containing different lengths of the upper stem in C. elegans and human pri-miRNAs. 130/138 cel-pri-miRNAs and 491/508 hsa-pri-miRNAs were selected for this analysis; the remaining were excluded as they contained multiple-loop structures. (F, H, J) Diagrams and sequences of (F, H) cel-pri-mir-36 and its variants and (J) hsa-pri-mir-30a and hsa-pri-mir-125a. The inserted nt are red letters. The deleted nt are shown in the red dashed box. (G, I) Gels showing the results from the in vitro cleavage assays of cDrosha and cMP. (K) Gel showing the results from the in vitro cleavage assays of cMP and hMP. In all panels of Figure 3, the blue and green arrowheads indicate the cleavage sites of cMP, determined by cDrosha and Pasha, respectively. The black arrowheads indicate the cleavage sites of the human Microprocessor, hMP.

PMC9976908

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The coordination of cDrosha and Pasha in determining the cleavage sites. (A, D) The diagrams and sequences of (A) cel-pri-mir-244, cel-pri-mir-36, and their variants, and (D) hsa-pri-mir-16–1 and hsa-pri-mir-342. The inserted nt are red letters. The deleted nt are shown in the red dashed box. (B, E) Gels showing the results of the in vitro cleavage assays of cMP and hMP. (C) The quantitative plots of the cleavage assays were conducted in triplicate, shown in (B). In all panels of Figure 4, the blue and green arrowheads indicate the cleavage sites of cMP, determined by cDrosha and Pasha, respectively. The black arrowheads indicate the cleavage sites of the human Microprocessor, hMP. The sizes of the circles indicate the relative cleavage efficiencies.

PMC9976908

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Structural basis of cDrosha measurement. (A) The 3D structure of cDrosha predicted by Alphafold2 (46,47) was superimposed onto that of hDROSHA in complex with RNA (PDB: 6V5B, or a similar model in PDB: 6LXD). The lower stem of the RNA is shown in slate, and the dsRBD, Belt helix, and β-sheet of cDrosha are shown in light pink, pale cyan, and hot pink, respectively. (B) The protein domains of hDROSHA and cDrosha. The numbers indicate the positions of the amino acids in the polypeptides, and the white rectangles show the deleted regions of the mutant cDrosha. (C) Mutations in the β-sheet changed the cleavage sites of cDrosha in the HT cleavage assays. When evaluating mutant and WT cDrosha, changes in the cleavage site were calculated using the Kullback-Leibler divergence. This was used to compare the distributions of cleavage accuracy scores from CL-5 to CL5 on the 5p-strand. (D) Mutations in the β-sheet reduced the relative cleavage efficiency scores of cDrosha. The cleavage efficiency scores of mutant cDrosha for each cel-pri-miRNA were calculated, as described for WT cDrosha. (E) Diagrams and sequences of cel-pri-mir-72, cel-pri-mir-64, cel-pri-mir-244 LS19, cel-pri-mir-244 LS16 (WT), and cel-pri-mir-36. The inserted nt are red letters. (F–H) Gels showing the results of the in vitro cleavage assays of WT and mutant cMPs on pri-miRNAs. (I) The cleavage accuracies of WT and mutant cMPs were calculated as the ratio of cleaved products at CL0 to the cleaved products at all the cleaved positions. The plots were generated from assays conducted in triplicate, as shown in (F–H). In all panels, the blue and green arrowheads indicate the cleavage sites of cMP (WT and mutants) at CL0, determined by cDrosha and Pasha, respectively. The gray arrowhead indicates the cleavage of cMP at other positions.

PMC9976908

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Structural basis of the Pasha measurement. (A) Diagrams and sequences of cel-pri-mir-36 and its variants. The inserted nt are red letters. The deleted nt are shown in the red dashed box. (B) Gel showing the results from the in vitro cleavage assays of cDrosha, cMP, and cDrosha-hDGCR8 (cDro-hD8). (C) The protein domains for hDGCR8 (hD8), Pasha, and mutant Pasha. Pasha-hRhed, Pasha-hlinker, and Pasha-hdsRBD contained the swapped Rhed, linker, and dsRBD from hDGCR8, respectively. The numbers indicate the positions of the amino acids in the polypeptides. Rhed, RNA-binding heme domain; linker, the connecting domain between Rhed and dsRBDs; dsRBD, double-stranded RNA-binding domain. (D) Schematics showing the five different complexes of cDrosha with Pasha, hDGCR8, Pasha-hRhed, Pasha-hlinker, or Pasha-hdsRBD. (E) Diagrams and sequences of cel-pri-mir-36 US28 and hsa-pri-mir-30a. (F, G) Gels showing the results of in vitro cleavage assays of WT and mutant cMPs (as shown in D) on the pri-miRNAs. (H) The cleavage accuracies of WT and mutant cMPs were calculated as the ratio of cleaved products at bJC16 (for cel-pri-mir-36 US28) or bJC15 (for hsa-pri-mir-30a), and aJC25 to the cleaved products at all positions. The plot was generated from the assays conducted in triplicate, as shown in (F, G). In all panels of Figure 6, the blue and green arrowheads indicate the cleavage sites of cMP (WT and mutants), determined by cDrosha and Pasha, respectively. The gray arrowhead indicates the cleavage of cMP at other positions.

PMC9976908

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A model of C. elegans Microprocessor action on cel-pri-miRNAs. (A) cDrosha measures ∼16 bp of the lower stem of cel-pri-miRNAs and determines its cleavage sites. The cDrosha measurement is supported by the β-sheet located in its central domain. Pasha measures ∼25 bp of the upper stem of cel-pri-miRNAs and determines the cleavage sites of cDrosha in this location. The Pasha measurement is aided by its dsRBDs and linker region. These two measuring mechanisms, which are regulated by the two subunits, are coordinated for cMP to achieve optimal cleavage activity. (B) The percentage of pri-miRNAs containing UG, UGU, CNNC, mGHG or midBMW motifs in each of the 45 listed species. (C, D) The percentage of pri-miRNAs containing different lengths of (C) lower and (D) upper stem in each of the 45 species listed.

PMC9976908

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In the Caenorhabditis elegans Microprocessor complex, Drosha and Pasha subunits are coordinated to determine the cleavage sites of the complex in pri-miRNAs.

PMC9976908

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Treatment course of a patient with with KMT2A::MLLT4-positive mixed phenotype acute leukemia (T cell ALL/AML). A Measurable residual disease (MRD, circles) and donor chimerism measurements (bone marrow: grey triangles, peripheral blood: black triangles) are depicted from initial diagnosis to diagnosis of second relapse. Treatments are indicated in the upper part: 1A, ALL-BFM induction protocol 1A; AIE, cytarabine, idarubicin, etoposide; HR1, ALL-BFM high-risk block 1 with dexamethasone, vincristine, methotrexate, cyclophosphamide, cytarabine, L-asparaginase, intrathecal triple therapy; HAM, high-dose cytarabine, mitoxantrone; HSCT, allogeneic hematopoietic stem cell transplantation; VCR, vincristine; ARA-C, cytarabine. Blast counts below the time axis relate to morphological bone marrow examinations. Time axis not regular. B Detailed description of combined treatment with daratumumab (DARA) and venetoclax (VEN). DLI, donor lymphocyte infusion; BM, bone marrow

PMC9977701

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731ac2ea270745d393fda321800c3eee

Conceptual model of the effect of inner context organizational constructs on EBP self-efficacy.

PMC9978605

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Simple slopes of therapist-level psychological safety predicting EBP self-efficacy for low (−1 SD), medium (mean), and high (+ 1 SD) levels of sustainment leadership.

PMC9978605

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dd25b015170540a3a3b9627e471db63b

Production and characterization of hESC-derived human neurons expressing BioID2-tagged tau or BioID2-tagged α-synuclein or controls expressing BioID2 alone.A, schematic illustrating the stepwise integration of piggyBAC transposon constructs into hESCs to generate human neurons expressing 0N4R tau[WT or P301L]-BioID2, α-synuclein[WT or A53T]-BioID2, or BioID2-only controls (CONT). B, immunofluorescent images of NGN2-neurons (no BioID2 transgene) 6 weeks postdifferentiation. The antibodies shown in each image include markers of glutamatergic neurons. The scale bar represents 20 μm. α-Syn, α-synuclein; BioID2, biotin ligase; DAPI, 4′,6-diamidino-2-phenylindole; DOX, doxycycline; EF1α, eukaryotic translation elongation factor 1α; hESC, human embryonic stem cell; MAP2, microtubule associated protein 2; MUT, mutant; NGN2, neurogenin-2; pA, poly(A) tail; puro, puromycin; TRE3G, Tet-ON 3G transactivator; VGLUT1, vesicular glutamate transporter 1; zeo, zeocin.

PMC9978635

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Experimental timelines and illustration of the ten conditions compared in this study. Experimental timelines of the experimental conditions compared in this study for A, 0N4R tau[WT]-BioID2 and 0N4R tau[P301L]-BioID2 neurons with and without K18 fibril seeds, and for B, α-Syn[WT]-BioID2 and α-Syn[A53T]-BioID2 neurons with and without α-synuclein PFFs. Tau and α-synuclein neurons are shown separately to emphasize that each of the ten conditions represented by a tissue culture dish was a separate trial to biotinylate and identify interacting proteins. C, schematic representing the biotinylation of interacting proteins by BioID2-conjugated tau or α-synuclein. Cellular proteins directly binding to BioID2-conjugated tau or α-synuclein (pink shapes) or coming within 10 nm of a BioID2-conjugated protein are biotinylated and classified as interacting proteins (blue, orange, and yellow shapes), unless similar biotinylation occurs in control neurons expressing free and unconjugated BioID2, indicating nonspecific binding. Red circles symbolize biotin that can be linked by BioID2 to cellular proteins interacting with or in close proximity (<10 nm) to a BioID2 fusion protein. Noninteractors (magenta and purple shapes) that are not within 10 nm of BioID2 are also depicted. Schematic also includes the workflow enabling quantitative comparisons of biotinylated proteins between experimental conditions. α-Syn, α-synuclein; BioID2, biotin ligase; CONT, control; DOX, doxycycline; MUT, mutant; PFF, preformed α-synuclein fibril; TMT, tandem mass tag; wk, week.

PMC9978635

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Expression of tau-BioID2 and α-synuclein in hESC-derived neurons. Western blots for A, total tau and for D, total α-synuclein using syn211 antibody in neuron lysates 24 h and 3 weeks after fibril or PBS treatment. The arrows mark the expected sizes of the BioID2 fusion proteins. B and E, streptavidin–HRP blots of neuron lysates labeling all biotinylated proteins 24 h or 3 weeks postfibril treatment. C, Western blot for 1% Triton-insoluble 4R tau using an in-house polyclonal antibody against the R2 region. F, Western blot for total α-synuclein in the 1% Triton-insoluble fractions of neuron lysates 3 weeks after fibril treatment. α-Syn, α-synuclein; BioID2, biotin ligase; hESC, human embryonic stem cell; HRP, horseradish peroxidase; K18, recombinant 4R repeat domain P301L fibril; PFF, preformed α-synuclein fibril.

PMC9978635

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Immunofluorescent staining of tau and α-synuclein in fibril-treated neurons. Immunofluorescent images of total tau or α-synuclein (tau12 and syn211) in neurons expressing tau-BioID2 or α-synuclein-BioID2. All images were taken 3 weeks after treatment with fibrils or PBS. A, disease-associated phospho-tau (pS202/pT205/pS208, AT8) is shown in red. Arrows indicate AT8+ puncta in WT neurons and strong AT8 staining in P301L cell bodies. B, similar images of WT and A53T α-syn-BioID2. Disease-associated phospho-α-syn (pS129, EP1536Y) is shown in red. Arrows indicate large phospho-α-syn+ puncta in WT neurons and strong phospho-α-syn staining in A53T cell bodies. α-Syn, α-synuclein; BioID2, biotin ligase; DAPI, 4′,6-diamidino-2-phenylindole; K18, recombinant 4R repeat domain P301L fibrils; MAP2, microtubule-associated protein 2; PFF, preformed α-synuclein fibril.

PMC9978635

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Heatmaps of biotinylated proteins identified in tau-BioID2 and α-synuclein-BioID2 neurons.A, Tau-BioID2 and B, α-synuclein-BioID2 TMT10plex data represented by heatmaps and clustered according to similarity. Colors represent the relative abundance of TMT reporter ions corresponding to each identified protein (average of three technical replicates). There were 1339 quantifiable proteins identified in the tau 10plex sample and 2158 quantifiable proteins identified in the α-synuclein 10plex sample. α-Syn, α-synuclein; BioID2, biotin ligase; K18, recombinant 4R repeat domain P301L fibrils; PFF, preformed α-synuclein fibril; TMT, tandem mass tag; wk, week.

PMC9978635

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Abundance of biotinylated proteins in fibril-treated versus fibril-untreated WT neurons and in mutant versus WT neurons. Plots displaying the abundance (3 weeks postfibrils) of biotinylated proteins in WT neurons. Abundance in A, tau[WT]-BioID2 neurons or B, α-synuclein[WT]-BioID2 neurons relative to the BioID2-only control was plotted on the y-axis, and the abundance in fibril-treated relative to untreated neurons was plotted on the x-axis. Labeled blue and pink dots represent interactors that met the ≥1.5-fold abundance threshold (over BioID2-only control) in either fibril-treated or fibril-untreated neurons at 3 weeks postseeding. Plots displaying the abundance of mutant-specific interactors. The abundance of biotinylated proteins in untreated C, mutant tau-BioID2 or D, α-synuclein-BioID2 neurons was plotted relative to their abundance in the BioID2-only control (y-axis) and relative to their abundance in WT neurons (x-axis). Labeled blue and pink dots represent proteins ≥1.5-fold more abundant in mutant neurons relative to WT and BioID2-only control neurons. α-Syn, α-synuclein; BioID2, biotin ligase; K18, recombinant 4R repeat domain P301L fibrils; PFF, preformed α-synuclein fibril; wk, week.

PMC9978635

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Comparison of tau-BioID2 and α-synuclein-BioID2 interactors. Venn diagrams showing the number of WT and mutant A, tau-BioID2 or C, α-synuclein-BioID2 interacting proteins identified at each time point. Proteins were included if they were present in either the fibril-treated or fibril-untreated neurons at ≥1.5-fold higher abundance than both BioID2-only controls (24 h and 3 weeks postseeding). Gene Ontology enrichment analysis of all B, tau-BioID2 and D, α-synuclein-BioID2 interactors. Enriched GO terms—molecular functions and cellular components—were determined by a PANTHER over-representation test. The top ten nonredundant terms were plotted with the accompanying −log10(FDR) plotted on the x-axis. The percentage of all tau-BioID2 or α-synuclein-BioID2 interactors associated with each GO term is listed adjacently in blue. α-Syn, α-synuclein; BioID2, biotin ligase; FDR, false discovery rate; GO, Gene Ontology; wk, week.

PMC9978635

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Interactome network of shared tau-BioID2 and α-synuclein-BioID2 interactors. Forty-five proteins were identified as being interactors of both tau-BioID2 and α-synuclein-BioID2. A, a STRING protein–protein interaction network of the shared interactors was visualized using the StringApp in Cytoscape. Two prominent clusters emerged: one related to microtubules (19 of 45 proteins) and the other related to Wnt signaling (10 of 45 proteins). There were also a significant number of proteins (8 of 45) that are known components of RNA stress granules. B, the top ten most enriched GO terms (molecular function and cellular component) were plotted according to their FDR, and the percentage of shared interactors associated with each GO term is labeled in blue. Of all the tau-BioID2 and α-synuclein-BioID2 shared interactors, 89% were associated with the lateral plasma membrane. BioID2, biotin ligase; FDR, false discovery rate; GO, Gene Ontology; STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.

PMC9978635

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14-3-3 isoforms differentially influence the fibrillization of recombinant WT and P301L 0N4R tau. 0N4R tau amyloid formation monitored by RT-QuIC in the presence of 14-3-3 proteins. A, WT tau (10 μM) was incubated at 37 °C for 1 week in the presence of heparin (10:1 ratio of tau:heparin) with alternating cycles of shaking and rest. Recombinant 14-3-3 proteins (ƞ, θ, ζ, or ƞ + ζ) were added at 2 μM. Fibrillization was monitored with the amyloid-sensitive dye ThT. B, identical reaction conditions but with P301L 0N4R tau. C, quantification of ThT fluorescence (total area under the curve). Reactions containing 14-3-3 proteins were compared with the WT or P301L tau-only controls (∗p ≤ 0.05, ∗∗∗ p ≤ 0.01). Each sample was run in triplicate, and means and standard deviations of AUCs are displayed. AUC, area under the curve; RFU, relative fluorescence unit; RT-QuIC, real-time quaking-induced conversion assay; ThT, thioflavin T.

PMC9978635

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BCR test in a 59-year-old male patient with PD. The mean BCR latency was 60.4 ms. It can be seen that the BCR latency was prolonged in this patient

PMC9979443

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EAS-EMG test in a 65-year-old female patient with MSA. EAS-EMG latency was 17.67 ms. EAS-EMG amplitude was 606 μV. In this patient, EAS-EMG latency was significantly prolonged, and satellite potential was observed

PMC9979443

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ROC curve analysis of each neurophysiological index of BCR and EAS-EMG in the identification of MSA and PD

PMC9979443

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The relationship between olfactory test grades, vaccination, clinical types, ethnicity, sex and input ways.

PMC9979703

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Line charts shows trends in OSIT-J scores for mild (A), moderate (B), and severe (C) patients on day 1, 5, 10, 15, and 20 after admission.

PMC9979703

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The relationship between olfactory test grades, vaccination, clinical types, ethnicity, sex and input ways.

PMC9979703

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Error bars show olfactory test scores(A), age(B), weight(C), IL-6(D) and PCT(E) for mild, moderate, and severe patients or healthy controls.

PMC9979703

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Scatter plots show the correlation of olfactory test grades (A) and vaccination(B) for clinical type (mild, moderate, and severe patients or healthy controls).

PMC9979703

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Bar plots show the fraction of sex (A), input ways (B), ethnicity (C), cough (D) and fever (E) for mild, moderate, and severe patients or healthy controls.

PMC9979703

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Error bars show CRP levels (A) for euosmia and dysosmia. Bar plots show the fraction of input ways(B), cough (C) and fever(D) for euosmia and dysosmia.

PMC9979703

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Error bars show ORF1ab (A), N (B), weight(C), IgM(D), IgG(E), IL6(F) and PCT(G) levels for indigenous cases and myanmar input.

PMC9979703

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Bar plots show the fraction of sex(A), cough(B), vaccination(C) and ethnicity(D) for indigenous cases and myanmar input.

PMC9979703

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Error bars show olfactory test scores(A) and IgG levels(B) for no vaccination, one vaccination, two vaccinations.

PMC9979703

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Bar plots show the fraction of cough(A)，fever(B) and sex(C) for no vaccination, one vaccination, two vaccinations.

PMC9979703

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Error bars show olfactory test scores(A) and age(B) for mild, moderate, and severe patients and healthy controls. It represents standard error of the mean (SEM).

PMC9979703

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Box plots: (A) A comparison of Simple Olfactory Test scores between patients with mild, moderate and severe groups. (C) A comparison of Simple Olfactory Test scores between no vaccination, one vaccination and two vaccinations groups. (E) A comparison of Simple Olfactory Test scores between Han, Dai, Burman, De'ang and Jingpo groups. Point graphs: (B) A correlation of Simple Olfactory Test scores between patients with mild, moderate and severe groups. (D) A correlation of Simple Olfactory Test scores between no vaccination, one vaccination and two vaccinations groups. (F) A correlation of Simple Olfactory Test scores between Han, Dai, Burman, De'ang and Jingpo groups.

PMC9979703

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Line charts shows trends in Simple Olfactory Test scores for mild (A), moderate (B), and severe (C) patients on day 1, 5, 10, 15, and 20 after admission.

PMC9979703

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A receiver operating characteristic (ROC) analysis for OSIT-J Test (A) and Simple Olfactory Test (B) in mild, moderate, and severe patients and healthy controls. The area under the ROC curve of the OSIT-J Test was 0.700 for Control versus Mild group, 0.862 for Control versus Moderate group, 0.975 for Control versus Severe group, 0.628 for Mild versus Moderate group, 0.882 for Mild versus Severe group and 0.828 for Moderate versus Severe group (A), whereas that for the Simple Test was 0.831, 0.897, 0.940, 0.594, 0.750 and 0.665, respectively (B).

PMC9979703

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A receiver operating characteristic (ROC) analysis for OSIT-J Test (A) and Simple Olfactory Test (B) in Myanmar input and Indigenous cases. The area under the ROC curve of the OSIT-J Test was 0.540 (A) for Myanmar input versus Indigenous cases, whereas that for the Simple Test was 0.585 (B).

PMC9979703

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A receiver operating characteristic (ROC) analysis for OSIT-J Test (A) and Simple Olfactory Test (B) in no vaccination, one vaccination and two vaccinations. The area under the ROC curve of the OSIT-J Test was 0.597 for no vaccination versus one vaccination, 0.583 for no vaccination versus two vaccinations, 0.683 for one vaccination versus two vaccinations (A), whereas that for the Simple Test was 0.574, 0.704 and 0.666, respectively (B).

PMC9979703

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Scatter plots show the correlation of olfactory test grades (A) and vaccination(B) for clinical type (mild, moderate, and severe patients or healthy controls).

PMC9979703

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Bar plots show the fraction of sex(A), input ways(B), cough(C) and fever(D) for mild, moderate, and severe patients or healthy controls.

PMC9979703

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Error bars show Leukocyte levels(A) for anosmia, hyposmia, and euosmia. Bar plots show the fraction of input ways (B), cough(C) and fever(D) for anosmia, hyposmia, and euosmia.

PMC9979703

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Bar plots show the fraction of ethnicity(A), fever(B) and vaccination(C) for indigenous cases and myanmar input.

PMC9979703

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Error bars show ORF1ab(A) and N(B) levels for no vaccination, one vaccination, two vaccinations.

PMC9979703

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Bar plots show the fraction of sex(A), ethnicity (B), cough(C) and fever(D) for no vaccination, one vaccination, two vaccinations.

PMC9979703

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The Box plot (A) shows the comparison of OSIT-J scores between patients with mild, moderate and severe groups. The point graph (B) of the correlation between olfactory identification ability (OSIT-J score) versus clinical type (mild, moderate and severe).

PMC9979703

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Participant disposition. ∗One participant in the V114 group was randomized but not vaccinated because of the physician’s decision.

PMC9979710

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Assessment of solicited AEs. The proportion of participants reporting solicited AEs within 14 days of vaccination is shown by the intensity. ∗For injection-site erythema, induration, and swelling, 0 to ≤1 in. was considered mild, >1 to ≤3 in. was considered moderate, and >3 in. was considered severe. V=V114, P=PCV13.

PMC9979710

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Serotype-specific IgG GMCs at 30 days after vaccination. The serotype-specific IgG GMCs and 95% confidence intervals on day 30 are shown for each vaccination group.

PMC9979710

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Serotype-specific OPA GMTs at 30 days after vaccination. The serotype-specific OPA GMTs and 95% confidence intervals on day 30 are shown for each vaccination group.

PMC9979710

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Subcortical structures affected by PTPN11 and SOS1 variants in Noonan syndrome. (A) Left: 95% confidence interval plot of PTPN11GMV effect sizes with cooler colors indicating larger negative values (NS < TD) and shapes and line types representing groups (PTPN11 and SOS1); Right: Effects of PTPN11 and SOS1 variants in Noonan syndrome on subcortical anatomy indicated by effect sizes mapped onto a three-dimensional representation of bilateral subcortical brain regions. (B) Boxplots representing subcortical volumes in the PTPN11, SOS1, and TD groups. In PTPN11, we found smaller bilateral caudate (ANCOVA: left: F(1, 65)=10.11, p=0.0060, d=−0.70; right: F(1, 65)=22.61, p=0.00012, d=−1.03), putamen (left: F(1, 65)=17.28, p=0.00031, d=−0.86; right: F(1, 65)=21.01, p=0.00012, d=−0.91), and pallidum (left: F(1, 65)=20.79, p=0.00012, d=−0.91; right: F(1, 65)=19.60, p=0.00015, d=−0.88) and smaller right hippocampal GMV (F(1, 65)=6.071, p=0.029, d=−0.53) relative to the TD group. Similar to PTPN11, we found smaller pallidum GMV, bilaterally, (t-test: left: t(39)=−2.94, p=0.038, d=−0.80; right: t(39)=−3.74, p=0.012, d=−1.03) in the SOS1 group compared to the TD group. Between-group differences are denoted for significance (*p<0.05, **p<0.01, ***p<0.001, ns: not statistically significant).

PMC9980214

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Significance (p-value) of changes in gray matter volume (GMV), surface area (SA), and cortical thickness (CT) in the PTPN11 group. Dorsal aspects of the frontal and parietal lobes, as well as medial temporal and occipital regions, were particularly affected by PTPN11 variants. (A) p-values of changes in gray matter volume (GMV), surface area (SA), and cortical thickness (CT) mapped to cortical ROIs with cooler colors indicating NS < TD and warmer colors indicating NS > TD, converted to −log10 (p) for visualization purposes. (B) p-values of changes in GMV, SA, and CT organized by hemisphere with rows for ROIs, columns for measures, dot color representing the direction of differences (blue: negative or NS < TD; red: positive or NS > TD), and dot size representing magnitude of p-values.

PMC9980214

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Effect sizes of gray matter volumes (GMV), surface area (SA), and cortical thickness in NS variants (PTPN11 and SOS1). PTPN11 and SOS1 variants in Noonan syndrome affect cortical anatomy of similar cortical regions, generally in the same direction, with PTPN11having a more pronounced effect than SOS1. (A) Effect sizes of gray matter volume (GMV), surface area (SA), and cortical thickness (CT) mapped to cortical ROIs with cooler colors indicating NS < TD and warmer colors indicating NS > TD (B) 95% confidence interval plots of PTPN11 and SOS1 effect sizes organized by hemisphere and measure (GMV, SA, CT) with rows for ROIs, colors indicating direction of effect size (cooler colors: negative or NS < TD; warmer colors: positive or NS > TD, gray: non-significant values), and shapes and line types representing groups (PTPN11 and SOS1) (C) Scatterplots illustrating the close coherence between effect sizes of NS status (PTPN11 or SOS1) on subcortical and cortical gray matter volumes and gray matter determinants (SA and CT) between the PTPN11 and SOS1 groups and permutation testing distributions (with 2,000 null r values) demonstrating that observed correlations are significantly greater than null expectations.

PMC9980214

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Disruption of normative anatomical-behavioral relationships relevant to attention and inhibition in Noonan syndrome. Pearson correlations between Auditory Attention or Inhibition scores and striatal volumes (in mm3) for each group and Fisher’s Exact Tests (with FDR corrected p-values) assessing differences between PTPN11 and TD groups in brain-behavioral correlations. Participants are represented by individual dots and distribution plots of the data are displayed on the outer x- and y-axes.

PMC9980214

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