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13 pages, 1679 KiB  
Article
Effect of Surface Treatments and Thermal Aging on Bond Strength Between Veneering Resin and CAD/CAM Provisional Materials
by Ali Robaian, Abdullah Mohammed Alshehri, Nasser Raqe Alqhtani, Abdulellah Almudahi, Khalid K. Alanazi, Mohammed A. S. Abuelqomsan, Eman Mohamed Raffat, Ali Elkaffas, Qamar Hashem and Tarek Ahmed Soliman
Polymers 2025, 17(5), 563; https://doi.org/10.3390/polym17050563 - 20 Feb 2025
Abstract
The oral environment significantly influences the esthetic appearance of CAD/CAM provisional restorative materials. Therefore, a veneering layer is required. Bonding veneering resin composites to these materials presents challenges, particularly under conditions of thermal aging. This study evaluated the impact of various surface treatments [...] Read more.
The oral environment significantly influences the esthetic appearance of CAD/CAM provisional restorative materials. Therefore, a veneering layer is required. Bonding veneering resin composites to these materials presents challenges, particularly under conditions of thermal aging. This study evaluated the impact of various surface treatments and thermal aging on the bond strength between veneering resin and CAD/CAM provisional materials. Fifty disk-shaped specimens of each CAD/CAM material (CAD-Temp, Everest C-Temp, and PEEK), measuring 10 mm in diameter and 3 mm in height, were fabricated. After being ultrasonically cleaned, specimens were embedded in acrylic resin blocks, leaving one surface exposed for surface treatments. Specimens were assigned to five groups at random. Group C: no surface treatments applied; DB: mechanically roughened with a diamond bur; DB + TC: DB group subjected to 5000 cycles of thermocycling; SB: treated with aluminum oxide airborne abrasion; SB + TC: SB group subjected to 5000 cycles of thermocycling. After the surface treatments, the primer and resin veneering composite were applied to the specimens. The shear bond strength (SBS) was calculated using a universal testing machine and the mode of failure was evaluated with an optical stereomicroscope with 40× magnification. Scanning electron microscopy evaluation was conducted to examine the surface topography of the materials’ surfaces after surface treatments. C-Temp in the SB group exhibited the highest SBS values (20.38 ± 1.04 MPa), while CAD-Temp in the C group showed the lowest values (4.60 ± 0.54 MPa). PEEK recorded significantly higher SBS values in DB + TC and SB + TC groups (9.26 ± 1.07 and 12.92 ± 0.97 MPa, respectively) compared to CAD-Temp in DB + TC and SB + TC groups (6.04 ± 0.76 and 8.82 ± 0.86 MPa, respectively). C-Temp exhibited higher SBS without surface treatment (13.11± 0.55 MPa), whereas PEEK showed higher SBS after diamond bur roughening and air particle abrasion (10.87 ± 1.02 MPa, and 14.37 ± 0.98 MPa, respectively). The thermocycling significantly reduced SBS values for C-Temp in the DB + TC and SB + TC groups (11.18 ± 0.92, 15.56 ± 0.87 MPa, respectively) and CAD-Temp in the DB + TC and SB + TC (6.04 ± 0.76 MPa and 8.82 ± 0.86 MPa, respectively). Conversely, the thermocycling had no significant effect on SBS values for PEEK material in the air particle abrasion group (12.92 ± 0.97 MPa). Full article
(This article belongs to the Special Issue Polymers in Restorative Dentistry: 2nd Edition)
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<p>Study design and specimens’ grouping.</p>
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<p>Mode of failure for all groups.</p>
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<p>SEM micrographs (1000): (<b>A</b>) CAD-TEMP control group, (<b>B</b>) CAD-TEMP bur roughening, (<b>C</b>) CAD-TEMP—air abrasion, (<b>D</b>) C-TEMP control group, (<b>E</b>) C-TEMP bur roughening, (<b>F</b>) C-TEMP—air abrasion, (<b>G</b>) PEEK Control group, (<b>H</b>) PEEK bur roughening, and (<b>I</b>) PEEK—air abrasion.</p>
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18 pages, 9157 KiB  
Article
Design Method of a Cylindrical Skiving Tool for Internal Gear with Circular Arcs
by Erkuo Guo, Mingfeng Chen, Xuechao Pan, Yayun Yuan and Hua Qiao
Machines 2025, 13(2), 95; https://doi.org/10.3390/machines13020095 - 25 Jan 2025
Viewed by 183
Abstract
Gear skiving is a highly productive method for manufacturing gears, especially internal gears. Circular arc internal gears are important parts of Rotary Vector (RV) reducers and harmonic reducers. This study presents the implementation of the gear skiving technique using a cylindrical tool to [...] Read more.
Gear skiving is a highly productive method for manufacturing gears, especially internal gears. Circular arc internal gears are important parts of Rotary Vector (RV) reducers and harmonic reducers. This study presents the implementation of the gear skiving technique using a cylindrical tool to enhance the precision and efficiency of machining circular arc internal gears. By establishing the mathematical model for skiving a circular arc internal gear based on the conjugation theory of two surfaces, the barrel-shaped conjugate surface was solved by deducing gear meshing equations. A design method is proposed for a cylindrical skiving tool by utilizing the barrel-shaped conjugate surface with an off-center tool position along the axis. The cutting edge of the tool rake face was then obtained through cubic spline interpolation from the conjugate surface. The influence of the tool rake face offsets on the cutting rake angle and clearance angle is also discussed by defining the normal cutting plane of the tool. The correctness of the proposed cylindrical skiving tool was validated through simulation and actual skiving experiments. The experimental results demonstrated that the tooth profile error of the gear fell within ±0.004 mm, thereby satisfying the accuracy requirement for pin wheel housing gears. These research findings can contribute to advancements in novel cylindrical skiving tools. Full article
(This article belongs to the Section Advanced Manufacturing)
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<p>Geometric model of the internal gear conjugated with a barrel-shaped surface [<a href="#B13-machines-13-00095" class="html-bibr">13</a>,<a href="#B14-machines-13-00095" class="html-bibr">14</a>].</p>
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<p>Basic geometry of gear skiving using a cylindrical tool.</p>
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<p>Tooth profile of the circular arc gear.</p>
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<p>Conjugate surface for the arc tooth profile.</p>
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<p>Geometric relationship between cross-sections of the tool on the conjugate surface: (<b>a</b>) conjugate surface; (<b>b</b>) constructive rake angle; (<b>c</b>) helix angle.</p>
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<p>Calculation of the cutting edge of the tool using cubic spline interpolation.</p>
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<p>Description of the cutting edge swept surface by discrete points.</p>
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<p>Calculation model of the swept surface involved in skiving.</p>
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<p>Mathematical model of the working angle of the tool.</p>
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<p>Working angles of the cylindrical skiving tool.</p>
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<p>Working angles of the cylindrical skiving tool varying from the tool rake face offset <span class="html-italic">e</span>.</p>
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<p>Manufacturing process of the cylindrical skiving tool: (<b>a</b>) roughing process; (<b>b</b>) finishing process; (<b>c</b>) rake face of the tool; (<b>d</b>) tool flank; (<b>e</b>) back face of the tool.</p>
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<p>Measurement of the tool cutting edge and gear profile: (<b>a</b>) extraction of the outline of the tool cutting edge on the optical inspection machine; (<b>b</b>) evaluation of the tool tooth profile error; (<b>c</b>) simulation of the gear skiving; (<b>d</b>) residual height of the tooth surface; (<b>e</b>) residual height of the tooth surface after magnification; (<b>f</b>,<b>g</b>) measurement report of the internal circular arc tooth gear.</p>
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17 pages, 3584 KiB  
Article
Exploration of the Role of Cyclophilins in Established Hepatitis B and C Infections
by Jennifer Molle, Sarah Duponchel, Jennifer Rieusset, Michel Ovize, Alexander V. Ivanov, Fabien Zoulim and Birke Bartosch
Viruses 2025, 17(1), 11; https://doi.org/10.3390/v17010011 - 25 Dec 2024
Viewed by 608
Abstract
Cyclophilin (Cyp) inhibitors are of clinical interest in respect to their antiviral activities in the context of many viral infections including chronic hepatitis B and C. Cyps are a group of enzymes with peptidyl-prolyl isomerase activity (PPIase), known to be required for replication [...] Read more.
Cyclophilin (Cyp) inhibitors are of clinical interest in respect to their antiviral activities in the context of many viral infections including chronic hepatitis B and C. Cyps are a group of enzymes with peptidyl-prolyl isomerase activity (PPIase), known to be required for replication of diverse viruses including hepatitis B and C viruses (HBV and HCV). Amongst the Cyp family, the molecular mechanisms underlying the antiviral effects of CypA have been investigated in detail, but potential roles of other Cyps are less well studied in the context of viral hepatitis. Furthermore, most studies investigating the role of Cyps in viral hepatitis did not investigate the potential therapeutic effects of their inhibition in already-established infections but have rather been performed in the context of neo-infections. Here, we investigated the effects of genetically silencing Cyps on persistent HCV and HBV infections. We confirm antiviral effects of CypA and CypD knock down and demonstrate novel roles for CypG and CypH in HCV replication. We show, furthermore, that CypA silencing has a modest but reproducible impact on persistent HBV infections in cultured human hepatocytes. Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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<p>HCV infection at 3 days post infection. Huh7.5 cells were infected with HCV at an MOI of 0.1 and fixed for immunofluorescence analysis 3 days later. Green: anti-HCV patient serum; blue: DAPI staining. A representative image is shown; scale bar: 50 µm.</p>
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<p>Effect of genetic cyclophilin knock down (siRNA) on intracellular HCV replication. Huh7.5 cells were infected at an MOI of 0.1. Then, 72 h later, when HCV replication was well established, cells were transfected with siRNAs targeting the indicated Cyps and harvested 5 days after transfection. Left panels: intracellular HCV replication determined by RTqPCR with GUS as housekeeping gene and standardized to scramble controls. Middle panels: Cyp expression was assessed by Western blotting, quantified using ImageJ, standardized to actin, and data were expressed relative to the scramble conditions. Representative Western blots are shown. Right panels: cytotoxicity was assessed by neutral red staining with data standardized to the scramble control. Means +/− STD, <span class="html-italic">n</span> = 3, with each experiment performed with at least three culture wells and each well representing a datapoint. One-way anova. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001; **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>Effect of genetic cyclophilin knock down (shRNA) on intracellular HCV replication. Huh7.5 cells were infected at an MOI of 0.1. Then, 72 h later, when HCV replication was well established, cells were transfected with shRNA vectors targeting the indicated Cyps and harvested 5 days after transfection. Left panels: intracellular HCV replication was determined by RTqPCR using GUS as a housekeeping gene. Data were standardized to HCV RNA levels observed in scramble controls. Middel panels: Cyp expression was assessed by Western blotting, quantified using ImageJ, standardized to actin, and data were expressed relative to the scramble conditions. Representative Western blots are shown. Right panels: cytotoxicity was assessed by neutral red staining with data standardized to scramble control. Means +/− STD, <span class="html-italic">n</span> = 3, with each experiment performed with at least two culture wells and each well representing a datapoint. One-way anova. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>Effect of genetic cyclophilin knock down on intracellular HBV replication. HepG2-hNTCP cells were seeded at 4.10<sup>5</sup>/well into 12 wells; cells were infected at day 3 at an MOI of 100 and transfected at day 10 with the indicated siRNAs. Cells were harvested 5 days after transfection to assess HBV replication and Cyp expression. Left panel: intracellular HBV replication was determined by qPCR using RPLP0 as a housekeeping gene. Results are expressed relative to scramble; middle panel: Cyp expression was assessed by Western blotting, quantified using ImageJ, standardized to actin, and data were expressed relative to the scramble conditions. Representative Western blots are shown. Right panel: cytotoxicity was assessed by neutral red staining with data standardized to the scramble control. Means +/− STD, <span class="html-italic">n</span> = 3, with each experiment performed with a minimum of three culture wells and each well representing a datapoint. One-way anova. *** <span class="html-italic">p</span> &lt; 0.001 and **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>HBs and HBe antigen secretion are not affected by Cyp knock down. HepG2-hNTCP cells were seeded at 4.10<sup>5</sup>/well into 12 wells, DMSO was added 1 day later for 24 h. Cells were then infected at an MOI of 100 and transfected 7 days later with the indicated siRNAs. Cell supernatants were harvested at the time of transfection at day 7 and 5 days after transfection to assess (<b>a</b>) HBe (PEIU/mL) and (<b>b</b>) HBs (UI/mL) antigen secretion. Data were standardized to values obtained for the HBV/scramble control at day 7 (time of transfection). Means +/− STD, <span class="html-italic">n</span> = 5. One-way anova: no statistically significant difference was observed between the conditions.</p>
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<p>Effect of genetic Cyp knock down on intracellular HBV replication in PHH. PHHs were infected (MOI 250) and transfected 7 days later with the siRNAs targeting the indicated Cyps. Cells were harvested 5 days after transfection. Left panels: intracellular HBV replication quantified by qPCR with RPLP0 as a housekeeping gene. Right panels: Cyclophilin expression by Western blotting, quantified with ImageJ, standardized to actin, and data were expressed relative to the scramble. Representative Western blots are shown. Means +/− STD, <span class="html-italic">n</span> = 3, with each experiment performed with at least three culture wells with each well representing a datapoint. One-way anova. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001 and **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>Cytotoxicity of genetic cyclophilin knock down by siRNA. PHHs were seeded at 1.10<sup>6</sup>/well into 12 wells. DMSO was added 1 day later for 24 h. Cells were then infected at an MOI of 250 and transfected 7 days later with the indicated siRNAs. Cells were harvested 5 days after transfection. Total protein (<b>left panel</b>) and DNA (<b>right panel</b>) were quantified as the read out for cell toxicity. <span class="html-italic">n</span> = 3, means +/− STD, with each experiment performed with at least three culture wells with each well representing a datapoint; One-way anova.</p>
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<p>HBs and HBe antigen secretion are not affected by Cyp knock out. PHHs were seeded at 1.10<sup>6</sup>/well into 12 wells. DMSO was added 1 day later for 24 h. Cells were then infected at an MOI of 250 and transfected 7 days later with the mixtures of siRNAs (as used in <a href="#viruses-17-00011-f006" class="html-fig">Figure 6</a>), targeting the indicated siRNAs. Cell supernatants were harvested at the time of transfection at day 7 and 5 days after transfection to assess (<b>a</b>) HBe (PEIU/mL) and (<b>b</b>) HBs (UI/mL) antigen secretion. Data were standardized to values obtained for the HBV/scramble control at day 7 (time of transfection). Means +/− STD, <span class="html-italic">n</span> = 4. One-way anova: no statistically significant difference was observed between the conditions.</p>
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21 pages, 6428 KiB  
Article
UV-C Exposure Enhanced the Cd2+ Adsorption Capability of the Radiation-Resistant Strain Sphingomonas sp. M1-B02
by Yunshi Li, Haoyuan Niu, Shuang Li, Ming Yue and Gaosen Zhang
Microorganisms 2024, 12(12), 2620; https://doi.org/10.3390/microorganisms12122620 - 18 Dec 2024
Viewed by 884
Abstract
Microbial adsorption is a cost-effective and environmentally friendly remediation method for heavy metal pollution. The adsorption mechanism of cadmium (Cd) by bacteria inhabiting extreme environments is largely unexplored. This study describes the biosorption of Cd2+ by Sphingomonas sp. M1-B02, which was isolated [...] Read more.
Microbial adsorption is a cost-effective and environmentally friendly remediation method for heavy metal pollution. The adsorption mechanism of cadmium (Cd) by bacteria inhabiting extreme environments is largely unexplored. This study describes the biosorption of Cd2+ by Sphingomonas sp. M1-B02, which was isolated from the moraine on the north slope of Mount Everest and has a good potential for biosorption. The difference in Cd2+ adsorption of the strain after UV irradiation stimulation indicated that the adsorption reached 68.90% in 24 h, but the adsorption after UV irradiation increased to 80.56%. The genome of strain M1-B02 contained antioxidant genes such as mutL, recA, recO, and heavy metal repair genes such as RS14805, apaG, chrA. Hydroxyl, nitro, and etceteras bonds on the bacterial surface were involved in Cd2+ adsorption through complexation reactions. The metabolites of the strains were significantly different after 24 h of Cd2+ stress, with pyocyanin, L-proline, hypoxanthine, etc., being downregulated and presumably involved in Cd2+ biosorption and upregulated after UV-C irradiation, which may explain the increase in Cd2+ adsorption capacity of the strain after UV-C irradiation, while the strain improved the metabolism of the antioxidant metabolite carnosine, indirectly increasing the adsorption capacity of the strains for Cd2+. Full article
(This article belongs to the Special Issue Role of Microbes in the Remediation of Pollutants in the Environment)
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<p>Screening and determination of the adsorption of Cd<sup>2+</sup> by <span class="html-italic">Sphingomonas</span> sp. M1-B02 ((<b>A</b>), screening of optimal adsorption strain; (<b>B</b>), colonies of the <span class="html-italic">Sphingomonas</span> spp.; (<b>C</b>), physiological characteristics of <span class="html-italic">Sphingomonas</span> sp. M1-B02; (<b>D</b>), Optimal adsorption conditions for <span class="html-italic">Sphingomonas</span> sp. M1-B02).</p>
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<p>Biosorption dynamic curves of <span class="html-italic">Sphingomonas</span> sp. M1-B02 ((<b>A</b>), Direct adsorption of Cd<sup>2+</sup>; (<b>B</b>), adsorption of Cd<sup>2+</sup> after UV stress).</p>
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<p>Electron microscopy comparison of strain M1-B02 before and after Cd<sup>2+</sup> adsorption. (<b>A1</b>,<b>B1</b>,<b>C1</b>) Scanning electron microscopy (SEM) images of strain M1-B02 under different conditions. Red circles highlight regions of Cd<sup>2+</sup>. (<b>A2</b>,<b>B2</b>,<b>C2</b>) Energy-dispersive X-ray spectroscopy (EDS) analysis of corresponding samples showing the elemental composition. The table summarizes the mass percentage (Mass%) and atomic percentage (Atom%) of carbon (C), oxygen (O), and cadmium (Cd). The bottom images in (<b>A2</b>,<b>B2</b>,<b>C2</b>) map the spatial distribution of Cd<sup>2+</sup> (green dots) on the bacterial surface.</p>
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<p>The effect on the ultrastructure of <span class="html-italic">Sphingomonas</span> sp. M1-B02 under FTIR. (<b>A1</b>) corresponds to untreated Sphingomonas sp. M1-B02. (<b>A2</b>) represents the bacterial cells after Cd<sup>2+</sup> adsorption. (<b>A3</b>) shows the cells exposed to UV treatment followed by Cd<sup>2+</sup> adsorption.</p>
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<p>Genome circos of <span class="html-italic">Sphingomonas</span> sp. M1-B02 with DNA repair and heavy metal repair genes.</p>
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<p>Metabolomics analysis of <span class="html-italic">Sphingomonas</span> sp. M1-B02 ((<b>A</b>,<b>B</b>), PCA scoring charts of metabolites; (<b>C</b>), Venn diagram of differential metabolites; (<b>D</b>), KEGG compound classification chart; (<b>E</b>), KEGG pathway statistics chart).</p>
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<p>Volcano plots illustrating the differential metabolites identified in pairwise comparisons of groups (B vs. A and C vs. B). (<b>A</b>) Volcano plot of metabolites in the comparison between group B and group A. (<b>B</b>) Volcano plot of metabolites in the comparison between group C and group B.</p>
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<p>Box plot of distribution of significantly different metabolites in Group A, B, and C. The abundance of nine metabolites was compared across three groups (A, B, and C), with statistical significance indicated above each comparison. The boxplots represent the abundance values for (<b>A</b>) Pyocyanin, (<b>B</b>) Xanthine, (<b>C</b>) Hypoxanthine, (<b>D</b>) L-Proline, (<b>E</b>) Oxidized Glutathione, (<b>F</b>) Glycerol 2-phosphate, (<b>G</b>) 2-Oxoarginine, (<b>H</b>) Carnosine, and (<b>I</b>) N-Succinyl-L,L-2,6-diaminopimelate. Data points are visualized as boxplots, where the middle line represents the median, and the upper and lower bounds of the box correspond to the interquartile range (IQR). Groups are color-coded as A (grey), B (orange), and C (blue). *** represents <span class="html-italic">p</span> &lt; 0.001.</p>
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5 pages, 8414 KiB  
Case Report
Spontaneous Ischemic Cholecystitis in a Patient with Hereditary Hemorrhagic Telangiectasia (HHT)
by Romain L’Huillier, Alexandre Garnaud and Olivier Monneuse
J. Clin. Med. 2024, 13(22), 6653; https://doi.org/10.3390/jcm13226653 - 6 Nov 2024
Viewed by 626
Abstract
Background/Objectives: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by abnormal blood vessel formation, leading to recurrent epistaxis, cutaneous and mucosal telangiectases, and visceral arteriovenous malformations (AVMs). Hepatic involvement may result in complications such as high-output heart failure, portal hypertension, and [...] Read more.
Background/Objectives: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by abnormal blood vessel formation, leading to recurrent epistaxis, cutaneous and mucosal telangiectases, and visceral arteriovenous malformations (AVMs). Hepatic involvement may result in complications such as high-output heart failure, portal hypertension, and biliary ischemia. We report an uncommon case of ischemic cholecystitis in a patient with HHT. Methods: A 57-year-old male with HHT type 1, including gastric telangiectases and hepatic AVMs, presented with anemia, melena, epigastric pain, and a history of recurrent epistaxis. Imaging revealed gastric telangiectases and liver AVMs, consistent with HHT. Following an episode of severe epistaxis and aspiration pneumonia, the patient developed right upper quadrant pain. Results: Abdominal CT and ultrasound identified thickening of the gallbladder wall, segmental enhancement defects, and a perivesicular fluid effusion, suggestive of acalculous cholecystitis. A laparoscopic cholecystectomy was performed, revealing ischemic cholecystitis with necrotic gallbladder walls. Conclusions: This case underscores the potential for ischemic cholecystitis in patients with HHT and liver involvement, particularly under conditions of acute hemodynamic instability. Clinicians should be vigilant in recognizing this rare complication, especially in patients with established HHT and associated hepatic vascular anomalies. Full article
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<p>(<b>A</b>) Axial CT at the arterial phase (40 keV reconstruction), showing telangiectases of the stomach body (orange arrows). (<b>B</b>) Axial CT at the arterial phase, with Maximum Intensity Projection (MIP) 25 mm, showing a voluminous arteriovenous shunt with early enhancement of the left hepatic vein (white arrowheads). (<b>C</b>) Coronal CT at the arterial phase (40 keV reconstruction), showing telangiectases of the stomach body (orange arrow). (<b>D</b>) Axial CT at the arterial phase (40 keV reconstruction), showing heterogeneous hepatic enhancement linked to the arteriovenous shunt between the left branch of the hepatic artery and the left hepatic vein.</p>
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<p>(<b>A</b>) Axial CT at the portal phase showing segmental enhancement defects of the gallbladder wall (orange arrowheads). (<b>B</b>,<b>C</b>) Oblique coronal CT at the arterial (<b>B</b>) and portal phase (<b>C</b>) showing a segmental enhancement defect of the hepatic side of the gallbladder wall (orange arrowheads). Again, we found that the heterogeneous hepatic enhancement was linked to the arteriovenous shunt between the left branch of the hepatic artery and the left hepatic vein at the arterial phase (<b>B</b>). (<b>D</b>) Axial CT at the portal phase showing thickening of the gallbladder wall with segmental enhancement defects of the gallbladder wall (orange arrowheads) and a perivesicular fluid effusion (white arrow). (<b>E</b>) Coronal CT at the arterial phase with MIP 30 mm, showing a significant enlargement of the hepatic artery. (<b>F</b>) Mode B ultrasound showing thickening of the gallbladder wall, with a hypoechoic area of the hepatic side of the gallbladder wall (orange arrowhead), corresponding to the areas of segmental enhancement defects visualized on CT. Ultrasound revealed no gallstones in the gallbladder.</p>
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25 pages, 1700 KiB  
Review
Applications of CRISPR/Cas as a Toolbox for Hepatitis B Virus Detection and Therapeutics
by Anuj Kumar, Emmanuel Combe, Léa Mougené, Fabien Zoulim and Barbara Testoni
Viruses 2024, 16(10), 1565; https://doi.org/10.3390/v16101565 - 2 Oct 2024
Viewed by 2389
Abstract
Hepatitis B virus (HBV) infection remains a significant global health challenge, leading to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Covalently closed circular DNA (cccDNA) and integrated HBV DNA are pivotal in maintaining viral persistence. Recent advances in CRISPR/Cas technology offer innovative [...] Read more.
Hepatitis B virus (HBV) infection remains a significant global health challenge, leading to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Covalently closed circular DNA (cccDNA) and integrated HBV DNA are pivotal in maintaining viral persistence. Recent advances in CRISPR/Cas technology offer innovative strategies to inhibit HBV by directly targeting both cccDNA and integrated HBV DNA or indirectly by degrading HBV RNAs or targeting host proteins. This review provides a comprehensive overview of the latest advancements in using CRISPR/Cas to inhibit HBV, with a special highlight on newer non-double-strand (non-DSB) break approaches. Beyond the canonical use of CRISPR/Cas for target inhibition, we discuss additional applications, including HBV diagnosis and developing models to understand cccDNA biology, highlighting the diverse use of this technology in the HBV field. Full article
(This article belongs to the Special Issue CRISPR/Cas in Viral Research 2024)
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<p>Schematic representation of the HBV transcripts and ORFs expressed from (<b>A</b>) cccDNA and from (<b>B</b>) the integrated HBV DNA. These HBV genomes are crucial for HBV chronicity, and they serve as targets for CRISPR/Cas9 approaches (pro: promoter; PreC: precore; DR: direct repeat; PAS: polyadenylation signal; Enh: enhancer) (adapted from [<a href="#B5-viruses-16-01565" class="html-bibr">5</a>,<a href="#B11-viruses-16-01565" class="html-bibr">11</a>,<a href="#B12-viruses-16-01565" class="html-bibr">12</a>,<a href="#B14-viruses-16-01565" class="html-bibr">14</a>]). Image created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p>
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<p>CRISPR/Cas-based approaches offer potential for both detecting and targeting cccDNA and integrated HBV DNA, which play crucial role in HBV chronicity. While Cas9 nuclease, base editors, and epigenetic editors can directly target viral genomes, Cas13b functions by targeting HBV RNAs. For detection purposes, Cas12 and Cas13 can be employed to detect HBV DNA or RNA, respectively. Although this figure primarily focuses on cccDNA and integrated DNA, Cas12 can also detect other HBV DNA species, including rcDNA. Image created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p>
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<p>Detection of HBV using Cas12 and Cas13 can be achieved through various readout methods, including fluorescence detection, a lateral-flow immunochromatographic paper-strip assay, electrochemiluminescence, colorimetry, surface-enhanced Raman spectroscopy (SERS), and a personal glucose meter (PGM) (adapted from [<a href="#B98-viruses-16-01565" class="html-bibr">98</a>,<a href="#B112-viruses-16-01565" class="html-bibr">112</a>,<a href="#B115-viruses-16-01565" class="html-bibr">115</a>]). Image created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p>
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12 pages, 1405 KiB  
Article
Portal Vein Pulsatility: A Valuable Approach for Monitoring Venous Congestion and Prognostic Evaluation in Acute Decompensated Heart Failure
by Mihai Grigore, Andreea-Maria Grigore and Adriana-Mihaela Ilieșiu
Diagnostics 2024, 14(18), 2029; https://doi.org/10.3390/diagnostics14182029 - 13 Sep 2024
Cited by 1 | Viewed by 794
Abstract
Background: The severity of systemic congestion is associated with increased portal vein flow pulsatility (PVP). Aim: To determine the usefulness of PVP as a marker of decongestion and prognosis in acute decompensated heart failure (ADHF) patients. Methods: 105 patients, 60% of whom were [...] Read more.
Background: The severity of systemic congestion is associated with increased portal vein flow pulsatility (PVP). Aim: To determine the usefulness of PVP as a marker of decongestion and prognosis in acute decompensated heart failure (ADHF) patients. Methods: 105 patients, 60% of whom were men, were hospitalized with ADHF, and their PVP index (PVPI) was calculated (maximum velocity–minimum velocity/maximum velocity) × 100 on admission and before discharge, along with their EVEREST score, inferior vena cava diameter (IVC), NT-proBNP, serum sodium, and glomerular filtration rate. A PVPI ≥ 50% was defined as a marker of systemic congestion. After treatment with loop diuretics, a decrease in PVPI of >50% before discharge was considered a marker of decongestion The patients were classified into two groups (G): G1-PVPI decrease ≥ 50% (54 patients) and G2-PVPI decrease < 50% (51 patients). Results: At discharge, compared to G2, G1 patients had lower mean PVPI (14.2 vs. 38.9; p < 0.001), higher serum Na (138 vs. 132 mmol/L, p = 0.03), and a higher number of patients with a significant (>30%) NT-proBNP decrease (42 vs. 27, p = 0.007). PVPI correlated with IVC (r = 0.55, p < 0.001), NT-proBNP (r = 0.21, p = 0.04), and serum Na (r = −0.202, p = 0.04). A total of 55% of patients had worsening renal failure (G1 63% vs. G2 48%, p = 0.17). After 90 days, G2 patients had higher mortality (27.45% vs. 3.7 p = 0.001) and rehospitalization (49.01% vs. 33.33%, p < 0.001). In multivariate regression analysis, PVPI was an independent predictor of rehospitalization (OR 1.05, 95% CI 1.00–1.10, p = 0.048). Conclusions: Portal vein flow pulsatility, a meaningful marker of persistent subclinical congestion, is related to short-term prognosis in ADHF patients. Full article
(This article belongs to the Special Issue Recent Advances in Echocardiography)
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<p>The two distinct types of portal vein Doppler patterns: continuous (<b>A</b>) and discontinuous (<b>B</b>).</p>
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<p>The patient selection process from this study.</p>
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<p>PVPI on admission and discharge in predicting patient readmissions PVPI (red)—admission, PVPI2 (blue)—discharge. On the left side are patients without rehospitalization and on the right side are patients with rehospitalization, showing that PVPI is higher both on admission and at discharge in patients with rehospitalization.</p>
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<p>ROC (Receiver Operating Characteristic) curve for the analysis of PVPI at discharge for predicting rehospitalization (blue line). Diagonal (red) line represents a random classifier, where the TPR (true positive rate) equals the FPR (false positive rate).</p>
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19 pages, 4180 KiB  
Article
Genomic Functional Analysis of Novel Radiation-Resistant Species of Knollia sp. nov. S7-12T from the North Slope of Mount Everest
by Xinyue Wang, Yang Liu, Zhiyuan Chen, Kexin Wang, Guangxiu Liu, Tuo Chen and Binglin Zhang
Microorganisms 2024, 12(9), 1748; https://doi.org/10.3390/microorganisms12091748 - 23 Aug 2024
Viewed by 1074
Abstract
Radiation protection is an important field of study, as it relates to human health and environmental safety. Radiation-resistance mechanisms in extremophiles are a research hotspot, as this knowledge has great application value in bioremediation and development of anti-radiation drugs. Mount Everest, an extreme [...] Read more.
Radiation protection is an important field of study, as it relates to human health and environmental safety. Radiation-resistance mechanisms in extremophiles are a research hotspot, as this knowledge has great application value in bioremediation and development of anti-radiation drugs. Mount Everest, an extreme environment of high radiation exposure, harbors many bacterial strains resistant to radiation. However, owing to the difficulties in studying them because of the extreme terrain, many remain unexplored. In this study, a novel species (herein, S7-12T) was isolated from the moraine of Mount Everest, and its morphology and functional and genomic characteristics were analyzed. The strain S7-12T is white in color, smooth and rounded, non-spore-forming, and non-motile and can survive at a UV intensity of 1000 J/m2, showing that it is twice as resistant to radiation as Deinococcus radiodurans. Radiation-resistance genes, including IbpA and those from the rec and CspA gene families, were identified. The polyphasic taxonomic approach revealed that the strain S7-12T (=KCTC 59114T =GDMCC 1.3458T) is a new species of the genus Knoellia and is thus proposed to be named glaciei. The in-depth study of the genome of strain S7-12T will enable us to gain further insights into its potential use in radiation resistance. Understanding how microorganisms resist radiation damage could reveal potential biomarkers and therapeutic targets, leading to the discovery of potent anti-radiation compounds, thereby improving human resistance to the threat of radiation. Full article
(This article belongs to the Section Microbiomes)
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<p>Neighbor-joining phylogenetic tree based on 16S rRNA gene sequences of the strain S7-12<sup>T</sup> and the type strains of other closely related species in the genus <span class="html-italic">Knoellia</span> and <span class="html-italic">Marihabitans</span>. <span class="html-italic">Marihabitans asiaticum</span> HG667<sup>T</sup> (AB286025) was used as an outgroup. Bar, 0.005 substitutions per nucleotide position.</p>
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<p>UBCG phylogenetic tree based on the up-to-date core gene set and pipeline of strain S7-12<sup>T</sup> and the type strains of other closely related species in the genus <span class="html-italic">Knoellia</span> and <span class="html-italic">Marihabitans</span>. <span class="html-italic">Marihabitans asiaticum</span> HG667<sup>T</sup> (AB286025) was used as an outgroup.</p>
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<p>Scanning electron microscope photos of the cells of strain S7-12<sup>T</sup>.</p>
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<p>Comparison of UV irradiation resistance and days to recovery of growth between strain S7-12<sup>T</sup> (<b>A</b>) and strain <span class="html-italic">D. radiodurans</span> (<b>B</b>).</p>
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<p>Genome comparisons of strain S7-12<sup>T</sup> and its related reference strains including the dDDH value (<b>A</b>), OrthoANI value (<b>B</b>), and AAI value (<b>C</b>). Furthermore, a–g represent S7-12<sup>T</sup>, <span class="html-italic">K. flava</span> TL1<sup>T</sup>, <span class="html-italic">K. subterranea</span> KCTC 19937<sup>T</sup>, <span class="html-italic">K. sinensis</span> KCTC 19936<sup>T</sup>, <span class="html-italic">K. remsis</span> ATCC BAA-1496<sup>T</sup>, <span class="html-italic">K. locipacati</span> DMZ1<sup>T</sup>, <span class="html-italic">K. aerolata</span> DSM 18566<sup>T</sup>, respectively.</p>
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<p>Distribution of CDS in 24 COG functional categories in strain S7-12<sup>T</sup>.</p>
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<p>Comparisons of orthologous protein groups in S7-12<sup>T</sup> and six related <span class="html-italic">Knoellia genomes</span>. (<b>A</b>) Percentage of core, dispensable, and unique genes in each of all eight genomes. (<b>B</b>) Venn diagram displaying the number of core and unique genes for each of the S7-12<sup>T</sup> and related type strains.</p>
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<p>Classification of COG functions annotated to different pan-genomes in the genus <span class="html-italic">Knoellia</span>.</p>
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<p>The number and functional gene classification of pan genomes between different <span class="html-italic">Knoellia</span> strains. The upset plot shows the number and functional classification of the core and unique genes in different <span class="html-italic">Knoellia</span> strains. The bar chart above represents the number of core and unique genes contained in each type of group. The strip at the bottom left represents the total number of genes in different <span class="html-italic">Knoellia</span> strains. The dot and line at the bottom right represent the types of different combinations (where only values above 10 and annotated genes are shown; further, unknown genes were not shown).</p>
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16 pages, 336 KiB  
Article
Leukemia Incidence by Occupation and Industry: A Cohort Study of 2.3 Million Workers from Ontario, Canada
by Konrad Samsel, Tanya Navaneelan, Nathan DeBono, Louis Everest, Paul A. Demers and Jeavana Sritharan
Int. J. Environ. Res. Public Health 2024, 21(8), 981; https://doi.org/10.3390/ijerph21080981 - 27 Jul 2024
Viewed by 1703
Abstract
Although a significant body of evidence has attributed certain occupational exposures with leukemia, such as benzene, formaldehyde, 1,3-butadiene and ionizing radiation, more research is needed to identify work environments at increased risk for this disease. Our study aimed to identify occupational and industry [...] Read more.
Although a significant body of evidence has attributed certain occupational exposures with leukemia, such as benzene, formaldehyde, 1,3-butadiene and ionizing radiation, more research is needed to identify work environments at increased risk for this disease. Our study aimed to identify occupational and industry groups associated with an elevated incidence of leukemia using a diverse cohort of workers’ compensation claimants from Ontario, Canada. A total of 2,363,818 workers in the Occupational Disease Surveillance System (ODSS) cohort, with claims between 1983–2019, were followed for malignant leukemia diagnoses up to 31 December 2019. We used a Cox proportional-hazards model to estimate the relative incidence of leukemia in specific occupation and industry groups. After adjusting for age and birth year, males in protective services (HR = 1.17, 95% CI = 1.02–1.35), metal machining (HR = 1.23, 95% CI = 1.07–1.41), transport (HR = 1.15, 95% CI = 1.06–1.25), and mining occupations (HR = 1.28, 95% CI = 1.02–1.60) had elevated risks of leukemia compared to other workers in the ODSS, with comparable findings by industry. Among female workers, slight risk elevations were observed among product fabricating, assembling, and repairing occupations, with other increased risks seen in furniture and fixture manufacturing, storage, and retail industries. These findings underscore the need for exposure-based studies to better understand occupational hazards in these settings. Full article
(This article belongs to the Special Issue Cancer Causes and Control)
19 pages, 1659 KiB  
Article
Prevalence of Specific Mood Profile Clusters among Elite and Youth Athletes at a Brazilian Sports Club
by Izabel Cristina Provenza de Miranda Rohlfs, Franco Noce, Carolina Wilke, Victoria R. Terry, Renée L. Parsons-Smith and Peter C. Terry
Sports 2024, 12(7), 195; https://doi.org/10.3390/sports12070195 - 18 Jul 2024
Viewed by 1091
Abstract
Those responsible for elite and youth athletes are increasingly aware of the need to balance the quest for superior performance with the need to protect the physical and psychological wellbeing of athletes. As a result, regular assessment of risks to mental health is [...] Read more.
Those responsible for elite and youth athletes are increasingly aware of the need to balance the quest for superior performance with the need to protect the physical and psychological wellbeing of athletes. As a result, regular assessment of risks to mental health is a common feature in sports organisations. In the present study, the Brazil Mood Scale (BRAMS) was administered to 898 athletes (387 female, 511 male, age range: 12–44 years) at a leading sports club in Rio de Janeiro using either “past week” or “right now” response timeframes. Using seeded k-means cluster analysis, six distinct mood profile clusters were identified, referred to as the iceberg, surface, submerged, shark fin, inverse iceberg, and inverse Everest profiles. The latter three profiles, which are associated with varying degrees of increased risk to mental health, were reported by 238 athletes (26.5%). The prevalence of these three mood clusters varied according to the response timeframe (past week > right now) and the sex of the athletes (female > male). The prevalence of the iceberg profile varied by athlete sex (male > female), and age (12–17 years > 18+ years). Findings supported use of the BRAMS as a screening tool for the risk of psychological issues among athletes in Brazilian sports organisations. Full article
(This article belongs to the Special Issue Advances in Sport Psychology)
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<p>Graphical representation of six mood profile clusters based on 15,692 participants [<a href="#B46-sports-12-00195" class="html-bibr">46</a>].</p>
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<p>Graphical representation of six mood profile clusters identified in the “right now” group.</p>
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<p>Graphical representation of six mood profile clusters identified in the “past week” group.</p>
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<p>Canonical discriminant functions for the “right now” group (n = 481).</p>
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<p>Canonical discriminant functions for the “past week” group (n = 417).</p>
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22 pages, 4148 KiB  
Article
Polyamine Catabolism Revisited: Acetylpolyamine Oxidase Plays a Minor Role due to Low Expression
by Olga N. Ivanova, Anna V. Gavlina, Inna L. Karpenko, Martin A. Zenov, Svetlana S. Antseva, Natalia F. Zakirova, Vladimir T. Valuev-Elliston, George S. Krasnov, Irina T. Fedyakina, Pavel O. Vorobyev, Birke Bartosch, Sergey N. Kochetkov, Anastasiya V. Lipatova, Dmitry V. Yanvarev and Alexander V. Ivanov
Cells 2024, 13(13), 1134; https://doi.org/10.3390/cells13131134 - 1 Jul 2024
Viewed by 1724
Abstract
Biogenic polyamines are ubiquitous compounds. Dysregulation of their metabolism is associated with the development of various pathologies, including cancer, hyperproliferative diseases, and infections. The canonical pathway of polyamine catabolism includes acetylation of spermine and spermidine and subsequent acetylpolyamine oxidase (PAOX)-mediated oxidation of acetylpolyamines [...] Read more.
Biogenic polyamines are ubiquitous compounds. Dysregulation of their metabolism is associated with the development of various pathologies, including cancer, hyperproliferative diseases, and infections. The canonical pathway of polyamine catabolism includes acetylation of spermine and spermidine and subsequent acetylpolyamine oxidase (PAOX)-mediated oxidation of acetylpolyamines (back-conversion) or their direct efflux from the cell. PAOX is considered to catalyze a non-rate-limiting catabolic step. Here, we show that PAOX transcription levels are extremely low in various tumor- and non-tumor cell lines and, in most cases, do not change in response to altered polyamine metabolism. Its enzymatic activity is undetectable in the majority of cell lines except for neuroblastoma and low passage glioblastoma cell lines. Treatment of A549 cells with N1,N11-diethylnorspermine leads to PAOX induction, but its contribution to polyamine catabolism remains moderate. We also describe two alternative enzyme isoforms and show that isoform 4 has diminished oxidase activity and isoform 2 is inactive. PAOX overexpression correlates with the resistance of cancer cells to genotoxic antitumor drugs, indicating that PAOX may be a useful therapeutic target. Finally, PAOX is dispensable for the replication of various viruses. These data suggest that a decrease in polyamine levels is achieved predominantly by the secretion of acetylated spermine and spermidine rather than by back-conversion. Full article
(This article belongs to the Special Issue Redox and Metabolic Profile of Cancer)
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<p>Transcription of genes encoding polyamine-metabolizing proteins in tumor- and non-tumor cell lines. (<b>a</b>) RNA-seq data depicting relative levels of mRNAs encoding proteins of polyamine metabolism and other proteins in tumor Huh7.5, HepG2, A549, HOS, and DBTRG cell lines as well as in non-tumor primary human hepatocytes (PHH) and hepatocyte-like HepaRG cells, normalized to levels of GUS mRNA and represented as binary logarithms of fold change LogFC (n = 3 for all datasets with the exception of data for A549 cells—n = 2). (<b>b</b>) Quantification of relative mRNA levels encoding enzymes and regulatory proteins of polyamine metabolism in cell lines by RT-qPCR, normalized to the levels of GUS mRNA (n = 3). (<b>c</b>) Relative levels of mRNAs encoding polyamine-metabolizing enzymes, normalized to GUS mRNA levels and to levels in untreated cells and expressed in Log2FC. Data are shown as means ± SD.</p>
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<p>PAOX activity is below the limit of detection in various human cell lines. A549 (<b>a</b>), DU145 (<b>b</b>), HeLa (<b>c</b>), and Huh7.5 (<b>d</b>) cells were lysed on ice; 5 nmol of N<sup>1</sup>-acetylspermine (AcSpm) was added to the clarified lysates that were kept at 37 °C for 30 min; and the possible conversion of AcSpm into spermidine (Spd) was monitored by HPLC analysis. Then, 1,6-Diaminohexane (Hex) and 1,7-diaminoheptane (Hep) were added to reaction mixtures as internal standards.</p>
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<p>In A549 cells treated with DENSpm, PAOX is expressed but plays only a minor role in polyamine catabolism. Polyamine levels were analyzed by HPLC in untreated A549 cells (<b>a</b>), treated with 10 µM DENSpm alone (<b>b</b>), or together with 50 µM MDL72.527 (<b>c</b>), and the results of quantification are presented as means ± S.D. (n = 3) (<b>e</b>). Panel (<b>d</b>) represents the elution profile for a control mixture of spermine (Spm), spermidine (Spd), and N1-acetylspermine (AcSpm), as well as 1,6-diaminohexane (Hex) and 1,7-diaminoheptane (Hep) used as internal standards. All chromatograms are representative of three independent analyses.</p>
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<p>Alternative PAOX isoforms have diminished enzymatic activity. (<b>a</b>) Comparison of open reading frames of PAOX1, PAOX4, and PAOX5 mRNAs. Exons present in all isoforms are in light blue; the exons that are missing in short isoforms are in green and orange. (<b>b</b>) Alignment of PAOX1, PAOX2, and PAOX4 sequences. Amino acid residues of PAOX1 and the same residues of alternative isoforms are given in gray. Amino acid residues that are critical for substrate binding and catalysis and are conserved between human and murine PAOX—in yellow and homologous—in blue. (<b>c</b>) Analysis of GC content in the protein coding region of PAOX1 mRNA. (<b>d</b>) Representative HPLC profiles showing the conversion of AcSpm into Spd by PAOX isoforms.</p>
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<p>Overexpression of PAOX1 does not affect the replication of RNA and DNA viruses. Naïve Huh7.5 or A549 cells (blue bars) or the cells overexpressing PAOX1 (red bars) were infected with (<b>a</b>) hepatitis C virus (HCV), (<b>b</b>) severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), (<b>c</b>,<b>d</b>) influenza A or B viruses (IAV, IBV), (<b>e</b>) poliovirus type 1 (PV1), (<b>f</b>) Newcastle Disease virus (NDV), (<b>g</b>) mumps virus (MuV), (<b>h</b>) Semliki virus (SeV), or (<b>i</b>) vaccinia virus (VacV). The graphs represent mean levels of infection ± S.D. (n = 3).</p>
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<p>Expression of PAOX does not induce resistance of hepatocarcinoma or glioblastoma cells to genotoxic antitumor drugs. Lung carcinoma (<b>a</b>–<b>c</b>), hepatocarcinoma (<b>d</b>–<b>f</b>) or glioblastoma (<b>g</b>) cells were seeded on 96-well plates, treated with doxorubicin (<b>a</b>,<b>d</b>,<b>g</b>), cisplatin (<b>b</b>,<b>e</b>) or temozolomide (<b>c</b>,<b>f</b>) for 48 h, and viability was assessed by the MTT test. Data are shown as means ± SD. * <span class="html-italic">p</span> ≤ 0.05 according to a mixed ANOVA with Sidak’s post-hoc test.</p>
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13 pages, 2716 KiB  
Review
After the Storm: Persistent Molecular Alterations Following HCV Cure
by Coline Seurre, Armando Andres Roca Suarez, Barbara Testoni, Fabien Zoulim and Boyan Grigorov
Int. J. Mol. Sci. 2024, 25(13), 7073; https://doi.org/10.3390/ijms25137073 - 27 Jun 2024
Viewed by 1767
Abstract
The development of direct-acting antivirals (DAAs) against hepatitis C virus (HCV) has revolutionized the management of this pathology, as their use allows viral elimination in a large majority of patients. Nonetheless, HCV remains a major public health problem due to the multiple challenges [...] Read more.
The development of direct-acting antivirals (DAAs) against hepatitis C virus (HCV) has revolutionized the management of this pathology, as their use allows viral elimination in a large majority of patients. Nonetheless, HCV remains a major public health problem due to the multiple challenges associated with its diagnosis, treatment availability and development of a prophylactic vaccine. Moreover, HCV-cured patients still present an increased risk of developing hepatic complications such as hepatocellular carcinoma. In the present review, we aim to summarize the impact that HCV infection has on a wide variety of peripheral and intrahepatic cell populations, the alterations that remain following DAA treatment and the potential molecular mechanisms implicated in their long-term persistence. Finally, we consider how recent developments in single-cell multiomics could refine our understanding of this disease in each specific intrahepatic cell population and drive the field to explore new directions for the development of chemo-preventive strategies. Full article
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<p>HCV cycle and the viral components targeted by DAA therapy. DAAs inhibit several HCV non-structural proteins, acting at different steps of the HCV cycle. NS3/4A inhibitors prevent polyprotein cleavage in the ER, thus blocking the formation of mature viral proteins. NS5B inhibitors target the RdRp, thereby inhibiting HCV translation and replication. NS5A inhibitors induce accumulation of this protein in the ER compartment, thus blocking its function during HCV replication and assembly. DAAs, direct-acting antivirals; ER, endoplasmic reticulum; HCV, hepatitis C virus; RdRp, RNA-dependent RNA polymerase; LDs, lipid droplets.</p>
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<p>Persistent molecular alterations following HCV cure. (<b>A</b>) In HCV-cured individuals, blood lipid levels may return to normal or even increase after DAA treatment, potentially increasing the risk of cardiovascular events. (<b>B</b>) Depending on the patient’s fibrosis score, glucose metabolism improves in non-cirrhotic patients or remains altered in cirrhotic patients. (<b>C</b>) HCV infection impacts myeloid cells (e.g., Kupffer cells) and their phenotype is not fully reverted after DAA treatment, as high levels of activation markers can still be detected (e.g., sCD163). (<b>D</b>) HCV impairs the function of several lymphoid cell populations, which are not fully restored post-DAA treatment: the global NK receptor repertoire is not restored (top), the number of MAIT cells increases but their cytotoxic abilities remain altered (center) and T-cell exhaustion phenotypes persist (bottom). (<b>E</b>) The persistence of HCV-induced epigenetic alterations (e.g., H3K9ac, H3K27ac) on ISGs, oncogenes and TSGs could contribute to the development of immune and metabolic complications, despite HCV elimination. CTLA4, cytotoxic T-lymphocyte associated protein 4; DAAs, direct-acting antivirals; HCV, hepatitis C virus; IFN, interferon; IR, insulin resistance; IRS-1, insulin receptor substrate-1; ISGs, interferon-stimulated genes; LDs, lipid droplets; MAIT, mucosal-associated invariant T cells; NK, natural killer cells; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; TSGs, tumor suppressor genes.</p>
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19 pages, 4389 KiB  
Article
Exploring the Complexity of the Human Respiratory Virome through an In Silico Analysis of Shotgun Metagenomic Data Retrieved from Public Repositories
by Talya Conradie, Jose A. Caparros-Martin, Siobhon Egan, Anthony Kicic, Sulev Koks, Stephen M. Stick and Patricia Agudelo-Romero
Viruses 2024, 16(6), 953; https://doi.org/10.3390/v16060953 - 13 Jun 2024
Cited by 2 | Viewed by 1693
Abstract
Background: Respiratory viruses significantly impact global morbidity and mortality, causing more disease in humans than any other infectious agent. Beyond pathogens, various viruses and bacteria colonize the respiratory tract without causing disease, potentially influencing respiratory diseases’ pathogenesis. Nevertheless, our understanding of respiratory microbiota [...] Read more.
Background: Respiratory viruses significantly impact global morbidity and mortality, causing more disease in humans than any other infectious agent. Beyond pathogens, various viruses and bacteria colonize the respiratory tract without causing disease, potentially influencing respiratory diseases’ pathogenesis. Nevertheless, our understanding of respiratory microbiota is limited by technical constraints, predominantly focusing on bacteria and neglecting crucial populations like viruses. Despite recent efforts to improve our understanding of viral diversity in the human body, our knowledge of viral diversity associated with the human respiratory tract remains limited. Methods: Following a comprehensive search in bibliographic and sequencing data repositories using keyword terms, we retrieved shotgun metagenomic data from public repositories (n = 85). After manual curation, sequencing data files from 43 studies were analyzed using EVEREST (pipEline for Viral assEmbly and chaRactEriSaTion). Complete and high-quality contigs were further assessed for genomic and taxonomic characterization. Results: Viral contigs were obtained from 194 out of the 868 FASTQ files processed through EVEREST. Of the 1842 contigs that were quality assessed, 8% (n = 146) were classified as complete/high-quality genomes. Most of the identified viral contigs were taxonomically classified as bacteriophages, with taxonomic resolution ranging from the superkingdom level down to the species level. Captured contigs were spread across 25 putative families and varied between RNA and DNA viruses, including previously uncharacterized viral genomes. Of note, airway samples also contained virus(es) characteristic of the human gastrointestinal tract, which have not been previously described as part of the lung virome. Additionally, by performing a meta-analysis of the integrated datasets, ecological trends within viral populations linked to human disease states and their biogeographical distribution along the respiratory tract were observed. Conclusion: By leveraging publicly available repositories of shotgun metagenomic data, the present study provides new insights into viral genomes associated with specimens from the human respiratory tract across different disease spectra. Further studies are required to validate our findings and evaluate the potential impact of these viral communities on respiratory tract physiology. Full article
(This article belongs to the Special Issue Virus Bioinformatics 2024)
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<p>The bibliographic search and data collection strategy used. A flow diagram depicting the two search strategies used for data collection, with the blue arrows representing search strategy 1, and orange arrows representing search strategy 2.</p>
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<p>The study-filtering strategy used. The flow diagram graphically represents the search strategy employed to identify relevant sequence data from public repositories. The number of studies excluded at each filtering step and the reasons for excluding these bioprojects are also indicated. A final 43 studies were identified that matched the selection criteria and were used for analysis in the present study.</p>
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<p>The distribution of eukaryotic viral contigs and bacteriophage contigs captured through EVEREST. (<b>A</b>) A pie chart depicting the 1414 captured contigs assigned to taxonomy, from which 1193 (84%) were identified as bacteriophages (red), and 221 (16%) were identified as eukaryotic viruses (blue). (<b>B</b>) Baltimore classification of viral contigs. The bar plot summarizes the number of eukaryote virus (blue) and bacteriophage (red) contigs within the indicated Baltimore classes, including those that could not be classified (unclassified).</p>
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<p>The distribution of taxonomic classification following the lowest common ancestor method included in EVEREST. (<b>A</b>) A bar plot showing the number of eukaryotic (blue) and bacteriophage (red) viral contigs classified at the indicated taxonomy ranks. (<b>B</b>). Taxonomic classification at the family level. The bar plots represent the 25 families identified among the bacteriophage (red) and eukaryotic (blue) viral contigs.</p>
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<p>Genome quality assessment of the viral contigs and taxonomic characterization of the complete and high-quality genomes. (<b>A</b>) Bar plots represent the distribution of the 1842 contigs classified based on their quality as determined by CheckV [<a href="#B34-viruses-16-00953" class="html-bibr">34</a>]. Blue bars represent viral genomes, while red bars represent proviruses. (<b>B</b>) Bar plots representing the number of complete (red) and high-quality (blue) genomes that were assigned at each taxonomic rank. (<b>C</b>) Bar plots representing the number of complete (red) or high-quality (blue) viral genomes that were assigned to the indicated viral families.</p>
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<p>An overview of the viral contigs recovered from the bioprojects analyzed in this study grouped by taxonomic viral families. The scatter plot shows the correlation between GC content and viral contig size. Density plots of viral families on the top and right sides represent contig size and GC content, respectively.</p>
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<p>(<b>A</b>–<b>F</b>) A projection of the samples included in this study in the two first components of the PCA model. (<b>A</b>) A biplot showing the PCA score plot and the loading plot. The left and bottom axes represent the PCA scores of the samples, and the top and right axes indicate how strong each feature (vector) influences the principal components. Vectors represent features with at least a 0.6 correlation coefficient with any of the two first components of the PCA model, and their project values on each principal component indicates how much weight they have on those specific components of the PCA model. The unclassified family within Caudovirales is negatively correlated with component 1 and represents the major source of variation along this component. Conversely, <span class="html-italic">Siphoviridae</span> exhibit a positive correlation with component 1. Distribution across component 2 is mostly driven by <span class="html-italic">Siphoviridae</span> (positive correlation) and to a lesser extent by the unclassified family within Caudovirales. For each PCA graph, dots represent individual samples. Samples are labelled based on whether they were obtained from adults (blue) or children (orange) (<b>B</b>), whether they were obtained from healthy individuals (orange) or individuals with disease (blue) (<b>C</b>), whether they were obtained from the lower (blue) or upper (orange) respiratory tract (<b>D</b>), the specific respiratory pathology (<b>E</b>), or the type of specimen used to sample the airways (<b>F</b>). ARI: acute respiratory infection; CF: cystic fibrosis; LTR: lung transplant recipient; BAL: bronchoalveolar lavage; NPS: nasopharyngeal swabs; NSA: nasopharyngeal aspirates.</p>
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<p>Shannon index diversity of viral families identified in lung samples. (<b>A</b>–<b>E</b>) Box plots displaying the comparison in alpha viral diversity between samples from the upper and lower respiratory tract (<b>A</b>), between samples collected from adults and children (<b>B</b>), between samples obtained from healthy controls or individuals with disease (<b>C</b>), between samples obtained from patients with different respiratory pathologies and healthy controls (<b>D</b>), and between bronchoalveolar lavage fluid and other type of specimens from the respiratory tract (<b>E</b>). Red dots represent individual datapoints. Only groups containing more than three datapoints were included in these analyses. The density plots (shaded blue area) represent the probability distribution for each data group. Differences between the indicated groups were evaluated using a Wilcoxon rank sum test and the resulting <span class="html-italic">p</span>-values are indicated in each panel. In A and B, notches in the boxplot represent the 95% confidence interval for the median. In D and E, <span class="html-italic">p</span>-values were corrected using the Bonferroni method. ARI: acute respiratory infection; LTR: lung transplant recipient; BAL: bronchoalveolar lavage; NSA: nasopharyngeal aspirates; NPS: nasopharyngeal swabs.</p>
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15 pages, 1122 KiB  
Review
Co-Transcriptional Regulation of HBV Replication: RNA Quality Also Matters
by Guillaume Giraud, Khadija El Achi, Fabien Zoulim and Barbara Testoni
Viruses 2024, 16(4), 615; https://doi.org/10.3390/v16040615 - 16 Apr 2024
Cited by 2 | Viewed by 1886
Abstract
Chronic hepatitis B (CHB) virus infection is a major public health burden and the leading cause of hepatocellular carcinoma. Despite the efficacy of current treatments, hepatitis B virus (HBV) cannot be fully eradicated due to the persistence of its minichromosome, or covalently closed [...] Read more.
Chronic hepatitis B (CHB) virus infection is a major public health burden and the leading cause of hepatocellular carcinoma. Despite the efficacy of current treatments, hepatitis B virus (HBV) cannot be fully eradicated due to the persistence of its minichromosome, or covalently closed circular DNA (cccDNA). The HBV community is investing large human and financial resources to develop new therapeutic strategies that either silence or ideally degrade cccDNA, to cure HBV completely or functionally. cccDNA transcription is considered to be the key step for HBV replication. Transcription not only influences the levels of viral RNA produced, but also directly impacts their quality, generating multiple variants. Growing evidence advocates for the role of the co-transcriptional regulation of HBV RNAs during CHB and viral replication, paving the way for the development of novel therapies targeting these processes. This review focuses on the mechanisms controlling the different co-transcriptional processes that HBV RNAs undergo, and their contribution to both viral replication and HBV-induced liver pathogenesis. Full article
(This article belongs to the Special Issue HBV Transcriptional and Post-transcriptional Regulation)
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Figure 1

Figure 1
<p>Regulators of HBV cccDNA transcription. Examples of host or viral factors activating (green) or silencing (red) cccDNA transcriptional activity associated with an active (green nucleosomes) or a silent (red nucleosomes) chromatin [<a href="#B37-viruses-16-00615" class="html-bibr">37</a>,<a href="#B38-viruses-16-00615" class="html-bibr">38</a>,<a href="#B39-viruses-16-00615" class="html-bibr">39</a>,<a href="#B40-viruses-16-00615" class="html-bibr">40</a>,<a href="#B43-viruses-16-00615" class="html-bibr">43</a>,<a href="#B47-viruses-16-00615" class="html-bibr">47</a>,<a href="#B48-viruses-16-00615" class="html-bibr">48</a>,<a href="#B49-viruses-16-00615" class="html-bibr">49</a>,<a href="#B50-viruses-16-00615" class="html-bibr">50</a>,<a href="#B52-viruses-16-00615" class="html-bibr">52</a>,<a href="#B53-viruses-16-00615" class="html-bibr">53</a>,<a href="#B54-viruses-16-00615" class="html-bibr">54</a>,<a href="#B56-viruses-16-00615" class="html-bibr">56</a>,<a href="#B57-viruses-16-00615" class="html-bibr">57</a>,<a href="#B58-viruses-16-00615" class="html-bibr">58</a>,<a href="#B59-viruses-16-00615" class="html-bibr">59</a>,<a href="#B60-viruses-16-00615" class="html-bibr">60</a>,<a href="#B62-viruses-16-00615" class="html-bibr">62</a>,<a href="#B63-viruses-16-00615" class="html-bibr">63</a>,<a href="#B65-viruses-16-00615" class="html-bibr">65</a>,<a href="#B66-viruses-16-00615" class="html-bibr">66</a>,<a href="#B67-viruses-16-00615" class="html-bibr">67</a>,<a href="#B68-viruses-16-00615" class="html-bibr">68</a>,<a href="#B70-viruses-16-00615" class="html-bibr">70</a>,<a href="#B74-viruses-16-00615" class="html-bibr">74</a>,<a href="#B75-viruses-16-00615" class="html-bibr">75</a>,<a href="#B76-viruses-16-00615" class="html-bibr">76</a>,<a href="#B77-viruses-16-00615" class="html-bibr">77</a>]. The image was created using Biorender.com.</p>
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<p>Dual role of m6A methylation of HBV RNAs. HBV RNAs are co-transcriptionally methylated at position 1907 corresponding to the basis of the ε-loop. The methylation is ensured by the two methyltransferases METTL3 and METTL14, which are recruited during HBV transcription by the HBx viral protein (top part). This important secondary structure is found twice in pgRNA but only once in sub-genomic RNAs. Depending on the localization of the ε-loop, m<sup>6</sup>A methylation of HBV RNAs has different effects. Indeed, modification of the residue of the 5′ structure allows its recognition by the viral Core protein and its subsequent encapsidation and reverse transcription by the viral polymerase, thus initiating a new cycle of viral replication. In contrast, m<sup>6</sup>A methylation at the 3′ ε-loop allows its recognition by the methylation reader YTHDC2, which recruits the ISG20 exonuclease and impairs HBV RNA stability. DR, direct repeat; RNAPII, RNA polymerase II; ISG20, interferon stimulated gene 20; YTHDC2, YTH domain containing 2; METTL, Methyltransferase-like. The figure was created using Biorender.com.</p>
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13 pages, 769 KiB  
Article
Mood Profile Clusters among Greek Exercise Participants and Inactive Adults
by Peter C. Terry, Renée L. Parsons-Smith, Symeon P. Vlachopoulos and Andrew M. Lane
Sci 2024, 6(2), 18; https://doi.org/10.3390/sci6020018 - 26 Mar 2024
Cited by 1 | Viewed by 1924
Abstract
Mood profile clusters have previously been identified in several cultural contexts. In the present study, six mood profile clusters referred to as the iceberg, inverse Everest, inverse iceberg, shark fin, submerged, and surface profiles, were investigated in a Greek population. The names of [...] Read more.
Mood profile clusters have previously been identified in several cultural contexts. In the present study, six mood profile clusters referred to as the iceberg, inverse Everest, inverse iceberg, shark fin, submerged, and surface profiles, were investigated in a Greek population. The names of the mood profiles reflect how they appear after raw scores for Tension, Depression, Anger, Vigor, Fatigue, and Confusion (in that order), are converted to T-scores and depicted graphically. A Greek translation of the Brunel Mood Scale (BRUMS-Greek) was completed by 1786 adults, comprising 1417 exercise participants and 369 physically inactive adults (male = 578, female = 1208) aged 18–64 years (M = 34.73 ± 11.81 years). Although the male–female ratio emphasized females, sample sizes of over 500 suggest some degree of representativeness. Seeded k-means cluster analysis clearly identified the six hypothesized mood profiles. Men were over-represented for the iceberg profile. For age, the 18–25 years group were under-represented for the iceberg profile, whereas the 46–55 and 56+ years groups were over-represented. The 56+ years group were under-represented for the inverse Everest, and the 18–25 years group were over-represented for the shark fin profile. For body mass index (BMI), participants in the obese weight category were over-represented for the inverse iceberg and shark fin profiles and under-represented for the submerged profile. Active participants were over-represented for the iceberg and submerged profiles, and under-represented for the inverse Everest, inverse iceberg, and surface profiles. Findings supported the cross-cultural equivalence of the mood profile clusters and confirmed the link between physical inactivity, obesity, and negative mood profiles. Full article
(This article belongs to the Special Issue Feature Papers—Multidisciplinary Sciences 2023)
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Figure 1
<p>Graphical representation of the 6-cluster solution (<span class="html-italic">N</span> = 1786).</p>
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<p>Graphical representation of the canonical discriminant functions (<span class="html-italic">N</span> = 1786).</p>
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