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5 pages, 785 KiB  
Editorial
Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus
by Ioannis Parodis and Christopher Sjöwall
Int. J. Mol. Sci. 2024, 25(18), 9965; https://doi.org/10.3390/ijms25189965 (registering DOI) - 15 Sep 2024
Abstract
The immense heterogeneity of the chronic, inflammatory, autoimmune disease systemic lupus erythematosus (SLE), both with regard to immunological aberrancies and clinical manifestations, poses diagnostic difficulties and challenges in the management of patients [...] Full article
(This article belongs to the Special Issue Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus)
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Figure 1
<p>Visual representation of the content of the Special Issue. AGEs: advanced glycation end-products; anti-oxLDL: anti-oxidised low-density lipoprotein; HSP: heat shock protein; IL: interleukin; sTfR: soluble transferrin.</p>
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18 pages, 702 KiB  
Article
Are Sleep Parameters and Chronotype Associated with Eating Disorder Risk? A Cross-Sectional Study of University Students in Spain
by Tomás Olivo Martins-de-Passos, Arthur E. Mesas, Nuria Beneit, Valentina Díaz-Goñi, Fernando Peral-Martinez, Shkelzen Cekrezi, Vicente Martinez-Vizcaino and Estela Jimenez-Lopez
J. Clin. Med. 2024, 13(18), 5482; https://doi.org/10.3390/jcm13185482 (registering DOI) - 15 Sep 2024
Abstract
Objectives: Eating disorders (EDs) have emerged as a growing public health concern. However, the role of sleep in this context remains underexplored. The aim of this cross-sectional study was to determine the associations between sleep parameters and chronotype with ED risk in a [...] Read more.
Objectives: Eating disorders (EDs) have emerged as a growing public health concern. However, the role of sleep in this context remains underexplored. The aim of this cross-sectional study was to determine the associations between sleep parameters and chronotype with ED risk in a sample of university students in Spain. Methods: ED risk was assessed via the Sick, Control, One stone, Fat, Food Questionnaire, and sleep quality was assessed via the Pittsburgh Sleep Quality Index. Other sleep parameters and chronotypes were self-reported. Sociodemographic, body composition, lifestyle, and depressive symptom data were collected. Logistic and linear regression models adjusted for the main confounders were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the study associations. Results: A total of 403 students (70.2% female) aged 18 to 30 years participated in the study. Those reporting poor sleep quality (OR = 1.85, 95% CI 1.08–3.17, p = 0.025) and ≤6 h of night-time sleep duration (OR = 4.14, 95% CI 2.00–8.57, p < 0.01) were more likely to be at risk of EDs in the adjusted analyses. The association between night-time sleep duration and the risk of ED did not remain significant when we adjusted for sleep quality. In addition, an evening chronotype was associated with an increased risk of EDs (OR = 1.68, 95% CI 1.07–2.66, p = 0.039) only before adjustment for confounders. Conclusions: Among university students, poorer sleep quality was cross-sectionally associated with EDs. Future prospective studies are needed to examine whether promoting sleep quality may serve as an effective strategy for preventing the risk of EDs. Full article
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<p>Logistic regression models of the risk of EDs (dependent variable: SCOFF score ≥ 2 points) in relation to night-time sleep duration (as a continuous variable) and the global sleep quality index (measured by the PSQI). The data are represented by dots (odds ratios) and lines (95% confidence intervals). (<b>a</b>) Crude and adjusted associations between the PSQI global score and ED risk; (<b>b</b>) crude and adjusted associations between night-time sleep duration and ED risk; (<b>c</b>) combined associations between sleep quality and night-time sleep duration in the regression model for ED groups. Note that night-time sleep duration lost statistical significance, whereas sleep quality remained significantly associated with the risk of EDs.</p>
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16 pages, 1683 KiB  
Article
De-Escalation of Axillary Surgery in Clinically Node-Positive Breast Cancer Patients Treated with Neoadjuvant Therapy: Comparative Long-Term Outcomes of Sentinel Lymph Node Biopsy versus Axillary Lymph Node Dissection
by Corrado Tinterri, Erika Barbieri, Andrea Sagona, Simone Di Maria Grimaldi and Damiano Gentile
Cancers 2024, 16(18), 3168; https://doi.org/10.3390/cancers16183168 (registering DOI) - 15 Sep 2024
Abstract
Backgrounds: This study compares the long-term outcomes of axillary lymph node dissection (ALND) versus sentinel lymph node biopsy (SLNB) in clinically node-positive (cN+) breast cancer (BC) patients treated with neoadjuvant therapy (NAT).Methods: We conducted a retrospective analysis of 322 cN+ BC patients who [...] Read more.
Backgrounds: This study compares the long-term outcomes of axillary lymph node dissection (ALND) versus sentinel lymph node biopsy (SLNB) in clinically node-positive (cN+) breast cancer (BC) patients treated with neoadjuvant therapy (NAT).Methods: We conducted a retrospective analysis of 322 cN+ BC patients who became clinically node-negative (ycN0) post-NAT. Patients were categorized based on the final type of axillary surgery performed: ALND or SLNB. Recurrence-free survival (RFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were evaluated and compared between the two groups. Results: Patients in the SLNB group had significantly better 3-, 5-, and 10-year RFS, DDFS, OS, and BCSS compared to those in the ALND group. The SLNB group also had a higher proportion of patients achieving pathologic complete response (pCR). Multivariate analysis identified pCR, ypN0 status, and SLNB as favorable prognostic factors for all survival metrics. Axillary recurrence rates were low for both groups (0.6–2.1%). Conclusions: SLNB may be a safe and effective alternative to ALND for selected cN+ BC patients who convert to ycN0 after NAT. These findings suggest that careful patient selection is crucial, and further research is needed to validate these results in more comparable populations. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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<p>Curves depicting recurrence-free survival and distant disease-free survival in clinically node-positive breast cancer patients who underwent neoadjuvant therapy and axillary surgery (sentinel lymph node biopsy versus axillary lymph node dissection). Footnotes: SLNB: Sentinel lymph node biopsy, ALND: Axillary lymph node dissection.</p>
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<p>Overall survival and breast cancer-specific survival curves of clinically node-positive patients with breast cancer treated with neoadjuvant therapy and axillary surgery (sentinel lymph node biopsy versus axillary lymph node dissection). Footnotes: SLNB: Sentinel lymph node biopsy, ALND: Axillary lymph node dissection.</p>
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<p>Comparison of recurrence-free survival and distant disease-free survival curves between ypN0 and ypN+ patients. Footnotes: ypN0: Complete pathologic axillary response, ypN+: Residual axillary disease.</p>
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<p>Comparison of overall survival and breast cancer-specific survival curves between ypN0 and ypN+ patients. Footnotes: ypN0: Complete pathologic axillary response, ypN+: Residual axillary disease.</p>
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30 pages, 3287 KiB  
Article
GABA(A) Receptor Activation Drives GABARAP–Nix Mediated Autophagy to Radiation-Sensitize Primary and Brain-Metastatic Lung Adenocarcinoma Tumors
by Debanjan Bhattacharya, Riccardo Barrile, Donatien Kamdem Toukam, Vaibhavkumar S. Gawali, Laura Kallay, Taukir Ahmed, Hawley Brown, Sepideh Rezvanian, Aniruddha Karve, Pankaj B. Desai, Mario Medvedovic, Kyle Wang, Dan Ionascu, Nusrat Harun, Subrahmanya Vallabhapurapu, Chenran Wang, Xiaoyang Qi, Andrew M. Baschnagel, Joshua A. Kritzer, James M. Cook, Daniel A. Pomeranz Krummel and Soma Senguptaadd Show full author list remove Hide full author list
Cancers 2024, 16(18), 3167; https://doi.org/10.3390/cancers16183167 (registering DOI) - 15 Sep 2024
Abstract
In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. We find that a [...] Read more.
In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. We find that a GABA(A) receptor activator, AM-101, impairs the viability and clonogenicity of NSCLC primary and brain-metastatic cells. Employing a human-relevant ex vivo ‘chip’, AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide-disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP–Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Cancer Treatment)
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Figure 1
<p>Activation of GABA(A) receptors triggers cell depolarization and death. (<b>A</b>) Type-A GABA (GABA(A)) receptors are ligand-gated chloride anion channels. Left, GABA(A) receptors move chloride anions (Cl<sup>−</sup>) out of the cell during embryonic stages of development but into the cell in mature or developed stages and are thereby depolarizing or hyperpolarizing, respectively. Right, GABA(A) receptors form hetero-pentameric structures with an α2β2γ1 stoichiometry. Two molecules of GABA (purple spheres) bind at the α-β interfaces to ‘activate’ receptor function (chloride anion transport). Commonly, one molecule of benzodiazepine (red sphere) binds at the α-γ interface to enhance flow of chloride anions. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a> (<b>B</b>) Left, GABRA5 or α5 protein in NSCLC patient-derived primary cell lines representing three histological subtypes (adenocarcinoma, A549, H1792; squamous cell, H1703; large cell, H460). Right, GABRA5 or α5 protein expression in patient-derived lung adenocarcinoma brain-metastatic cell line (UW-lung-16), and primary human lung adenocarcinoma cell line (H1792). The presence of protein confirmed by Western blotting of SDS (4–15% gradient) gels. GAPDH is used as a loading control. Cropped gel lanes from original blots, see <a href="#app1-cancers-16-03167" class="html-app">Figure S8</a>. (<b>C</b>) NSCLC primary (left) and brain-metastatic (right) patient tumor tissue from the same patient (or matched) stains for GABRA5 or α5 protein, as shown by immunohistochemistry staining at 30× magnification. Arrows show GABRA5 staining in large tumor cells within primary and brain-metastatic lung adenocarcinoma tissue sections. (<b>D</b>) AM-101 (QH-II-066) (274.32 g/mol) is a benzodiazepine analog (left). A representative single cell patch clamp electrophysiology trace of patient-derived adenocarcinoma lung cell line H1792 (right). Cells are responsive to GABA or electro-physiologically functional. Perfusion of cells with AM-101 plus GABA elicits an enhanced response, indicating that GABA(A) receptors are benzodiazepine-responsive or ‘activated’. Representative raw current trace recording with the following parameters: GABA, 1 µM; AM-101, 4 µM. (<b>E</b>) Lung adenocarcinoma (H1792) cells incubated with AM-101 are depolarized, as assessed by the TMRE assay and Fluorescence-Activated Cell Sorting (FACS) analysis. Shown is the degrees of depolarization relative to DMSO-alone treatment and FCCP, which provide negative and positive controls in this experiment, respectively. Parameters: AM-101, 2 µM; FCCP, 10 µM. (<b>F</b>) Half-maximal inhibitory concentration (IC<sub>50</sub>) values of patient-derived lung primary and brain-metastatic lines representative of three histological lung cancer subtypes, as measured using a viability (MTS) assay and AM-101. Indicated is the KRAS and TP53 mutational status of lines, where M represents mutant, and WT represents wild-type.</p>
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<p>GABA(A) receptor activation potentiates radiation. (<b>A</b>) Illustration of a human-relevant ex vivo ‘chip’ employed to test AM-101 and docetaxel (DTX) efficacy. Lung adenocarcinoma cancer cells (H1792-GFP, green) can be co-cultured with primary human alveolar and pulmonary endothelial cells and exposed to air (air–liquid interface) on-chip. Cancer cells form clusters that grow and spread through the epithelial compartment of the chip over time (<a href="#app1-cancers-16-03167" class="html-app">Figure S3</a>). (<b>B</b>) Testing of AM-101 and DTX ex vivo or ‘on-chip’ reveals that AM-101 is as cytotoxic as DTX but at a significantly lower concentration. The chip is a 3-D ex vivo model, and, to achieve the cytotoxicity that AM-101 generates in 5 μM concentration, DTX is required in 10 mM concentrations. To determine <span class="html-italic">p</span>-values between two groups, one-way ANOVA with Tukey’s multiple comparisons test was performed. ** <span class="html-italic">p</span> &lt; 0.001 and *** <span class="html-italic">p</span> &lt; 0.0001. Images acquired from chips were subjected to background signal removal and analysis using Fiji (Image J). To generate bar graphs, acquired images were evaluated through background subtraction and signal thresholding. Subsequently, particle analysis was performed using a Fiji plugin to estimate the number of GFP+ cells per field of view under each testing condition. (<b>C</b>) A clonogenic assay was employed to examine the radio-sensitizing effect of AM-101 in H1792 cells. The survival curves showing surviving fraction of H1792 cells following radiation exposure at two separate doses with and without AM-101. Cell cultures were treated with either AM-101 (2.5 μM) combined with two separate doses of radiation (3 Gy and 6 Gy) versus DMSO (vehicle) and two separate doses of radiation (3 Gy and 6 Gy). H1792 cells in culture were treated with AM-101 (2.5 μM) or DMSO (vehicle) 1 h before radiation and maintained in the medium after irradiation. According to the experimental design the media containing AM-101 or DMSO in all groups was replaced with fresh media 72 h after treatment. Colony-forming efficiency was determined 14 days later, and survival curves were generated. The vehicle in this experiment is DMSO, since DMSO is used as the solvent to solubilize AM-101. (<b>D</b>) Schematic of the efficacy experiment in H1792 subcutaneous heterotopic bilateral xenograft tumors generated in NSG mice. Mice in vehicle or drug treatment groups received i.p., vehicle, AM-101 (2.5 mg/kg), or DTX (8 mg/kg), on day 36 post-implantation and then six injections once per day. Mice in radiation (RT) or combo groups received a single fraction of radiation (5 Gy) to left flank only at 2 h before vehicle or drug on the first day of treatment. (<b>E</b>) At experimental endpoint, tumors from left (L) and right (R) flanks of each mouse were resected. H1792 subcutaneous xenograft tumor growth in NSG mice from different treatment groups: vehicle, radiation (RT), AM-101 ± RT, DTX ± RT. Number of mice per treatment group: <span class="html-italic">n</span> = 6 for vehicle, <span class="html-italic">n</span> = 4 for RT; <span class="html-italic">n</span> = 7 for AM-101 and <span class="html-italic">n</span> = 7 for AM-101 + RT, <span class="html-italic">n</span> = 5 for DTX + RT and <span class="html-italic">n</span> = 6 for DTX. (<b>F</b>) Tumor volume of left and right flank tumors was measured over time using Vernier calipers. The tumor growth delay curves show the tumor volumes of mice treated with a vehicle, radiation (RT), AM-101, and AM-101 plus RT. Each point on the curve represents the mean tumor volume after treatment, with error bars indicating the standard error (SE). Statistical significance is indicated by <span class="html-italic">p</span> &lt; 0.001.</p>
Full article ">Figure 3
<p>GABA(A) receptor activation increases survival of mice bearing lung brain-metastatic tumors. (<b>A</b>) Bar graphs representing the number of colonies generated from clonogenic assay to determine the radiosensitizing effect of AM-101 when combined with radiation treatment (RT) versus AM-101 (2.5 μM) or RT (3 Gy) alone in patient-derived brain-metastatic UW-lung-16 cells. The combination of AM-101 plus RT (combo group) imparts the most significant impact on colony formation, a three-fold suppression of colony numbers than control and two-fold suppression of colony numbers than AM-101 and RT applied alone. Control is DMSO treated, as DMSO is the diluent of AM-101. Data are represented as mean ± S.E. One-way ANOVA with Tukey’s multiple comparisons test was performed to determine the <span class="html-italic">p</span>-values between two treatment groups. The one-way ANOVA <span class="html-italic">p</span> &lt; 0.0001. Based on Tukey’s multiple comparisons test, Control vs. AM-101, *** <span class="html-italic">p</span> = 0.0001; Control vs. RT ** <span class="html-italic">p</span> = 0.0019; Control vs. Combo **** <span class="html-italic">p</span> &lt; 0.0001; AM-101 vs. RT, ns (not significant), <span class="html-italic">p</span> = 0.308; AM-101 vs. Combo *** <span class="html-italic">p</span> = 0.0001; RT vs. Combo **** <span class="html-italic">p</span> &lt; 0.0001. (<b>B</b>) Schematic of efficacy experiment in intracranial xenograft tumors generated in athymic nude mice. Mice received a stereotaxic intracranial injection of cells (UW-lung-16) from a brain lesion of a patient with lung cancer. Mice (<span class="html-italic">n</span> = 21) were separated into three treatment groups (<span class="html-italic">n</span> = 7 per group). Ten days post-injection, mice received (1) vehicle, an i.p. injection of formulation; (2) radiation (RT), 2.5 Gy dose/day to the whole mouse brain for 5 consecutive days; (3) AM-101 plus RT, i.p. injection of formulated AM-101 (5 mg/kg) and RT (2.5 Gy dose/day/mouse for 5 days) to the whole mouse brain using a XenX irradiator (Xstahl Ltd.) and the supplied mouse gantry. The day of intracranial injection of tumor cells was assigned as day zero. Tumors were followed by bioluminescent imaging (BLI) over time. (<b>C</b>) BLI study of mice with brain metastatic lung tumors and treated with vehicle, radiation (RT), or RT plus AM-101. Mice were imaged at indicated time points post-intracranial injection of tumor cells. (<b>D</b>) Kaplan–Meier survival curve with <span class="html-italic">p</span>-value (log rank test) calculated for statistical significance. Kaplan–Meier curves were used to estimate the survival of mice in each group in mouse intracranial xenograft experiments. Statistical significance was determined by using the log-rank test.</p>
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<p>GABA(A) receptor activation enhances autophagic puncta and the flux and triggers multimerization of GABARAP and Nix. (<b>A</b>) Shown are confocal immunofluorescence microscopic images of H1792 cells under various treatments: DMSO or control; AM-101 (3 µM); radiation (RT); and AM-101 plus RT (combo) (scale bar, 20 µm). Radiation dose was 3 Gy. Cells were stained for DNA with DAPI (blue fluorescent) and LC3B (left) using LC3B antibody. LC3B puncta were quantified per 3 cells for each experimental group and plotted, as shown in the bar graph, where * <span class="html-italic">p</span> = 0.0108 (control vs. AM-101); ** <span class="html-italic">p</span> = 0.0037 (control vs. RT); **** <span class="html-italic">p</span> &lt; 0.0001 (control vs. combo) (right), which reveals a similar effect between AM-101 versus RT, but combining these two has a statistically pronounced impact on puncta formation. (<b>B</b>) Confocal immunofluorescence microscopic images of H1792 cells under various treatments that were then stained for DAPI and Nix to identify and quantify Nix puncta (left). Nix puncta were quantified per 3 cells for each experimental group and plotted, as shown in the bar graph, where *** <span class="html-italic">p</span> = 0.0008 (control vs. AM-101); ** <span class="html-italic">p</span> = 0.006 (control vs. RT); **** <span class="html-italic">p</span> &lt; 0.0001 (control vs. combo) (right), which reveals a pronounced effect of AM-101 on puncta formation and an increase in puncta when AM-101 is combined with radiation (RT) (combo treatment group). For statistical calculations, one-way ANOVA was performed and followed up with Dunnett’s multiple comparisons test. (<b>C</b>) Immunoblotting (using 4–15% gradient gel PAGE) demonstrates enhanced autophagic flux with LC3B-II as a marker in H1792 cells following co-treatment with AM-101 and bafilomycin A1. A representative immunoblot probed with an LC3B antibody shows the results from cell lysates of control (DMSO-treated) and three treatment groups: BafA1 alone, AM-101 alone, and AM-101 combined with BafA1. H1792 cells were treated with 3 μM AM-101 for 48 h, followed by either 50 nM bafilomycin A1 (AM-101 + BafA1) or DMSO (vehicle) for an additional 4 h. Control cells were treated with DMSO for 48 h and then with either 50 nM bafilomycin A1 or DMSO for 4 h. The right panel shows LC3B-II band intensities quantified using ImageJ, with bar graphs representing the fold increase in LC3B-II for each treatment group relative to the vehicle control (data shown as mean ± SEM, <span class="html-italic">n</span> = 2). Co-treatment of AM-101 and bafilomycin A1 significantly increased LC3B-II compared to AM-101 or bafilomycin A1 alone. GAPDH is used as loading control. To measure the statistical significance, ordinary one-way ANOVA (one-way ANOVA <span class="html-italic">p</span> &lt; 0.0006) with Tukey’s multiple comparison test was performed to compare the means of each group. ** <span class="html-italic">p</span> = 0.0051 (BafA1 vs. AM-101); ** <span class="html-italic">p</span> = 0.0029 (BafA1 vs. AM-101 + BafA1); and *** <span class="html-italic">p</span> = 0.0005 (AM-101 vs. AM-101 + BafA1). (<b>D</b>) Modified immunoblotting of SDS gels (4–15% gradient gel) showing the effect of AM-101 on monomeric GABARAP expression and its oligomeric state in H1792 cells. (<b>E</b>) Modified immunoblotting of SDS gels (4–15% gradient gel) showing the effect of AM-101 on monomeric Nix protein expression and its oligomeric state in H1792 cells. AM-101 (3.0 µM) triggers a multimerization of GABARAP and an apparent increase in abundance at 72 h (left). Nix abundance is also enhanced as well as formation of dimer by AM-101 (3 µM) in a concentration-dependent manner in H1792 cells. GAPDH is used as a loading control for both experiments in (<b>D</b>,<b>E</b>). D: dimer; M: monomer. Original western blots are presented in <a href="#app1-cancers-16-03167" class="html-app">Figure S9</a>.</p>
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<p>Change in abundance or utilization of autophagy biomarkers in response to GABA(A) activation. (<b>A</b>) ATG7 immunoblot (4–15% gradient polyacrylamide gel) of patient-derived lung adenocarcinoma primary (H1792) and brain-metastatic (UW-lung-16) cells following treatment with AM-101. Left, immunoblot showing increased expression of one isoform of ATG7 protein in primary H1792 cells of following treatment with 3.0 µM of AM-101 for 48 h compared to the control. Control: DMSO treated. Right, immunoblot showing change in ATG7 protein levels over time in lung cancer brain-metastatic UW-lung-16 cells treated with 3.0 µM AM-101 compared to the control. Significant increase in ATG7 protein is observed at 72 h. Control: DMSO treated. (<b>B</b>) Immunoblots showing the effect of in vitro AM-101 treatment on protein levels of ATG-12-ATG5 conjugate in primary H1792 cells (<b>left</b> panel) and patient-derived lung cancer brain metastatic UW-lung-16 (<b>right</b> panel) cells. In case of H1792 cells (<b>left</b> panel) sample was collected at 72 h after AM-101 treatment and in case of UW-lung-16 cells (<b>right</b> panel), samples were collected from both 48 h and 72 time points post treatment. (<b>C</b>) p62 immunoblots of SDS gels of lung adenocarcinoma primary (H1792) and brain-metastatic (UW-lung-16) cells following treatment with AM-101. Left, changes in expression of p62 protein as assessed by immunoblotting of lysates from H1792 cells treated with AM-101, radiation (3 Gy), and a combination of radiation (RT) plus AM-101 only. Control, DMSO. Middle, evaluation of the time-dependent utilization of p62 after AM-101 (3.0 µM) treatment in primary lung cancer cell (H1792). Right, patient-derived brain-metastatic lung adenocarcinoma cell line UW-lung-16 (right). Control, DMSO. GAPDH is used as a loading control. (<b>D</b>) Left, immunoblot showing Beclin-1 protein levels in control and AM-101 treated H1792 cells (treated for 72 h). Control, DMSO. Right, immunoblot shows Beclin-1 protein levels in patient-derived lung brain-metastatic UW-lung-16 cells treated with AM-101, radiation (3 Gy), and radiation (3 Gy) along with AM-101. Original western blots are presented in <a href="#app1-cancers-16-03167" class="html-app">Figure S10</a>.</p>
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<p>GABARAP–Nix abrogation inhibits AM-101 cytotoxicity. (<b>A</b>) Combined treatment of lung adenocarcinoma (H1792) cells with AM-101 plus Pen3-<span class="html-italic">ortho</span> (P3<span class="html-italic">o</span>), a stapled-peptide that binds to GABARAP and abrogates Nix binding, inhibits the cytotoxicity of AM-101. The inhibitory effect of P3<span class="html-italic">o</span> is enhanced with an increased concentration of the inhibitor. **** <span class="html-italic">p</span> &lt; 0.0001 [AM-101 vs. P3<span class="html-italic">o</span> (15 μM) + AM-101]; **** <span class="html-italic">p</span> &lt; 0.0001 [AM-101 vs. P3<span class="html-italic">o</span> (25 μM) + AM-101]; **** <span class="html-italic">p</span> &lt; 0.0001 [P3<span class="html-italic">o</span> (25 μM) vs. P3<span class="html-italic">o</span> (25 μM) + AM-101]. One-way ANOVA with Tukey’s multiple comparisons test was performed. (<b>B</b>) Treatment of H1792 cells with two different concentrations of P3<span class="html-italic">o</span> does not impact GABARAP protein abundance, as observed by immunoblot of SDS gel probed for GABARAP. (<b>C</b>) Treatment of H1792 cells with P3<span class="html-italic">o</span> reduces both Nix dimer and monomer protein levels, as observed by immunoblot of SDS gel probed for Nix. D: dimer, M: monomer. GAPDH is used as a loading control. Original western blots are presented in <a href="#app1-cancers-16-03167" class="html-app">Figure S11</a>.</p>
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<p>Model of GABA(A)-receptor-mediated autophagy. (<b>A</b>) NSCLC cells possess intrinsic GABA(A) receptors (chloride anion channels). (<b>B</b>) AM-101 activates GABA(A) receptors, which in turn depolarize mitochondria. Changes in the cancer cell by binding of AM-101 to the receptor in combination with radiation include (i) enhanced expression–abundance of key genes involved in autophagy, including <span class="html-italic">ATG7</span> and <span class="html-italic">BECLIN-1</span>; (ii) increased phosphorylation of the histone variant H2AX to generate γ-H2AX. (<b>C</b>) Depolarization induces key autophagic events in synergy with radiation: (i) enhanced expression and dimerization of GABA(A) receptor-associated protein, GABARAP; (ii) stabilization and dimerization of Nix, coupling GABARAP to mitochondria; (iii) enhanced expression of autophagy-associated proteins Beclin-1 and ATG7; (iv) utilization of ubiquitin-binding protein p62. Nix dimerization increases its stability and coordinates the nucleation of autophagosome formation. In this manner, GABA(A) receptor activation induces complex multimerization, activating autophagy. (<b>D</b>) Over time, GABARAP multimerizes commensurate with multimerization of the GABA(A) receptor, which enhances its activity. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p>
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64 pages, 16567 KiB  
Review
Composite Track-Etched Membranes: Synthesis and Multifaced Applications
by Anastassiya A. Mashentseva, Duygu S. Sutekin, Saniya R. Rakisheva and Murat Barsbay
Polymers 2024, 16(18), 2616; https://doi.org/10.3390/polym16182616 (registering DOI) - 15 Sep 2024
Abstract
Composite track-etched membranes (CTeMs) emerged as a versatile and high-performance class of materials, combining the precise pore structures of traditional track-etched membranes (TeMs) with the enhanced functionalities of integrated nanomaterials. This review provides a comprehensive overview of the synthesis, functionalization, and applications of [...] Read more.
Composite track-etched membranes (CTeMs) emerged as a versatile and high-performance class of materials, combining the precise pore structures of traditional track-etched membranes (TeMs) with the enhanced functionalities of integrated nanomaterials. This review provides a comprehensive overview of the synthesis, functionalization, and applications of CTeMs. By incorporating functional phases such as metal nanoparticles and conductive nanostructures, CTeMs exhibit improved performance in various domains. In environmental remediation, CTeMs effectively capture and decompose pollutants, offering both separation and detoxification. In sensor technology, they have the potential to provide high sensitivity and selectivity, essential for accurate detection in medical and environmental applications. For energy storage, CTeMs may be promising in enhancing ion transport, flexibility, and mechanical stability, addressing key issues in battery and supercapacitor performance. Biomedical applications may benefit from the versality of CTeMs, potentially supporting advanced drug delivery systems and tissue engineering scaffolds. Despite their numerous advantages, challenges remain in the fabrication and scalability of CTeMs, requiring sophisticated techniques and meticulous optimization. Future research directions include the development of cost-effective production methods and the exploration of new materials to further enhance the capabilities of CTeMs. This review underscores the transformative potential of CTeMs across various applications and highlights the need for continued innovation to fully realize their benefits. Full article
(This article belongs to the Section Polymer Composites and Nanocomposites)
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<p>Symmetric and asymmetric polymeric nanochannels fabricated using the track etching technique (adapted with permission from ref. [<a href="#B72-polymers-16-02616" class="html-bibr">72</a>]. Copyright 2021 American Chemical Society).</p>
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<p>General synthesis routes for the preparation of CTeMs.</p>
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<p>The scheme of chitosan ECD in the pores of PC TeM (adapted with permission from ref. [<a href="#B100-polymers-16-02616" class="html-bibr">100</a>]. Copyright 2005 Royal Society of Chemistry).</p>
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<p>SEM images of the surface of CTeM with copper NTs obtained using various types of reducing agents (adapted with permission from ref. [<a href="#B122-polymers-16-02616" class="html-bibr">122</a>]. Copyright 2023 MDPI with license under CC BY 4.0).</p>
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<p>Scheme of Cu<sub>2</sub>O/ZnO@PET CTeM formation by galvanic substitution and SEM images of the studied composites (adapted with permission from ref. [<a href="#B124-polymers-16-02616" class="html-bibr">124</a>]. Copyright 2022 MDPI with license under CC BY 4.0).</p>
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<p>(<b>a</b>) Diagram showing the effects of different radiation dose rates on metal nanoparticle size (top panel). Diagram illustrating how the reduction rate affects the synthesis of bimetallic nanoparticles (bottom panel). Schematic representation of metal ion reduction in solution through ionizing radiation in the presence of a stabilizer (left panel). The blue cloudy shell around the ions or nanoparticles represents the capping/stabilizing organic phase, such as grafted polymer chains in a functionalized TeM. (<b>b</b>) Production methodology including grafting, sorption, and radiolysis for the synthesis of copper nanostructure-containing CTeMs using e-beam and gamma rays. The digital pictures and SEM images of the composite membranes are shown on the right ((<b>b</b>) is adapted with permission from ref. [<a href="#B128-polymers-16-02616" class="html-bibr">128</a>]. Copyright 2023 MDPI with license under CC BY 4.0).</p>
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<p>SEM images of Ar ion beam-etched PET TeMs with embedded Au microtubes (<b>a</b>), Ni dendrite structures on the unetched surface (<b>b</b>). SEM images (<b>c</b>), EDS spectra and mapping (<b>d</b>,<b>e</b>), and XRD patterns (<b>f</b>) of the core-shell Au/Ni microtubesand elemental composition (<b>j</b>). Ni@Au with gold needles: SEM (<b>g</b>), TEM (<b>h</b>), EDX-mapping (<b>i</b>), and elemental composition (<b>k</b>). Digital photographs and SEM images of the composite membranes are also shown on the right (adapted with permission from ref. [<a href="#B104-polymers-16-02616" class="html-bibr">104</a>] Copyright 2022 MDPI with license under CC BY 4.0).</p>
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<p>(<b>a</b>) UV spectra for reaction mixture, (<b>b</b>) calculated apparent rate constants for Ag and Au CTeMs (adapted with permission from ref. [<a href="#B116-polymers-16-02616" class="html-bibr">116</a>]. Copyright 1990 IOP Publishing Ltd.).</p>
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<p>(<b>a</b>) The UV vis spectra of reduction of <span class="html-italic">p</span>-NP by Pd-based CTeMs synthesized by green approach, (<b>b</b>) graph of ln(a/a<sub>0</sub>) vs. time for the reduction in <span class="html-italic">p</span>-NP in the presence of Pd-based CTeMs (adapted with permission from ref. [<a href="#B156-polymers-16-02616" class="html-bibr">156</a>]. Copyright 1999 Royal Society of Chemistry).</p>
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<p>Mechanistic pathway of <span class="html-italic">p</span>-nitrophenol reduction on copper-based CTeM in the presence of NaBH<sub>4</sub>: Steps of the Langmuir–Hinshelwood mechanism, including adsorption, intermediate formation, and product desorption, involved in the catalytic reduction of <span class="html-italic">p</span>-nitrophenol on nanocatalyst surface (adapted with permission from ref. [<a href="#B32-polymers-16-02616" class="html-bibr">32</a>]. Copyright 2020 MDPI with license under CC BY 4.0).</p>
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<p>The mechanism of Congo red decomposition in the presence of NaBH<sub>4</sub> (adapted with permission from ref. [<a href="#B30-polymers-16-02616" class="html-bibr">30</a>]. Copyright 2016 Elsevier).</p>
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<p>The change in color from blue to colorless was visually noted as a sign of MB (0.1 mg/L) degradation by the composite catalyst over various periods (adapted with permission from ref. [<a href="#B143-polymers-16-02616" class="html-bibr">143</a>] Copyright 2021 MDPI with license under CC BY 4.0).</p>
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<p>The mechanism for the photocatalytic decomposition of MB dye under UV irradiation in the presence of Cu@PET-<span class="html-italic">g</span>-PAA CTeMs (adapted with permission from ref. [<a href="#B128-polymers-16-02616" class="html-bibr">128</a>] Copyright 2023 MDPI with license under CC BY 4.0).</p>
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<p>The reusability of the Pd_Asc@PVP-<span class="html-italic">g</span>-PET catalyst: change in the degradation degree (D, %) of MTZ in repeated use (adapted with permission from ref. [<a href="#B66-polymers-16-02616" class="html-bibr">66</a>] Copyright 2023 from the Royal Society of Chemistry).</p>
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<p>Schematic representation of installation (adapted with permission from ref [<a href="#B185-polymers-16-02616" class="html-bibr">185</a>]. Copyright 2021 Springer Nature).</p>
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<p>(<b>a</b>) Impact of contact time on the sorption of As (III) (50 ppm) by the composite TeMs, (<b>b</b>) dependence of As (III) removal (%) to pH during 420 min (<b>c</b>) (adapted with permission from ref. [<a href="#B119-polymers-16-02616" class="html-bibr">119</a>] Copyright 2021 MDPI with license under CC BY 4.0).</p>
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<p>Sorption of Pb(II) as a function of solution pH (Pb(II) concentration: 50 ppm; contact time: 120 min) (<b>a</b>); pH point zero charge (pH<sub>PZC</sub>) plot (<b>b</b>); effect of contact time on the sorption of Pb(II) ions (<b>c</b>) and equilibrium sorption capacity (<b>d</b>) (adapted with permission from ref. [<a href="#B122-polymers-16-02616" class="html-bibr">122</a>] Copyright 2023 MDPI with license under CC BY 4.0).</p>
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<p>SEM of a nanoparticle composite membrane (nominal pore diameter 1000 nm; nanoparticle diameter 200–230 nm): filled pores before coupling reaction over-night (<b>a</b>), cross-section after coupling reaction and complete washing (<b>b</b>), cross-section detail demonstrating the distance between neighbored bound nanoparticles (<b>c</b>) and and depiction of the mass transfer and catalytic reaction behavior for the conventional enzyme membrane (<b>above</b>) and the nanoparticle composite enzyme membrane (<b>below</b>) (adapted with permission from ref. [<a href="#B204-polymers-16-02616" class="html-bibr">204</a>] Copyright 2006 Elsevier).</p>
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<p>SEM images of the polycarbonate porous membranes without PNIPAM grafts (<b>a</b>,<b>b</b>), with PNIPAM grafts (<b>c</b>,<b>d</b>), without PNIPAM grafts after silver nanoparticles synthesized in situ (<b>e</b>), grafted with PNIPAM and after silver nanoparticles synthesized in situ (<b>f</b>–<b>h</b>) (adapted with permission from ref. [<a href="#B206-polymers-16-02616" class="html-bibr">206</a>]. Copyright 2014 Wiley with license under CC BY 3.0).</p>
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<p>The preparation of arrays of copper ultramicrowires (CuUWs) by using porous membranes as templates track-etched polycarbonate (PC) and anodized aluminum oxide (AAO) for efficient substrates for surface enhanced Raman spectroscopy (SERS) (adapted with permission from ref. [<a href="#B208-polymers-16-02616" class="html-bibr">208</a>]. Copyright 2021 MDPI with license under CC BY 4.0).</p>
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<p>SEM image of metallized TMs surface elongated to deformation of 5% (<b>a</b>) and 15% (<b>b</b>), SERS spectra of malachite green molecules adsorbed on a surface metallized with a silver (<b>c</b>), and gold (<b>d</b>) (adapted with permission from ref. [<a href="#B209-polymers-16-02616" class="html-bibr">209</a>]. Copyright 2022 AIP Publishing).</p>
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<p>(<b>a</b>) SEM top view of the TeM, (<b>b</b>) Ag-NWs bundles array (Ag-NWs diameter of 100 nm and their length of 12 µm), and (<b>c</b>) mechanism of action for surface-enhanced Raman scattering (SERS) with metal nanowires (NWs) grown in pores of polymer TeMs and enhancement of Raman signal for 4-Mercaptophenylboronic acid (4-MPBA) adsorbed on the “wet” (green line) and “dry” (red line) substrates) (adapted with permission from ref. [<a href="#B87-polymers-16-02616" class="html-bibr">87</a>]. Copyright 2021 MDPI with license under CC BY 4.0).</p>
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<p>The SEM images illustrating metasurfaces featuring vertically standing nanowires (NWs) with varying diameters and surface pore densities: the substrate surface with NWs of 200 (<b>a</b>,<b>b</b>), 100 (<b>c</b>,<b>d</b>), and 60 nm (<b>e</b>,<b>f</b>) diameter and 10 µm length. (adapted with permission from ref. [<a href="#B137-polymers-16-02616" class="html-bibr">137</a>]. Copyright 2022 MDPI with license under CC BY 4.0).</p>
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<p>(<b>a</b>) Scheme of SERS experiment, (<b>b</b>) SERS spectra for various concentrations of MB, and (<b>c</b>) SERS intensity depending on the concentration of the 1624 cm<sup>−1</sup> shift (adapted with permission from ref. [<a href="#B130-polymers-16-02616" class="html-bibr">130</a>]. Copyright 2021 Elsevier).</p>
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<p>SEM images and SEM-EDX results of Ni-Au nanotubes (<b>a</b>) and their SERS spectra for different concentrations of R6G (<b>b</b>) (adapted with permission from ref. [<a href="#B214-polymers-16-02616" class="html-bibr">214</a>] Copyright 2022 Elsevier).</p>
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<p>Top view of the NTNW before surface etching (<b>a</b>), SEM top view image of NiCo-LDH@Ni-NTNWs after 120 sec of hydroxide electrodeposition (<b>b</b>) and schematic representation of the NTNW electrode fabrication (<b>c</b>) (adapted with permission from ref. [<a href="#B216-polymers-16-02616" class="html-bibr">216</a>]. Copyright 2021 Elsevier).</p>
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<p>(<b>a</b>) Construction of PI/PEO/LiTFSI composite, (<b>b</b>) cross-sectional SEM image with zoomed-in aligned nanopores, (<b>c</b>) SEM image of PI/PEO/LiTFSI composite, (<b>d</b>) cross-sectional SEM image of the PI membrane (adapted with permission from ref. [<a href="#B219-polymers-16-02616" class="html-bibr">219</a>]. Copyright 2019 Springer Nature).</p>
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<p>(<b>a</b>) SEM image of an SK Innovation separator, (<b>b</b>) surface of a PET TeM with an average pore diameter of approximately 100 nm and a pore density of 2.5 × 10<sup>9</sup> cm<sup>−2</sup>, and (<b>c</b>) cross-section of the PET TeM (adapted with permission from ref. [<a href="#B227-polymers-16-02616" class="html-bibr">227</a>]. Copyright 2021 IOP Publishing Ltd. with license under CC 4.0).</p>
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<p>The cycling performance of lithium-sulfur coin cells utilizing PET etched ion track membranes, placed between two separators from SK Innovation, was assessed under a constant pore density (10<sup>9</sup> cm<sup>−2</sup>) while varying the pore diameter. (<b>a</b>) Solid symbols represent charge capacities, and empty symbols indicate discharge capacities; (<b>b</b>) Coulombic efficiency as a function of pore size (adapted with permission from ref. [<a href="#B227-polymers-16-02616" class="html-bibr">227</a>]. Copyright 2021 IOP Publishing Ltd. with license under CC 4.0).</p>
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<p>Schematic representation of the PI/hBN separator fabrication process (adapted with permission from ref. [<a href="#B236-polymers-16-02616" class="html-bibr">236</a>]. Copyright 2022 American Chemical Society).</p>
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<p>Images of various separators after the addition of electrolyte on the surfaces: (<b>a</b>) PP, (<b>b</b>) PI TeM, and (<b>c</b>) PI/hBN. Contact angle experiments between separators and electrolytes: (<b>d</b>) PP, (<b>e</b>) PI TeM, and (<b>f</b>) PI/hBN separator (adapted with permission from ref. [<a href="#B236-polymers-16-02616" class="html-bibr">236</a>]. Copyright 2022 American Chemical Society).</p>
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<p>Gas separation mechanism of PdPt BNP decorated track-etched polymer membranes and gas separation performance of the UV functionalized PdPt BNP dipped PET membrane series (adapted with permission from ref. [<a href="#B241-polymers-16-02616" class="html-bibr">241</a>]. Copyright 2024 Royal Society of Chemistry with license under CC BY-NC 3.0).</p>
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<p>(<b>a</b>) schematic of AuNTs synthesis and (<b>b</b>) DNA biosensor setup using AuNTs electrodes. Biosensor includes working electrode (WE), reference electrode (RE), and counter electrode (CE). AuNTs array electrodes showed improved electron transfer compared to bare Au electrodes. Biosensor detected DNA in linear range of 0.01 ng/µL to 100 ng/µL, with a limit of detection of 0.05 ng/µL (adapted with permission from ref. [<a href="#B33-polymers-16-02616" class="html-bibr">33</a>]. Copyright 2016 Elsevier).</p>
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<p>Measures for the further development and adaptation of CTeMs. The figure summarizes critical steps to advance CTeM technology, including enhanced fabrication techniques, material optimization, integration of smart materials, scaling up production, focus on promising applications, sensor technology improvements, ensuring safety and regulatory compliance, fostering interdisciplinary collaboration, and exploring technological integration.</p>
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15 pages, 3249 KiB  
Article
The InterVision Framework: An Enhanced Fine-Tuning Deep Learning Strategy for Auto-Segmentation in Head and Neck
by Byongsu Choi, Chris J. Beltran, Sang Kyun Yoo, Na Hye Kwon, Jin Sung Kim and Justin Chunjoo Park
J. Pers. Med. 2024, 14(9), 979; https://doi.org/10.3390/jpm14090979 (registering DOI) - 15 Sep 2024
Abstract
Adaptive radiotherapy (ART) workflows are increasingly adopted to achieve dose escalation and tissue sparing under dynamic anatomical conditions. However, recontouring and time constraints hinder the implementation of real-time ART workflows. Various auto-segmentation methods, including deformable image registration, atlas-based segmentation, and deep learning-based segmentation [...] Read more.
Adaptive radiotherapy (ART) workflows are increasingly adopted to achieve dose escalation and tissue sparing under dynamic anatomical conditions. However, recontouring and time constraints hinder the implementation of real-time ART workflows. Various auto-segmentation methods, including deformable image registration, atlas-based segmentation, and deep learning-based segmentation (DLS), have been developed to address these challenges. Despite the potential of DLS methods, clinical implementation remains difficult due to the need for large, high-quality datasets to ensure model generalizability. This study introduces an InterVision framework for segmentation. The InterVision framework can interpolate or create intermediate visuals between existing images to generate specific patient characteristics. The InterVision model is trained in two steps: (1) generating a general model using the dataset, and (2) tuning the general model using the dataset generated from the InterVision framework. The InterVision framework generates intermediate images between existing patient image slides using deformable vectors, effectively capturing unique patient characteristics. By creating a more comprehensive dataset that reflects these individual characteristics, the InterVision model demonstrates the ability to produce more accurate contours compared to general models. Models are evaluated using the volumetric dice similarity coefficient (VDSC) and the Hausdorff distance 95% (HD95%) for 18 structures in 20 test patients. As a result, the Dice score was 0.81 ± 0.05 for the general model, 0.82 ± 0.04 for the general fine-tuning model, and 0.85 ± 0.03 for the InterVision model. The Hausdorff distance was 3.06 ± 1.13 for the general model, 2.81 ± 0.77 for the general fine-tuning model, and 2.52 ± 0.50 for the InterVision model. The InterVision model showed the best performance compared to the general model. The InterVision framework presents a versatile approach adaptable to various tasks where prior information is accessible, such as in ART settings. This capability is particularly valuable for accurately predicting complex organs and targets that pose challenges for traditional deep learning algorithms. Full article
(This article belongs to the Section Methodology, Drug and Device Discovery)
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<p>The proposed InterVision framework. (1) illustrates the general model training using the original dataset, the training set and the validation set is divided using the original dataset. (2) illustrates the progress of the general fine-tuning model. The general fine-tuning model is using 1 personalized patient data for the training. For the evaluation, other fraction of the personalized patient data will be used. (3) shows the workflow of the InterVision framework. (3-1), (3-2) and (3-3) show the process of generating InterVision dataset.</p>
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<p>Conceptual representation of generating the InterVision dataset. A deformable vector is created by comparing each slide. Utilizing this deformable vector, we generate intermediate images between each slide. Consequently, we nearly doubled the size of the personalized dataset.</p>
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<p>Concept of calculating deformation vectors using control points. Images within the original image are repositioned based on the deformation vectors derived from each control point. The degree of deformation applied to a voxel increases as its proximity to the control point decreases.</p>
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<p>The architecture of Swin-Unet comprises an encoder, bottleneck, decoder, and skip connections. All components—the encoder, bottleneck, and decoder—are constructed using Swin Transformer blocks.</p>
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<p>Overview of the Swim Transformer block structure.</p>
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<p>Visual results of the optic chiasm (<b>a</b>), L cochlea (<b>b</b>) and L parotid (<b>c</b>) achieved by the general model, the general fine-tuning model and the InterVision model comparing with the manual contours in yellow.</p>
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12 pages, 3140 KiB  
Article
Study of Intergranular Corrosion Behaviors of Mn-Increased 5083 Al Alloy with Controlled Precipitation States of Al6Mn Formed during Homogenization Annealing
by Peng Zhang, Yue Wang, Pizhi Zhao, Zhengyi Jiang, Yinbao Tian, Yang Yang and Jian Han
Metals 2024, 14(9), 1053; https://doi.org/10.3390/met14091053 (registering DOI) - 15 Sep 2024
Abstract
In this study, as a vital part of the production of Mn-increased 5083 Al alloy, i.e., homogenization annealing before hot rolling, the target states of key Al6Mn precipitation, including the dispersed, initial coarsening and intensive coarsening states, were designed, and the [...] Read more.
In this study, as a vital part of the production of Mn-increased 5083 Al alloy, i.e., homogenization annealing before hot rolling, the target states of key Al6Mn precipitation, including the dispersed, initial coarsening and intensive coarsening states, were designed, and the corresponding precipitates formed via the control of the temperature and holding time in the annealing process. By means of metallographic corrosion and nitric acid mass loss tests (NAMLT) for assessing the intergranular corrosion (IGC) resistance, temperatures ranging from 175 °C to 225 °C were determined to induce a transition from sensitization to stabilization for this innovative 5083. At a temperature of 175 °C for a duration of up to 24 h (2 h, 4 h, 8 h, 16 h, 24 h), the results show that when the soak time is 24 h, the sample with initially coarsened Al6Mn phases has a lower degree of sensitization (DOS) compared to the samples with Al6Mn phases in both the dispersed and intensive coarsening states, and its NAMLT is reduced by 11% and 15%, respectively. Subsequently, transmission electron microscopy (TEM) analysis has investigated that for the sample with the best IGC resistance, i.e., that with initially coarsened Al6Mn phases, plate-like Al6Mn particles (200~500 nm) can act as heterogenous nucleation sites for β phases, driving their preferential precipitation on Al6Mn particles and resisting their precipitation along grain boundaries, ultimately improving the IGC resistance of 5083 Al alloy after homogenization annealing. Full article
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<p>(<b>a</b>) DSC curve and (<b>b</b>) Al<sub>6</sub>Mn state variations with homogenization process.</p>
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<p>TEM bright-field micrographs of (<b>a</b>,<b>d</b>) initially coarsened, (<b>b</b>,<b>e</b>) intensively coarsened and (<b>c</b>) dispersed Al<sub>6</sub>Mn.</p>
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<p>Corrosion results for samples held at (<b>a</b>–<b>d</b>) 175 °C, (<b>e</b>–<b>h</b>) 200 °C, and (<b>i</b>–<b>l</b>) 225 °C for 4, 8, 16 and 24 h.</p>
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<p>The NAMLT results after being heat-treated at different sensitization temperatures.</p>
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<p>Observation of β phase: (<b>a</b>) no precipitation, (<b>b</b>,<b>c</b>) continuous precipitation and EDS of Mg, and (<b>d</b>–<b>f</b>) triple junction precipitation and EDS of Mg.</p>
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<p>The NAMLT results of different Al<sub>6</sub>Mn states in 175 °C.</p>
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<p>TEM bright-field micrographs and EDS of (<b>a</b>–<b>c</b>) plate-like Al<sub>6</sub>Mn and (<b>d</b>) rod-like Al<sub>6</sub>Mn.</p>
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<p>TEM bright-field micrographs and EDS of rhombic Al<sub>6</sub>Mn precipitated during homogenization stage (<b>a</b>) initial coarsening and (<b>b</b>) intensive coarsening.</p>
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33 pages, 3210 KiB  
Review
Diet and Nutrients in Rare Neurological Disorders: Biological, Biochemical, and Pathophysiological Evidence
by Marilena Briglia, Fabio Allia, Rosanna Avola, Cinzia Signorini, Venera Cardile, Giovanni Luca Romano, Giovanni Giurdanella, Roberta Malaguarnera, Maria Bellomo and Adriana Carol Eleonora Graziano
Nutrients 2024, 16(18), 3114; https://doi.org/10.3390/nu16183114 (registering DOI) - 15 Sep 2024
Abstract
Background/Objectives: Rare diseases are a wide and heterogeneous group of multisystem life-threatening or chronically debilitating clinical conditions with reduced life expectancy and a relevant mortality rate in childhood. Some of these disorders have typical neurological symptoms, presenting from birth to adulthood. Dietary [...] Read more.
Background/Objectives: Rare diseases are a wide and heterogeneous group of multisystem life-threatening or chronically debilitating clinical conditions with reduced life expectancy and a relevant mortality rate in childhood. Some of these disorders have typical neurological symptoms, presenting from birth to adulthood. Dietary patterns and nutritional compounds play key roles in the onset and progression of neurological disorders, and the impact of alimentary needs must be enlightened especially in rare neurological diseases. This work aims to collect the in vitro, in vivo, and clinical evidence on the effects of diet and of nutrient intake on some rare neurological disorders, including some genetic diseases, and rare brain tumors. Herein, those aspects are critically linked to the genetic, biological, biochemical, and pathophysiological hallmarks typical of each disorder. Methods: By searching the major web-based databases (PubMed, Web of Science Core Collection, DynaMed, and Clinicaltrials.gov), we try to sum up and improve our understanding of the emerging role of nutrition as both first-line therapy and risk factors in rare neurological diseases. Results: In line with the increasing number of consensus opinions suggesting that nutrients should receive the same attention as pharmacological treatments, the results of this work pointed out that a standard dietary recommendation in a specific rare disease is often limited by the heterogeneity of occurrent genetic mutations and by the variability of pathophysiological manifestation. Conclusions: In conclusion, we hope that the knowledge gaps identified here may inspire further research for a better evaluation of molecular mechanisms and long-term effects. Full article
(This article belongs to the Special Issue The Effect of Nutrients on Neurological Disorders)
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<p>Main characteristics of rare neurological diseases and possible investigations for symptomatic treatments (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>, accessed on 3 September 2024).</p>
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<p>Factors that influence alimentary wellness by modulator effects on the main homeostatic functions (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>, accessed on 27 June 2024).</p>
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<p><span class="html-italic">In vitro</span> models as tools in rare neurological disease research and therapeutic development (partially created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>, accessed on 7 August 2024).</p>
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<p>Animal models for rare neurological diseases (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>, accessed on 3 September 2024).</p>
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<p>MeCP2 gene structure and its activity on target genes. The meCP2 gene has N-terminal (NTD); methyl binding (MBD); intervening (ID); transcription repression (TRD); and C-terminal (CTD) domains. MeCP2 recruits a transcriptional corepressor complex containing Sin3A and histone deacetylase (HDAC) to methylated CpG islands and induces transcription inhibition in the target gene (TRD, transcriptional repression domain; MBD, methyl-CpG-binding domain). MeCP2 can activate gene transcription by recruiting CREB and other transcriptional factors to non-methylated CG DNA regions (partially created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>, accessed on 10 August 2024).</p>
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22 pages, 2851 KiB  
Article
Enhanced Three-Axis Frame and Wand-Based Multi-Camera Calibration Method Using Adaptive Iteratively Reweighted Least Squares and Comprehensive Error Integration
by Oleksandr Yuhai, Yubin Cho, Ahnryul Choi and Joung Hwan Mun
Photonics 2024, 11(9), 867; https://doi.org/10.3390/photonics11090867 (registering DOI) - 15 Sep 2024
Viewed by 69
Abstract
The accurate transformation of multi-camera 2D coordinates into 3D coordinates is critical for applications like animation, gaming, and medical rehabilitation. This study unveils an enhanced multi-camera calibration method that alleviates the shortcomings of existing approaches by incorporating a comprehensive cost function and Adaptive [...] Read more.
The accurate transformation of multi-camera 2D coordinates into 3D coordinates is critical for applications like animation, gaming, and medical rehabilitation. This study unveils an enhanced multi-camera calibration method that alleviates the shortcomings of existing approaches by incorporating a comprehensive cost function and Adaptive Iteratively Reweighted Least Squares (AIRLS) optimization. By integrating static error components (3D coordinate, distance, angle, and reprojection errors) with dynamic wand distance errors, the proposed comprehensive cost function facilitates precise multi-camera parameter calculations. The AIRLS optimization effectively balances the optimization of both static and dynamic error elements, enhancing the calibration’s robustness and efficiency. Comparative validation against advanced multi-camera calibration methods shows this method’s superior accuracy (average error 0.27 ± 0.22 mm) and robustness. Evaluation metrics including average distance error, standard deviation, and range (minimum and maximum) of errors, complemented by statistical analysis using ANOVA and post-hoc tests, underscore its efficacy. The method markedly enhances the accuracy of calculating intrinsic, extrinsic, and distortion parameters, proving highly effective for precise 3D reconstruction in diverse applications. This study represents substantial progression in multi-camera calibration, offering a dependable and efficient solution for intricate calibration challenges. Full article
(This article belongs to the Special Issue Recent Advances in 3D Optical Measurement)
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<p>Workflow of the proposed optimized multi-camera calibration process.</p>
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<p>Experimental setup.</p>
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<p>Calibration and validation tools: (<b>a</b>) three-axis calibration frame employed for initial multi-camera parameter estimation and calibration wand used to optimize the initial parameters; (<b>b</b>) 390 mm commercial calibration wand employed for validation tracking data collection; (<b>c</b>) 500 mm commercial calibration wand employed for validation tracking data collection.</p>
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<p>Sensitivity analysis of static and dynamic error components of the proposed cost function. (<b>a</b>) Analysis of static errors based on 3D coordinates, distance, angle, and reprojection errors. (<b>b</b>) Dynamic error analysis based on the dynamic distance errors between wand markers. (<b>c</b>) Combined analysis of static and dynamic errors.</p>
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<p>Sensitivity analysis of static and dynamic error components of the proposed cost function. (<b>a</b>) Analysis of static errors based on 3D coordinates, distance, angle, and reprojection errors. (<b>b</b>) Dynamic error analysis based on the dynamic distance errors between wand markers. (<b>c</b>) Combined analysis of static and dynamic errors.</p>
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5 pages, 154 KiB  
Editorial
Advanced Engineering Technology in Orthopedic Research
by Rongshan Cheng, Huizhi Wang and Cheng-Kung Cheng
Bioengineering 2024, 11(9), 925; https://doi.org/10.3390/bioengineering11090925 (registering DOI) - 15 Sep 2024
Viewed by 100
Abstract
Musculoskeletal injuries are increasing in conjunction with the aging of populations and the rising frequency of exercise [...] Full article
(This article belongs to the Special Issue Advanced Engineering Technology in Orthopaedic Research)
43 pages, 4610 KiB  
Review
Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases
by Dong Guo, Zhihao Liu, Jinglin Zhou, Chongrong Ke and Daliang Li
Int. J. Mol. Sci. 2024, 25(18), 9947; https://doi.org/10.3390/ijms25189947 (registering DOI) - 15 Sep 2024
Viewed by 186
Abstract
Programmed cell death (PCD) is a form of cell death distinct from accidental cell death (ACD) and is also referred to as regulated cell death (RCD). Typically, PCD signaling events are precisely regulated by various biomolecules in both spatial and temporal contexts to [...] Read more.
Programmed cell death (PCD) is a form of cell death distinct from accidental cell death (ACD) and is also referred to as regulated cell death (RCD). Typically, PCD signaling events are precisely regulated by various biomolecules in both spatial and temporal contexts to promote neuronal development, establish neural architecture, and shape the central nervous system (CNS), although the role of PCD extends beyond the CNS. Abnormalities in PCD signaling cascades contribute to the irreversible loss of neuronal cells and function, leading to the onset and progression of neurodegenerative diseases. In this review, we summarize the molecular processes and features of different modalities of PCD, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and other novel forms of PCD, and their effects on the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), multiple sclerosis (MS), traumatic brain injury (TBI), and stroke. Additionally, we examine the key factors involved in these PCD signaling pathways and discuss the potential for their development as therapeutic targets and strategies. Therefore, therapeutic strategies targeting the inhibition or facilitation of PCD signaling pathways offer a promising approach for clinical applications in treating neurodegenerative diseases. Full article
(This article belongs to the Special Issue Cell Apoptosis, 3rd Edition)
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<p>The execution mechanisms of apoptosis, necroptosis, and pyroptosis are described in detail. (<b>a</b>) Both the intrinsic and extrinsic pathways of apoptosis are illustrated, highlighting the key signaling molecules and processes involved; (<b>b</b>) the assembly and function of various necroptosome structures are depicted, emphasizing the key proteins and their roles; (<b>c</b>) the pathways of pyroptosis execution are presented, detailing the stimuli and their effects on cellular components. The red line in the image signifies obstruction or limited functionality. Please refer to the original text for a detailed description of this content. Abbreviations: AIFs, apoptosis-inducing factors; Apaf-1, apoptosis protease activating factor-1; APP, amyloid precursor protein; ASC, apoptosis-associated speck-like protein containing a CARD; BH3-only proteins, Bcl-2 homology 3 domain only proteins; BID, BH3-interacting-domain death agonist; CARD, caspase recruitment domain; CTCs, circulating tumor cells; Cyt-c, cytochrome-c; DISC, death inducing signaling complex; DR6, death receptor 6; dsDNA, double-stranded DNA; ER, endoplasmic reticulum; FADD, Fas-associated death domain; GSDM, gasdermin; IAPs, inhibitors of apoptosis proteins; IFNARs, interferon alpha receptors; IFNs, interferons; IL-18, interleukin-18; IL-1β, interleukin-1β; K, potassium; LPS, lipopolysaccharide; MLKL, mixed-lineage kinase-like; NK, natural killer; NLR, nucleotide-binding oligomerization domain-like receptor; NLRP3, NLR family pyrin domain containing 3; NLS, nuclear localization signal; PD-1, programmed death 1; PD-L1, programmed cell death-ligand 1; PRRs, pattern recognition receptors; PtpB, protein tyrosine phosphatase B; RHIM, RIP (receptor-interacting protein) homology interaction motifs; RIPK1, serine/threonine protein kinase 1; RIPK3, serine/threonine protein kinase 3; Smac, small mitochondria-derived activator of caspase; SpeB, streptococcal pyrogenic exotoxin B; TAK1, TGF-β-activated kinase 1; T-BID, truncated BID; TLR3, toll-like receptor 3; TLR4, toll-like receptor 4; TRADD, TNF receptor-associated death domain; TRIF, TIR-domain-containing adapter-inducing interferon-β; YopJ, yersinia outer protein J; ZBP1, Z-DNA/RNA-binding protein; Z-dsDNA/RNA, Z-form double-stranded DNA/RNA.</p>
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<p>The pathways of cuproptosis and ferroptosis are illustrated. (<b>a</b>) Ferroptosis is a form of iron-dependent programmed cell death resulting from intracellular iron overload. The figure depicts the lipid peroxidation induced by dysregulated iron metabolism and the subsequent execution of ferroptosis; (<b>b</b>) abnormal copper metabolism and accumulation can lead to protein toxicity, mitochondrial damage, and cuproptosis. For details, refer to the corresponding section of this article. Abbreviations: Cu, copper; DSF, disulfiram; ES, elesclomol; FDX1, ferredoxin 1; Fe, iron; NCOA4, nuclear receptor coactivator 4; NRAMP2 (also known as SLC11A2), natural resistance-associated macrophage protein 2; ROS, reactive oxygen species; S, sulfur; SLC25A3, solute carrier family 25 member 3; STEAP, six-transmembrane epithelial antigen of prostate; TCA, tricarboxylic acid cycle; TF, transferrin; TFR1, transferrin receptor 1.</p>
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<p>An overview of the mechanisms of various other forms of PCD. (<b>a</b>) MPT-driven necrosis is mediated by the activation of CYPD and the formation of PTPC, leading to a loss of selective permeability of the inner mitochondrial membrane, resulting in cell swelling and membrane rupture; (<b>b</b>) oxeiptosis is a form of cell death induced by oxygen radicals and mediated by the hyperactivation of the KEAP1-PGAM5-AIFM1 signaling cascade; (<b>c</b>) LDCD is a form of cell death caused by changes in lysosomal membrane permeability, resulting in the leakage of lysosomal contents and subsequent alterations in mitochondrial outer membrane permeability; (<b>d</b>) parthanatos is a form of cell death induced by DNA damage, resulting in the overactivation of PARP1; (<b>e</b>) alkaliptosis is a form of cell death induced by intracellular alkalinization caused by JTC-801, an opioid receptor-like 1 (ORL1) receptor selective antagonist [<a href="#B5-ijms-25-09947" class="html-bibr">5</a>]; (<b>f</b>) in cells with high SLC7A11 expression, increased cystine uptake leads to NADPH depletion, abnormal disulfide bond formation, cytoskeletal collapse, and disulfidptosis; (<b>g</b>) aberrant autophagy leads to excessive ER-phagy, excessive mitophagy, and ADCD. For details, refer to the corresponding section of this article. The red line in the image signifies obstruction or limited functionality. Please refer to the original text for a detailed description of this content. Abbreviations: ADCD, autophagy-dependent cell death; AIFM1, apoptosis-inducing factor mitochondria-associated 1; ATP, adenosine triphosphate; ATP6V0D1, ATPase H+ transporting V0 subunit d1; ATPase, adenosine triphosphatase; CA9, carbonic anhydrase 9; CYPD, cyclophilin D; Cyt-c, cytochrome c; DRAM1, DNA damage-regulated autophagy modulator 1; DRP1, dynamin-related protein 1; ER, endoplasmic reticulum; Fe, iron; IMS, intermembrane space; K, potassium; KEAP1, kelch-like ECH-associated protein 1; LDCD, lysosome-dependent cell death; LMP, lysosomal membrane permeabilization; Mito, mitochondria; MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition; Na, sodium; NADH, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor κB; PARP1, poly(ADP-ribose) polymerase 1; PGAM, phosphoglycerate mutase; PGAM5, PGAM family member 5; pH, potential of hydrogen; reticulophagy, selective autophagy of the endoplasmic reticulum; PINK1, PTEN-induced kinase 1; PTPC, permeability transition pore complex; ROS, reactive oxygen species; S, sulfur; SLC7A11, solute carrier family 7 member 11; STAT3, signal transducer and activator of transcription 3; UPR, unfolded protein response.</p>
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<p>The pathways of NETosis and Entosis are depicted. (<b>a</b>) Cellular stress responses induce autophagy, granzyme release and translocation, chromatin decondensation, and cell membrane pore formation, leading to the release of web-like DNA–protein structures and resulting in NETosis; (<b>b</b>) cells undergo entosis, an intracellular cell death process, by inserting themselves into neighboring cells through adhesion proteins. For details, refer to the corresponding section of this article. Abbreviations: Ca, calcium; CTNNA1, catenin alpha 1; ENTosis, entotic cell death; ERK, extracellular signal-regulated kinase; GSDM, gasdermin; GSDMD-N,Gasdermin D N-terminal; LC3, microtubule-associated protein 1 light chain 3; LPS, lipopolysaccharide; MEK, MAP kinase kinase; MPO, myeloperoxidase; mtDNA, mitochondrial DNA; mtROS, mitochondrial reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; NE, neutrophil elastase; NETosis, neutrophil extracellular trap cell death; NETs, neutrophil extracellular traps; PAD4, peptidylarginine deiminase 4; PKC, protein kinase C; RAF, RAF proto-oncogene serine/threonine-protein kinase; TLR, toll-like receptor.</p>
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<p>The process of programmed cell death in the development of AD, PD and HD is significant. (<b>a</b>) Various forms of programmed cell death play roles in the pathogenesis and progression of AD, including their effects on Tau protein hyperphosphorylation, Aβ plaque formation, and neuronal cell death; (<b>b</b>) in PD, various forms of PCD induce dopaminergic neuronal loss and death by promoting αSyn aggregation, leading to mitochondrial dysfunction and neuroinflammation. (<b>c</b>) In HD, mHTT induces mitochondrial dysfunction and neuroinflammation by promoting the expression of pro-apoptotic factors and activating necroptosis and ferroptosis. Additionally, the aggregation of mHTT proteins is associated with impaired autophagy, further exacerbating neuronal damage. For details, refer to the corresponding section of this article. The red line in the image signifies obstruction or limited functionality. Please refer to the original text for a detailed description of this content. Abbreviations: AD, Alzheimer’s disease; Akt, protein kinase B; APP, amyloid precursor protein; Aβ, amyloid β; BAX, Bcl-2 associated x-protein; Bcl-2, B-cell lymphoma-2; BDNF, brain-derived neurotrophic factor; BIM, Bcl-2 interacting mediator of cell death; CGA, cytosine-guanine-adenine triplet; CREB, cAMP-response element binding protein; Cu, cuprum; CYPD, cyclophilin D; Cyt-c, cytochrome-c; ER, endoplasmic reticulum; Fe, ferrum; GPX4, glutathione peroxidase 4; GSDMD, gasdermin-D; GSK-3β, glycogen synthase kinase 3β; HD, Huntington’s disease; ICAM-1, intercellular adhesion molecule-1; IL-18, interleukin-18; IL-1β, interleukin-1β; JAK, janus kinase; JNK, c-Jun N-terminal kinase; LFA-1, lymphocyte function-associated antigen 1; LRP1, low-density lipoprotein receptor-related protein 1; LRRK2, leucine-rich repeat kinase 2; MAPK, mitogen-activated protein kinase; mHTT, mutant huntingtin; MLKL, mixed lineage kinase domain-like protein; MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition; mTOR, mammalian target of rapamycin; NET, neutrophil extracellular traps; NFTs, neurofibrillary tangles; NF-κB, nuclear factor κB; NLRP3, NLR family pyrin domain containing 3; NLR, nucleotide-binding oligomerization domain-like receptor; NO, nitric oxide; PARK7, parkinsonism associated deglycase; PARP1, poly(ADP-ribose) polymerase 1; PCD, programmed cell death; PD, Parkinson’s disease; PI3K, phosphoinositide 3-kinase; PINK1, PTEN induced kinase 1; polyQ, polyglutamine; PRKN, parkin RBR E3 ubiquitin protein ligase; RIPK1, receptor-interacting serine/threonine-protein kinase 1; RIPK3, receptor-interacting serine/threonine-protein kinase 3; ROS, reactive oxygen species; SNCA, alpha-synuclein; αSyn, α-synuclein; STAT, signal transducer and activator of transcription; Tau, microtubule-associated protein Tau; TNF-α, tumor necrosis factor-α; TrkB, tropomyosin receptor kinase B.</p>
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<p>The role of PCD in the progression of ALS, SMA and MS is critical. The figure illustrates the involvement of PCD pathways in the pathogenesis of ALS, SMA, and MS, highlighting both the factors that contribute to disease progression and those that are beneficial for disease control. Additionally, it describes the common pathways through which PCD exerts its effects across these diseases. For more details, refer to the corresponding section of this article. Abbreviations: ADCD, autophagy-dependent cell death; ALS, amyotrophic lateral sclerosis; Bcl-2, B-cell lymphoma-2; C9ORF72, chromosome 9 open reading frame 72; Cu, cuprum; CYPD, cyclophilin D; Fe, ferrum; FUS, fused in sarcoma/translocated in liposarcoma; GSDMD, gasdermin-D; IL-18, interleukin-18; IL-1β, interleukin-1β; JNK, c-Jun N-terminal kinase; KO, knockout; MPT, mitochondrial permeability transition; mPTP, mitochondrial permeability transition pore; MS, multiple sclerosis; NET, neutrophil extracellular traps; NETosis, neutrophil extracellular trap cell death; PARP1, poly(ADP-ribose) polymerase 1; PCD, programmed cell death; RIPK1, receptor-interacting serine/threonine-protein kinase 1; RIPK3, receptor-interacting serine/threonine-protein kinase 3; ROS, reactive oxygen species; SMA, spinal muscular atrophy; SMN, survival motor neuron; SOD1, superoxide dismutase 1; TARDBP, TAR DNA-binding protein; TDP-43, TAR DNA-binding protein 43.</p>
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<p>The role of programmed cell death (PCD) in the progression of traumatic brain injury (TBI) and stroke. The figure illustrates various aspects that contribute to disease progression, revealing the role of PCD in these conditions and considerations beneficial for disease control and treatment. Additionally, it describes the pathways through which PCD exerts its effects both individually and collectively in TBI and stroke. For details, refer to the corresponding section of this article. The upward and downward arrows represent an increase and decrease in content or concentration, respectively. The circular arrow signifies that "apoptosis in neurons of the ischemic penumbra may be recoverable." The red line in the image signifies obstruction or limited functionality. Please refer to the original text for a detailed description of this content. Abbreviations: ADCD, autophagy-dependent cell death; ATP, adenosine triphosphate; Bcl-2, B-cell lymphoma-2; Ca, calcium; CNS, central nervous system; Cu, cuprum; CYPD, cyclophilin D; DRGs, dorsal root ganglions; ER, endoplasmic reticulum; FasL, Fas ligand; Fe, ferrum; HIF-1α, hypoxia-inducible factor 1α; HMGB1, high-mobility group box 1; IL-1β, interleukin-1β; IP, ischemic penumbra; K, kalium; LDCD, lysosome-dependent cell death; Mito, mitochondria; MLKL, mixed lineage kinase domain-like protein; MPT, mitochondrial permeability transition; Na, natrium; NAD, nicotinamide adenine dinucleotide; NET, neutrophil extracellular traps; PAD4, peptidylarginine deiminase 4; PARP1, poly(ADP-ribose) polymerase 1; PCD, programmed cell death; RIPK1, receptor-interacting serine/threonine-protein kinase 1; RIPK3, receptor-interacting serine/threonine-protein kinase 3; ROS, reactive oxygen species; TBI, traumatic brain injury; TNF-α, tumor necrosis factor-α; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.</p>
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24 pages, 2304 KiB  
Systematic Review
Targeting NETosis in Acute Brain Injury: A Systematic Review of Preclinical and Clinical Evidence
by Marzia Savi, Fuhong Su, Elda Diletta Sterchele, Elisa Gouvêa Bogossian, Zoé Demailly, Marta Baggiani, Giuseppe Stefano Casu and Fabio Silvio Taccone
Cells 2024, 13(18), 1553; https://doi.org/10.3390/cells13181553 (registering DOI) - 14 Sep 2024
Viewed by 360
Abstract
Acute brain injury (ABI) remains one of the leading causes of death and disability world-wide. Its treatment is challenging due to the heterogeneity of the mechanisms involved and the variability among individuals. This systematic review aims at evaluating the impact of anti-histone treatments [...] Read more.
Acute brain injury (ABI) remains one of the leading causes of death and disability world-wide. Its treatment is challenging due to the heterogeneity of the mechanisms involved and the variability among individuals. This systematic review aims at evaluating the impact of anti-histone treatments on outcomes in ABI patients and experimental animals and defining the trend of nucleosome levels in biological samples post injury. We performed a search in Pubmed/Medline and Embase databases for randomized controlled trials and cohort studies involving humans or experimental settings with various causes of ABI. We formulated the search using the PICO method, considering ABI patients or animal models as population (P), comparing pharmacological and non-pharmacological therapy targeting the nucleosome as Intervention (I) to standard of care or no treatment as Control (C). The outcome (O) was mortality or functional outcome in experimental animals and patients affected by ABI undergoing anti-NET treatments. We identified 28 studies from 1246 articles, of which 7 were experimental studies and 21 were human clinical studies. Among these studies, only four assessed the effect of anti-NET therapy on circulating markers. Three of them were preclinical and reported better outcome in the interventional arm compared to the control arm. All the studies observed a significant reduction in circulating NET-derived products. NETosis could be a target for new treatments. Monitoring NET markers in blood and cerebrospinal fluid might predict mortality and long-term outcomes. However, longitudinal studies and randomized controlled trials are warranted to fully evaluate their potential, as current evidence is limited. Full article
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<p>PRISMA flowchart of the review.</p>
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<p>Summary of preclinical and clinical findings and future directions for the clinical application of research on NETosis (illustration created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>). Acronyms: NET: neutrophil extracellular trap; ABI: acute brain injury; TBI: traumatic brain injury; SAH: subarachnoid aneurysmal haemorrhage; MPO-DNA: myeloperoxidase-deoxy-ribonuclease acid; CSF: cerebral spinal fluid.</p>
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<p>The main pathways of NET formation involved in neuroinflammation (illustration created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>).</p>
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17 pages, 2921 KiB  
Article
Decision Regret and Vaccine Hesitancy among Nursing Students and Registered Nurses in Italy: Insights from Structural Equation Modeling
by Alice Silvia Brera, Cristina Arrigoni, Silvia Belloni, Gianluca Conte, Arianna Magon, Marco Alfredo Arcidiacono, Malgorzata Pasek, Galyna Shabat, Luigi Bonavina and Rosario Caruso
Vaccines 2024, 12(9), 1054; https://doi.org/10.3390/vaccines12091054 (registering DOI) - 14 Sep 2024
Viewed by 240
Abstract
This study focused on vaccine hesitancy and decision regret about the COVID-19 vaccine among nursing students (BScN and MScN) and Registered Nurses (RNs) in Italy. The primary aim was to describe decision regret and vaccine hesitancy among these groups and to understand what [...] Read more.
This study focused on vaccine hesitancy and decision regret about the COVID-19 vaccine among nursing students (BScN and MScN) and Registered Nurses (RNs) in Italy. The primary aim was to describe decision regret and vaccine hesitancy among these groups and to understand what influences vaccine hesitancy. Data were collected through an e-survey conducted from March to June 2024. The Decision Regret Scale and the Adult Vaccine Hesitancy Scale were employed to assess regret and hesitancy levels, assessing trust, concerns, and compliance regarding vaccination. Among the participants, 8.64% were not vaccinated. The results indicated moderate to high levels of decision regret and diverse levels of trust, concerns, and compliance with COVID-19 vaccination. Structural equation modeling revealed that decision regret significantly predicted Trust (R2 = 31.3%) and Concerns (R2 = 26.9%), with lower regret associated with higher trust and lower concerns about vaccine safety. The number of COVID-19 vaccine boosters was a significant predictor of Trust and Concerns, with more boosters associated with higher trust and lower concerns. MScN students exhibited higher Compliance compared to RNs (R2 = 2.9%), highlighting the role of advanced education. These findings suggest that addressing decision regret and providing comprehensive vaccine information could enhance trust and compliance. Full article
(This article belongs to the Special Issue Advancing the Science on Vaccine Hesitancy to Inform Interventions)
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<p>Distribution of DRS and aVHS scores.</p>
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<p>Correlogram. The plot illustrates the relationships between Age, DRS, Trust, Concerns, Compliance, Sex, and the number of boosters. The diagonal plots show the distribution of each variable, with density plots for continuous variables and bar plots for categorical variables. The lower triangle displays scatter plots and smooth density plots, highlighting pairwise relationships, such as the positive correlation between lower decision regret and higher trust. The upper triangle presents Pearson correlation coefficients, summarizing the strength and direction of these relationships, with statistical significance indicated by asterisks. Box plots for categorical variables, such as Sex and Number of Boosters, depict how continuous variables vary across different categories. * indicates <span class="html-italic">p</span>-values lower than 0.05, *** indicates <span class="html-italic">p</span>-values lower than 0.001.</p>
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16 pages, 275 KiB  
Article
Characterization and Automatic Discrimination between Predominant Hypoperfusion and Hyperperfusion Stages of NPDR
by Luís Mendes, Luísa Ribeiro, Inês Marques, Conceição Lobo and José Cunha-Vaz
J. Pers. Med. 2024, 14(9), 977; https://doi.org/10.3390/jpm14090977 (registering DOI) - 14 Sep 2024
Viewed by 213
Abstract
Background/Objectives: Diabetic retinopathy (DR) is a common diabetes complication that can lead to blindness through vision-threatening complications like clinically significant macular edema and proliferative retinopathy. Identifying eyes at risk of progression using non-invasive methods could help develop targeted therapies to halt diabetic retinal [...] Read more.
Background/Objectives: Diabetic retinopathy (DR) is a common diabetes complication that can lead to blindness through vision-threatening complications like clinically significant macular edema and proliferative retinopathy. Identifying eyes at risk of progression using non-invasive methods could help develop targeted therapies to halt diabetic retinal disease progression. Methods: A set of 82 imaging and systemic features was used to characterize the progression of nonproliferative diabetic retinopathy (NPDR). These features include baseline measurements (static features) and those capturing the temporal dynamic behavior of these static features within one year (dynamic features). Interpretable models were trained to distinguish between eyes with Early Treatment Diabetic Retinopathy Study (ETDRS) level 35 and eyes with ETDRS levels 43–47. The data used in this research were collected from 109 diabetic type 2 patients (67.26 ± 2.70 years; diabetes duration 19.6 ± 7.26 years) and acquired over 2 years. Results: The characterization of the data indicates that NPDR progresses from an initial stage of hypoperfusion to a hyperperfusion response. The performance of the classification model using static features achieved an area under the curve (AUC) of the receiver operating characteristics equal to 0.84 ± 0.07, while the model using both static and dynamic features achieved an AUC of 0.91 ± 0.05. Conclusion: NPDR progresses through an initial hypoperfusion stage followed by a hyperperfusion response. Characterizing and automatically identifying this disease progression stage is valuable and necessary. The results indicate that achieving this goal is feasible, paving the way for the improved evaluation of progression risk and the development of better-targeted therapies to prevent vision-threatening complications. Full article
(This article belongs to the Special Issue Pathophysiology of Retinopathy in Precision Medicine Era)
19 pages, 6389 KiB  
Article
A Breast Tumor Monitoring Vest with Flexible UWB Antennas—A Proof-of-Concept Study Using Realistic Breast Phantoms
by Rakshita Dessai, Daljeet Singh, Marko Sonkki, Jarmo Reponen, Teemu Myllylä, Sami Myllymäki and Mariella Särestöniemi
Micromachines 2024, 15(9), 1153; https://doi.org/10.3390/mi15091153 (registering DOI) - 14 Sep 2024
Viewed by 254
Abstract
Breast cancers can appear and progress rapidly, necessitating more frequent monitoring outside of hospital settings to significantly reduce mortality rates. Recently, there has been considerable interest in developing techniques for portable, user-friendly, and low-cost breast tumor monitoring applications, enabling frequent and cost-efficient examinations. [...] Read more.
Breast cancers can appear and progress rapidly, necessitating more frequent monitoring outside of hospital settings to significantly reduce mortality rates. Recently, there has been considerable interest in developing techniques for portable, user-friendly, and low-cost breast tumor monitoring applications, enabling frequent and cost-efficient examinations. Microwave technique-based breast cancer detection, which is based on differential dielectric properties of malignant and healthy tissues, is regarded as a promising solution for cost-effective breast tumor monitoring. This paper presents the development process of the first proof-of-concept of a breast tumor monitoring vest which is based on the microwave technique. Two unique vests are designed and evaluated on realistic 3D human tissue phantoms having different breast density types. Additionally, the measured results are verified using simulations carried out on anatomically realistic voxel models of the electromagnetic simulations. The radio channel characteristics are evaluated and analyzed between the antennas embedded in the vest in tumor cases and reference cases. Both measurements and simulation results show that the proposed vest can detect tumors even if only 1 cm in diameter. Additionally, simulation results show detectability with 0.5 cm tumors. It is observed that the detectability of breast tumors depends on the frequency, antenna selection, size of the tumors, and breast types, causing differences of 0.5–30 dB in channel responses between the tumorous and reference cases. Due to simplicity and cost-efficiency, the proposed channel analysis-based breast monitoring vests can be used for breast health checks in smaller healthcare centers and for user-friendly home monitoring which can prove beneficial in rural areas and developing countries. Full article
(This article belongs to the Special Issue Biomaterials, Biodevices and Tissue Engineering, Second Edition)
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<p>(<b>a</b>) Three cylindrical-shaped glandular phantoms: (1) reference, (2) with 1 cm tumor, and (3) with a 2 cm tumor; (<b>b</b>) breast phantom “Very Dense” with 0.5 cm thick fat layer; (<b>c</b>) breast phantom “Dense” with the glandular phantom inserted into the fat phantom; (<b>d</b>) measurement setup with phantoms set on the mannequin torso (1), above which the muscle phantom is first assembled (2), fat (3), glandular (4), and skin (5) phantoms [<a href="#B30-micromachines-15-01153" class="html-bibr">30</a>].</p>
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<p>Antennas used in the vest. (<b>a</b>) UWB monopole antenna design, (<b>b</b>) UWB monopole with flexible laminate substrate, (<b>c</b>) UWB monopole with conductive textile material, (<b>d</b>) Kapton polyamide substrate-based larger monopole [<a href="#B31-micromachines-15-01153" class="html-bibr">31</a>].</p>
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<p>(<b>a</b>) Tissue layer model used in antenna characteristics simulations, (<b>b</b>) S11 parameters of small and larger flexible antennas, (<b>c</b>–<b>h</b>) radiation patterns of small flexible antenna (left side of figure) and larger flexible antenna (right side of figure) at 3 GHz, 5 GHz, and 7 GHz.</p>
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<p>(<b>a</b>) Tissue layer model used in antenna characteristics simulations, (<b>b</b>) S11 parameters of small and larger flexible antennas, (<b>c</b>–<b>h</b>) radiation patterns of small flexible antenna (left side of figure) and larger flexible antenna (right side of figure) at 3 GHz, 5 GHz, and 7 GHz.</p>
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<p>The developed breast tumor monitoring vest types used in the evaluations: (<b>a</b>) Vest I with smaller flexible antennas and (<b>b</b>) Vest II with larger flexible antennas [<a href="#B31-micromachines-15-01153" class="html-bibr">31</a>]. The numbers above the antenna pockets indicate the antenna number.</p>
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<p>(<b>a</b>) Emma (<b>left</b>) and Laura (<b>right</b>) voxel models used in the simulations, (<b>b</b>) cross-section of Emma voxel (scattered fibroglandular tissue, <b>left</b>) and cross-section of Laura voxel (heterogeneous glandular breast tissue, <b>right</b>).</p>
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<p>Channel evaluations between (<b>a</b>) antennas 2 and 5 (Case 1a) and (<b>b</b>) antennas 2 and 7 (Case 1b) for Vest I with Antenna 1 and “Dense” breast phantom.</p>
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<p>Channel evaluations between the (<b>a</b>) antennas 2 and 5 (Case 2a) and (<b>b</b>) antennas 2 and 7 (Case 2b) for Vest I with Antenna 1 and “Less Dense” breast phantom.</p>
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<p>Channel evaluations in Case 3 between the (<b>a</b>) antennas 2 and 5 (Case 3a) and (<b>b</b>) antennas 2 and 7 (Case 3b) for Vest I with Antenna 2 and “Dense” breast phantom.</p>
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<p>Channel evaluations between in Case 4 (<b>a</b>) antennas 2 and 5 (Case 4a) and (<b>b</b>) antennas 2 and 7 (Case 4b) for Vest I with Antenna 2 and “Less Dense” breast phantom.</p>
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<p>Channel evaluations for Case 5 between the (<b>a</b>) antennas 1 and 6 (Case 5a) and (<b>b</b>) antennas 3 and 6 (Case 5b) for Vest II with Antenna 3 and “Dense” breast phantom.</p>
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<p>Channel evaluations for Case 6 between (<b>a</b>) antennas 1 and 6 (Case 6a) and (<b>b</b>) antennas 3 and 6 (Case 6b) for Vest II with Antenna 3 and “Less Dense” breast phantom.</p>
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<p>Case 7: Simulation-based channel evaluations with different tumor sizes: (<b>a</b>) S26 results using Emma voxel (Case 7a) and (<b>b</b>) S16 results using Laura voxel (Case 7b).</p>
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<p>Time-domain channel evaluations with different tumor sizes and different IFFT lengths: (<b>a</b>) Impulse response IR26 results using Emma voxel with full band IFFT conversion, (<b>b</b>) IR16 results using Laura voxel, with full band IFFT conversion, (<b>c</b>) IR16 results using Laura, with IFFT conversion to 4.5–5.8 GHz.</p>
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