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16 pages, 272 KiB  
Review
Anderson–Fabry Disease: An Overview of Current Diagnosis, Arrhythmic Risk Stratification, and Therapeutic Strategies
by Chiara Tognola, Giacomo Ruzzenenti, Alessandro Maloberti, Marisa Varrenti, Patrizio Mazzone, Cristina Giannattasio and Fabrizio Guarracini
Diagnostics 2025, 15(2), 139; https://doi.org/10.3390/diagnostics15020139 - 9 Jan 2025
Viewed by 407
Abstract
Anderson–Fabry disease (AFD) is a rare X-linked lysosomal storage disorder characterized by the accumulation of globotriaosylceramide, leading to multi-organ involvement and significant morbidity. Cardiovascular manifestations, particularly arrhythmias, are common and pose a considerable risk to affected individuals. This overview examines current approaches to [...] Read more.
Anderson–Fabry disease (AFD) is a rare X-linked lysosomal storage disorder characterized by the accumulation of globotriaosylceramide, leading to multi-organ involvement and significant morbidity. Cardiovascular manifestations, particularly arrhythmias, are common and pose a considerable risk to affected individuals. This overview examines current approaches to arrhythmic risk stratification in AFD, focusing on the identification, assessment, and management of cardiac arrhythmias associated with the disease. We explore advancements in diagnostic techniques, including echocardiography, cardiac MRI, and ambulatory ECG monitoring, to enhance the detection of arrhythmogenic substrate. Furthermore, we discuss the role of genetic and biochemical markers in predicting arrhythmic risk and the implications for personalized treatment strategies. Current therapeutic interventions, including enzyme replacement therapy and antiarrhythmic medications, are reviewed in the context of their efficacy and limitations. Finally, we highlight ongoing research and future directions with the aim of improving arrhythmic risk assessment and management in AFD. This overview underscores the need for a multidisciplinary approach to optimize care and outcomes for patients with AFD. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Cardiac Arrhythmias 2025)
14 pages, 610 KiB  
Perspective
Overcoming Resistance in Anderson–Fabry Disease: Current Therapeutic Challenges and Future Perspectives
by Maria Cristina Carella, Cinzia Forleo, Pierpaolo Caretto, Maria Ludovica Naccarati, Ilaria Dentamaro, Marco Maria Dicorato, Paolo Basile, Eugenio Carulli, Michele Davide Latorre, Andrea Baggiano, Gianluca Pontone, Marco Matteo Ciccone and Andrea Igoren Guaricci
J. Clin. Med. 2024, 13(23), 7195; https://doi.org/10.3390/jcm13237195 - 27 Nov 2024
Viewed by 837
Abstract
Anderson–Fabry disease (AFD) remains a therapeutic challenge despite advances in early diagnosis and the availability of enzyme replacement therapies (ERTs). While early initiation of therapy can mitigate disease progression, resistance mechanisms—such as the development of anti-drug antibodies—limit the efficacy of current treatments, particularly [...] Read more.
Anderson–Fabry disease (AFD) remains a therapeutic challenge despite advances in early diagnosis and the availability of enzyme replacement therapies (ERTs). While early initiation of therapy can mitigate disease progression, resistance mechanisms—such as the development of anti-drug antibodies—limit the efficacy of current treatments, particularly in patients with severe genetic variants. Chaperone therapy provides a targeted option for a subset of patients, yet significant gaps remain in treating those with complete enzyme deficiency. This perspective article explores the existing therapeutic landscape and reflects on emerging treatments, such as mRNA and gene therapies, which hold promise for overcoming the resistance mechanisms. By addressing the limitations of current pharmacological options and considering future innovations, this article aims to outline the path forward for more effective and personalized treatment strategies in Anderson–Fabry disease. Full article
(This article belongs to the Section Cardiology)
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<p>Case of a 57year-old male with Anderson–Fabry disease and coexisting sarcomeric mutations. The patient, initially presenting with mild left ventricular hypertrophy and recurrent palpitations, underwent extensive evaluation following the discovery of cornea verticillata and angiokeratomas. Genetic testing confirmed a pathogenic <span class="html-italic">GLA</span> gene variant, diagnostic of Anderson–Fabry disease, along with two sarcomeric variants of uncertain significance. Cardiac MRI revealed intramyocardial edema and late gadolinium enhancement (LGE), while blood tests showed elevated LysoGb3 levels. ERT with agalsidase-α was initiated, resulting in transient clinical improvement. However, the patient demonstrated progressive ventricular hypertrophy, increased cardiac mass, and a small cerebral hemorrhage on MRI. Persistent acroparesthesias and fluctuating LysoGb3 levels, despite ERT, indicated resistance to therapy. It is important to note that the sarcomeric mutations identified were of uncertain clinical significance and were unlikely to influence the AFD phenotype or the fluctuating LysoGb3 levels but may have contributed to the overall complexity of the cardiomyopathy phenotype observed. (<b>A</b>) Parasternal long-axis view shows severe concentric hypertrophy of the left ventricle; (<b>B</b>) left ventricular ejection fraction measured by the Simpson biplane method is preserved; (<b>C</b>) a reduction is detected in the GLS values.</p>
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8 pages, 725 KiB  
Case Report
Septal Myectomy in Patients with Hypertrophic Cardiomyopathy and Nonclassical Anderson–Fabry Disease
by Alexandr Gurschenkov, Sofiya Andreeva, Vadim Zaitsev, Pavel Khazov, Gleb Ischmukhametov, Alexandra Kozyreva, Polina Sokolnikova, Olga Moiseeva, Anna Kostareva and Mikhail Gordeev
J. Cardiovasc. Dev. Dis. 2024, 11(9), 293; https://doi.org/10.3390/jcdd11090293 - 20 Sep 2024
Viewed by 955
Abstract
Anderson–Fabry disease (AFD) results from decreased enzyme activity of lysosomal enzymes and intralysosomal storage of nonhydrolyzed forms. Cardiovascular complications, mainly in the form of HCM, contribute substantially to AFD patient mortality. Here, we report three new cases of obstructive HCM (HOCM) in nonclassical [...] Read more.
Anderson–Fabry disease (AFD) results from decreased enzyme activity of lysosomal enzymes and intralysosomal storage of nonhydrolyzed forms. Cardiovascular complications, mainly in the form of HCM, contribute substantially to AFD patient mortality. Here, we report three new cases of obstructive HCM (HOCM) in nonclassical presentations of AFD and isolated cardiac involvement. In all three cases, the diagnosis of AFD was made postoperatively by routine genetic and morphological testing. Together with previously published cases, this report illustrates the potential safety and beneficial effect of septal surgical myectomy in patients with AFD-HOCM, as well as underlines the need for more thorough screening for clinical signs of AFD-associated cardiomyopathy and GLA variants among patients with HOCM. Full article
(This article belongs to the Special Issue Hypertrophic Cardiomyopathy: Pathogenesis, Diagnosis and Management)
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<p>Cardiac MRI before and after SSM. (<b>a</b>)—Patient 1, A—diastolic view before SSM, long left ventricular axis, B—diastolic view before SSM, short left ventricular axis, C—diastolic view after SSM, long left ventricular axis, D—diastolic view after SSM, short left ventricular axis; (<b>b</b>)—Patient 3, A,B—diastolic view before SSM, long left ventricular axis, C,D—diastolic view before SSM, short left ventricular axis; (<b>c</b>)—Patient 1, ECG; (<b>d</b>)—Patient 3, ECG.</p>
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19 pages, 5511 KiB  
Article
Biomass Equations and Carbon Stock Estimates for the Southeastern Brazilian Atlantic Forest
by Tatiana Dias Gaui, Vinicius Costa Cysneiros, Fernanda Coelho de Souza, Hallefy Junio de Souza, Telmo Borges Silveira Filho, Daniel Costa de Carvalho, José Henrique Camargo Pace, Graziela Baptista Vidaurre and Eder Pereira Miguel
Forests 2024, 15(9), 1568; https://doi.org/10.3390/f15091568 - 6 Sep 2024
Viewed by 1315
Abstract
Tropical forests play an important role in mitigating global climate change, emphasizing the need for reliable estimates of forest carbon stocks at regional and global scales. This is essential for effective carbon management, which involves strategies like emission reduction and enhanced carbon sequestration [...] Read more.
Tropical forests play an important role in mitigating global climate change, emphasizing the need for reliable estimates of forest carbon stocks at regional and global scales. This is essential for effective carbon management, which involves strategies like emission reduction and enhanced carbon sequestration through forest restoration and conservation. However, reliable sample-based estimations of forest carbon stocks require accurate allometric equations, which are lacking for the rainforests of the Atlantic Forest Domain (AFD). In this study, we fitted biomass equations for the three main AFD forest types and accurately estimated the amount of carbon stored in their above-ground biomass (AGB) in Rio de Janeiro state, Brazil. Using non-destructive methods, we measured the total wood volume and wood density of 172 trees from the most abundant species in the main remnants of rainforest, semideciduous forest, and restinga forest in the state. The biomass and carbon stocks were estimated with tree-level data from 185 plots obtained in the National Forest Inventory conducted in Rio de Janeiro. Our locally developed allometric equations estimated the state’s biomass stocks at 70.8 ± 5.4 Mg ha−1 and carbon stocks at 35.4 ± 2.7 Mg ha−1. Notably, our estimates were more accurate than those obtained using a widely applied pantropical allometric equation from the literature, which tended to overestimate biomass and carbon stocks. These findings can be used for establishing a baseline for monitoring carbon stocks in the Atlantic Forest, especially in the context of the growing voluntary carbon market, which demands more consistent and accurate carbon stock estimations. Full article
(This article belongs to the Section Forest Ecology and Management)
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<p>Geographic location of the sites where data were collected. Triangles represent sites where aboveground biomass data were collected: Rainforest (RAF; green triangles), Semideciduous Forest (SF; yellow triangles), and Restinga Forest (RF; blue triangles), in the Atlantic Forest of Rio de Janeiro state (Brazil). Circles represent sampling units of the National Forest Inventory conducted in Rio de Janeiro (NFI-RJ; red dots). Data from the NFI-RJ were used to plan the biomass sampling design and estimate the total above-ground biomass stocks of the state’s forest cover.</p>
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<p>Conceptual diagram summarizing (<b>a</b>) data collection, (<b>b</b>) model selection and validation, and (<b>c</b>) biomass estimation for the entire Rio de Janeiro state. DBH = diameter at breast height, MSH = mid-stem height, AGB = predicted aboveground biomass (Mg), Ht = total tree height (m), RAF = Rainforest, SF = Semideciduous Forest, RF = Restinga Forest.</p>
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<p>Equivalence test (regression-based TOST using Bootstrap) for comparing means or similarities between field-measured biomass and the estimates produced by the forest-specific, local-generic, and pantropical equations. The analyses were based on biomass samples taken from 172 trees measured on site: (<b>a</b>) Distribution of AGB values across the different equations for measured trees on site. There were no significant differences (<span class="html-italic">p</span>-value &gt; 0.01) between the observed values (measured on site) and those obtained using either local-generic equations or the forest-specific, though there was a significant difference when compared to values based on pantropical equation. The letters “a” and “b” represent the statistically significant difference between the treatments. (<b>b</b>) Relationship between AGB estimated based on specific equation per forest types and measured AGB. (<b>c</b>) Relationship between AGB estimated from the generic equation and measured AGB. (<b>d</b>) Relationship between AGB estimated from the pantropical equation and measured AGB. (<b>e</b>) Relationship between AGB estimated from pantropical equation and AGB estimated based on specific equation per forest types. (<b>f</b>) Relationship between AGB estimated from pantropical equation and AGB estimated from a generic equation for all forest types. (<b>g</b>) Relationship between AGB estimated from generic equation for all forest types and AGB estimated based on specific equation per forest types. RMSEs are expressed as the percentage of mean square value (PRMSE).</p>
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<p>Equivalence test (regression-based TOST using Bootstrap) to compare means or similarities between the estimates generated by the forest-specific, local-generic, and pantropical equations. The analyses were based on field-measured biomass samples from 185 plots. (<b>a</b>) Distribution of AGB values across the different equations: Generic equation for all forest types, pantropical equation, and specific allometric equation for all forest types. Both AGBs estimated based on generic and specific per-forest types were significantly different for the pantropical equation. The letters “a” and “b” represent the statistically significant difference between the treatments. (<b>b</b>) Relationship between AGB estimated from the pantropical equation and AGB estimates based on specific equation per forest type. (<b>c</b>) Relationship between AGB estimated from the pantropical equation and AGB estimates from the generic equation. (<b>d</b>) AGB estimates from the generic equation and AGB estimates based on the specific equation per forest type. RMSEs are expressed as the percentage of mean square value (PRMSE).</p>
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7 pages, 1355 KiB  
Communication
A Non-Invasive Technique to Unveil Renal Implications in Anderson–Fabry Disease
by Matteo Gravina, Dario Troise, Barbara Infante, Luciano Tartaglia, Bruno Minopoli, Costanza Allegra, Grazia Casavecchia, Marcella Gambacorta, Carmen Montanile, Silvia Mercuri, Luca Macarini and Giovanni Stallone
Biomedicines 2024, 12(9), 1950; https://doi.org/10.3390/biomedicines12091950 - 26 Aug 2024
Viewed by 1284
Abstract
Background: Anderson–Fabry disease (AFD) is a rare genetic disorder characterized by a deficiency of α-galactosidase A activity and the accumulation of glycosphingolipids in tissues, which leads to multiorgan damage. Cardiovascular magnetic resonance (CMR) and the T1 mapping technique are essential tools for the [...] Read more.
Background: Anderson–Fabry disease (AFD) is a rare genetic disorder characterized by a deficiency of α-galactosidase A activity and the accumulation of glycosphingolipids in tissues, which leads to multiorgan damage. Cardiovascular magnetic resonance (CMR) and the T1 mapping technique are essential tools for the assessment of AFD cardiac involvement. Moreover, the T1 mapping technique has proved to be a successful non-invasive method for the early detection of patients most at risk for kidney disease. We evaluated the application of MRI in patients with AFD to assess renal involvement. Methods: We conducted a retrospective analysis of 19 patients (Group A) with histologically proven AFD who underwent routine CMR examinations for the evaluation of cardiac involvement, selecting specific sequences that also showed the left kidney, compared to a control population (Group B, 19 patients) without kidney disease. A Spearman’s rank-order correlation was run to assess the relationship between the T1 mapping values of the heart and kidney in Group A and between the kidneys of Groups A and B. Results: There was a positive correlation between the heart and kidney T1 values in Group A (rho = 0.32). More interestingly, we observed a negative correlation between the kidney values of both groups (Group A mean 1284 ± 137 ms, Group B mean 1073 ± 57 ms, rho = −0.38), which is probably related to the presence of microvascular damage and infiltrates in the kidneys of AFD patients. Conclusions: To our knowledge, these results are the first to highlight the key value of T1 mapping in assessing pathological changes and aiding in the non-invasive diagnosis of renal involvement in AFD. Full article
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<p>Spearman’s analysis shows a positive correlation between heart and kidney T1 mapping values in Group A and a negative correlation between kidney T1 mapping values in Group A and Group B.</p>
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<p>T1 cardiac and kidney values of representative patients. (<b>a</b>) Regions of interest (ROIs) at the level of the heart and renal cortex of AFD patients (mean values: 1048 vs. 1391 ms). Purple arrow: heart. Yellow arrow: kidney. (<b>b</b>) Regions of interest (ROIs) at the level of the heart and renal cortex of the control patient (mean values: 1002 vs. 958 ms). Purple arrow: heart. Blue arrow: kidney.</p>
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18 pages, 2904 KiB  
Article
Relationship between Capillaroscopic Architectural Patterns and Different Variant Subgroups in Fabry Disease: Analysis of Cases from a Multidisciplinary Center
by Denise Cristiana Faro, Francesco Lorenzo Di Pino, Margherita Stefania Rodolico, Luca Costanzo, Valentina Losi, Luigi Di Pino and Ines Paola Monte
Genes 2024, 15(8), 1101; https://doi.org/10.3390/genes15081101 - 21 Aug 2024
Viewed by 1176
Abstract
Anderson–Fabry disease (AFD) is a genetic lysosomal storage disorder caused by mutations in the α-galactosidase A gene, leading to impaired lysosomal function and resulting in both macrovascular and microvascular alterations. AFD patients often exhibit increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), [...] Read more.
Anderson–Fabry disease (AFD) is a genetic lysosomal storage disorder caused by mutations in the α-galactosidase A gene, leading to impaired lysosomal function and resulting in both macrovascular and microvascular alterations. AFD patients often exhibit increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating non-atherosclerotic arterial thickening and the potential for cardiovascular events. Nailfold capillaroscopy, a non-invasive diagnostic tool, has shown potential in diagnosing and monitoring microcirculatory disorders in AFD, despite limited research. This study evaluates nailfold capillaroscopy findings in AFD patients, exploring correlations with GLA gene variant subgroups (associated with classical or late-onset phenotypes and variants of uncertain significance (VUSs)), and assessing morpho-functional differences between sexes. It aims to determine whether capillaroscopy can assist in the early identification of individuals with multiorgan vascular involvement. A retrospective observational study was conducted with 25 AFD patients from AOUP “G. Rodolico-San Marco” in Catania (2020–2023). Patients underwent genetic testing, enzyme activity evaluation, and nailfold capillaroscopy using Horus basic HS 200 videodermatoscopy. Parameters like angiotectonic disorder, vascular areas, capillary density, and intimal thickening were assessed. The study identified significant differences in capillaroscopy findings among patients with different GLA gene variant subgroups. Classic AFD variant patients showed reduced capillary length and signs of erythrocyte aggregation and dilated subpapillary plexus. No correlation was found between enzymatic activity and capillaroscopy parameters. However, Lyso-Gb3 levels were positively correlated with average capillary length (ῤ = 0.453; p = 0.059). Sex-specific differences in capillaroscopy findings were observed in neoangiogenesis and average capillary length, with distinct implications for men and women. This study highlights the potential of nailfold capillaroscopy in the diagnostic process and clinical management of AFD, particularly in relation to specific GLA gene mutations, as a valuable tool for the early diagnosis and monitoring of AFD. Full article
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<p>Distribution of GLA variant subgroups in the study population.</p>
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<p>Distribution of specific genetic variants in male and female patients.</p>
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<p>Summary of capillaroscopic findings according to GLA.</p>
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<p>One-way ANOVA: intima-media thickness in right common carotid in sub-groups.</p>
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<p>Correlation between alfa-gal A, Lyso-Gb3, and IMT levels. Abbreviations: see in the text.</p>
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<p>Comparison of nailfold capillaroscopy findings in men and women from our sample. The figure shows greater alteration in capillary length in males (M), while there is more neovascularization in females (F), in the absence of other statistically significant differences.</p>
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<p><span class="html-italic">Upper</span>: Capillaroscopic picture in a 71-year-old female patient with a classic Fabry variant, showing moderate angiotectonic disorder and heterogeneity, reduced capillary density (<b>A</b>,<b>B</b>), increased average length, limited pseudovascular areas, 10–30% ectasias, loop tortuosity of 20–50%, rare microhemorrhages, and moderate neoangiogenesis (<b>C</b>,<b>D</b>). <span class="html-italic">Bottom:</span> Male, 45 years old, VUS, predominantly ischemic Raynaud’s phenomenon. The picture is characterized by diffuse anomalies in capillary architecture and morphology (<b>A</b>,<b>B</b>), widespread capillary ectasias, isolated mega capillaries, rare microhemorrhages, and neoangiogenesis (<b>C</b>,<b>D</b>).</p>
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<p>Relation between capillaroscopic alterations and left ventricular hypertrophy in the study population. Legend: “0 (blue bar)” means that the alteration is “absent” and “1 (red bar)” means that the alteration is present.</p>
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22 pages, 1698 KiB  
Article
Augmented Feature Diffusion on Sparsely Sampled Subgraph
by Xinyue Wu and Huilin Chen
Electronics 2024, 13(16), 3249; https://doi.org/10.3390/electronics13163249 - 15 Aug 2024
Viewed by 676
Abstract
Link prediction is a fundamental problem in graphs. Currently, SubGraph Representation Learning (SGRL) methods provide state-of-the-art solutions for link prediction by transforming the task into a graph classification problem. However, existing SGRL solutions suffer from high computational costs and lack scalability. In this [...] Read more.
Link prediction is a fundamental problem in graphs. Currently, SubGraph Representation Learning (SGRL) methods provide state-of-the-art solutions for link prediction by transforming the task into a graph classification problem. However, existing SGRL solutions suffer from high computational costs and lack scalability. In this paper, we propose a novel SGRL framework called Augmented Feature Diffusion on Sparsely Sampled Subgraph (AFD3S). The AFD3S first uses a conditional variational autoencoder to augment the local features of the input graph, effectively improving the expressive ability of downstream Graph Neural Networks. Then, based on a random walk strategy, sparsely sampled subgraphs are obtained from the target node pairs, reducing computational and storage overhead. Graph diffusion is then performed on the sampled subgraph to achieve specific weighting. Finally, the diffusion matrix of the subgraph and its augmented feature matrix are used for feature diffusion to obtain operator-level node representations as inputs for the SGRL-based link prediction. Feature diffusion effectively simulates the message-passing process, simplifying subgraph representation learning, thus accelerating the training and inference speed of subgraph learning. Our proposed AFD3S achieves optimal prediction performance on several benchmark datasets, with significantly reduced storage and computational costs. Full article
(This article belongs to the Special Issue Motion-Centric Video Processing)
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<p>Overview of the framework of model AFD3S. The colored nodes are for differentiation; each node corresponds to its row in the matrix (e.g., node 1 to the first row of <span class="html-italic">X</span>). Nodes <span class="html-italic">i</span> and <span class="html-italic">j</span> (1 and 6, marked in red) are the target nodes for link prediction, with the dashed line and red question mark indicating an uncertain edge connection. The goal is to predict the connection probability <math display="inline"><semantics> <msub> <mi>p</mi> <mrow> <mi>i</mi> <mi>j</mi> </mrow> </msub> </semantics></math> using our model. The matrix <span class="html-italic">H</span> enhances each node’s features by fusing them with those of neighboring nodes. The matrix <span class="html-italic">Z</span>, shown in the red box, is generated through feature diffusion with the diffusion matrix <span class="html-italic">M</span>.</p>
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<p>Schematic diagram of concatenated local feature augment. The yellow circles on the graph correspond to neighboring nodes, generating features from local neighborhood distributions. The different nodes are emphasized by color to differentiate their roles in the process. Specifically, the nodes to be enhanced are represented by green or purple nodes, the yellow nodes are domain nodes of the corresponding nodes, and the other white nodes are non-domain nodes (irrelevant). Then, the original and generated features are inputs for downstream GNNs.</p>
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<p>Target node pair (u, v) extraction sampled subgraph. The dashed line and red question mark indicating an uncertain edge connection.</p>
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<p>The average AUC of all models on attributed and non-attributed datasets (over 10 runs).</p>
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<p>The average AP of all models on attributed and non-attributed datasets (over 10 runs).</p>
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<p>Experimental results of link prediction AUC using AFD3S and its three variants.</p>
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<p>Experimental results of link prediction AP using AFD3S and its three variants.</p>
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<p>AUC and AP results of AFD3S on Power under different sampled subgraph sizes.</p>
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<p>AUC and AP results of AFD3S on Cora under different sampled subgraph sizes.</p>
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<p>t-SNE plots on three datasets, with and without the use of our AFD3S. (<b>a</b>) Citeseer without AFD3S. (<b>b</b>) Citeseer with AFD3S. (<b>c</b>) Cora without AFD3S. (<b>d</b>) Cora with AFD3S. (<b>e</b>) PubMed without AFD3S. (<b>f</b>) PubMed with AFD3S.</p>
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<p>Heatmap visualizations of the effects of the number of hidden layers and the number of walks. (<b>a</b>) AUC heatmap of results on AFD3S variants. (<b>b</b>) AUC and AP Heatmaps on Cora. (<b>c</b>) AUC and AP Heatmaps on Power.</p>
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29 pages, 2224 KiB  
Review
Inflammation, Oxidative Stress, and Endothelial Dysfunction in the Pathogenesis of Vascular Damage: Unraveling Novel Cardiovascular Risk Factors in Fabry Disease
by Denise Cristiana Faro, Francesco Lorenzo Di Pino and Ines Paola Monte
Int. J. Mol. Sci. 2024, 25(15), 8273; https://doi.org/10.3390/ijms25158273 - 29 Jul 2024
Cited by 1 | Viewed by 2222
Abstract
Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A (GLA) gene, disrupts lysosomal function, leading to vascular complications. The accumulation of globotriaosylceramide (Gb3) in arterial walls triggers upregulation of adhesion molecules, decreases endothelial nitric oxide synthesis, and induces reactive oxygen [...] Read more.
Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A (GLA) gene, disrupts lysosomal function, leading to vascular complications. The accumulation of globotriaosylceramide (Gb3) in arterial walls triggers upregulation of adhesion molecules, decreases endothelial nitric oxide synthesis, and induces reactive oxygen species production. This cascade results in fibrotic thickening, endothelial dysfunction, hypercontractility, vasospasm, and a pro-thrombotic phenotype. AFD patients display increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating heightened cardiovascular risk. Nailfold capillaroscopy (NFC) shows promise in diagnosing and monitoring microcirculatory disorders in AFD, though it remains underexplored. Morphological evidence of AFD as a storage disorder can be demonstrated through electron microscopy and immunodetection of Gb3. Secondary pathophysiological disturbances at cellular, tissue, and organ levels contribute to the clinical manifestations, with prominent lysosomal inclusions observed in vascular, cardiac, renal, and neuronal cells. Chronic accumulation of Gb3 represents a state of ongoing toxicity, leading to increased cell turnover, particularly in vascular endothelial cells. AFD-related vascular pathology includes increased renin-angiotensin system activation, endothelial dysfunction, and smooth muscle cell proliferation, resulting in IMT increase. Furthermore, microvascular alterations, such as atypical capillaries observed through NFC, suggest early microvascular involvement. This review aims to unravel the complex interplay between inflammation, oxidative stress, and endothelial dysfunction in AFD, highlighting the potential connections between metabolic disturbances, oxidative stress, inflammation, and fibrosis in vascular and cardiac complications. By exploring novel cardiovascular risk factors and potential diagnostic tools, we can advance our understanding of these mechanisms, which extend beyond sphingolipid accumulation to include other significant contributors to disease pathogenesis. This comprehensive approach can pave the way for innovative therapeutic strategies and improved patient outcomes. Full article
(This article belongs to the Special Issue New Cardiovascular Risk Factors)
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<p>Endothelial disfunction, pathogenetic bases, mechanisms of endothelial dysfunction and biomarkers. Lyso-Gb3, lyso-globotriaosylceramide; ROS, reactive oxygen species; eNOS, endothelial nitric oxide synthase; KCa3.1, calcium-activated potassium channel 3.1; RAAS, renin-angiotensin-aldosterone system; PBMC, peripheral blood mononuclear cells; iNKT, Invariant natural killer T cells; ADA, antidrug antibodies; CMP, cardiomyopathy; CKD, chronic kidney disease; ECM, extracellular matrix; TNF, tumor necrosis factor; TNFR2, tumor necrosis factor receptor 2; IL, interleukin; TGF, transforming growth factor; FGF, fibroblast growth factor; VEFG-A, vascular endothelial growth factor; MMP, matrix metalloproteinase; CAMs, cell adhesion molecules; GDF-15, growth differentiation factor 15; SDMA, symmetric dimethylarginine; ADMA, asymmetric dimethylarginine. Credits: Some parts of the image were generated with the help of an artificial intelligence algorithm and then manually combined and annotated.</p>
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<p>Overview of Anderson-Fabry Disease Complications related to cardiac and vascular inflammation are classified according to the mechanism (heart, macrovascular, and microvascular). Abbreviations: LV, left ventricular; HFpEF, heart failure with preserved ejection fraction; MVD, microvascular dysfunction; AMI, acute myocardial infarction; AVB, atrioventricular block; AF, atrial fibrillation; V-AR, ventricular arrhythmias; SCD, sudden cardiac death; IMT, intimal-media thickness; NF, nailfold. Credits: Some parts of the image were generated with the help of an artificial intelligence algorithm and then manually combined and annotated.</p>
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11 pages, 2787 KiB  
Article
The Missense Variant in the Signal Peptide of α-GLA Gene, c.13 A/G, Promotes Endoplasmic Reticular Stress and the Related Pathway’s Activation
by Sabrina Bossio, Ida Daniela Perrotta, Danilo Lofaro, Daniele La Russa, Vittoria Rago, Renzo Bonofiglio, Rosita Greco, Michele Andreucci, Antonio Aversa, Antonella La Russa and Anna Perri
Genes 2024, 15(7), 947; https://doi.org/10.3390/genes15070947 - 19 Jul 2024
Cited by 1 | Viewed by 1280
Abstract
Anderson–Fabry disease (AFD) is an X-linked multisystemic disorder with a heterogeneous phenotype, resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) and leading to globotriaosylceramide systemic accumulation. Lysosomal storage is not the unique player in organ failure and different mechanisms could [...] Read more.
Anderson–Fabry disease (AFD) is an X-linked multisystemic disorder with a heterogeneous phenotype, resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) and leading to globotriaosylceramide systemic accumulation. Lysosomal storage is not the unique player in organ failure and different mechanisms could drive tissue damage, including endoplasmic reticulum (ER) stress and its related signaling pathway’s activation. We identified a new missense variant in the signal peptide of α-GLA gene, c.13 A/G, in a 55-year-old woman affected by chronic kidney disease, acroparesthesia, hypohidrosis, and deafness and exhibiting normal values of lysoGb3 and αGLA activity. The functional study of the new variant performed by its overexpression in HEK293T cells showed an increased protein expression of a key ER stress marker, GRP78, the pro-apoptotic BAX, the negative regulator of cell cycle p21, the pro-inflammatory cytokine, IL1β, together with pNFkB, and the pro-fibrotic marker, N-cadherin. Transmission electron microscopy showed signs of ER injury and intra-lysosomal inclusions. The proband’s PBMC exhibited higher expression of TGFβ 1 and pNFkB compared to control. Our findings suggest that the new variant, although it did not affect enzymatic activity, could cause cellular damage by affecting ER homeostasis and promoting apoptosis, inflammation, and fibrosis. Further studies are needed to demonstrate the variant’s contribution to cellular and tissue damage. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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<p>mRNA expression of αGLA in HEK293T transfected with Gene A and Gene G. Negative control (NEG), cells transfected with empty vector (CTRL).</p>
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<p>Electron micrographs showing HEK293T cells untransfected and transfected with Gene A and Gene G. Untransfected cell (<b>A</b>); cell transfected with Gene A (<b>B</b>): in both cells, mitochondria display regular shapes with parallel cristae regularly distributed within the matrix. The ER exhibits a tubular appearance. The nucleus maintains a uniform, spheroid shape with a well-defined nuclear membrane and contains multiple nucleoli. (<b>C</b>–<b>F</b>) Cell transfected with Gene G. (<b>C</b>,<b>D</b>) Cell contains large aggregates of altered ER membranes. The ER aggregates are frequently found in multilayered concentric whorls that enclose portions of the cytoplasm. (<b>E</b>) Increased number of lysosomes that often exhibit an abnormal morphology and contain storage material with granular and fingerprint profiles. (<b>F</b>) Accumulated autophagosomes. (<b>G</b>) The percentage of cells with ER abnormalities was calculated based on 100 cells per condition.</p>
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<p>Protein expression levels of markers of ER stress, apoptosis, inflammation, and fibrosis in HEK293T transfected with Gene A and Gene G. Immunoblotting showing GRP78 (<b>A</b>), BAX (<b>B</b>), p21 (<b>C</b>), IL1β (<b>D</b>), pNFkB (<b>E</b>), and N-Cadherin (<b>F</b>) in HEK293T transfected with Gene A and Gene G. GAPDH was used as a loading control. The bars represent the mean ± SD of three separate experiments, in which the band intensities were evaluated as the optical density and are represented as fold change for Gene G vs. Gena A normalized for the loading control. * <span class="html-italic">p</span> &lt; 0.05.</p>
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<p>Increased TGFβ1 and pNFkB protein expression in patient’s PBMCs. Immunoblotting showing TGFβ1 (<b>A</b>) and pNFkB (<b>B</b>) protein expression of PBMCs from a healthy subject (Ctrl) and the patient. GAPDH was used as a loading control. The bars represent the mean ± SD of three separate experiments, in which the band intensities were evaluated as the optical density and are represented as fold change for patient vs. control (CTRL) normalized for the loading control. * <span class="html-italic">p</span> &lt; 0.05.</p>
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30 pages, 7168 KiB  
Review
Expanding the Neurological Phenotype of Anderson–Fabry Disease: Proof of Concept for an Extrapyramidal Neurodegenerative Pattern and Comparison with Monogenic Vascular Parkinsonism
by Marialuisa Zedde, Ilaria Romani, Alessandra Scaravilli, Sirio Cocozza, Luigi Trojano, Michele Ragno, Nicola Rifino, Anna Bersano, Simonetta Gerevini, Leonardo Pantoni, Franco Valzania and Rosario Pascarella
Cells 2024, 13(13), 1131; https://doi.org/10.3390/cells13131131 - 29 Jun 2024
Viewed by 1984
Abstract
Anderson–Fabry disease (AFD) is a genetic sphingolipidosis involving virtually the entire body. Among its manifestation, the involvement of the central and peripheral nervous system is frequent. In recent decades, it has become evident that, besides cerebrovascular damage, a pure neuronal phenotype of AFD [...] Read more.
Anderson–Fabry disease (AFD) is a genetic sphingolipidosis involving virtually the entire body. Among its manifestation, the involvement of the central and peripheral nervous system is frequent. In recent decades, it has become evident that, besides cerebrovascular damage, a pure neuronal phenotype of AFD exists in the central nervous system, which is supported by clinical, pathological, and neuroimaging data. This neurodegenerative phenotype is often clinically characterized by an extrapyramidal component similar to the one seen in prodromal Parkinson’s disease (PD). We analyzed the biological, clinical pathological, and neuroimaging data supporting this phenotype recently proposed in the literature. Moreover, we compared the neurodegenerative PD phenotype of AFD with a classical monogenic vascular disease responsible for vascular parkinsonism and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A substantial difference in the clinical and neuroimaging features of neurodegenerative and vascular parkinsonism phenotypes emerged, with AFD being potentially responsible for both forms of the extrapyramidal involvement, and CADASIL mainly associated with the vascular subtype. The available studies share some limitations regarding both patients’ information and neurological and genetic investigations. Further studies are needed to clarify the potential association between AFD and extrapyramidal manifestations. Full article
(This article belongs to the Section Cells of the Nervous System)
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<p>MRI of a patient with “classical” AFD. Panels (<b>A</b>,<b>B</b>) show axial FLAIR sequences highlighting the WMHs and lacunar burden at the baseline and after 1 year, respectively. In Panel (<b>C</b>), T2* sequence points out to the microbleeds’ burden in the pons and in the basal ganglia and external capsule.</p>
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<p>Reconstructed tracts in a 29-year-old female healthy control. Reconstructions of the cortico-spinal, the cortico-striatal, and thalamo-cortical tracts are showed from the left to right (left tracts in red, right tracts in blue), with the green and yellow areas indicating the left and right precentral gyri, respectively. Finally, the dark blue (middle image) and purple regions (on the right) of interests represent the left striatum (as the sum of the caudate nucleus and putamen) and the thalamus, while orange (middle image) and light blue (on the right) indicate the contralateral regions. Reprinted from [<a href="#B163-cells-13-01131" class="html-bibr">163</a>].</p>
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<p>Network-based statistics results from 10.1093/braincomms/fcac187. Image shows coronal (<b>A</b>), axial (<b>B</b>), and sagittal (<b>C</b>) views of the subnetwork with decreased structural connectivity in Fabry disease patients compared with HCs emerging from a network-based statistics analysis with a primary threshold of t = 3.0. Its eight nodes, whose sizes reflect the number of connections in the subnetwork (i.e., node’s degree), are the left thalamus (THA.L), right inferior frontal gyrus—opercular part (IFGoperc.L), left inferior frontal gyrus—triangular part (IFGtriang.L), right anterior cingulate and paracingulate gyri (ACG.R), right superior frontal gyrus (SFGdor.R), right middle frontal gyrus (MFG.R), right inferior frontal gyrus—triangular part (IFGtriang.R), and right inferior frontal gyrus—orbital part (ORBinf.R). Reprinted from [<a href="#B160-cells-13-01131" class="html-bibr">160</a>].</p>
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<p>Brain MRI of a patient genetically diagnosed as having CADASIL. In panel (<b>A</b>), the axial FLAIR slices show only mildest temporal WMHs and bilateral involvement of the external capsule with old and recent subcortical infarctions. The recent one is in the left corona radiate, and it is hyperintense in DWI-MRI (<b>B</b>) and hypointense on the ADC map (<b>C</b>). The burden of deep and lobar cerebral MBS is illustrated in panel (<b>D</b>).</p>
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10 pages, 882 KiB  
Article
Genetic Foundation of Male Spur Length and Its Correlation with Female Egg Production in Chickens
by Anqi Chen, Xiaoyu Zhao, Xiurong Zhao, Gang Wang, Xinye Zhang, Xufang Ren, Yalan Zhang, Xue Cheng, Xiaofan Yu, Huie Wang, Menghan Guo, Xiaoyu Jiang, Xiaohan Mei, Guozhen Wei, Xue Wang, Runshen Jiang, Xing Guo, Zhonghua Ning and Lujiang Qu
Animals 2024, 14(12), 1780; https://doi.org/10.3390/ani14121780 - 13 Jun 2024
Viewed by 1156
Abstract
Spurs, which mainly appear in roosters, are protrusions near the tarsometatarsus on both sides of the calves of chickens, and are connected to the tarsometatarsus by a bony core. As a male-biased morphological characteristic, the diameter and length of spurs vary significantly between [...] Read more.
Spurs, which mainly appear in roosters, are protrusions near the tarsometatarsus on both sides of the calves of chickens, and are connected to the tarsometatarsus by a bony core. As a male-biased morphological characteristic, the diameter and length of spurs vary significantly between different individuals, mainly related to genetics and age. As a specific behavior of hens, egg-laying also varies greatly between individuals in terms of traits such as age at first egg (AFE), egg weight (EW), and so on. At present, there are few studies on chicken spurs. In this study, we investigated the inheritance pattern of the spur trait in roosters with different phenotypes and the correlations between spur length, body weight at 18 weeks of age (BW18), shank length at 18 weeks of age (SL18), and the egg-laying trait in hens (both hens and roosters were from the same population and were grouped according to their family). These traits related to egg production included AFE, body weight at first egg (BWA), and first egg weight (FEW). We estimated genetic parameters based on pedigree and phenotype data, and used variance analysis to calculate broad-sense heritability for correcting the parameter estimation results. The results showed that the heritability of male left and right spurs ranged from 0.6 to 0.7. There were significant positive correlations between left and right spur length, BW18, SL18, and BWA, as well as between left and right spur length and AFE. We selected 35 males with the longest spurs and 35 males with the shortest spurs in the population, and pooled them into two sets to obtain the pooled genome sequencing data. After genome-wide association and genome divergency analysis by FST, allele frequency differences (AFDs), and XPEHH methods, we identified 7 overlapping genes (CENPE, FAT1, FAM149A, MANBA, NFKB1, SORBS2, UBE2D3) and 14 peak genes (SAMD12, TSPAN5, ENSGALG00000050071, ENSGALG00000053133, ENSGALG00000050348, CNTN5, TRPC6, ENSGALG00000047655,TMSB4X, LIX1, CKB, NEBL, PRTFDC1, MLLT10) related to left and right spur length through genome-wide selection signature analysis and a genome-wide association approach. Our results identified candidate genes associated with chicken spurs, which helps to understand the genetic mechanism of this trait and carry out subsequent research around it. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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<p>The location of the spur and method to measure spur length.</p>
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<p>Manhattan plot and Q–Q plot for spur length by Pool-GWAS (<b>A</b>), FST (<b>B</b>), AFD (<b>C</b>), and XPEHH (<b>D</b>). Each point in the graph corresponds to the SNPs or regions in the dataset. The line in (<b>A</b>) represents the FDR value less than 1 × 10<sup>−16</sup> (<span class="html-italic">p</span> value &lt; 5.42 × 10<sup>−20</sup>), the lines in (<b>B</b>–<b>D</b>) represent the FST value of 0.098, the AFD of 0.346, and the XPEHH value of 1.94. The vertical axis (<span class="html-italic">y</span>-axis) of the Manhattan plot represents −log10 observed <span class="html-italic">p</span>-values of SNPs and the FST, AFD, and XPEHH values of SNPs compared between two groups (long spur, short spur). The horizontal axes (<span class="html-italic">x</span>-axes) all represent the position of these SNPs on the chromosome.</p>
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30 pages, 8584 KiB  
Article
MDE and LLM Synergy for Network Experimentation: Case Analysis of Wireless System Performance in Beaulieu-Xie Fading and κ-µ Co-Channel Interference Environment with Diversity Combining
by Dragana Krstic, Suad Suljovic, Goran Djordjevic, Nenad Petrovic and Dejan Milic
Sensors 2024, 24(10), 3037; https://doi.org/10.3390/s24103037 - 10 May 2024
Cited by 3 | Viewed by 1476
Abstract
Channel modeling is a first step towards the successful projecting of any wireless communication system. Hence, in this paper, we analyze the performance at the output of a multi-branch selection combining (SC) diversity receiver in a wireless environment that has been distracted by [...] Read more.
Channel modeling is a first step towards the successful projecting of any wireless communication system. Hence, in this paper, we analyze the performance at the output of a multi-branch selection combining (SC) diversity receiver in a wireless environment that has been distracted by fading and co-channel interference (CCI), whereby the fading is modelled by newer Beaulieu-Xie (BX) distribution, and the CCI is modelled by the κ-µ distribution. The BX distribution provides the ability to include in consideration any number of line-of-sight (LOS) useful signal components and non-LOS (NLOS) useful signal components. This distribution contains characteristics of some other fading models thanks to its flexible fading parameters, which also applies to the κ-µ distribution. We derived here the expressions for the probability density function (PDF) and cumulative distribution function (CDF) for the output signal-to-co-channel interference ratio (SIR). After that, other performances are obtained, namely: outage probability (Pout), channel capacity (CC), moment-generating function (MGF), average bit error probability (ABEP), level crossing rate (LCR), and average fade duration (AFD). Numerical results are presented in several graphs versus the SIR for different values of fading and CCI parameters, as well as the number of input branches in the SC receiver. Then, the impact of parameters on all performance is checked. From our numerical results, it is possible to directly obtain the performance for all derived and displayed quantities for cases of previously known distributions of fading and CCI by inserting the appropriate parameter values. In the second part of the paper, a workflow for automated network experimentation relying on the synergy of Large Language Models (LLMs) and model-driven engineering (MDE) is presented, while the previously derived expressions are used for evaluation. Due to the aforementioned, the biggest value of the obtained results is the applicability to the cases of a large number of other distributions for fading and CCI by replacing the corresponding parameters in the formulas for the respective performances. Full article
(This article belongs to the Special Issue Recent Trends and Advances in Telecommunications and Sensing)
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<p>Model of multi-branch SC diversity receiver.</p>
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<p>PDF of SIR <span class="html-italic">z</span> at the multi-branch SC receiver output for different values of fading parameters <span class="html-italic">m</span> and κ<sub>x</sub>. Other parameters are: κ<sub>y</sub> = 1, µ = 1, <span class="html-italic">L</span> = 2, Ω = 1, and <span class="html-italic">s</span> = 1.</p>
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<p>PDF versus SIR <span class="html-italic">z</span> at the multi-branch SC receiver output for variable CCI parameters κ<sub>y</sub> and µ, and number of branches <span class="html-italic">L</span>. Other parameters are: κ<sub>x</sub> = 1, <span class="html-italic">m</span> = 1, Ω = 1, and <span class="html-italic">s</span> = 1.</p>
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<p>Outage probability of multi-branch SC receiver depending on SIR versus different values of fading parameters κ<span class="html-italic"><sub>x</sub></span> and <span class="html-italic">m</span>.</p>
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<p>Pout of multi-branch SC receiver versus SIR considering different values of CCI parameters κ<sub>y</sub> and µ, and number of branches <span class="html-italic">L</span>.</p>
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<p>Normalized channel capacity for different values of BX fading parameters κ<sub>x</sub> and <span class="html-italic">m</span>.</p>
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<p>Normalized channel capacity for different values of CCI parameters κ<sub>y</sub> and µ and number of branches <span class="html-italic">L</span>.</p>
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<p>ABEP for BFSK modulation: parameters κ<sub>x</sub> and <span class="html-italic">m</span> are changing, and constant parameters are κ<sub>y</sub> = 1, µ = 1, <span class="html-italic">L</span> = 2, Ω = 1, <span class="html-italic">s</span> = 1.</p>
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<p>ABEP for BFSK modulation: changeable CCI parameters κ<sub>y</sub> and µ, and number of branches <span class="html-italic">L</span>; and constant are κ<sub>x</sub> = 1, <span class="html-italic">m</span> = 1, Ω = 1, <span class="html-italic">s</span> = 1.</p>
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<p>ABEP for BDPSK modulation when parameters κ<sub>x</sub> and <span class="html-italic">m</span> are changing. Other parameters values are constant: κ<sub>y</sub> = 1, µ = 1, <span class="html-italic">L</span> = 2, and powers: Ω = 1, <span class="html-italic">s</span> = 1.</p>
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<p>MGF-based ABEP for BDPSK modulation: CCI parameters κ<sub>y</sub> and µ are varying, and number of branches <span class="html-italic">L,</span> while constant are fading parameters κ<sub>x</sub> = 1, <span class="html-italic">m</span> = 1, and powers Ω = 1, <span class="html-italic">s</span> = 1.</p>
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<p>The LCR, normalized by Doppler frequency f<sub>m</sub>, versus output SIR for different sets of BX fading parameters κ<sub>x</sub> and m; CCI parameters are: κ<sub>y</sub> = 1 and µ = 1, and powers: Ω = 1, s = 1.</p>
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<p>Normalized LCR depending on SIR with variable CCI parameters κ<span class="html-italic"><sub>y</sub></span> and µ and number of branches <span class="html-italic">L</span>, while BX fading parameters remain constant: κ<span class="html-italic"><sub>x</sub></span> = 1 and <span class="html-italic">m</span> = 1, as well as powers Ω = 1 and <span class="html-italic">s</span> = 1.</p>
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<p>The AFD depending on output SIR for different values of BX fading parameters κ<sub>x</sub> and m; while CCI parameters are: κ<sub>y</sub> = 1 and µ = 1, number of branches L = 2 and powers: Ω = 1, s = 1.</p>
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<p>The AFD versus SIR considering different values of CCI parameters κ<sub>y</sub> and µ and number of branches L, while BX fading parameters are: κ<sub>x</sub> = 1 and m = 1, and powers Ω = 1 and s = 1.</p>
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<p>MDE and LLM synergy-based workflow for next-generation network experimentation and planning: 1—Natural language text experiment description and constraints; 2—Taking user-defined input to Prompt construction script; 3—Eclipse Ecore-based metamodel representation; 4—Prompt1 and Prompt 2 executions; 5—Model instance; 6—Experiment template; 7—Model instance as input for code generation; 8—OCL rules for verification of model instance; 9—Verified model instance; 10—Prompt3 execution; 11—Parametrized experiment; 12—Performance estimations, such as Pout, CC, ABEP, LCR, AFD.</p>
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<p>Network experimentation metamodel.</p>
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14 pages, 1542 KiB  
Article
Phenotypic Expression and Outcomes in Patients with the p.Arg301Gln GLA Variant in Anderson–Fabry Disease
by Rocío Blanco, Yolanda Rico-Ramírez, Álvaro Hermida-Ameijeiras, Israa Mahmoud Sanad Abdullah, Kolja Lau, Jorge Alvarez-Rubio, Elena Fortuny, Amparo Martínez-Monzonís, Albina Nowak, Peter Nordbeck, Carlos Veras-Burgos, Jaume Pons-Llinares, Emiliano Rossi, Fiama Caimi-Martínez, Teresa Bosch-Rovira, Marta Alamar-Cervera, Virginia Ruiz-Pizarro, Laura Torres-Juan, Damian Heine-Suñer and Tomás Ripoll-Vera
Int. J. Mol. Sci. 2024, 25(8), 4299; https://doi.org/10.3390/ijms25084299 - 12 Apr 2024
Viewed by 1971
Abstract
The p.Arg301Gln variant in the α -galactosidase A gene (GLA) has been poorly described in the literature. The few reports show controversial information, with both classical and nonclassical Anderson–Fabry Disease (AFD) presentation patterns. The aim of this study was to analyze [...] Read more.
The p.Arg301Gln variant in the α -galactosidase A gene (GLA) has been poorly described in the literature. The few reports show controversial information, with both classical and nonclassical Anderson–Fabry Disease (AFD) presentation patterns. The aim of this study was to analyze the penetrance, clinical phenotype, and biochemical profile of an international cohort of patients carrying the p.Arg301Gln genetic variant in the GLA gene. This was an observational, international, and retrospective cohort case series study of patients carrying the p.Arg301Gln variant in the GLA gene associated with AFD disease. Forty-nine p.Arg301Gln GLA carriers, 41% male, were analyzed. The penetrance was 63% in the entire cohort and 1.5 times higher in men. The mean age of symptoms onset was 41 years; compared to women, men presented symptoms earlier and with a shorter delay to diagnosis. The typical clinical triad—cornea verticillate, neuropathic pain, and angiokeratomas—affected only 20% of the cohort, with no differences between genders. During follow-up, almost 20% of the patients presented some type of nonfatal cardiovascular and renal event (stroke, need for dialysis, heart failure, and arrhythmias requiring intracardiac devices), predominantly affecting men. Residual levels were the most common finding of α-GAL A enzyme activity, only a few women had a normal level; a small proportion of men had undetectable levels. The incidence of combined outcomes including all causes of death was 33%, and the cumulative incidence of all-cause mortality was 9% at the follow-up. Patients carrying the p.Arg301Gln GLA variant have a high penetrance, with predominantly cardiorenal involvement and clinical onset of the disease in middle age. Only a small proportion showed the classic clinical presentation of AFD. As in other X-linked diseases, males were more affected by severe cardiovascular and renal events. This genotype–phenotype correlation could be useful from a practical clinical point of view and for future decision making. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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<p>p.Arg301Gln carriers and clinically affected patients by gender (green: male, orange: female) (<b>a</b>) and age-related penetrance (<b>b</b>).</p>
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<p>Clinical event incidence by gender (%).</p>
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<p>Cardiac MRI findings (T1 mapping and LGE) and differences by gender.</p>
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<p>Combined Kaplan–Meier curve of events during follow-up.</p>
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<p>Example of family pedigree. AFD affected (filled square); <span class="html-italic">GLA</span> carrier—AFD not affected (partially filled square); unknown (?); not carrier (N).</p>
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10 pages, 3377 KiB  
Case Report
Anderson–Fabry Disease Homozygosity: Rare Case of Late-Onset Variant
by Gabriela Dostalova, Jaroslav Januska, Michaela Veselá, Petra Reková, Anna Taborska, Martin Pleva, David Zemanek and Aleš Linhart
Cardiogenetics 2024, 14(2), 74-83; https://doi.org/10.3390/cardiogenetics14020006 - 7 Apr 2024
Cited by 1 | Viewed by 2381
Abstract
Anderson–Fabry Disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to the progressive accumulation of glycosphingolipids and the structural and functional impairment [...] Read more.
Anderson–Fabry Disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to the progressive accumulation of glycosphingolipids and the structural and functional impairment of affected organs. Due to the inheritance pattern, male patients are hemizygous with more severe manifestations of the disease as compared to females who, in most cases, are heterozygous with delayed and variable clinical presentation caused by uneven X-chromosome inactivation. Fabry disease cases are often identified by targeted screening programs in high-risk groups, such as in patients with end-stage renal disease, premature stroke, or unexplained cardiomyopathy. Here, we describe a unique case of a homozygous female patient identified by a nationwide screening program in hypertrophic cardiomyopathy patients. Before the systematic screening, the patient had a diagnosis of hypertrophic obstructive cardiomyopathy and was treated accordingly, including with alcohol septal ablation to reduce the obstructive gradient. The confirmation of Fabry disease led to the discovery of the same variant in several members of her family. The identified variant was c.644A>G, p.Asn215Ser (p.N215S), which is known to cause predominant cardiac involvement with late onset of the disease. This variant is amenable to oral therapy with the small-molecule chaperone migalastat, which was started and then interrupted due to the recurrence of the patient’s migraine and then re-initiated again after two years. During this period, the patient received enzyme replacement therapy with agalsidase beta but developed progressively worsening venous access. Our case illustrates the importance of the systematic screening of patients with clinical evidence of hypertrophic cardiomyopathy in whom the routine diagnostic process fails to discover Fabry disease, in particular variants with late-onset cardiac manifestations. Many of the late-onset variants are amenable to orally active therapy with migalastat, which significantly improves the comfort of the treatment. Its long-term results are being analyzed by a large international “Follow-me” registry, which was designed to verify the validity of pivotal trials with migalastat in Fabry disease. Full article
(This article belongs to the Special Issue Metabolic and Genetic Bases of Cardiovascular Diseases)
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<p>Pedigree of the index patient (proband). Square: Represents a male individual in the family tree. Circle: Signifies a female individual. Line: Depicts the relationship between family members (e.g., marriage, parent-child connection). Black colour—full homozygote, half heterozygotes. Arrow—the proband.</p>
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<p>ECG—abnormal ECG curve showing normal sinus rhythm, normal PQ interval (150 ms), left ventricular hypertrophy with QRS widening (122 ms) with right bundle branch pattern and repolarization abnormalities, prolonged QTc interval (Qtc 465 ms). V1-5Voltage criteria for hypertrophy with repolarization abnormalities.</p>
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<p>Echocardiography—parasternal long- and short-axis views showing massive hypertrophy particularly within the posterior wall superseding the thickening of the interventricular septum. Blue line—ECG line, Heart Freq. 70 and 79 beats per minute.</p>
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<p>(<b>A</b>–<b>D</b>) MRI scan. (<b>A</b>,<b>B</b>) Steady-state free precession cardiovascular magnetic resonance end-diastolic and end-systolic mages in long-axis views presenting dominant midventricular hypertrophy of left ventricle (including papillary muscles) and wall thinning in the apex (arrows) due to dynamic midventricular obstruction. (<b>C</b>,<b>D</b>) Late gadolinium enhancement in long-axis views demonstrating focal myocardial fibrosis in the inferoseptum and basal inferolateral wall, diffuse mid-wall fibrosis in the anterolateral wall, and scar in the apical part of inferior wall (arrows).</p>
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<p>(<b>A</b>–<b>D</b>) MRI scan. (<b>A</b>,<b>B</b>) Steady-state free precession cardiovascular magnetic resonance end-diastolic and end-systolic mages in long-axis views presenting dominant midventricular hypertrophy of left ventricle (including papillary muscles) and wall thinning in the apex (arrows) due to dynamic midventricular obstruction. (<b>C</b>,<b>D</b>) Late gadolinium enhancement in long-axis views demonstrating focal myocardial fibrosis in the inferoseptum and basal inferolateral wall, diffuse mid-wall fibrosis in the anterolateral wall, and scar in the apical part of inferior wall (arrows).</p>
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<p><b>Eye involvement</b>—conjunctival vessel tortuosity.</p>
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15 pages, 4908 KiB  
Article
Electromechanical Properties of Smart Vitrimers Reinforced with Carbon Nanotubes for SHM Applications
by Javier Gómez-Sánchez, Xoan F. Sánchez-Romate, Francisco Javier Espadas, Silvia G. Prolongo and Alberto Jiménez-Suárez
Sensors 2024, 24(3), 806; https://doi.org/10.3390/s24030806 - 26 Jan 2024
Cited by 1 | Viewed by 1702
Abstract
The Structural Health Monitoring (SHM) capabilities of a well-studied self-healing epoxy resin based on disulfide bonds, through the addition of carbon nanotubes (CNTs), are studied. Since these materials demonstrated, in recent works, a high dependency of the dynamic hardener content on the repair [...] Read more.
The Structural Health Monitoring (SHM) capabilities of a well-studied self-healing epoxy resin based on disulfide bonds, through the addition of carbon nanotubes (CNTs), are studied. Since these materials demonstrated, in recent works, a high dependency of the dynamic hardener content on the repair performance, this study aimed to analyze the effect of the vitrimeric chemistry on the electromechanical properties by studying different 2-aminophenyl disulfide (2-AFD) hardener and CNT contents. The electrical conductivity increases with both the CNT and AFD contents, in general. Moreover, an excess of AFD close to the stoichiometric ratio with a low CNT content improved the tensile strength by 45%, while higher AFD contents promoted its detriment by 41% due to a reduced crosslinking density. However, no significant difference in the mechanical properties was observed at a higher CNT content, regardless of the AFD ratio. The developed materials demonstrate a robust electromechanical response at quasi-static conditions. The sensitivity significantly increases at higher AFD ratios, from 0.69 to 2.22 for the 0.2 wt.%. CNT system, which is advantageous due to the enhanced repair performance of these vitrimeric materials with a higher hardener content. These results reveal the potential use of self-healing vitrimers as integrated SHM systems capable of detecting damages and self-repairing autonomously. Full article
(This article belongs to the Special Issue Advanced Sensors Using Smart Materials)
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Graphical abstract

Graphical abstract
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<p>Scheme of the tensile electromechanical test, and real images for the tensile (<b>a</b>,<b>b</b>) and bending (<b>c</b>,<b>d</b>) specimens prior to and after the test, respectively.</p>
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<p>Electrical conductivity plots as a function of the epoxy/AFD ratio and CNT content.</p>
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<p>Schematics of the CNT and AFD influence on CNT distribution.</p>
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<p>FEG-SEM micrographs of the cross-section of specimens with a (<b>a</b>) stoichiometric content of AFD (R = 1) and 0.1 wt.% CNT (<b>b</b>) 10% of AFD excess (R = 1.1) and 0.1 wt.% CNT; (<b>c</b>) stoichiometric content of AFD (R = 1) and 0.2 wt.% CNT; and (<b>d</b>) 20% of AFD excess (R = 1.2) and 0.2 wt.% CNT; marked in yellow and zoomed in on a region with agglomerated CNTs.</p>
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<p>SEM images of (<b>a</b>) R = 1, (<b>c</b>) R = 1.1, and (<b>e</b>) R = 1.2 AFD ratios with a 0.1 wt.% CNT content, and (<b>b</b>) R = 1, (<b>d</b>) R = 1.1, and (<b>f</b>) R = 1.2 (microcracks arrowed) AFD ratios with a 0.2 wt.% CNT content.</p>
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<p>Load–strain and resistance–strain curves of tensile tests of (<b>a</b>) R = 1, (<b>c</b>) R = 1.1, and (<b>e</b>) R = 1.2 AFD ratios with a 0.1 wt.% CNT content, and (<b>b</b>) R = 1, (<b>d</b>) R = 1.1, and (<b>f</b>) R = 1.2 AFD ratios with a 0.2 wt.% CNT content.</p>
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<p>Strain sensitivity as a function of the AFD content for the tensile tests.</p>
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<p>Load–strain and resistance–strain curves of three-point bending tests of (<b>a</b>) R = 1, (<b>c</b>) R = 1.1, and (<b>e</b>) R = 1.2 AFD ratios with a 0.1 wt.% CNT content, and (<b>b</b>) R = 1, (<b>d</b>) R = 1.1 and (<b>f</b>) R = 1.2 AFD ratios with a 0.2 wt.% CNT content.</p>
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<p>Strain sensitivity as a function of the AFD content for the three-point bending tests.</p>
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