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15 pages, 1462 KB  
Article
Mechanistic Insights into Iron–Sulfur Clusters for Direct Coal Liquefaction: A Combined First-Principles and Machine Learning Study
by Jing Xie, Caoran Li, Shansong Gao, Zhening Chen, Rongheng Gou, Lei Gong, Xiangfeng Yu and Dao Li
Chemistry 2026, 8(5), 66; https://doi.org/10.3390/chemistry8050066 (registering DOI) - 18 May 2026
Abstract
Direct Coal Liquefaction (DCL) is a promising route for converting abundant coal resources into liquid fuels, yet its efficiency remains strongly dependent on catalyst performance. In this work, we present an integrated computational framework combining density functional theory (DFT) calculations with machine learning [...] Read more.
Direct Coal Liquefaction (DCL) is a promising route for converting abundant coal resources into liquid fuels, yet its efficiency remains strongly dependent on catalyst performance. In this work, we present an integrated computational framework combining density functional theory (DFT) calculations with machine learning (ML) to investigate iron–sulfur (FeS) cluster catalysts for DCL. DFT calculations were employed to examine hydrogen-donor dissociation and coal-derived radical hydrogenation on representative FeS clusters. The results indicate that the most favorable catalytic pathways arise from the cooperation between metallic Fe sites (Fe_2) and interfacial Fe sites adjacent to sulfur (Fe_1), while sulfur atoms mainly play an indirect structural and electronic modulation role. Based on these mechanistic insights, a database containing thermodynamic and kinetic data for 636 reactions across 50 FeS cluster models was constructed. This dataset was then used to train three ML classifiers, among which the Random Forest model showed the best performance, reaching accuracies of 80% for H-donor cleavage and 93% for radical hydrogenation on the held-out test sets. SHapley Additive exPlanations (SHAP) analysis further showed that descriptors associated with Fe active-site identity were among the most influential variables in both tasks. Overall, this work provides a mechanistically informed and interpretable computational framework for understanding FeS-catalyzed DCL chemistry and for the preliminary screening of catalyst motifs within the chemical space covered by the present FeS cluster library. Full article
(This article belongs to the Special Issue AI and Big Data in Chemistry)
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21 pages, 1653 KB  
Article
Novel Thiazolylimidazole Hybrids as Promising Antileishmanial Agents: Rational Design and Biological Evaluation
by Cristoper Ramírez-Sandoval, María Elena Campos-Aldrete and María Estela Meléndez-Camargo
Pathogens 2026, 15(5), 544; https://doi.org/10.3390/pathogens15050544 (registering DOI) - 18 May 2026
Abstract
Leishmaniasis remains a major neglected tropical disease with limited therapeutic options, challenged by drug toxicity and emerging resistance to current treatments like miltefosine. In this study, a virtual library of approximately 150 azole-derived compounds was screened in silico to identify promising thiazole and [...] Read more.
Leishmaniasis remains a major neglected tropical disease with limited therapeutic options, challenged by drug toxicity and emerging resistance to current treatments like miltefosine. In this study, a virtual library of approximately 150 azole-derived compounds was screened in silico to identify promising thiazole and imidazole scaffolds, leading to the rational design of novel hybrid molecules. Molecular docking against thioredoxin reductase (PDB ID: 4CBQ), a key enzyme in the redox metabolism of Leishmania mexicana, showed improved binding affinity compared to miltefosine, with compound 3f showing the most favourable interaction profile. Among the synthesized series 3af, compound 3f (4-NO2Ph) exhibited the most favourable predicted binding parameters within the series (∆G = −16.08, Ki = 0.0019 nM). Biological evaluation was performed against L. mexicana promastigotes as an early-stage phenotypic screening model to identify active compounds with potential relevance during the initial infective phase, and a markedly improved in vitro inhibitory effect (IC50 = 22.41 µM) compared to miltefosine (IC50 = 132.42 µM), representing a six-fold increase in molar potency. Furthermore, hybrid thiazolyl–imidazole systems (series 3) consistently outperformed single-core analogues, likely due to enhanced molecular planarity and lipophilicity provided by the imine linkage. Cytotoxicity assays in Vero cells revealed a high safety margin for the lead compounds, with compound 3f achieving a Selectivity Index (SI) of around 89, significantly outperforming the reference drug. Acute toxicity studies (LD50) in murine models further confirmed the safety profile, with values exceeding 2000 mg/kg for the most active derivatives. These findings identify thiazolyl–imidazole hybrids as promising early-stage scaffolds for antileishmanial drug discovery, particularly for early infection/prophylactic screening. Full article
(This article belongs to the Special Issue Leishmania spp. and Leishmaniasis)
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22 pages, 1917 KB  
Systematic Review
Global Prevalence of Alloimmunization in Adults with Sickle Cell Disease Receiving Red Blood Cell Transfusions: A Systematic Review and Meta-Analysis
by Mortadah Alsalman, Jawad S. Alnajjar, Sarra Riyadh Alhassan, Hussain A. Almarzoug, Qusai A. Alobaid, Reham Riyadh Alhassan, Maryam Mohammed Alshams, Bdoor Abdulaziz Almoqren, Nabeel Baqer Al Besher and Abdullah Almaqhawi
J. Clin. Med. 2026, 15(10), 3828; https://doi.org/10.3390/jcm15103828 - 15 May 2026
Viewed by 193
Abstract
Background/Objectives: Blood transfusion is a crucial component in the treatment of individuals with sickle cell disease [SCD]; nonetheless, multiple transfusions can lead to considerable complications, notably alloimmunization. However, the prevalence of alloimmunization and its predictors remain incompletely explained. This review aimed to [...] Read more.
Background/Objectives: Blood transfusion is a crucial component in the treatment of individuals with sickle cell disease [SCD]; nonetheless, multiple transfusions can lead to considerable complications, notably alloimmunization. However, the prevalence of alloimmunization and its predictors remain incompletely explained. This review aimed to determine its global prevalence and identify associated risk factors. Method: Our protocol was registered in PROSPERO [ID: CRD420251167042] in accordance with the PRISMA 2020 criteria. A thorough literature search was conducted across PubMed, Embase, Web of Science, Scopus, and the Cochrane Library to identify studies reporting the prevalence of alloimmunization in adults with confirmed sickle cell disease who have received blood transfusions. This search included all publications up to 16 April 2026. Two reviewers independently screened and extracted data, and the Newcastle–Ottawa Scale was used to evaluate the study’s quality. After the Freeman–Tukey transformation, a random-effects model was used to estimate the pooled prevalence. We examined disparities among groups and geographies, study designs, and matching procedures to determine their differences. We additionally employed meta-regression to identify potential predictors. Results: Nine studies [n = 1711; 1978–2026] met the inclusion criteria. The overall rate of alloimmunization was 28.9% [95% CI 22.4–35.4; I2 = 88.5%]. The most prevalent antibodies were those of the Rh and Kell systems, with anti-E antibodies being the most frequent, followed by anti-C and anti-K antibodies. A higher number of transfusions and the HbSβ0 genotype were both persistent risk factors, while older age at first transfusion appeared protective. Extended antigen matching dramatically reduced prevalence, though approximately 9% of individuals remained affected. Conclusions: Alloimmunization continues to challenge transfusion management in adults with SCD. Broader implementation of extended antigen matching and genotype-informed transfusion strategies may help mitigate this risk. Full article
(This article belongs to the Section Hematology)
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17 pages, 2811 KB  
Article
Efficacy of Spectral-Aided Visual Enhancer in Classification of Esophageal Cancer
by Kok-Yean Koh, Arvind Mukundan, Riya Karmakar, Chaudhary Tirth Atulbhai, Tsung-Hsien Chen, Wei-Chun Weng and Hsiang-Chen Wang
Cancers 2026, 18(10), 1609; https://doi.org/10.3390/cancers18101609 - 15 May 2026
Viewed by 210
Abstract
Background/Objectives: Esophageal cancer is one of the major global causes of cancer mortality, and the 5-year survival rate remains below 20% because many cases are detected late. In this study, a Spectral-Aided Vision Enhancer (SAVE) algorithm was utilized to convert conventional white-light endoscopic [...] Read more.
Background/Objectives: Esophageal cancer is one of the major global causes of cancer mortality, and the 5-year survival rate remains below 20% because many cases are detected late. In this study, a Spectral-Aided Vision Enhancer (SAVE) algorithm was utilized to convert conventional white-light endoscopic images (WLI) into hyperspectral-like narrow-band imaging (NBI) images for machine-learning classification of Dysplasia, Normal, and Squamous Cell Carcinoma (SCC). Methods: A total of 762 WLI images obtained from Kaohsiung Medical University were augmented to 1074 using the Al bumentations library, employing vertical flipping, horizontal flipping, and rotations. The SAVE conversion pipeline employs a 24-patch Macbeth color checker for calibration, γ-correction, CIE XYZ transformation, and multivariate regression to interpolate spectral bands, yielding an average color difference of 2.79 (CIEDE2000) from true NBI. The training outcomes and performance metrics illustrate the versatility of the machine learning/deep learning models—Random Forest (RF), Support Vector Machine (SVM), and Convolutional Neural Network (CNN)—which were trained and evaluated on both the original WLI and SAVE datasets. Performance metrics were analyzed based on precision, recall, accuracy, and F1-score. Results: The CNN sample achieved an accuracy of 100 percent on SAVE data, compared to 93 percent for WLI. The accuracy of RF improved, with WLI at 91% and SAVE at 96%, while SVM increased from 79% to 84%. These improvements indicate the diagnostically valuable spectral variations that can be amplified with SAVE, resulting in significant enhancements in pre-cancer/SCC sensitivity. Conclusions: The proposed SAVE method demonstrates significant potential for enhancing endoscopic imaging and advancing computer-aided diagnosis in esophageal cancer screening, with applicability in other gastrointestinal imaging scenarios as well. Full article
(This article belongs to the Special Issue Advances in Endoscopic Management of Esophageal Cancer)
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32 pages, 1963 KB  
Article
Anti-Inflammatory Evaluation of Pyrazino[2,1-b]quinazoline-3,6-dione Derivatives Inspired by Fiscalin B
by Márcia S. Martins, Madalena M. M. Pinto, Isabel F. Almeida, Maria T. Cruz and Emília Sousa
Pharmaceuticals 2026, 19(5), 775; https://doi.org/10.3390/ph19050775 (registering DOI) - 15 May 2026
Viewed by 92
Abstract
Background/Objectives: Chronic inflammatory skin diseases are frequently associated with pruritus, in which the neurokinin-1 receptor (NK1R) and its ligand substance P (SP) play a central role. The development of compounds combining anti-inflammatory and antipruritic effects represents a promising therapeutic strategy. This [...] Read more.
Background/Objectives: Chronic inflammatory skin diseases are frequently associated with pruritus, in which the neurokinin-1 receptor (NK1R) and its ligand substance P (SP) play a central role. The development of compounds combining anti-inflammatory and antipruritic effects represents a promising therapeutic strategy. This study aims to identify fiscalin B derivatives as anti-inflammatory agents with high affinity to NK1R using an integrated in silico and in vitro approach. Methods: A library of fiscalin B derivatives was screened through molecular docking against NK1R to identify high-affinity ligands. Selected compounds were further evaluated using in silico ADMET and toxicity predictions. In vitro assays were conducted in HaCaT keratinocytes, RAW264.7 macrophages, and NIH/3T3 fibroblasts to assess cytotoxicity, nitric oxide production, inflammatory proteins expression, and cell migration. Results: Docking studies identified several derivatives with predicted binding affinities comparable to or exceeding those of aprepitant, a well-established NK1R antagonist. Several compounds, particularly 2, 3, 4, 6, and 7, reduced lipopolysaccharide-induced nitric oxide production to 41–51% without relevant cytotoxicity. This effect was associated with reduced iNOS protein levels, suggesting modulation of inflammatory pathways rather than direct nitric oxide scavenging. Most compounds showed positive safety profiles, although in silico analysis indicated limited biodegradability and potential aquatic toxicity. Conclusions: The fiscalin B derivatives, 2, 3, and 4, demonstrate potential as anti-inflammatory agents, in vitro, and as NK1R high affinity ligands, in silico. These findings support their potential as lead compounds for topical therapies for inflammatory skin disorders associated with pruritus, although further optimization and validation are required. Full article
(This article belongs to the Section Medicinal Chemistry)
17 pages, 2552 KB  
Article
Multi-Target Inhibition of F10/F2/PAR1 Through In Silico Drug Repurposing of Avodart and Naldemedine to Prevent Thrombotic-Induced Sudden Cardiac Arrest
by Abeer M. Al-Subaie and Sayed AbdulAzeez
Biomedicines 2026, 14(5), 1120; https://doi.org/10.3390/biomedicines14051120 - 15 May 2026
Viewed by 219
Abstract
Background: Thrombotic disorders remain one of the leading causes of global mortality, necessitating the discovery of anticoagulants with broader therapeutic windows and multi-target efficacy. This study aimed to identify FDA-approved drugs capable of simultaneously inhibiting three critical nodes of the coagulation cascade: Factor [...] Read more.
Background: Thrombotic disorders remain one of the leading causes of global mortality, necessitating the discovery of anticoagulants with broader therapeutic windows and multi-target efficacy. This study aimed to identify FDA-approved drugs capable of simultaneously inhibiting three critical nodes of the coagulation cascade: Factor X (F10), Proteinase-activated receptor 1 (PAR1) and Prothrombin (F2). Methods: High-confidence 3D structures of coagulation cascade proteins were established using AlphaFold2 and validated via MolProbity (Favored regions > 91%). A library of 1657 compounds from the Zinc database was screened using PyRx, followed by rigorous ADMET profiling to evaluate pharmacokinetic viability. The structural integrity and binding kinetics of the top candidate drugs were further analyzed through Molecular Dynamics simulation for 100 ns. Results: Virtual screening and downstream analysis identified 30 multi-target drugs. Avodart and Naldemedine were observed to have superior pharmacokinetic equilibrium. Compared to the other two drugs (Digoxin and Ledipasvir), Avodart and Naldemedine showed high affinity, higher adherence to drug likeness, lower metabolic inhibition risks and lack of acute toxicity, and were therefore the most suitable candidates. The 100 ns MD simulations revealed Avodart and Naldemedine to have the highest level of interaction stability and favorable MM-GBSA energies with Factor X, whereas Ledipasvir and Digoxin exhibited significant structural instability. Conclusions: The study proposes Avodart and Naldemedine as promising candidates for drug repurposing in antithrombotic therapy. This study provides a computational blueprint for the development of next-generation, broad-spectrum anticoagulants. Full article
(This article belongs to the Special Issue Innovative Approaches in Drug Discovery)
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20 pages, 4652 KB  
Article
Structure-Based Drug Design Targeting Topoisomerase II Alpha: Discovery of Potential Antitumor Xanthone Derivatives
by Thi Thuy Huong Le, Thi Nguyet Hang Nguyen, Minh Quan Pham, Thi Thu Thuy Tran, Tu Thi Dinh, Thi Hoai Van Tran, Van Lang Tran and Quoc Long Pham
Molecules 2026, 31(10), 1670; https://doi.org/10.3390/molecules31101670 - 15 May 2026
Viewed by 171
Abstract
Cancer represents a major global health challenge, contributing to an estimated 19 million new cases annually. While conventional chemotherapeutic approaches continue to advance, target-based therapeutic strategies are increasingly recognized as effective pathways in modern drug development. A prominent biological target in current anticancer [...] Read more.
Cancer represents a major global health challenge, contributing to an estimated 19 million new cases annually. While conventional chemotherapeutic approaches continue to advance, target-based therapeutic strategies are increasingly recognized as effective pathways in modern drug development. A prominent biological target in current anticancer research is the selective inhibition of Topoisomerase II alpha (TOP2A). TOP2A, a crucial DNA topoisomerase, is vital for maintaining genomic integrity by mediating the cleavage and re-ligation of double-stranded DNA during essential cellular processes, such as DNA replication and transcription. Inhibiting TOP2A effectively disrupts these processes, leading to cell death. This study employed computer-aided drug design approaches to virtually screen a library of 3000 xanthone derivatives against the TOP2A target, and the results were preliminarily validated through cytotoxicity assays on the A549 and HepG2 cancer cell lines. The computational methods utilized included molecular docking, pharmacological modeling, molecular dynamics simulations, and steered molecular dynamics simulations. The virtual screening identified two highly promising HIT compounds, CID162372098 and CID156619937, that exhibited the most favorable interactions and stability profiles in relation to the TOP2A active site. The experimental results demonstrated that both hit compounds effectively exhibited significant anti-proliferative activities against the HepG2 cell line, with IC50 values of 9.54 ± 0.26 µg mL−1 (CID162372098) and 10.03 ± 0.36 12.69 ± 0.31 µg mL−1 (CID156619937), respectively. Collectively, these findings demonstrate the potential of xanthone-based scaffolds as inhibitors of TOP2A and provide a rational framework for the screening and development of novel anticancer agents. Full article
(This article belongs to the Special Issue Phenolic Compounds: Chemistry and Health Benefits)
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11 pages, 627 KB  
Systematic Review
Prevalence and Risk Factors of Potentially Malignant Oral Lesion in Prison Population: A Systematic Review
by Erika Roncarati, Saverio Ceraulo, Antonio Barbarisi, Gianluigi Caccianiga, Francesco Carinci and Dorina Lauritano
Dent. J. 2026, 14(5), 302; https://doi.org/10.3390/dj14050302 - 14 May 2026
Viewed by 95
Abstract
Background: Potentially malignant oral disorders (OPMDs) and oral carcinomas represent a significant oncological concern in incarcerated populations, where multiple modifiable risk factors such as tobacco use, illicit drug consumption, oncogenic human papillomavirus infections, and poor oral hygiene coexist with limited access to preventive [...] Read more.
Background: Potentially malignant oral disorders (OPMDs) and oral carcinomas represent a significant oncological concern in incarcerated populations, where multiple modifiable risk factors such as tobacco use, illicit drug consumption, oncogenic human papillomavirus infections, and poor oral hygiene coexist with limited access to preventive and routine dental care. This combination may increase the risk of delayed diagnosis and malignant transformation. Objective: This PRISMA-compliant systematic review aimed to evaluate the prevalence of OPMDs and associated risk factors in prison populations, with a particular focus on identifying gaps in the current evidence. Methods. A systematic literature search was conducted in PubMed, Scopus and Cochrane Library using predefined search strategies. The final search yielded 24 records, which were screened according to PRISMA 2020 guidelines. After title and abstract screening, 10 full-text articles were assessed for eligibility, and 5 cross-sectional studies were included in the qualitative synthesis following independent review. Results: The included studies revealed a substantial burden of oral mucosal lesions in incarcerated populations. Premalignant lesions were reported in a significant proportion of inmates, with oral submucous fibrosis particularly prevalent in some cohorts. Additionally, a high prevalence of oral high-risk HPV infection and widespread oral manifestations were observed. Tobacco use, often combined with betel quid, alcohol, or illicit drugs, emerged as the primary and consistently associated risk factor for oral lesions. Conclusions: Prison populations appear to represent a high-risk group for OPMDs due to the combined effect of behavioral and structural risk factors. However, the limited number of available studies, their cross-sectional design, and methodological heterogeneity prevent definitive conclusions. Further longitudinal and methodologically robust studies are needed to better define prevalence patterns and support targeted screening and prevention strategies in correctional settings. Full article
25 pages, 1542 KB  
Article
Machine Learning Integration of In-Silico QSAR, Graph Neural Networks and Docking Reveal Natural Products Inhibitors Against Mycobacterium tuberculosis
by Sakthidhasan Periasamy, Rajesh Ramasamy, Rajasekar Chinnaiyan and Arun Sridhar
Sci. Pharm. 2026, 94(2), 39; https://doi.org/10.3390/scipharm94020039 - 14 May 2026
Viewed by 80
Abstract
Background/Objectives: Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health challenge, exacerbated by the emergence of multidrug-resistant strains and limited efficacy of existing therapies. Given the involvement of multiple essential mycobacterial proteins, multitarget drug discovery represents a rational therapeutic strategy. [...] Read more.
Background/Objectives: Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health challenge, exacerbated by the emergence of multidrug-resistant strains and limited efficacy of existing therapies. Given the involvement of multiple essential mycobacterial proteins, multitarget drug discovery represents a rational therapeutic strategy. Methods: In this study, an integrated in silico pipeline combining machine learning–based quantitative structure–activity relationship modeling, graph neural network–driven drug–target affinity prediction, molecular docking, molecular dynamics (MD) simulations, and pharmacokinetic–toxicity profiling was employed to identify potential antitubercular leads from natural products. Results: A curated library of over 0.69 million compounds from the COCONUT database was systematically screened against seven essential M. tuberculosis protein targets. Machine learning and heterogeneous graph neural network models effectively captured complex ligand–protein interaction patterns, enabling high-confidence multitarget prioritization. Structure-based docking and MM-GBSA analyses revealed favorable binding affinities, further supported by 100 ns Molecular Dynamics simulations demonstrating stable binding and conformational integrity. In silico ADMET and toxicity predictions identified pharmacokinetically balanced candidates, while density functional theory calculations corroborated favorable electronic properties. Conclusion: Notably, a myricetin-based flavonoid glycoside exhibited consistent multitarget binding and dynamic stability across all targets. Overall, this study underscores the potential of integrated artificial intelligence and structure-based approaches in accelerating natural product-based antitubercular drug discovery and supports further experimental validation of prioritized leads. Full article
12 pages, 496 KB  
Systematic Review
An Update on Umbilical Cord Abnormalities and Associated Thrombosis: A Systematic Review
by Marco La Verde, Eleonora Braca, Antonio Cerillo, Maria Fatigati, Pasquale De Franciscis, Davide Pisani, Mario Fordellone, Mariavictoria De Simone, Carlo Pietro Campobasso and Alessandro Feola
Clin. Pract. 2026, 16(5), 92; https://doi.org/10.3390/clinpract16050092 (registering DOI) - 14 May 2026
Viewed by 109
Abstract
Background and objective: Umbilical cord abnormalities (UCAs) such as hypercoiling, velamentous or marginal cord insertion, or reduced Wharton’s jelly are associated with umbilical thrombosis. UCAs increase the risk of vascular obstruction and impaired fetal blood flow, resulting in hypoxia or stillbirth. We [...] Read more.
Background and objective: Umbilical cord abnormalities (UCAs) such as hypercoiling, velamentous or marginal cord insertion, or reduced Wharton’s jelly are associated with umbilical thrombosis. UCAs increase the risk of vascular obstruction and impaired fetal blood flow, resulting in hypoxia or stillbirth. We examined the association between the UCAs and the umbilical cord thrombosis. Methods: According to PRISMA, five electronic databases (PubMed, Scopus, Embase, Cochrane Library, and Clinicaltrial.gov) were screened. Only studies that analyzed umbilical cord insertion abnormalities and abnormalities of the umbilical cord associated with thrombosis were included in this systematic review. Studies without thrombosis were excluded (PROSPERO ID: CRD420251087525). Results: Only 12 articles out of 1105 screened records satisfied the inclusion criteria, comprising 3 retrospective cohort studies, 3 case series and 6 case reports. The publication years ranged from 1983 to 2025. A total of 126 cases of umbilical vascular thromboembolism (UVTE) were identified, among which 84 cases of UCAs represented by 16 cases of stricture, 14 cases of hypercoiling, 16 cases of too-short cords (≤40 cm), 11 cases of too-long cords (≥70 cm), 5 cases of velamentous or furcate cord insertions, 12 cases of nuchal cord insertions, 13 cases of funistisis, 11 cases of true knots, and 3 cases of Wharton jelly abnormalities. Conclusions: UCAs, including true knots, abnormal coiling, and furcate or velamentous cord insertion, were highly associated with UVTE. Future studies should involve developing standardized criteria for the diagnosis and reporting of UCAs. Full article
(This article belongs to the Section Reproductive Medicine and Women’s Health)
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21 pages, 1699 KB  
Systematic Review
Temporomandibular Joint Changes Assessed by CBCT or MRI Following Functional Appliance Therapy in Skeletal Class II Patients: A Systematic Review
by Gaia Lopponi, Alessio Verdecchia, Nicolò Sicca, Giulia Benedetti, Alaa Alsafadi, Teresa Cobo and Enrico Spinas
Children 2026, 13(5), 674; https://doi.org/10.3390/children13050674 (registering DOI) - 13 May 2026
Viewed by 174
Abstract
Background/Objectives: Skeletal Class II malocclusion due to mandibular retrusion is frequently treated with functional appliances, yet their impact on temporomandibular joint (TMJ) structures, specifically the articular disc, remains debated. This systematic review aimed to critically assess quantitative morphological and positional TMJ changes [...] Read more.
Background/Objectives: Skeletal Class II malocclusion due to mandibular retrusion is frequently treated with functional appliances, yet their impact on temporomandibular joint (TMJ) structures, specifically the articular disc, remains debated. This systematic review aimed to critically assess quantitative morphological and positional TMJ changes (disc, condyle and glenoid fossa) evaluated with CBCT or MRI in growing skeletal Class II patients treated with functional appliances and to explore whether these changes are associated with the onset or prevention of temporomandibular disorders (TMDs). Methods: The review followed PRISMA guidelines and was registered in PROSPERO (CRD420251028803). Electronic searches were performed in PubMed, Scopus, Web of Science, Cochrane Library, and Embase from inception to December 2025, complemented by manual screening. Inclusion criteria comprised controlled clinical studies in patients aged 8–16 years with skeletal Class II malocclusion due to mandibular deficiency, treated with removable or fixed functional appliances, with pre- and post-CBCT/MRI quantitative TMJ assessment. Risk of bias was evaluated using RoB 2 (RCTs) and ROBINS-I (non-randomized studies); overall certainty was appraised with GRADE. Results: From 937 records, 8 studies met the inclusion criteria. Articular disc outcomes were reported in fewer studies: disc position/morphology was generally stable, and when changes were observed they were favourable (partial improvement/normalization in selected cases). Importantly, no included study reported new treatment-induced disc displacement or new-onset TMD symptoms at the end of treatment. Across studies, the most consistent findings concerned condylar adaptations, commonly described as anterior and/or superior positional changes and remodelling of the condyle–fossa unit. Evidence certainty was limited by heterogeneity and methodological constraints, resulting in low to very low confidence for several outcomes. Conclusions: Functional appliance therapy in growing skeletal Class II patients may be associated with TMJ adaptations, predominantly involving the mandibular condyle, while limited available data may suggest disc stability and no reported short-term clinical TMD onset in included controlled studies. However, due to the limited and heterogeneous evidence base, these findings should be interpreted cautiously, and well-designed prospective studies with standardized 3D imaging outcomes and longer follow-up are needed, particularly for disc-specific endpoints. Full article
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13 pages, 2742 KB  
Article
High-Affinity Nanobody Against the LEDGF PWWP Domain Inhibits Chromatin Binding In Vitro
by Thibault Vantieghem, Sofie Jansen, Thatcher Zinabu Akele, Pieterjan Van Maele, Sam Noppen, Dominique Schols, Maarten Dewilde, Zeger Debyser and Sergei V. Strelkov
Biomolecules 2026, 16(5), 716; https://doi.org/10.3390/biom16050716 (registering DOI) - 13 May 2026
Viewed by 188
Abstract
Background and objectives: The PWWP domain of lens epithelium-derived growth factor p75 (LEDGF/p75) mediates chromatin engagement through recognition of histone H3 lysine 36 di- and trimethylation (H3K36me2/3) and nucleosomal DNA. LEDGF/p75 plays a role in multiple human diseases. In particular, its interaction with [...] Read more.
Background and objectives: The PWWP domain of lens epithelium-derived growth factor p75 (LEDGF/p75) mediates chromatin engagement through recognition of histone H3 lysine 36 di- and trimethylation (H3K36me2/3) and nucleosomal DNA. LEDGF/p75 plays a role in multiple human diseases. In particular, its interaction with HIV-1 integrase enables viral genome integration. However, the LEDGF PWWP domain remains difficult to target with small molecules as it lacks optimally shaped binding pockets. Here, we report the generation of high-affinity nanobodies (Nbs) to investigate the structure and function of this domain. Methods: Camelids were immunized with recombinant LEDGF PWWP domain, and immune phage display libraries were screened for affinity. Selected Nbs were recombinantly expressed in E. coli and purified. Their interaction with the PWWP domain of LEDGF and its close homolog HRP-2 was characterized using size-exclusion chromatography and surface plasmon resonance. Structural characterization of the Nbs was performed using X-ray crystallography. Functional effects on chromatin engagement were evaluated using an AlphaScreen assay. Results: Nine sequence-distinct Nbs were identified, seven of which were confirmed to bind the LEDGF PWWP domain with nanomolar affinities. Five Nbs also bound the HRP-2 domain, consistent with conserved functional surfaces, while two showed reduced affinity. The crystal structures of two Nbs (NbC03 and NbH10) confirmed there were canonical immunoglobulin folds, while the latter additionally revealed a domain-swapped dimer. Moreover, NbH10 dose-dependently inhibited the interaction between full-length LEDGF/p75 and H3K36me3-modified nucleosomes in vitro. Conclusions: This work establishes a validated panel of Nbs targeting the LEDGF PWWP domain and identifies one Nb capable of functionally disrupting the LEDGF–chromatin interaction. These Nbs serve as valuable tools for functional studies and structure-based drug design. Full article
(This article belongs to the Section Molecular Biology)
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15 pages, 2130 KB  
Review
Somatosensory Mismatch Negativity in Children: A Narrative Review of Current Evidence and Methodological Considerations
by Adelina Amalia Ardelean, Laura Alexandra Nussbaum and Andrei Brînzeu
Diagnostics 2026, 16(10), 1471; https://doi.org/10.3390/diagnostics16101471 - 12 May 2026
Viewed by 122
Abstract
Somatosensory mismatch negativity (sMMN) constitutes an electrophysiological marker that initially reflects preattentional processing and subsequently indexes automatic somatosensory deviance detection. While its application in adult populations is gradually expanding, the establishment of a standardized and reproducible methodology for eliciting and analyzing sMMN in [...] Read more.
Somatosensory mismatch negativity (sMMN) constitutes an electrophysiological marker that initially reflects preattentional processing and subsequently indexes automatic somatosensory deviance detection. While its application in adult populations is gradually expanding, the establishment of a standardized and reproducible methodology for eliciting and analyzing sMMN in pediatric populations remains uncertain. To determine whether the published literature provides a clear, consistent, and standardized methodology for sMMN assessment in individuals under 18 years. A search was conducted in PubMed (11), Scopus (6), Web of Science (6), DOAJ (1), Europe PMC (6), Embase (0), ClinicalKey (0), Cochrane Library (0) and ClinicalTrials.gov (0) database from inception to 18 August 2025. Eligible studies included research assessing sMMN using somatosensory oddball paradigms in participants <18 years. Inclusion criteria (participants younger than 18 years, the use of the oddball paradigm to evaluate somatosensory mismatch negativity, and clinical reports, single-case reports or experimental studies including both typically developing children and children with neurological conditions, published in English), and exclusion criteria (exclusivity for adult participants, and narrative reviews or editorials) were defined a priori, as well as the screening procedures and quality assessment methods. Two reviewers independently performed study selection and data extraction, with a third reviewer resolving disagreements. Risk of bias was assessed using the MMAT (mixed methods appraisal tool). Due to substantial heterogeneity in paradigms and outcome reporting, results were synthesized narratively. Four studies met inclusion criteria. Methodological diversity was pronounced across everything except task type that was passive. There is not a consensus regarding stimulation parameters. Risk of bias assessment revealed frequent concerns related to incomplete reporting and variability in analytic choices. The small number of studies, inconsistent methodological reporting, and absence of harmonized protocols limited comparability. Current evidence does not support the existence of a standardized methodology for assessing sMMN in children. Future studies should adopt harmonized stimulation paradigms and transparent, reproducible reporting standards to enable cross-study comparability and clinical translation. Full article
(This article belongs to the Section Clinical Diagnosis and Prognosis)
27 pages, 4468 KB  
Article
A Molecular–Protein Fusion Framework for Rapid Virtual Screening: Accelerating Lead Discovery for “Undruggable’’ Oncogenic Targets
by Chenxi Zhou, Yanni Zhu, Chenrui Yang, Yu Gao, Jianyang Lu and Dengming Ming
Pharmaceuticals 2026, 19(5), 753; https://doi.org/10.3390/ph19050753 (registering DOI) - 12 May 2026
Viewed by 270
Abstract
Background/Objectives: KRAS G12D is one of the most frequent oncogenic mutations in pancreatic ductal adenocarcinoma (PDAC) and remains challenging to target because of its limited druggable binding pockets. This study aimed to develop a machine learning-based framework for rapid virtual screening of [...] Read more.
Background/Objectives: KRAS G12D is one of the most frequent oncogenic mutations in pancreatic ductal adenocarcinoma (PDAC) and remains challenging to target because of its limited druggable binding pockets. This study aimed to develop a machine learning-based framework for rapid virtual screening of potential KRAS G12D inhibitors. Methods: A molecular–protein fusion prediction framework, MPFF-IS, was constructed by integrating the ESM2 protein language model with an MPNN-GNN molecular graph network to enable joint representation learning of protein and compound features. The model was trained using a KRAS G12D inhibitor dataset and applied to screen compounds from multiple chemical libraries. AutoDock Vina docking and 300 ns GROMACS molecular dynamics simulations were subsequently performed for structural validation. Results: MPFF-IS achieved favorable predictive performance on the test dataset and identified 2663 candidate compounds from more than 134,000 screened molecules. Several candidate ligands exhibited favorable binding affinity, stable proteinligand interactions, and enhanced structural stability compared with reference inhibitors, including MRTX1133 and BI-2852. Molecular dynamics analyses further supported the stability of the predicted complexes and the involvement of key binding residues within the KRAS G12D pocket. Conclusions: These findings demonstrate that MPFF-IS can efficiently identify potential KRAS G12D inhibitors and may provide a useful computational framework for precision drug discovery targeting difficult oncogenic proteins. Full article
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30 pages, 1717 KB  
Systematic Review
Maritime Integrated Systems Architecture in the Digital Era: A Systematic Review of Model-Based Approaches, Interoperability, and Resilience
by Ernesto José García Fernández de Castro, Leonardo Lizcano, Daladier Jabba, Miguel Jimeno, Wilson Nieto Bernal and Andrés Pedraza
Appl. Syst. Innov. 2026, 9(5), 98; https://doi.org/10.3390/asi9050098 (registering DOI) - 12 May 2026
Viewed by 329
Abstract
Background: Maritime operations increasingly rely on integrated, secure, and resilient architectures, yet the associated body of knowledge remains fragmented across conceptual, operational, logical, methodological, and governance-oriented perspectives. Objective: Our aim is to systematically review the literature on maritime integrated systems architecture in order [...] Read more.
Background: Maritime operations increasingly rely on integrated, secure, and resilient architectures, yet the associated body of knowledge remains fragmented across conceptual, operational, logical, methodological, and governance-oriented perspectives. Objective: Our aim is to systematically review the literature on maritime integrated systems architecture in order to identify dominant themes, methodological tendencies, enabling technologies, and unresolved research gaps. Eligibility criteria: Peer-reviewed studies published in English were included when they addressed integrated systems architecture, or closely related architectural approaches, in maritime or naval contexts. Studies centred exclusively on isolated components, non-maritime settings without clear architectural transferability, or insufficient technical or methodological detail were excluded. Information sources: ACM Digital Library, IEEE Xplore, SpringerLink, ScienceDirect, MDPI, and IMarEST. Searches were carried out between January and March 2025, with the final search update for all sources completed in March 2025. Methods: The review was conducted and reported in accordance with PRISMA 2020. Three reviewers independently screened titles, abstracts, and full texts. Two reviewers independently extracted data, assessed methodological limitations and risk of bias using a review-specific qualitative appraisal framework, and evaluated the risk of bias due to missing results at the synthesis level. Disagreements were resolved through discussion and consensus, with third-reviewer arbitration when necessary. The synthesis combined qualitative thematic analysis across eleven predefined analytical categories with descriptive bibliometric and thematic mapping procedures. Results: Of 300 identified records, 60 studies met the inclusion criteria. Across non-mutually exclusive analytical categories, the literature was concentrated in Integrated Systems Architecture (52 studies), Development Processes (42), and Conceptual Models (37), whereas Zachman-based Methodology (4) and Maturity Models (3) were only marginally represented. Three recurrent patterns were observed across the corpus: the central role of cybersecurity and risk governance in architectural design; the growing importance of information technology and operational technology convergence for resilient monitoring, coordination, and decision support; and the increasing use of model-based and model-driven approaches to address architectural complexity. Overall confidence in the principal synthesized findings was judged to be moderate. Limitations: The review was limited to six databases and English-language publications, and the included studies varied in reporting depth, methodological transparency, and degree of empirical validation. Conclusions: The review organizes the field into a multilevel taxonomy spanning conceptual and operational models, logical and layered views, development processes, reference architectures, enabling technologies, and maturity-related perspectives. Taken together, the findings suggest that research in this area has progressed more clearly in architectural representation and integration than in long-term evaluation, particularly with regard to the practical operationalization of Zachman-based approaches and the development of maritime-specific maturity assessment frameworks. Funding: This review received no external funding. Registration: The review was not prospectively registered, and no publicly accessible protocol was prepared. Full article
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