Search Results (2,801)

Today, the right to easy access to medical care for all citizens is one of the universal rights promoted by the WHO to achieve the health goals of sustainable development. Furthermore, an intelligent reevaluation of hospital management is becoming an absolute necessity in light of the pressure that healthcare and public health establishments worldwide face. A management based on the capitalization and exploitation of vast quantities of knowledge. In the 21st century, medicine has already moved to the “in silico” phase, where healthcare professionals must use knowledge bases to make clinical decisions. Indeed, knowledge gains greater value when it’s actively engaged with through dynamic knowledge bases. There is a plethora of research on hospital management, but few studies have approached it from the angle of informational intelligence governed by knowledge management. In this article, we adopt a positivist posture, using deductive logic and the Delphi method based on expert opinion and consensus. We aim to approach hospital management from an informational intelligence perspective, inspired by knowledge representation systems and the object approach. We present an initial vision of the intelligent hospital management model, showing its strengths in relation to its predecessors, as well as its potential uses. Full article

Adaptor Protein-1 (AP-1) is a heterotetrameric essential for intracellular vesicular trafficking and polarized localization of somato-dendritic proteins in neurons. Variants in the AP1G1 gene, encoding the gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), have recently been associated with Usmani–Riazuddin syndrome (USRISD, MIM#619467), a very rare human genetic disorder characterized by intellectual disability (ID), speech and neurodevelopmental delays. Here we report a novel variant (c.196G>A; p.Gly66Arg) identified by exome sequencing analysis in a young girl showing overlapping clinical features with USRIS, such as motor and speech delay, intellectual disability and abnormal aggressive behavior. In silico analysis of the missense de novo variant suggested an alteration in AP1G1 protein folding. Patient’s fibroblasts have been studied with immunofluorescence techniques to analyze the intracellular distribution of AP-1. Zebrafish are widely regarded as an excellent vertebrate model for studying human disease pathogenesis, given their transparent embryonic development, ease of breeding, high genetic similarity to humans, and straightforward genetic manipulation. Leveraging these advantages, we investigated the phenotype, locomotor behavior, and CNS development in zebrafish embryos following the microinjection of human wild-type and mutated AP1G1 mRNAs at the one-cell stage. Knockout (KO) of the AP1G1 gene in zebrafish led to death at the gastrula stage. Lethality in the KO AP1G1 fish model was significantly rescued by injection of the human wild-type AP1G1 mRNA, but not by transcripts encoded by the Gly66Arg missense allele. The phenotype was also not rescued when ap1g1−/− zebrafish embryos were co-injected with both human wild-type and mutated mRNAs, supporting the dominant-negative effect of the new variant. In this study, we defined the effects of a new AP1G1 variant in cellular and animal models of Usmani–Riazzudin syndrome for future therapeutic approaches. Full article

Although traditionally contraindicated, the coadministration of tamoxifen and estradiol may hold clinical relevance in specific contexts, particularly in breast cancer survivors with premature menopause and a high risk of osteoporosis, thereby justifying the need to re-evaluate this therapeutic combination. This study presents an innovative physiologically based pharmacokinetic (PBPK) modeling approach to evaluate the coadministration of tamoxifen and estradiol in women with breast cancer and a high risk of osteoporosis. Using GastroPlus^® software, PBPK models were developed and validated for both drugs, based on physicochemical and kinetic data obtained from the literature and, where necessary, supplemented by estimates generated in ADMET Predictor^®. The simulations considered different hormonal profiles (pre and postmenopausal) and therapeutic regimens, evaluating potential interactions mediated by the CYP3A4 enzyme. Analysis of the pharmacokinetic parameters (F, C_max, T_max and AUC) revealed strong agreement between the simulated and experimental values, with prediction errors of less than twofold. The drug interaction studies, carried out in dynamic and stationary modes, indicated that estradiol does not significantly alter the pharmacokinetics of tamoxifen, even at increasing doses or in enlarged virtual populations. These results represent the first in silico evidence that, under certain conditions, the concomitant use of estradiol does not compromise the pharmacokinetic efficacy of tamoxifen. Although the study is computational, it provides a solid scientific basis for re-evaluating this therapeutic combination and proposes a pioneering model for personalized strategies in complex oncological contexts. All simulations assumed average enzyme abundance/activity without CYP polymorphism parameterization; findings are restricted to parent-tamoxifen pharmacokinetics and do not infer metabolite (e.g., endoxifen) exposure or phenotype effects. Full article

Trehalose-6-phosphate phosphatase (TPP) modulates the Trehalose-6-phosphate–trehalose balance, a key regulatory node in plant carbon sensing and stress resilience. However, its functional roles in vegetative crops such as potato (Solanum tuberosum, St) remains poorly understood. Here, we conducted a genome-wide identification of the StTPP gene family and identified nine distinct loci distributed across five chromosomes. Phylogenetic analysis categorized these loci into three clades, supported by conserved HAD-box motifs and distinct exon–intron structures. Family expansion was driven by segmental duplication under purifying selection. In silico promoter analysis revealed cis-elements responsive to hormones, light, and stress, while network modeling identified 64 transcription factors potentially involved in regulating StTPP expression. A biphasic transcriptional response was observed in the salt-tolerant cultivar Xisen6: rapid induction of StTPP2/3/9 early in salt exposure, followed by late repression of most members. Subcellular localization assays indicated that StTPP3 is present in the nucleus and cytosol, suggesting multifunctional roles. These findings suggest that StTPPs integrate developmental and environmental signals, providing a molecular basis for improving potato stress tolerance and yield stability. Full article

Background: Glucose homeostasis is a crucial physiological process, and its disruption is closely linked to the onset of Type 2 Diabetes Mellitus (T2DM), a major global health issue. Objective: This study presents a novel mathematical model to describe glucose dynamics in both healthy individuals and those with prediabetic risk factors. Methods: We analyzed 311 days of continuous glucose monitoring data from 43 participants (14 healthy and 29 at risk, aged 25–55), using a Dual Extended Kalman Filter to estimate parameters and unmeasurable variables, while accounting for parametric variability. We applied the Levenberg–Marquardt algorithm to minimize estimation error. Results: Based on average parameter values and standardized inputs, 311 simulations were conducted, showing strong agreement with experimental data (r = 0.98, p < 0.01). Conclusions: The model provides an accurate representation of glucose regulation and serves as a valuable in-silico tool for advancing preventive strategies against T2DM, marking one of the first models specifically tailored to individuals with prediabetes. Full article

Human immunodeficiency virus (HIV-1) and SARS-CoV-2 continue to co-burden global health, motivating discovery of broad-spectrum small molecules. Conessine, a steroidal alkaloid, has reported membrane-active and antimicrobial properties but remains underexplored as a dual antiviral chemotype. To interrogate conessine’s multi-target antiviral potential against key enzymatic and entry determinants of HIV-1 and SARS-CoV-2 and to benchmark performance versus approved comparators. Eight targets were modeled: HIV-1 reverse transcriptase (RT, 3V81), protease (PR, 1HVR), integrase (IN, 3LPT), gp120–gp41 trimer (4NCO); and SARS-CoV-2 main protease (M^pro, 6LU7), papain-like protease (PL^pro, 6W9C), RNA-dependent RNA polymerase (RdRp, 7BV2), spike RBD (6M0J). Ligands (conessine; positive controls: dolutegravir for HIV-1, nirmatrelvir for SARS-CoV-2) were prepared with standard protonation, minimized, and docked using AutoDock Vina v 1.2.0exhaustiveness 4; 20 poses). Binding modes were profiled in 2D/3D. Protocol robustness was verified by re-docking co-crystallized ligands (RMSD ≤ 2.0 Å). Atomistic MD (explicit TIP3P, OPLS4, 300 K/1 atm, NPT; 50–100 ns) assessed pose stability (RMSD/RMSF), pocket compaction (Rg, volume), and interaction persistence; MM/GBSA provided qualitative energy decomposition. ADMET was predicted in silico. Conessine showed coherent, hydrophobically anchored binding across both viral panels. Best docking scores (kcal·mol⁻¹) were: HIV-1—PR −6.910, RT −6.672, IN −5.733; SARS-CoV-2—spike RBD −7.025, M^pro −5.745, RdRp −5.737, PL^pro −5.024. Interaction maps were dominated by alkyl/π-alkyl packing to catalytic corridors (e.g., PR Ile50/Val82, RT Tyr181/Val106; M^pro His41/Met49; RBD L455/F486/Y489) with occasional carbon-/water-mediated H-bonds guiding orientation. MD sustained low ligand RMSD (typically ≤1.6–2.2 Å) and damped RMSF at catalytic loops, indicating pocket rigidification; MM/GBSA trends (≈ −30 to −40 kcal·mol⁻¹, dispersion-driven) supported persistent nonpolar stabilization. Benchmarks behaved as expected: dolutegravir bound strongly to IN (−6.070) and PR (−7.319) with stable MD; nirmatrelvir was specific for M^pro and displayed weaker, discontinuous engagement at PL^pro/RdRp/RBD under identical settings. ADMET suggested conessine has excellent permeability/BBB access (high logP), but liabilities include poor aqueous solubility, predicted hERG risk, and CYP2D6 substrate dependence.Conessine operates as a hydrophobic, multi-target wedge with the most favorable computed engagement at HIV-1 PR/RT and the SARS-CoV-2 spike RBD, while maintaining stable poses at M^pro and RdRp. The scaffold merits medicinal-chemistry optimization to improve solubility and de-risk cardiotoxicity/CYP interactions, followed by biochemical and cell-based validation against prioritized targets. Full article

Enteropathogenic Escherichia coli (EPEC) is a significant diarrheagenic pathotype responsible for severe gastrointestinal infections, particularly in vulnerable populations. The aim of this study is to utilize genome-based in silico analysis to study the structural and functional characteristics of the Type III Secretion System (T3SS) and its core effector proteins in EPEC strains. Representative proteins were selected, with particular interest placed on EscV and EscD as major parts of the export apparatus and the basal body, while the EspA effector protein forms the filamentous structure. Several in silico-based techniques were employed, revealing key structural proteins, core effectors, and adhesion-related proteins among the sequenced isolates. Of the 27 isolates analyzed, only 3 (11%) were found to carry LEE-encoded proteins associated with T3SS structural components (escV, escN, escD, and escU) and core effector proteins (espA, espD, espG, and eae). Structural predictions and Ramachandran plot validations suggested stability and potential functional conservation of T3SS proteins, with EscV and EspA selected for detailed 3D structural modelling. Insights into transmembrane domains, protein–protein interaction, and secondary structures were obtained, providing a comprehensive understanding of T3SS assembly and function. These findings suggest that the T3SS in EPEC consists of stable proteins that enable the system to remain functional. The structural and functional properties of the LEE genes encoding the T3SS in the EPEC pathotype represent promising targets for developing virulence blockers to disrupt the pathogenesis of a broad range of bacteria. This study is the first to report EPEC strains with functional T3SS in South Africa, emphasizing the importance of continued surveillance and molecular characterization of EPEC strains. The findings contribute to the development of targeted interventions to mitigate foodborne infections and improve public health. Full article

Background: Telomere shortening and chronic inflammation are well-established hallmarks of aging and age-related diseases, often resulting in impaired cellular function. Identifying compounds with anti-aging potential is therefore crucial to promote healthy aging and extend lifespan. Virtual screening has emerged as a rapid and cost-effective strategy to assess the biological activity of large compound libraries. In parallel, the zebrafish (Danio rerio) model offers unique advantages for in vivo aging research and phenotypic screening. The integration of in silico and in vivo approaches has proven to enhance the efficiency and precision of therapeutic discovery. Methods: In this study, we combined ligand- and structure-based virtual screening to identify resveratrol-like polyphenols from the DrugBank database and evaluated their anti-aging effects in zebrafish models. Results: Among the top eight candidates, resveratrol and sakuranetin significantly improved telomerase-related parameters, while apigenin, genistein, and hesperetin exhibited notable anti-inflammatory activity. Conclusions: These findings underscore the value of combining computational and experimental models to accelerate the discovery of therapeutic agents targeting aging-related processes. The dual computational approach (pharmacophore similarity plus consensus docking) provided a robust prioritization pipeline directly validated in zebrafish assays. Full article

Composite modular panels are increasingly used in modern buildings, yet their layered behavior makes mechanical characterization and modeling difficult. This study presents a novel hybrid framework that integrates analytical, numerical, and AI-driven approaches for the mechanical characterization of composite panels. The system combines a layered concrete configuration with embedded steel reinforcement, and its performance was evaluated through experimental testing, analytical formulation, finite element simulations, and artificial intelligence techniques. Full-scale bending and shear tests were conducted and results in terms of displacements were compared with in silico simulations. The equivalent elastic modulus and thickness were suggested via a closed-form analytical procedure and validated numerically, showing less than 3% deviation from experiments. These equivalent parameters were used to simulate the dynamic response of a two-storey prototype building under harmonic excitation, with simulated modal periods differing by less than 10% from experimental data. To generalize the method, a parametric dataset of 218 panel configurations was generated by varying material and geometric properties. Machine learning models including Artificial Neural Network, Random Forest, Gradient Boosting, and Extra Trees were trained on this dataset, achieving R² > 0.98 for both targets. A graphical user interface was developed to integrate the trained models into an engineering tool for fast prediction of equivalent properties. The proposed methodology provides a unified and computationally efficient approach that combines physical accuracy with practical usability, enabling rapid design and optimization of composite panel structures. Full article

Background: In 2015, it was discovered that mutations in the TEX11 gene are associated with azoospermia in general and meiotic maturation arrest in particular. TEX11 is a component of the ZZS complex (comprising Zip2-, Zip4- and Spo16 and originally described in Saccharomyces cerevisiae). During meiosis, this complex is required for the promotion of double-strand break (DSB) repair and thus the maintenance of genomic integrity. Since the initial discovery, several variants and deletions in TEX11 have been reported in patients with spermatogenesis defects. However, many of these new variants have not been functionally validated, which makes it difficult to confirm their direct impact on meiosis. The exonic in-frame deletion TEX11-c.652del237bp has been recurrently identified in infertile men. However, mice models carrying this deletion remain fertile—suggesting that these models may not faithfully replicate human meiotic phenotypes. To address this discrepancy, we functionally validated the TEX11-c.652del237bp variant in vitro. Methods: After amplification in Escherichia Coli DH5α, the pIRES2-EGFP plasmid containing either the wild-type TEX11 sequence or the TEX11-c.652del237bp sequence was transfected into the HEK293 human embryonic kidney cell line. qPCR and Western blot analyses were then used to evaluate the presence and expression levels of TEX11 mRNA and TEX11 protein. Results: The qPCR and Western blot analyses showed that truncated mRNA and protein were produced in cells transfected with the c.652del237bp variant. Hence, the deletion probably leads to the transcription and translation of TEX11 in human testis. Furthermore, in silico modeling suggested that the deletion does not have a significant impact on the ZZS complex. Conclusions: Our in vitro and in silico data demonstrate that the c.652del237bp in-frame deletion results in a truncated TEX11 protein and thus question the deletion’s pathogenic role in human meiosis. However, the absence of a meiotic phenotype in the corresponding mouse model is suggestive of species-specific differences in TEX11 endogenous function. Further studies (such as co-immunoprecipitation experiments with other ZZS complex proteins) are needed to fully assess the functional impact of TEX11-c.652del237bp. These experiments might also provide novel insights into the specific role of the TEX11 SPO22 domain in human spermatogenesis. Full article

Background/Objectives: Direct oral anticoagulants (DOACs) have transformed the prevention of thromboembolic events, but their efficacy and safety remain highly variable across individuals. DD217, a novel oral direct factor Xa inhibitor, has demonstrated potent anticoagulant activity in preclinical and clinical studies. No pharmacogenetic data are currently available for this compound. Based on in silico predictions of metabolic pathways and transporter involvement, and evidence from other DOACs, we hypothesized that variants in CYP2C and P-glycoprotein genes may contribute to variability in pharmacokinetics (PK) and clinical outcomes. Methods: Fifty-two patients undergoing total knee arthroplasty were enrolled, of whom 34 received the investigational drug (40 mg/day, n = 16; 60 mg/day, n = 18). DNA was extracted from peripheral blood cells, and genotyping of CYP2C9, CYP2C19, CYP2C8, CYP3A4, CYP3A5, and ABCB1 was performed by real-time PCR. Pharmacokinetics (PK) parameters (T_max, AUC_last, C_max) were assessed. In silico docking and pathway modeling predicted CYP2C and P-glycoprotein (ABCB1) involvement in drug disposition. Associations of genetic variants with PK parameters and adverse events (thrombosis, bleeding) were analyzed. Results: Carriers of reduced-function CYP2C9 alleles (intermediate [IM] or poor metabolizers [PM]) in the 60 mg group had a significantly shorter T_max compared with normal metabolizers (p = 0.005227), with trends toward higher AUC_last (p = 0.06926) and C_max (p = 0.1259). No significant associations were observed for CYP2C19, CYP3A4/5, or CYP2C8. In contrast, ABCB1 polymorphisms were associated with systemic exposure: carriers of the C allele at rs1045642 had higher AUC_last and C_max compared to TT (wild-type) homozygotes, while rs2032582 T allele carriers showed lower exposure (p < 0.05). At the haplotype level, the C–G–C–T combination of ABCB1 was more frequent in patients with thrombotic events at the 40 mg dose (p = 0.038). Overall, 5 thrombosis events and 1 bleedings were recorded on DD217, with no consistent associations to single SNPs. Conclusions: This first pharmacogenetic evaluation of DD217 shows that CYP2C9 variants are associated with differences in early-phase pharmacokinetics (T_max), while ABCB1 polymorphisms appear to modulate systemic exposure (AUC_last, C_max) and may influence thrombotic risk. These observations are consistent with in silico predictions of metabolic and transporter pathways. Despite limitations in sample size and event frequency, the study highlights the feasibility and importance of early pharmacogenetic evaluation during the drug development cycle of novel DOACs. Full article

Plant viral infections continue to pose a significant and ongoing threat to global food security, especially in the context of climatic instability and intensive agricultural practices. The CRISPR/Cas system has emerged as a powerful tool for developing virus-resistant crops by enabling precise modifications to viral genomes or plant susceptibility factors. Nonetheless, the efficacy and dependability of CRISPR-based antiviral approaches are limited by challenges in guide RNA design, off-target effects, insufficiently annotated datasets, and the intricate biological dynamics of plant–virus interactions. This paper summarizes the latest advancements in the incorporation of artificial intelligence (AI) methodologies, including machine learning and deep learning algorithms, into the CRISPR design and optimization framework. It examines how convolutional and recurrent neural networks, transformer architectures, and generative models like AlphaFold2, RoseTTAFold, and ESMFold can be used to predict protein structures, score sgRNAs, and model host–virus interactions. AI-enhanced methods have been proven to improve target specificity, Cas protein performance, and in silico validation. This paper aims to establish a foundation for next-generation genome editing strategies against plant viruses and promote the adoption of AI-powered CRISPR technologies in sustainable agriculture. Full article

Glioblastoma (GB) is an extremely aggressive tumor for which effective therapy is still in its infancy. Although several candidate therapeutics have been identified in functional preclinical assays, clinical trials have not supported their effectiveness in GB patients. The poor clinical efficacy of the treatments can be attributed to the insufficient mimicry of GB in patients by the preclinical models used. In this review article, we provide a comprehensive overview of the available GB preclinical models, which are classified according to their origin (animal or human), species, type and modeling strategy (two- or three-dimensional cell culture, in vivo grafting or in silico modeling). Moreover, the article compares developing cutting-edge technologies, including GB-derived organoids, bioprinting, microfluidic devices, and their multimodal integration in GB-on-chip systems, which aim to replicate the GB microenvironment with high precision. In silico and in vivo approaches are also reviewed, including zebrafish transplantation models. The costs, benefits, applications and clinical relevance of each model system and/or modeling strategy are discussed in detail and compared. We highlight that the most appropriate, or combination of, GB preclinical models must be selected (or even customized) based on the specific aims and constraints of each study. Finally, to improve the reliability and translational relevance of GB research, we propose a practical roadmap that addresses critical challenges in preclinical assay development, ranging from short-term adjustments to long-term strategic planning. Full article

Background/Objectives: Physiologically based kinetics (PBK) modelling provides (internal) exposure concentrations. We used a PBK model parameterized exclusively with in silico and in vitro data in a bottom-up approach to predict the pharmacokinetics of oxybenzone, a UV filter, present in two formulations (for which dose-normalized C_max and AUC from clinical studies were different). Methods: Skin absorption data were used to refine chemical-specific dermal absorption parameters for oxybenzone in a lotion and spray. The Transdermal Compartmental Absorption and Transit (TCAT) model in GastroPlus^® 9.9 was used to estimate vehicle and skin layer diffusion and partitioning and then used to simulate systemic exposure. The model was validated according to the OECD 331 guideline. Results: PK profiles simulated for both formulations after single and repeated applications correlated with clinical data profiles (used only to validate our approach), with a deviation from the C_max and AUC of <2-fold. Sensitivity and uncertainty analyses indicated that most input parameters had a medium to high reliability, whereas only a few parameters related to dermal delivery had a low reliability: the partition coefficient between vehicle and water for spray and the diffusion coefficient in stratum corneum for lotion. In vitro skin absorption results suggested that absorption kinetics were not statistically different between the formulations; however, parameters such as vehicle evaporation time were different. The fine-tuned TCAT model containing the absorption data suggested that the variability in clinical data might be due to other factors, e.g., the small number of subjects. Conclusions: These results demonstrate how formulation-dependent absorption kinetics improve confidence in estimated exposure, thanks to the PBK model with its bottom-up approach for nonanimal-based safety assessments. Full article

Background/Objectives: Primary dysmenorrhea is a prevalent condition that causes severe uterine cramps in women worldwide. The objective of this work was to synthesize and characterize a novel immediate-release system using vitexin and ZIF-8, and to evaluate its pharmacological action in a model of primary dysmenorrhea. Methods: A 2² full factorial design guided the synthesis of the system. Physicochemical characterization was performed by FT-IR, TG, DSC, SEM, XRD, and in vitro release tests. Pharmacological activity was assessed in an oxytocin-induced dysmenorrhea model in mice. In addition, in silico molecular docking and molecular dynamics simulations were conducted to explore the potential mechanism of action of vitexin. Results: Optimal yield and loading capacity were achieved at the high levels of the factorial design. Characterization analyses confirmed the successful formation of the vitexin@ZIF-8 (VIT@ZIF-8) system. The release study demonstrated a markedly enhanced dissolution rate of vitexin. Both isolated vitexin and VIT@ZIF-8 reduced abdominal writhing when administered orally at 3 and 30 mg/kg, while intraperitoneal activity was observed only at 30 mg/kg. Computational analyses revealed favorable interactions of vitexin with aldose reductase (AKR1C3), suggesting this enzyme as a potential molecular target in dysmenorrhea. Conclusions: The VIT@ZIF-8 system represents a promising strategy to improve the dissolution profile of vitexin, although pharmacological activity in this model was not superior to the isolated compound. The combined in vivo and in silico evidence supports vitexin as a potential antidysmenorrheic agent, possibly through modulation of AKR1C3. These findings open avenues for future studies addressing the molecular pathways of vitexin and for the development of novel therapeutic approaches for primary dysmenorrhea. Full article