Search Results (70)

Residual particles embedded at the bond coat/substrate (BC/SUB) interface after grit blasting can affect the failure behavior of thermal barrier coatings (TBCs) under thermal cycling. This study employed a 2D finite element model combining the cohesive zone method (CZM) and extended finite element method (XFEM) to analyze the effect of interfacial grit particles. Specifically, the CZM was used to simulate crack propagation at the BC/thermally grown oxide (TGO) interface, while XFEM was applied to model the arbitrary crack propagation within the BC layer. Three models were analyzed: no grit inclusion, 20 μm grit particles, and 50 μm grit particles at the BC/SUB interface. This systematic variation allowed isolating the influence of particle size on the location of crack propagation onset, stress distribution, and crack growth behavior. The results showed that grit particles at the SUB/BC interface had negligible influence on the crack propagation location and rate at the BC/TGO interface, due to their spatial separation. However, their presence significantly altered the radial tensile stress distribution within the BC layer. Larger grit particles induced more intense stress concentrations and promoted earlier and more extensive vertical crack propagation within the BC. However, due to plastic deformation and stress redistribution in the BC, the crack propagation was progressively suppressed in the later stages of thermal cycling. Overall, grit particles primarily promoted vertical crack propagation within the BC layer. Optimizing grit blasting to control grit particle size is crucial for improving the durability of TBCs. Full article

Cattle breeding has traditionally focused on improving production traits; however, recent interest in positive animal welfare has shifted attention toward selecting for more robust animals that balance productivity with health and well-being. The aim of the current study was to assess whether behavioural responses during milking in dual-purpose cattle are associated with genetic markers, previously linked to temperament traits in dairy and beef breeds. We focused on 185 lactating cows belonging to the Simmental strain (Romanian Spotted, national name), which were evaluated for their milking behaviour. Genotyping was performed using an 88-SNP panel selected based on prior associations with dairy and beef cattle temperament. We identified five SNPs that were significantly associated with milking reactivity in the Romanian Spotted breed, located in genes previously linked to neural development, stress response and behavioural regulation (USH2A, ADAMTS7, TBC1D2B and ZMAT4). Our findings suggest that milking behaviour in dual-purpose Simmental cattle is influenced by genetics, supporting the potential for including behavioural traits in future selection strategies. This study contributes to a better understanding of the genetic mechanisms underlying stress-related behaviours in dual-purpose cattle breeds. Full article

Disorders of vesicular trafficking and genetic defects in autophagy play a critical role in the development of metabolic and neurometabolic diseases. These processes govern intracellular transport and lysosomal degradation, thereby maintaining cellular homeostasis. In this article, we present two siblings with a novel homozygous variant in VPS51 (Vacuolar protein sorting 51) gene (c.1511C>T; p.Thr504Met), exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. This study aimed to investigate the effects of the novel VPS51 gene variation at the RNA and protein level in fibroblasts derived from patients. A comparative proteomic analysis, which has not been previously elucidated, was performed to identify uncharacterized proteins associated with vesicular trafficking. Furthermore, the impact of disrupted pathways on mitochondria–lysosome contact sites was assessed, offering a thorough pathophysiological evaluation of GARP/EARP (Golgi Associated Retrograde Protein / Endosome Associated Retrograde Protein) complex dysfunction. An analysis of mRNA expression indicated decreased levels of the VPS51 gene, alongside modifications in the expression of autophagy-related genes (LC3B, p62, RAB7A, TBC1D15). Western blotting demonstrated a reduction in VPS51 and autophagy-related protein levels. Proteomic profiling revealed 585 differentially expressed proteins, indicating disruptions in vesicular trafficking, lysosomal function, and mitochondrial metabolism. Proteins involved in mitochondrial β-oxidation and oxidative phosphorylation exhibited downregulation, whereas pathways related to glycolysis and lipid synthesis showed upregulation. Live-cell confocal microscopy revealed a notable increase in mitochondria–lysosome contact sites in patient fibroblasts, suggesting that VPS51 protein dysfunction contributes to impaired organelle communication. The findings indicate that the novel VPS51 gene variation influences intracellular transport, autophagy, and metabolic pathways, offering new insights into its involvement in neurometabolic disorders. Full article

Phelan–McDermid syndrome (PMS; #MIM: 606232) is a rare neurodevelopmental disorder primarily caused by the haploinsufficiency of the SHANK3 gene, most often due to deletions encompassing the gene or single nucleotide variants within it. Individuals with PMS display a wide range of clinical abnormalities and considerable genetic heterogeneity. This study aims to investigate genotype–phenotype correlations in a cohort of 213 individuals with PMS and to identify novel candidate genes, beyond SHANK3, that may contribute to the syndrome’s diverse clinical manifestations. Unsupervised clustering based on deletion size and Global Functional Assessment of the Patient (GFAP, previously described and developed by our group), along with additional analytical approaches, were employed to explore genotype–phenotype relationships. Deletion size within the 22q13.3 region emerged as a major determinant of phenotype, with larger deletions associated with more severe global functional impairment. Furthermore, CERK, TBC1D22A, CELSR1, and GRAMD4 were identified as candidate genes within 22q13.3, potentially contributing to core PMS phenotypes, and their putative interactions were explored. Our findings support the central role of SHANK3 in PMS, while also indicating that it does not account for the full phenotypic spectrum. This study underscores the variable impact of distinct genetic alterations in PMS and proposes additional loci implicated in its pathogenesis. These insights may inform future therapeutic strategies, emphasizing the importance of patient stratification and precision medicine. Full article

Breast cancer (BC) is among the most prevalent malignancies and remains the leading cause of cancer-related mortality in women worldwide. While prior studies have highlighted the associations between insulin resistance (IR) and both tumorigenesis and cancer progression, the prognostic relevance of IR in BC has not been fully elucidated. In this study, we employed a suite of machine learning algorithms and statistical methods to construct a robust prognostic model for BC based on insulin resistance-related genes (IRGs). The model’s prognostic value was subsequently validated in four independent validate cohorts, including METABRIC and three GSE datasets. The resulting IR signature, comprising seven hub IRGs (LIFR, EZR, TBC1D4, NSF, RPL5, SAA1, and PGK1), demonstrated high predictive power for overall survival (OS) across public datasets. Notably, a lower insulin resistance risk score (IRRS) was significantly associated with more favorable clinical outcomes, including enhanced responses to neoadjuvant therapy. Based on single-cell RNA sequencing data, we found that the hub genes were more enriched in T cells, B cells, and epithelial cells. Furthermore, we used machine learning methods to perform feature selection and reduction, which generated a clinically applicable scoring system consisting of the seven hub genes for predicting clinical outcomes in BC patients. This novel IR-based prognostic signature offers a valuable tool for stratifying BC patients by risk and tailoring personalized therapeutic strategies, thus enhancing precision oncology in breast cancer care. Full article

Background: Macrocephaly can be a component manifestation of several monogenic conditions, in association with intellectual disability/developmental delay (ID/DD) behaviour abnormalities, including autism spectrum disorders (ASD), and variable additional features. On the other hand, idiopathic ASD can present with developmental delay and macrocephaly. Methods: We carried out a retrospective analysis of a cohort of 78 patients who were tested from February 2017 to December 2024 by high-throughput sequencing of a panel of 27 genes (ABCC9, AKT1, AKT2, AKT3, BRWD3, DIS3L2, DNMT3A, EZH2, GPC3, GPC4, HERC1, MED12, MTOR, NFIA, NFIX, NSD1, PDGFRB, PIK3CA, PIK3R1, PIK3R2, PPP2R1A, PPP2R5D, PTEN, RAB39B, RNF135, SETD2, and TBC1D7) because of neurodevelopmental impairment, including ID/DD, ASD/behaviour abnormalities associated with macrocephaly, mimicking to a large extent idiopathic ASD. Results: Pathogenic variants leading to the diagnosis of monogenic conditions were detected in 22 patients (28%), including NSD1 (2), PTEN (16), and PPP2R5D (4). Distinctive of the PTEN-associated phenotype were true macrocephaly (100%), ASD or behaviour abnormalities (92%), mild/borderline ID (79%), and no facial dysmorphisms. Typical of the PPP2R5D-associated phenotype were relative macrocephaly (75%), a few unspecific peculiar facial characteristics (50%), and a more variable presentation of the neurodevelopmental phenotype. Conclusions: Pathogenic variants in PTEN and PPP2R5D are the most recurrent gene mutations in a patient-oriented procedure for the genetic diagnosis of apparently idiopathic ASD and behaviour abnormalities associated with macrocephaly. The clinical applicability of the presented diagnostic strategy is discussed. Full article

In this study, SmFeN/YSZ thermal barrier coating (TBC) composites with SmFeN mass fractions of 25 wt.%, 30 wt.%, and 50 wt.% were synthesized using plasma spraying technology. Testing methods, including scanning electron microscopy (SEM), X-ray diffraction (XRD), and the coaxial method, were comprehensively employed to systematically and thoroughly investigate the influence of SmFeN content on the microstructure, electromagnetic wave absorption performance, and the underlying mechanism of the composites. The research results show that during the plasma spraying process, a significant phase transformation occurred in the SmFeN/YSZ mixed powder, where the original Sm₂Fe₁₂N_2.9 phase transformed into Fe₄N and Sm₃Fe₅O₁₂ phases. However, this phase transformation did not have an adverse effect on the electromagnetic wave absorption performance of the coating. On the contrary, further research revealed that the newly formed Fe₄N phase plays a decisive role in the electromagnetic wave absorption performance of the coating. When the SmFeN mass fraction was 30%, the proportion of Fe₄N in the coating reached its peak. At this time, the impedance matching characteristics of the coating were significantly optimized, and the dipole orientation polarization rate was significantly increased. This enhanced the dielectric relaxation loss capacity of the coating and broadened the electromagnetic wave absorption frequency band. Specifically, the coating exhibited a minimum reflection loss (RL_min) of −52.371 dB and an effective absorption bandwidth (EAB) as high as 2.1588 GHz, covering a frequency range from 11.0739 GHz to 13.2327 GHz. This result indicates that there is great application potential in preparing electromagnetic wave absorption coatings using SmFeN/YSZ mixed powder. Full article

Benzene, a well-known carcinogenic airborne pollutant, poses significant health risks, particularly in industries such as petroleum, shoemaking, and painting. Despite strict regulations, chronic occupational exposure persists, contributing to the onset of acute myeloid leukemia (AML) and other malignancies. Benzene’s carcinogenicity stems from its metabolic activation, leading to increased oxidative stress, DNA damage, and cancer transformation. While its toxicity is well-documented, the link between genetic and epigenetic alterations and cancer susceptibility in exposed workers remains underexplored. This study aims to identify early biomarkers of benzene exposure and AML risk by analyzing gene expression and DNA methylation datasets from GEO DataSets, integrated with molecular pathway analyses, as well as miRNA-target and protein-protein network evaluations. This multi-approach led to the identification of nine deregulated genes (CRK, CXCR6, GSPT1, KPNA1, MECP2, MELTF, NFKB1, TBC1D7, ZNF331) in workers exposed to benzene, with NFKB1 showing strong discriminatory potential. Also, dose-dependent DNA methylation changes were observed in CXCR6 and MELTF, while selected miRNAs such as let-7d-5p, miR-126-3p, and miR-361-5p emerged as key post-transcriptional regulators. Furthermore, functional enrichment linked these genes to immune response, inflammation, cell proliferation, and apoptosis pathways. While network analyses highlighted NFKB1, CRK, and CXCR6 as central to benzene-associated leukemogenesis. Altogether, these findings provide novel insights into an early biomarker fingerprint for benzene exposure and AML susceptibility, supporting the future development of biomolecular-based targeted occupational health monitoring and personalized preventive strategies for at-risk workers. Full article

Accurately characterizing the internal porosity rate of thermal barrier coatings (TBCs) was essential for prolonging their service life. This work concentrated on atmospheric plasma spray (APS)-prepared TBCs and proposed the utilization of terahertz non-destructive detection technology to evaluate their internal porosity rate. The internal porosity rates were ascertained through a metallographic analysis and scanning electron microscopy (SEM), followed by the reconstruction of the TBC model using a four-parameter method. Terahertz time-domain simulation data corresponding to various porosity rates were generated employing the time-domain finite difference method. In simulating actual test signals, white noise with a signal-to-noise ratio of 10 dB was introduced, and various wavelet transforms were utilized for denoising purposes. The effectiveness of different signal processing techniques in mitigating noise was compared to extract key features associated with porosity. To address dimensionality challenges and further enhance model performance, kernel principal component analysis (kPCA) was employed for data processing. To tackle issues related to limited sample sizes, this work proposed to use the Siamese neural network (SNN) and generative adversarial network (GAN) algorithms to solve this challenge in order to improve the generalization ability and detection accuracy of the model. The efficacy of the constructed model was assessed using multiple evaluation metrics; the results indicate that the novel hybrid WT-kPCA-GAN model achieves a prediction accuracy exceeding 0.9 while demonstrating lower error rates and superior predictive performance overall. Ultimately, this work presented an innovative, convenient, non-destructive online approach that was safe and highly precise for measuring the porosity rate of TBCs, particularly in scenarios involving small sample sizes facilitating assessments regarding their service life. Full article

Chronic venous disease (CVD) is a prevalent condition in adults, significantly affecting the global elderly population, with a higher incidence in women than in men. The modulation of gene expression through microRNA (miRNA) partly regulated the development of cardiovascular disease (CVD). Previous research identified a functional analysis of seven genes (CDS2, HDAC5, PPP6R2, PRRC2B, TBC1D22A, WNK1, and PABPC3) as targets of miRNAs related to CVD. In this context, miRNAs emerge as essential candidates for CVD diagnosis, representing novel molecular and biological knowledge. This work aims to identify, by network analysis, the miRNAs involved in CVD as potential biomarkers, either by interacting with small molecules such as toxins and pollutants or by searching for new drugs. Our study shows an updated landscape of the signaling pathways involving miRNAs in CVD pathology. This latest research includes data found through experimental tests and uses predictions to propose both miRNAs and genes as potential biomarkers to develop diagnostic and therapeutic methods for the early detection of CVD in the clinical setting. In addition, our pharmacological network analysis has, for the first time, shown how to use these potential biomarkers to find small molecules that may regulate them. Between the small molecules in this research, toxins, pollutants, and drugs showed outstanding interactions with these miRNAs. One of them, hesperidin, a widely prescribed drug for treating CVD and modulating the gene expression associated with CVD, was used as a reference for searching for new molecules that may interact with miRNAs involved in CVD. Among the drugs that exhibit the same miRNA expression profile as hesperidin, potential candidates include desoximetasone, curcumin, flurandrenolide, trifluridine, fludrocortisone, diflorasone, gemcitabine, floxuridine, and reversine. Further investigation of these drugs is essential to improve the treatment of cardiovascular disease. Additionally, supporting the clinical use of miRNAs as biomarkers for diagnosing and predicting CVD is crucial. Full article

Ramon syndrome (MIM 266270) is an extremely rare genetic syndrome, characterized by gingival fibromatosis, cherubism-like lesions, epilepsy, intellectual disability, hypertrichosis, short stature, juvenile rheumatoid arthritis, and ocular abnormalities. Hereditary or non-syndromic gingival fibromatosis (HGF) is also rare and considered to represent a heterogeneous group of disorders characterized by benign, slowly progressive, non-inflammatory gingival overgrowth. To date, two genes, ELMO2 and TBC1D2B, have been linked to Ramon syndrome. The objective of this study was to further investigate the genetic variants associated with Ramon syndrome as well as HGF. Clinical, radiographic, histological, and immunohistochemical examinations were performed on affected individuals. Exome sequencing identified rare variants in TBC1D2B in both conditions: a novel homozygous variant (c.1879_1880del, p.Glu627LysfsTer61) in a Thai patient with Ramon syndrome and a rare heterozygous variant (c.2471A>G, p.Tyr824Cys) in a Cambodian family with HGF. A novel variant (c.892C>T, p.Arg298Cys) in KREMEN2 was also identified in the individuals with HGF. With support from mutant protein modeling, our data suggest that TBC1D2B variants contribute to both Ramon syndrome and HGF, although variants in additional genes might also contribute to the pathogenesis of HGF. Full article

Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype–phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype–phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients. Full article

Objective: Circulating exosome-enriched extracellular vesicles (EVs) have drawn considerable importance in obesity-related insulin-resistance (IR). We sought to compare the proteomics profile of serum exosomes from normal individuals and those with obesity and IR. Methods: We isolated serum exosomes from male subjects with obesity and insulin resistance (Ob-IR, HOMA-IR > 2.0) and lean/overweight insulin-sensitive (Normal (N), HOMA-IR < 2.0) individuals. The differential protein expression between the two groups was detected by a label-free quantitative mass spectrometry analysis followed by GO annotation and ingenuity pathway analysis (IPA). Results: We identified 23 upregulated and 46 downregulated proteins between Ob-IR and N groups. Some of these proteins are involved in altering insulin signaling (VPS13C, TBC1D32, TTR, and ADIPOQ), inflammation (NFκB and CRP), and B-cell proliferation/activation (IGLV4-69, IGKV1D-13, and IGHV4-28). GO analysis revealed that the differentially expressed proteins (DEPs) are mainly involved in regulating immune cell activation and are located in extracellular space. IPA analysis showed that top molecules mediating IR, inflammation and B-cell activation were upregulated in Ob-IR subjects compared to N subjects. Conclusions: Serum exosomal proteins can be used as biomarkers to identify the future risk of diabetes and a therapeutic target to prevent or slow down the progression of diabetes in high-risk individuals. Full article

Impaired skeletal muscle glucose uptake is a key feature in the development of insulin resistance and type 2 diabetes. Skeletal muscle glucose uptake can be enhanced by a variety of different stimuli, including insulin and contraction as the most prominent. In contrast to the clearance of glucose from the bloodstream in response to insulin stimulation, exercise-induced glucose uptake into skeletal muscle is unaffected during the progression of insulin resistance, placing physical activity at the center of prevention and treatment of metabolic diseases. The two Rab GTPase-activating proteins (RabGAPs), TBC1D1 and TBC1D4, represent critical nodes at the convergence of insulin- and exercise-stimulated signaling pathways, as phosphorylation of the two closely related signaling factors leads to enhanced translocation of glucose transporter 4 (GLUT4) to the plasma membrane, resulting in increased cellular glucose uptake. However, the full network of intracellular signaling pathways that control exercise-induced glucose uptake and that overlap with the insulin-stimulated pathway upstream of the RabGAPs is not fully understood. In this review, we discuss the current state of knowledge on exercise- and insulin-regulated kinases as well as hypoxia as stimulus that may be involved in the regulation of skeletal muscle glucose uptake. Full article