Search Results (96)

WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a member of the homologous to E6AP C-terminus-type E3 ubiquitin protein ligase family. Although WWP1 plays a role in several human diseases, including infectious diseases, neurological disorders, and cancers, there is emerging evidence that WWP1 is also associated with metabolic disorders. In this review, we discuss the regulation and molecular function of WWP1 and its contribution to obesity-related metabolic disorders, particularly in white adipose tissue and the liver. We highlight the need for further research to deepen our understanding of how WWP1 may be implicated in metabolic dysfunction and facilitate the development of novel therapeutic strategies that target WWP1. Full article

WWOX and HIF1α proteins are involved in cancer progression; their functions are closely related. WWOX binds HIF1α through its WW domains, sequestering it in the cytoplasm and inhibiting its transcriptional activity. This study evaluates the prognostic significance of the WWOX/HIF1A interaction across cancers, breast cancer subtypes, glioblastoma (GBM), low-grade glioma (LGG), and hepatocellular carcinoma (HCC) through gene expression and pathway analysis focused on metabolism, ECM, and epithelial–mesenchymal transition. In breast cancer, metabolic pathways correlated with good prognosis in basal subtypes. HER2 subtypes showed enrichment in DNA replication pathways. Luminal A subtypes showed favourable prognosis via TNF and PI3K/AKT signalling, while luminal B subtypes had poor prognosis tied to metabolic activity; genes associated with good prognosis mirrored those tied to poor prognosis in luminal A. In HCC, enhanced metabolic activity was associated with good prognosis. In contrast, poor prognosis involved TNF signalling and cytoskeleton-related pathways, indicating more aggressive tumour behaviour. In LGG, good prognosis was linked to metabolic and cAMP pathways, while poor outcomes involved TNF, cell cycle, apoptosis, and focal adhesion pathways. GBM showed similar patterns: metabolic and cAMP pathways indicated better outcomes, while NFKB, TNF, JAK-STAT, and PI3K/AKT pathways marked poor prognosis. These findings suggest the WWOX/HIF1A ratio is a robust prognostic marker and a possible guide for developing targeted treatments. Full article

Doxorubicin (DOX) is an anthracycline chemotherapeutic agent that is clinically limited by doxorubicin-induced cardiotoxicity (DIC), with ferroptosis and apoptosis identified as key mechanisms. As an antioxidant enzyme, GPX4 undergoes ubiquitin-mediated degradation during myocardial ischemia–reperfusion injury; however, the role of its ubiquitination in DIC remains unclear. This study revealed that GPX4 undergoes ubiquitinated degradation during DIC, exacerbating ferroptosis and apoptosis in cardiomyocytes. NEDD4L was found to interact with GPX4, and its expression was upregulated in DOX-treated mouse myocardial tissues and cardiomyocytes. NEDD4L knockdown alleviated DIC, as well as ferroptosis and apoptosis in cardiomyocytes. Mechanistically, NEDD4L recognizes GPX4 through its WW domain and mediates K48-linked ubiquitination and degradation of GPX4 under DOX stimulation via its HECT domain. Knockdown of NEDD4L reduced DOX-induced GPX4 ubiquitination levels and subsequent degradation. Notably, while NEDD4L knockdown mitigated DOX-induced cell death, concurrent GPX4 knockdown attenuated this protective effect, indicating that GPX4 is a key downstream target of NEDD4L in regulating cardiomyocyte death. These findings identify NEDD4L as a potential therapeutic target for preventing and treating DIC. Full article

Měnglà virus (MLAV) is a member of the genus Dianlovirus in the family Filoviridae, which also includes Ebola virus (EBOV) and Marburg virus (MARV). Whether MLAV poses a threat to human health is uncertain. However, the MLAV VP35 and VP40 proteins can impair IFNα/β gene expression and block IFNα/β-induced Jak-STAT signaling, respectively, suggesting the capacity to counteract human innate immune defenses. In this study, MLAV VP40 is demonstrated to impair the Sendai virus (SeV)-induced activation of the IFNβ promoter. Inhibition is independent of the MLAV VP40 PPPY late-domain motif that interacts with host proteins possessing WW-domains to promote viral budding. Similar IFNβ promoter inhibition was not detected for EBOV or MARV VP40. MLAV VP40 exhibited lesser capacity to inhibit TNFα activation of an NF-κB reporter gene. MLAV VP40 impaired IFNβ promoter activation by an over-expressed, constitutively active form of RIG-I and by the over-expressed IRF3 kinases TBK1 and IKKε. However, MLAV VP40 did not inhibit IFNβ promoter activation by constitutively active IRF3 5D. Consistent with these findings, MLAV VP40 inhibited SeV-induced IRF3 phosphorylation. Although IRF3 phosphorylation occurs in the cytoplasm, MLAV VP40 exhibits substantial nuclear localization, accumulating in foci in HeLa cell nuclei. In contrast, the VP40 of EBOV and MARV exhibited lower degrees of nuclear localization and did not accumulate in foci. MLAV VP40 interacts with importin alpha-1 (IMPα1), suggesting entry via the IMPα/IMPβ nuclear import pathway. Cumulatively, these data identify novel features that distinguish MLAV VP40 from its homologues in EBOV and MARV. Full article

Food quality and safety are paramount in preserving the culinary authenticity and cultural integrity of Chinese cuisine, characterized by intricate ingredient combinations, diverse cooking techniques (e.g., stir-frying, steaming, and braising), and region-specific flavor profiles. Traditional non-destructive detection methods often struggle with the unique challenges posed by Chinese dishes, including complex textural variations in staple foods (e.g., noodles, dumplings), layered seasoning compositions (e.g., soy sauce, Sichuan peppercorns), and oil-rich cooking media. This study pioneers a hyperspectral imaging framework enhanced with domain-specific deep learning algorithms (spatial–spectral convolutional networks with attention mechanisms) to address these challenges. Our approach effectively deciphers the subtle spectral fingerprints of Chinese-specific ingredients (e.g., fermented black beans, lotus root) and quantifies critical quality indicators, achieving an average classification accuracy of 97.8% across 15 major Chinese dish categories. Specifically, the model demonstrates high precision in quantifying chili oil content in Mapo Tofu with a Mean Absolute Error (MAE) of 0.43% w/w and assessing freshness gradients in Cantonese dim sum (Shrimp Har Gow) with a classification accuracy of 95.2% for three distinct freshness levels. This approach leverages the detailed spectral information provided by hyperspectral imaging to automate the classification and detection of Chinese dishes, significantly improving both the accuracy of image-based food classification by >15 percentage points compared to traditional RGB methods and enhancing food quality safety assessment. Full article

Background/Objectives: Bovine viral diarrhea virus (BVDV) causes significant economic losses in the cattle industry worldwide. The current vaccines have limited efficacy against diverse BVDV genotypes. Currently, multi-antigen target design and nanocarrier display technologies can provide ideas for broad-spectrum and efficient BVDV vaccine design. Methods: Here we developed a trivalent mRNA vaccine encoding the domains I-II of envelope glycoprotein E2 from three BVDV genotypes (3E2), introduced with bovine IgG1 Fc (bFc), STABILON (hStab), and artificial virus-like particle (ARVLP) containing CD80 transmembrane (TM) domain, FcγRII cytoplasmic domain, and WW domain of ITCH. Then, in vitro expression, in vivo immunogenicity and neutralizing antibody analysis were performed to evaluate the vaccines. Results: The in vitro expression results showed that bFc and hStab dramatically enhanced antigen expression and immunogenicity. In addition, the ARVLP further enhanced the secretion and potency of neutralizing antibodies. Finally, the immunogenicity of the bFc_BVDV_3E2_ARVLP_hStab mRNA vaccine was evaluated in mice, guinea pigs, and lactating goats and high levels of neutralizing antibodies against all three BVDV genotypes were detected. Conclusions: Our trivalent design strategy with bFc, hStab, and ARVLP shows highly efficient expression as well as strong immunogenicity and provides a promising approach for next-generation BVDV vaccines with broader and stronger protection. Full article

Objectives: Survival from lung cancer is worse in the UK than in some other countries, with late stage at diagnosis implicated in poor prognosis. The route and referral urgency by which patients obtain a diagnosis influence outcomes. This study investigated whether socio-demographic factors are associated with lung cancer routes to diagnosis in England. Materials and Methods: A total of 181,763 primary invasive lung cancers (ICD-10 C34.0-C34.9) diagnosed from 1 January 2012 to 31 December 2016 were abstracted from the English National Cancer Registration Database. Multivariable logistic regression was used to examine associations between patients’ socio-demographic characteristics and likelihood (adjusted odds ratios) of (i) emergency presentation versus all primary care-initiated routes and (ii) urgent (“two-week wait”/2WW) versus standard primary care-initiated referral. Models included the following factors: deprivation quintile of area of residence at diagnosis (IMD income domain); sex; age; ethnic group; rural/urban residence; and (in the emergency model) region. Results: Socio-demographic variations in diagnosis routes were observed. Patients presenting as emergencies (35.2%) were more likely to be 80 years of age or older, female, of non-White ethnicity, and resident in areas of greater deprivation or the London region. In contrast, 2WW patients (28.3%) were more likely to be aged between 50 and 69 years old, of White ethnicity, and resident in an area of greater deprivation or resident outside of an urban centre; diagnosis through 2WW did not vary by sex. Conclusions: Routes to diagnosis are subject to distinct socio-demographic patterning. Action is needed to ensure that new referral guidelines and lung cancer screening roll-out do not widen socio-demographic inequalities in diagnosis. Full article

With the continuous change of climate, drought stress has emerged as the primary constraint on crop growth, posing a significant threat to the stability of global grain reserves. Arbuscular mycorrhizal fungi (AMF), as a kind of widely distributed root endophytes, enhance the drought tolerance of maize (Zea mays L.) through regulating the physiological and molecular responses. However, comprehensive transcriptome analysis to reveal the molecular mechanism of drought tolerance in the symbiotic process between AMF and maize is still limited. In the potted plant experiment, maizes inoculated with and without arbuscular mycorrhizal fungus Funneliformis mosseae were grown under well-watered (WW) or drought-stressed (DS) conditions. By using RNA-Seq and transcriptome analysis on maize roots and leaves, this work aimed to investigate the differential expressed genes (DEGs) related to the Ca²⁺ signaling pathway induced by AMF symbiosis under drought stress. Our findings indicated that F. mosseae inoculation resulted in a decrease in the net fluxes of Ca²⁺, while simultaneously elevating Ca²⁺ contents in the maize roots and leaves under well-watered or drought-stressed conditions. Notably, 189 DEGs were regulated not only by AMF symbiosis and drought stress, but also exhibited preferential expression in either leaves or roots. The annotation and enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that most of the DEGs were significantly enriched in Ca²⁺ signaling pathway genes, related to signal transduction, cellular process, and defense response. A high number of DEGs with this function (including calcineurin B-like protein (CBL), CBL-interacting protein kinase (CIPK), mitogen-activated protein kinase (MAPK), and calcium-dependent protein kinase (CDPK) receptor kinases) were upregulated-DEGs or downregulated-DEGs in F. mosseae-inoculated maizes under drought stress. Furthermore, some DEGs belong to transcription factor (TF) families, including bHLH ERF, and, MYB, were speculated to play key roles in improving the drought tolerance of maize. Based on the expression data and co-expression analysis between TF and Ca²⁺ signaling pathway genes, Whirly1 with CBL11, and BRI1-EMS-SUPPRESSOR 1 (BES1) with CBL10, CIPK24, CDPK1, CDPK14, CDPK19, and MAPK9 genes showed significant positive correlations, while B3 domain-containing transcription factors (B3 TFs) with MAPK1 and both CBL9 genes showed significant negative correlations in response to both F. mosseae inoculation and drought stress. The regulation of Ca²⁺ signaling pathways by AMF symbiosis was an important response mechanism of maize to improve their drought resistance. This study provides insightful perspectives on how AMF-induced modulation of gene expression within the Ca²⁺ signaling pathway can enhance the drought tolerance of mycorrhizal maize in the future. Full article

Obesity is defined as abnormal or excessive accumulation of body fat and contributes to several metabolic disorders. White adipose tissue (WAT) releases energy as free fatty acids and glycerol from triglycerides through a process called lipolysis. People with obesity have impaired catecholamine-stimulated lipolysis, but comprehensive understanding of this lipolysis is still unclear. We previously showed that expression of WW domain-containing E3 ubiquitin ligase 1 (WWP1), a member of the HECT-type E3 family of ubiquitin ligases, was increased in WAT of obese mice. In this study, we generated Wwp1 knockout (KO) mice to evaluate the effect of WWP1 in WAT of obese mice. The mRNA levels of beta-3 adrenergic receptor (Adrb3), which were decreased with a high-fat diet, were increased by Wwp1 KO in WAT. Moreover, Wwp1 KO mice showed increased phosphorylated hormone-sensitive lipase levels in WAT. In contrast, noradrenaline and its metabolism were not altered in WAT of obese Wwp1 KO mice. These findings indicate that WWP1, which is increased in adipocytes because of obesity, is a candidate for suppressing lipolysis independently of noradrenaline metabolism. We anticipate that inhibition of WWP1 is a promising approach for a new treatment of obesity and type-2 diabetes using Adrb3 agonists. Full article

The eco-friendly flame retardancy of polycarbonate (PC) was achieved by blending with phosphorylated-PC in the range of 1–5% w/w. Dynamic properties were characterized using broadband dielectric relaxation spectroscopy (DRS), while structural and thermal properties were investigated using Fourier transform infrared spectroscopy, wide-angle X-ray diffraction, small-angle X-ray scattering, differential scanning calorimetry, and thermogravimetric analysis. A reduction in the single glass transition temperature with increasing phosphorylated-PC content was observed, indicating that the blends were miscible. No crystalline phases were detected in any of the samples. The thermo-oxidative stability and UL-94 ratings of flame-retardant polycarbonates (FRPCs) improved compared to neat PC, with char residue increasing as the phosphorylated-PC content rose. DRS analysis revealed the formation of a well-defined local (β) relaxation in the FRPC samples, originating from the motion of phosphorylated branches. All samples exhibited the segmental (α) relaxation of PC chains above the glass transition temperature. The size of the cooperatively rearranging domain played a significant role in the dynamic fragility of the rigid FRPCs. Additionally, DRS analysis highlighted the presence of physical crosslinks from nanoclusters of phosphorylated polar groups, approximately 14 nm in size. Full article

Objectives: Head and neck squamous cell carcinoma (HNSCC) is characterized by complex genetic alterations. This study aimed to identify WBP5 as a promising therapeutic target and evaluate the effect of WBP5 expression on prognosis and treatment response in HNSCC. Methods: Publicly available datasets were comprehensively analyzed to investigate WBP5 expression through comprehensive bioinformatics analysis and functional validation. Results: WBP5 was particularly overexpressed in HNSCC, as analyzed through the Gene Expression Profiling Interactive Analysis version 2 (GEPIA2) database and validated using multiple Gene Expression Omnibus (GEO) datasets. Analysis with UALCAN confirmed that WBP5 expression was significantly higher in advanced cancer stages and tumor grades than that of normal samples. A Kaplan–Meier analysis demonstrated that patients overexpressing WBP5 had a poor prognosis. Moreover, WBP5 expression correlated with the overexpression of the epidermal growth factor receptor in HNSCC. In vitro experiments revealed that WBP5 knockdown significantly reduced FaDu cell proliferation and viability. Furthermore, silencing WBP5 enhanced cisplatin sensitivity, indicating its potential role in chemoresistance. Conclusions: These results indicate that WBP5 could act as a prognostic marker and a viable therapeutic target in HNSCC. Modulating WBP5 expression may represent a novel strategy to enhance treatment efficacy. Future studies should elucidate the precise mechanisms of WBP5 action and develop targeted therapies. This integrated approach, combining a comprehensive analysis of publicly available datasets with in vitro experimental validation provides strong evidence for the clinical significance of WBP5 in HNSCC. Full article

Background/Objectives: Bladder urothelial carcinoma is a frequent malignant tumor of the urinary system, characterized by its high rates of recurrence and resistance to chemotherapy. This study explored the beneficial effects of overexpressing WW domain-containing oxidoreductase (WWOX) in AY-27 cells encapsulated in an injectable gelatin hydrogel for potential therapeutic applications in bladder cancer. Methods: AY-27 cells were genetically transduced with lentiviruses (LV) to overexpress WWOX (LV-WWOX) and subsequently encapsulated in a gelatin hydrogel. The mechanical properties and morphology of the hydrogels were assessed using transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The therapeutic efficacy of this approach was evaluated using an F344/AY-27 rat orthotopic bladder cancer model, in which the LV-WWOX-hydrogel (H-LV-WWOX) was administered via intravesical instillation. Results: The gelatin hydrogel formulation demonstrated excellent biocompatibility, stability, and controlled release. In a rat orthotopic model, intravesical instillation of H-LV-WWOX significantly enhanced local immune responses, resulting in notable tumor regression. Compared to the sham-treated group, this approach reduced systemic toxicity and improved overall treatment outcomes. The anticancer effect of WWOX can be attributed to its ability to amplify TNF-α-induced reactive oxygen species (ROS) generation. This ROS-mediated pathway leads to enhanced apoptosis and DNA damage in cancer cells, highlighting the potential mechanism through which WWOX exhibits tumor-suppressive activities. Conclusions: These findings support the therapeutic potential of WWOX overexpression in gelatin hydrogels for bladder cancer treatment and warrant further clinical investigation. Full article

Waxy cuticle covers plant aerial organs and protects plants against environmental challenges. Although improved cuticle-associated traits are aimed at the wheat breeding programs, the mechanism governing wheat cuticular wax biosynthesis remains to be elucidated. Herein, wheat WW domain-containing protein TaCFL1 is characterized as a negative regulator of wax biosynthesis. The knockdown of TaCFL1 expression results in a 15% increase in wax accumulation and decreased leaf cuticle permeability in bread wheat. Furthermore, wheat class IV homeodomain transcription factors TaHDG1.1 and TaHDG1.2 are identified as partially redundant activators of wax biosynthesis. The silencing of TaHDG1.1 or TaHDG1.2 expression leads to an 11% reduction in epidermal wax accumulation and an increase in leaf cuticle permeability wax, while the co-silencing of TaHDG1.1 and TaHDG1.2 results in a 31% reduction in epidermal wax accumulation and a further increase in wax in the leaf cuticle permeability. Moreover, wheat 3-Ketoacyl-CoA synthase TaKCS10 is isolated as an essential component of the wax biosynthetic machinery. The silencing of TaKCS10 expression results in a 22% reduction in wax accumulation and increased leaf cuticle permeability. In addition, we demonstrated that the TaKCS10 expression is activated by TaHDG1.1 and TaHDG1.2, and that TaCFL1 attenuates the TaHDG1-mediated transcriptional activation of TaKCS10. This evidence supports that the WW domain-containing protein TaCFL1 negatively regulates wax biosynthesis via attenuating the transcriptional activation of the TaKCS10 gene mediated by HD-ZIP IV transcription factor TaHDG1. Full article

This study articulates findings from research pertaining to the utilisation of recycled geogrid in asphalt concrete. The issue of contamination of reclaimed waste with geosynthetic materials persists as a significant concern that warrants attention. In Poland, the allowable quantity of geogrid contaminants within the mineral–asphalt composition is 0.1% w/w. The preliminary evaluation of the validity of the research topic was conducted based on an analysis of correspondence and survey outcomes. The fundamental material research was executed employing elements of experimental design theory. The experimental domain considered two qualitative factors: the type of bituminous mixture for the binding layer (AC16W and AC22W) and the type of geogrid material (glass, carbon), in addition to two quantitative factors: the length of the recycled geogrid fibres ranging from 1 cm to 5 cm, and the quantity of recycled geogrid fibres varying from 0.2% to 1%. A generalised linear model was employed for the analysis, enabling the consideration of dependent qualitative factors in forecasting characteristics. The qualitative evaluation of the resultant solution was conducted using multi-criteria optimisation via the Harrington function. Consequently, recycled carbon mesh fibres demonstrated a notably positive impact, enhancing the material’s quality by 22%. Regarding glass mesh, the fibre content should not exceed 0.2% in the AC22W mixture, whereas it can be increased to 1% in the AC16W mixture. Comparing all evaluated mixtures, it was ascertained that surpassing the allowable contamination limit of 0.1% in geogrid form does not result in a significant reduction in the quality of asphalt concrete compared to the reference mix. Full article

The adenomas in Cushing’s disease frequently exhibit mutations in exon 14, within a binding motif for the regulatory protein 14-3-3 located between the catalytic domain (DUB), responsible for ubiquitin hydrolysis, and the WW-like domain that mediates autoinhibition, resulting in constantly active USP8. The exact molecular mechanism of deubiquitinase activity disruption in Cushing’s disease remains unclear. To address this, Sanger sequencing of USP8 was performed to identify mutations in corticotropinomas. These mutations were subjected to computational screening, followed by molecular dynamics simulations to assess the structural alterations that might change the biological activity of USP8. Eight different variants of the USP8 gene were identified both within and outside the “hotspot” region. Six of these had previously been reported in Cushing’s disease, while two were detected for the first time in our patients with CD. One of the two new variants, initially classified as benign during screening, was found in the neighboring SH3 binding motif at a distance of 20 amino acids. This variant demonstrated pathogenicity patterns similar to those of known pathogenic variants. All USP8 variants identified in our patients caused conformational changes in the USP8 protein in a similar manner. The identified mutations, despite differences in annotation results—including evolutionary conservation assessments, automated predictor data, and variations in localization within exon 14—exhibit similar patterns of protein conformational change. This suggests a pathogenic effect that contributes to the development of CD. Full article