Search Results (1,870)

Background: The knee joint performs a vital function in human movement, supporting significant loads and ensuring stability during daily activities. Methods: The objective of this study was to develop and validate a subject-specific framework to model knee flexion–extension by integrating 3D gait data with individualized musculoskeletal (MS) and finite element (FE) models. In this proof of concept, gait data were collected from a 52-year-old woman using Xsens inertial sensors. The MS model was based on the same subject to define realistic loading, while the 3D knee FE model, built from another individual’s MRI, included all major anatomical structures, as subject-specific morphing was not possible due to unavailable scans. Results: The FE simulation showed principal stresses from –28.67 to +44.95 MPa, with compressive stresses between 2 and 8 MPa predominating in the tibial plateaus, consistent with normal gait. In the ACL, peak stress of 1.45 MPa occurred near the femoral insertion, decreasing non-uniformly with a compressive dip around –3.0 MPa. Displacement reached 0.99 mm in the distal tibia and decreased proximally. ACL displacement ranged from 0.45 to 0.80 mm, following a non-linear pattern likely due to ligament geometry and local constraints. Conclusions: These results support the model’s ability to replicate realistic, patient-specific joint mechanics. Full article

This study presents a numerical and experimental evaluation of axial load transfer mechanisms in deep foundations constructed in stratified cohesive soils in İzmir, Türkiye. A full-scale bi-directional static load test equipped with strain gauges was conducted on a barrette pile to investigate depth-dependent mobilization of shaft resistance. A finite element model was developed and calibrated using field-observed load–settlement and strain data to replicate the pile–soil interaction and deformation behavior. The analysis revealed a shaft-dominated load transfer behavior, with progressive mobilization concentrated in intermediate-depth cohesive layers. Sensitivity analysis identified the undrained stiffness (E_u) as the most influential parameter governing pile settlement. A strong polynomial correlation was established between calibrated E_u values and SPT N₆₀, offering a practical tool for preliminary design. Additionally, strain energy distribution was evaluated as a supplementary metric, enhancing the interpretation of mobilization zones beyond conventional stress-based methods. The integrated approach provides valuable insights for performance-based foundation design in layered cohesive ground, supporting the development of site-calibrated numerical models informed by full-scale testing data. Full article

Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of tumors with a complex molecular profile. Despite therapeutic advances, patient prognosis remains poor, emphasizing the need for more effective treatment strategies. Traditional chemotherapy, with cisplatin and 5-fluorouracil (5-FU), remains the gold standard but is limited by toxicity and tumor resistance. Immunotherapy, particularly immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1), has improved overall survival, especially in patients with high PD-L1 expression. In parallel, targeted therapies such as poly (ADP-ribose) polymerase 1 (PARP1) inhibitors—which impair DNA repair and increase replication stress—have shown promising activity in HNSCC. Cyclin-dependent kinase (CDK) inhibitors are also under investigation due to their potential to correct dysregulated cell cycle control, a hallmark of HNSCC. This review aims to summarize current and emerging pharmacotherapies for HNSCC, focusing on chemotherapy, immunotherapy, and PARP and CDK inhibitors. It also discusses the evolving role of targeted therapies in improving clinical outcomes. Future research directions include combination therapies, nanotechnology-based delivery systems to enhance treatment specificity, and the development of diagnostic tools such as PARP1-targeted imaging to better guide personalized treatment approaches. Full article

Cells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical cellular response, low-level stress-DDR (LoL-DDR), has recently been described. LoL-DDR prevents the accumulation of premutagenic oxidized bases (8-oxoguanine) through the production of ROS in an adaptive way. The production of RS-induced ROS (RIR) is tightly controlled: RIR are excluded from the nucleus and are produced by the NADPH oxidases DUOX1/DUOX2, which are controlled by NF-κB and PARP1; then, RIR activate the FOXO1-detoxifying pathway. Increasing the intensity of RS suppresses RIR via p53 and ATM. Notably, LoL-DDR is dysregulated in cancer cell lines, in which RIR are not produced by NADPH oxidases, are not detoxified under high-level stress, and favor the accumulation of 8-oxoguanine. LoL-DDR dysregulation occurred at an early stage of cancer progression in an in vitro model. Since, conversely, ROS trigger RS, this establishes a vicious cycle that continuously jeopardizes genome integrity, fueling tumorigenesis. These data reveal a novel type of ROS-controlled DNA damage response and demonstrate the fine-tuning of the cellular response to stress. The effects on genomic stability and carcinogenesis are discussed here. Full article

At the Politecnica Salesiana University (UPS) in Guayaquil, Ecuador, urban mobility challenges were addressed with the aim of improving students’ quality of life and promoting sustainability. This study evaluated the technical, economic, and social feasibility of implementing a shared transportation (carpooling) system using a quantitative-descriptive approach. Surveys were applied to a stratified sample of 256 students to analyze transportation habits. Route planning was performed using ArcGIS software, and costs were calculated with Microsoft Excel. Social impact assessment involved focus groups and analysis of variables such as changes in mobility patterns, system acceptance, and perceived safety, comfort, and accessibility. Key indicators included the percentage of students willing to participate in the pilot (82.7%), satisfaction with travel time savings (85.7% fully satisfied), and positive perceptions of safety and comfort. The results suggest that the proposed system is not only economically viable but also widely accepted by students, contributing to reduced stress, travel time, and single-occupancy vehicle use. This study demonstrates the feasibility of shared transport in urban universities and provides a replicable model to guide sustainable mobility policies that improve safety, comfort, and efficiency in student commuting. Full article

Poliovirus represents an oncolytic agent for human glioblastoma—one of the most aggressive types of cancer. Since interference of viruses with metabolic and redox pathways is often linked to their pathogenesis, drugs targeting metabolic enzymes are regarded as potential enhancers of oncolysis. Our goal was to reveal an imprint of poliovirus on the metabolism of glioblastoma cell lines and to assess the dependence of the virus on these pathways. Using GC-MS, HPLC, and Seahorse techniques, we show that poliovirus interferes with amino acid, purine and polyamine metabolism, mitochondrial respiration, and glycolysis. However, many of these changes are cell line- and culture medium-dependent. 2-Deoxyglucose, the pharmacologic inhibitor of glycolysis, was shown to enhance the cytopathic effect of poliovirus, pointing to its possible repurposing as an enhancer of oncolysis. Inhibitors of polyamine biosynthesis, pyruvate import into mitochondria, and fatty acid oxidation exhibited antiviral activity, albeit in a cell-dependent manner. We also demonstrate that poliovirus does not interfere with the production of superoxide anions or with levels of H₂O₂, showing an absence of oxidative stress during infection. Finally, we showed that a high rate of poliovirus replication is associated with fragmentation of the mitochondrial network, pointing to the significance of these organelles for the virus. Full article

Chemotherapeutic agents and radiotherapy are highly effective in treating malignancies. However, they carry a significant risk of harming the gonads and may lead to endocrine dysfunction and reproductive issues. This review outlines the molecular mechanisms of gonadotoxic therapies, focusing on radiation, alkylating agents, and platinum compounds. It discusses the loss of PMFs due to gonadotoxic exposure, including DNA double-strand breaks, oxidative stress, and dysregulated signaling pathways like PI3K/PTEN/Akt/mTOR and TAp63-mediated apoptosis. Furthermore, it explores strategies to mitigate gonadal damage, including GnRH agonists, AMH, imatinib, melatonin, sphingolipid metabolites, G-CSF, mTOR inhibitors, AS101, and LH. These therapies, paired with existing fertility preservation methods, could safeguard reproductive and hormonal functions and improve the quality of life for young cancer patients. Despite the progress made in recent years in understanding gonadotoxic mechanisms, gaps remain due to questionable reliance on mouse models and the lack of models replicating human ovarian dynamics. Long-term studies are vital for wider analyses and exploration of protective strategies based on various animal models and clinical trials. It is essential to verify that these substances do not hinder the anti-cancer effectiveness of treatments or cause lasting DNA changes in granulosa cells, raising the risk of miscarriages and infertility. Full article

Genome instability is a hallmark of cancer, often driven by mutations and altered expression of genome maintenance factors involved in DNA replication and repair. Rap1 Interacting Factor 1 (RIF1) plays a crucial role in genome stability and is implicated in cancer pathogenesis. Cells express two RIF1 splice variants, RIF1-Long and RIF1-Short, which differ in their ability to protect cells from DNA replication stress. Here, we investigate differential expression and splicing of RIF1 in cancer cell lines following replication stress and in patients using matched normal and tumour data from The Cancer Genome Atlas (TCGA). Overall RIF1 expression is altered in several cancer types, with increased transcript levels in colon and lung cancers. RIF1 also exhibits distinct splicing patterns, particularly in specific breast cancer subtypes. In Luminal A (LumA), Luminal B (LumB), and HER2-enriched breast cancers (HER2E), RIF1 Exon 31 tends to be excluded, favouring RIF1-Short expression and correlating with poorer clinical outcomes. These breast cancer subtypes also tend to exclude other short exons, suggesting length-dependent splicing dysregulation. Basal breast cancer also shows exon exclusion, but unlike other subtypes, it shows no short-exon bias. Surprisingly, however, in basal breast cancer, RIF1 Exon 31 is not consistently excluded, which may impact prognosis since RIF1-Long protects against replication stress. Full article

The life cycle of the hepatitis C virus (HCV) is closely linked to lipid metabolism. Recently, the stress defence transcription factor, nuclear factor erythroid 2 related factor-1 (Nrf1), has been described as a cholesterol sensor that protects the liver from excess cholesterol. Nrf1, like its homologue Nrf2, further responds to oxidative stress by binding with small Maf proteins (sMaf) to the promotor antioxidant response element (ARE). Given these facts, investigating the crosstalk between Nrf1 and HCV was a logical next step. In HCV-replicating cells, we observed reduced levels of Nrf1. Furthermore, activation of Nrf1-dependent target genes is impaired due to sMaf sequestration in replicase complexes. This results in a shortage of sMaf proteins in the nucleus, trapping Nrf1 at the replicase complexes and further limiting its function. Weakened Nrf1 activity contributes to impaired cholesterol removal, which occurs alongside an elevated intracellular cholesterol level and inhibited LXRα promoter activation. Furthermore, inhibition of Nrf1 activity correlated with a kinome profile characteristic of steatosis and enhanced inflammation—factors contributing to HCV pathogenesis. Our results indicate that activation of Nrf1-dependent target genes is impaired in HCV-positive cells. This, in turn, favours viral morphogenesis, as evidenced by enhanced replication and increased production of viral progeny. Full article

Background: Protein kinase R (PKR) inhibits general mRNA translation by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). PKR also modulates NF-κB signaling during viral infections, but comparative studies of PKR-mediated NF-κB responses across mammalian species and their regulation by viral inhibitors remain largely unexplored. This study aimed to characterize the conserved antiviral and inflammatory roles of mammalian PKR orthologs and investigate their modulation by poxviral inhibitors. Methods: Using reporter gene assays and quantitative RT-PCR, we assessed the impact of 17 mammalian PKR orthologs on general translation inhibition, stress-responsive translation, and NF-κB-dependent induction of target genes. Congenic human and rabbit cell lines infected with a myxoma virus strain lacking PKR inhibitors were used to compare the effects of human and rabbit PKR on viral replication and inflammatory responses. Site-directed mutagenesis was employed to determine key residues responsible for differential sensitivity to the viral inhibitor M156. Results: All 17 mammalian PKR orthologs significantly inhibited general translation, strongly activated stress-responsive ATF4 translation, and robustly induced NF-κB target genes. Inhibition of these responses was specifically mediated by poxviral K3 orthologs that effectively suppressed PKR activation. Comparative analyses showed human and rabbit PKRs similarly inhibited virus replication and induced cytokine transcripts. Amino acid swaps between rabbit PKRs reversed their sensitivity to viral inhibitor M156 and NF-κB activation. Conclusions: Our data show that the tested PKR orthologs exhibit conserved dual antiviral and inflammatory regulatory roles, which can be antagonized by poxviral K3 orthologs that exploit eIF2α mimicry to modulate the PKR-NF-κB axis. Full article

The objective of this study was to investigate alterations in nutrient utilization, standardized ileal digestibility of amino acids (SIDAA), and intestinal health in response to heat stress (HS) in Pekin ducks. A total of 240 healthy 28-day-old male Pekin ducks were randomly allocated to three groups: a normal control (NC) group, an HS group, and a pair-fed (PF; provided an amount of feed equal to that consumed by the HS group to eliminate the effects of feed intake) group, each with eight replicate cages of ten birds. The results showed that HS significantly reduced the apparent utilization of dietary energy, ether extract, and crude protein compared to both the NC and PF groups (p < 0.05), but yielded comparable SIDAA to the PF group. The HS group exhibited reduced mRNA levels of EAAT3 and PepT1, along with elevated mRNA levels of CAT1, GLUT5, and FATP6 in the jejunum compared to the NC or PF groups, respectively (p < 0.05). Furthermore, HS resulted in a significant deterioration of jejunal morphology and goblet cell count compared to the NC and PF groups (p < 0.05). Serum fluorescein isothiocyanate-dextran levels were significantly higher in HS ducks than in NC ducks (p < 0.05), but did not differ from PF ducks. At order-level classification of ileal mucosal microbiota, HS markedly increased the relative abundance of Bacillales, Deferribacterales, and Actinomycetales versus NC (p < 0.05), while significantly decreasing Bifidobacteriales abundance relative to PF (p < 0.05). Collectively, HS induces a leaky gut and microbiota dysbiosis that compromises gut health, thereby reducing dietary nutrient utilization in Pekin ducks. The observed reduction in feed intake constitutes a primary driver of intestinal health deterioration in heat-stressed Pekin ducks. Full article

The mesoscopic-scale discrete element method (DEM) modeling approach demonstrated high compatibility with macroporous recycled concrete (MRC). However, existing DEM models failed to adequately balance modeling accuracy and computational efficiency for recycled aggregate (RA), replicate the three distinct interfacial transition zone (ITZ) types and pore structure of MRC, or establish a systematic calibration methodology. In this study, PFC 3D was employed to establish a randomly polyhedral RA composite model and an MRC model. A systematic methodology for parameter testing and calibration was proposed, and compressive test simulations were conducted on the MRC model. The model incorporated all components of MRC, including three types of ITZs, achieving an aggregate volume fraction of 57.7%. Errors in simulating compressive strength and elastic modulus were 3.8% and 18.2%, respectively. Compared to conventional concrete, MRC exhibits larger strain and a steeper post-peak descending portion in stress–strain curves. At peak stress, stress is concentrated in the central region and the surrounding arc-shaped zones. After peak stress, significant localized residual stress persists within specimens; both toughness and toughness retention capacity increase with rising porosity and declining compressive strength. Failure of MRC is dominated by tension rather than shear, with critical bonds determining strength accounting for only 1.4% of the total. The influence ranking of components on compressive strength is as follows: ITZ (new paste–old paste) > ITZ (new paste–natural aggregates) > new paste > old paste > ITZ (old paste–natural aggregates). The Poisson’s ratio of MRC (0.12–0.17) demonstrates a negative correlation with porosity. Predictive formulas for peak strain and elastic modulus of MRC were established, with errors of 2.6% and 3.9%, respectively. Full article

Cowpea (Vigna unguiculata [L.] Walp) is a vital food security crop in sub-Saharan Africa, including Eswatini. The productivity of the crop is low (<600 kg/ha) in the country due to a lack of improved, locally adapted, and farmer-preferred varieties with biotic and abiotic stress tolerance. The objective of the study was to assess the agronomic performance of newly developed elite cowpea mutants to select best-yielding and adapted pure lines for production and genetic improvement in Eswatini. A total of 30 cowpea genotypes, including 24 newly developed advanced mutant lines, their 3 founder parents and 3 local checks, were profiled for major agronomic traits in two selected sites (Lowveld Experiment and Malkerns Research Stations) using a 6 × 5 alpha lattice design with three replications. A combined analysis of variance revealed that the genotype x location interaction effects were significant (p < 0.05) for germination percentage (DG %), days to flowering (DTF), days to maturity (DMT), number of pods per plant (NPP), pod length (PDL), number of seeds per pod (NSP), hundred seed weight (HSW), and grain yield (GYD). Elite mutant genotypes, including NKL9P7, BRR4P11, SHR9P5, and NKL9P7-2 exhibited higher grain yields at 3158.8 kg/ha, 2651.6 kg/ha, 2627.5 kg/ha, and 2255.8 kg/ha in that order. The highest-yielding mutant, NKL9P7, produced 70%, 61%, and 54% more grain yield than the check varieties Mtilane, Black Eye, and Accession 792, respectively. Furthermore, the selected genotypes displayed promising yield components such as better PDL (varying from 13.1 to 26.3 cm), NPP (15.9 to 26.8), and NSP (9.8 to 16.2). Grain yield had significant positive correlations (p < 0.05) with DG %, NSP, and NPP. The principal component analysis (PCA) revealed that 81.5% of the total genotypic variation was attributable to the assessed quantitative traits. Principal component (PC) 1 accounted for 48.6%, while PC 2 and PC 3 contributed 18.9% and 14% of the overall variation, respectively. Key traits correlated with PC1 were NPP with a loading score of 0.91, NSP (0.83), PDL (0.73), GYD (0.68), HSW (0.58), DMT (−0.60), and DTF (−0.43) in a desirable direction. In conclusion, genotypes NKL9P7, BRR4P11, SHR9P5, NKL9P7-2, Bira, SHR3P4, and SHR2P7 were identified as complementary parents with relatively best yields and local adaptation, making them ideal selections for direct production or breeding. The following traits, NPP, NSP, PDL, GYD, and HSW, offered unique opportunities for genotype selection in the cowpea breeding program in Eswatini. Full article

The seasonal patterns of viral diseases in farm animals present significant challenges to global livestock productivity, with cold stress emerging as a potential modulator of host–pathogen interactions. This review synthesizes current knowledge on the expression dynamics of heat shock protein 70 (HSP70) in farm animals under cold-stress conditions and its potential roles as (1) a viral replication facilitator and (2) an immune response regulator. This review highlights cold-induced HSP70 overexpression in essential organs, as well as its effects on significant virus life cycles, such as porcine epidemic diarrhea virus (PEDV), porcine reproductive and respiratory syndrome virus (PRRSV), and bovine viral diarrhea virus (BVDV), through processes like viral protein chaperoning, replication complex stabilization, and host defense modulation. By integrating insights from thermophysiology, virology, and immunology, we suggest that HSP70 serves as a crucial link between environmental stress and viral disease seasonality. We also discuss translational opportunities targeting HSP70 pathways to break the cycle of seasonal outbreaks, while addressing key knowledge gaps requiring further investigation. This article provides a framework for understanding climate-driven disease patterns and developing seasonally adjusted intervention strategies. Full article

Work-related musculoskeletal disorders (WMSDs) are among the most prevalent occupational health issues, particularly affecting public transport drivers due to prolonged sitting, constrained postures, and poorly adaptable cabins. This study addresses the ergonomic risks associated with tram driving, aiming to evaluate biomechanical load and postural stress in relation to drivers’ anthropometric characteristics. A combined methodological approach was applied, integrating two standardized observational tools—RULA and REBA—with anthropometric modeling based on three representatives European morphotypes (SmallW, MidM, and TallM). ErgoFellow 3.0 software was used for digital posture evaluation, and lumbar moments at the L4/L5 vertebral level were calculated to estimate lumbar loading. The analysis was simulation-based, using digital human models, and no real subjects were involved. The results revealed uniform REBA (Rapid Entire Body Assessment) and RULA (Rapid Upper Limb Assessment) scores of 6 across all morphotypes, indicating moderate to high risk and a need for ergonomic intervention. Lumbar moments ranged from 51.35 Nm (SmallW) to 101.67 Nm (TallM), with the tallest model slightly exceeding the recommended ergonomic thresholds. These findings highlight a systemic mismatch between cabin design and user variability. In conclusion, ergonomic improvements such as adjustable seating, better control layout, and driver education are essential to reduce the risk of WMSDs. The study proposes a replicable methodology combining anthropometric, observational, and biomechanical tools for evaluating and improving transport workstation design. Full article