Search Results (57)

Cancer metastasis, the spread of tumour cells from the primary site to distant organs, is responsible for over 90% of cancer deaths, yet effective treatments remain elusive due to incomplete understanding of the molecular drivers involved. Podocalyxin (PODXL), a protein overexpressed in many aggressive cancers, links the cell membrane to the internal skeleton through its interaction with Ezrin, an actin cytoskeleton cross-linker. Despite its therapeutic relevance, the PODXL–Ezrin interface remains structurally uncharacterised and pharmacologically intractable. Here, we employed an integrated computational approach combining protein–protein docking, molecular dynamics (MD) simulations, and virtual screening to investigate the structural basis of the PODXL–Ezrin interaction. Using AlphaFold-predicted structures, we modelled PODXL and Ezrin complexes, revealing that PODXL’s cytoplasmic domain stabilises upon Ezrin binding, with Arg495 mediating temporally distinct electrostatic interactions essential for initial complex assembly. Particularly, we characterised the R495W missense mutation in PODXL’s Ezrin-binding domain, demonstrating that substitution of arginine with bulky, hydrophobic tryptophan may allosterically destabilise Ezrin’s dormant conformation. This mutation slightly increases the intramolecular distance between the F3 subdomain and C-terminal domain from 2.59 Å to 3.40 Å, thus leading to potential partial unmasking of the Thr567 phosphorylation site that could plausibly prime Ezrin for activation. Molecular dynamics simulations in the WT state with a total simulation time of 100 ns revealed enhanced structural rigidity and reduced radius of gyration fluctuations in the mutant complex, consistent with a potential “locked,” activation-prone state that amplifies oncogenic signalling. Through virtual screening, we identified NSC305787 as a selective destabiliser of the R495W mutant complex by disrupting key Trp495–pre-C-terminal loop Ezrin interactions and causing steric hindrance to PIP2 recruitment. Our findings identified mutation-dependent changes in drug binding that can guide the development and repurposing of compounds for targeting PODXL-related cancers and improve patient outcomes in PODXL-altered malignancies. Full article

Background: Preserving fertility in young women with cancer is crucial for comprehensive care. Based on GBD 2023 estimates, approximately 1000 women aged 15–39 are diagnosed with haematological malignancies annually in Italy. Guidelines recommend timely fertility preservation (FP) counselling for all at-risk patients, yet real-world access data remain limited. Methods: This multicentre, retrospective observational study analysed FP counselling for women aged 15–39 with haematological malignancies from 2015 to 2023. Counselling data were extracted from the Italian Assisted Reproductive Technology Registry (IARTR). This data collection system, known as PreFerIta, was developed within a project supported by the Italian Ministry of Health to collect data on Fertility Preservation (FP) treatments in oncology patients and/or those at risk of iatrogenic infertility, provided in seven specialised ART centres across Italy. The PreFerIta database includes data on both oocyte cryopreservation and ovarian tissue cryopreservation. Annual visits were related to the estimated regional incidence of new haematological malignancies (GBD 2023). Counselling-to-incidence ratios, absolute/relative gaps, and 95% confidence intervals (CIs) were calculated. Results: From 2015 to 2023, an estimated 4473 new haematological malignancies occurred in the catchment regions. Concurrently, 1200 FP counselling visits were recorded. While incidence modestly declined, counselling activity remained high. The counselling-to-incidence ratio increased from 17.33% in 2015 to 31.92% in 2018, stabilising between 26% and 31% thereafter (30.98% in 2023). The relative counselling gap decreased from 82.67% to 69.02%. These ratios represent lower-bound estimates of access to specialised oncofertility consultations. Conclusions: In this Italian network, approximately one in four to one in three incident haematological malignancies in young women were associated with specialised FP counselling. This reflects a substantial integration of oncofertility services into haematology care, highlighting opportunities to further strengthen referral pathways and achieve full guideline concordance. Full article

Ground-based full-physical experiments for space rendezvous and docking serve as a critical step in verifying the reliability of docking technology. The high-precision active attitude setting of spacecraft simulators represents a key technology for ground-based full-physical experiments. In order to satisfy the requirement for high-precision attitude control in these experiments, this paper proposes an enhanced method based on auto disturbance rejection control (ADRC). This paper addresses the limitations of traditional deadband–hysteresis relay controllers, which exhibit low steady-state accuracy and insufficient disturbance rejection capability. This approach employs a nonlinear extended state observer (NESO) to estimate and compensate for total system disturbances in real time. Concurrently, it incorporates an adaptive mechanism for deadband and hysteresis parameters, dynamically adjusting controller parameters based on disturbance estimates and attitude errors. This overcomes the trade-off between accuracy and power consumption that is inherent in fixed-parameter controllers. Furthermore, the method incorporates a nonlinear tracking differentiator (NTD) to schedule transitions, enabling rapid attitude settling without overshoot. The stability analysis demonstrates that the proposed controller achieves local asymptotic stability and global uniformly bounded convergence. The simulation results demonstrate that under three typical operating conditions (conventional attitude setting, pre-separation connector stabilisation, and docking initial condition establishment), the steady-state attitude error remains within ±0.01°, with convergence times under 3 s and no overshoot. These results closely match ground test data. This approach has been demonstrated to enhance the engineering applicability of the control system while ensuring high precision and robust performance. Full article

Objectives: This study investigates the effects of 600 mg/day Ashwagandha root extract on physiological stress biomarkers, perception of recovery, muscle strength and aerobic capacity in team sports athletes during pre-season training, a period associated with elevated cortisol and accumulated training stress. Methods: Fifty-six athletes (26.8 ± 4.4 years, 1.74 ± 0.10 m, 79.4 ± 17.3 kg, 11.0 ± 7.1 career years) across rugby, water polo and football were randomly assigned to an Ashwagandha (ASH; n = 28, 14 males and 14 females) or placebo (PLA; n = 28, 14 males and 14 females) group for 42 days. Salivary biomarkers were assessed after training, muscle strength and aerobic capacity were measured during training, and perception of recovery was evaluated with Hooper Index (HI) the following day. Mixed ANOVA was used to determine group × time interactions and Bonferroni post hoc analyses were conducted for multiple pairwise comparisons. Results: In female athletes, salivary cortisol increased significantly in PLA (p = 0.001), while recovery parameters such as the overall HI score (p = 0.001), Delayed Onset Muscle Soreness (DOMS) (p = 0.008) and perception of fatigue (p = 0.026) scores improved significantly in ASH. In males, salivary cortisone increased significantly in PLA (p = 0.022), while Countermovement Jump (CMJ) improved significantly in ASH (p = 0.018). Pull-up performance increased in both PLA (p = 0.004) and ASH (p < 0.0001) in males. Conclusions: Supplementation with 600 mg/day of Ashwagandha root extract for 42 days may stabilise stress biomarkers, improve perception of recovery and enhance muscle strength in team sports athletes during pre-season training. The trial is registered on ClinicalTrials.gov with the ID NCT07041853. Full article

Vaginal microbiome composition has been linked to risk of preterm birth (PTB), a persistent global health challenge. 16S rRNA microbial profiling has identified specific vaginal community state types (CSTs) that have been associated with PTB risk. Diagnostic profiling requires standardised pre-analytical protocols. We evaluated two storage methods and validated a curated, vagina-specific 16S rRNA gene database (VagDB) to enhance annotation. Paired Copan FLOQ swabs from 22 women at high PTB risk were processed for either (a) dry/immediate freezing or (b) Amies-stabilisation/refrigeration. Amplicon sequence variants were generated via 16S rRNA gene (V4) PCR and Illumina sequencing. We assessed diversity, composition, and community state type (CST) allocation. Amies-stabilised samples yielded significantly higher DNA (p = 0.003), but this did not alter species richness, evenness, or community structure. VagDB enhanced species-level resolution. PCoA showed robust clustering by participant and CST (p < 0.001), irrespective of storage; CST concordance exceeded 90%. Routinely collected vaginal swabs in stabilisation medium with an 8–72 h refrigeration window yield reliable data, supporting the integration of vaginal microbiome profiling into clinical PTB risk assessment. Full article

In the Mediterranean region, the persimmon cultivar ‘Rojo Brillante’ may experience up to four waves of fruit drop. The first is a physiological event during fruit set that is common in woody species, while the subsequent waves are induced by rising temperatures and prolonged summer water stress. These summer drops represent the main limiting factor, leading to yield losses of up to 90%. Organ abscission is a complex process regulated by genetic, hormonal, nutritional, and environmental factors. We hypothesise that calcium (Ca) plays a protective role in the abscission zone (AZ) by inhibiting cell wall-degrading enzymes such as polygalacturonase (PG) and pectin methylesterases (PMEs). Calcium applications every 15 days from anthesis onwards significantly reduced fruit drop. Treatments preserved polar auxin transport—through DkPIN1 expression—and inhibited stage C of the abscission process, decreasing the relative expression of the DkIDL6 gene in the AZ. Moreover, PME and PG activities were significantly lower in Ca-treated fruits, confirming the stabilising effect of calcium on AZ integrity. In summary, pre-anthesis calcium sprays reduced premature fruit drop by about 30% under heat–drought stress by down-regulating key abscission genes (DkIDL6, DkPG20, DkPME41) and preserving cell wall integrity and fruit firmness, supporting the use of Ca treatments as a climate-smart approach to stabilise persimmon yield. Full article

Thallium is a soft metal with a grey or silvery hue. It commonly occurs in two oxidation states in chemical compounds: Tl⁺ and Tl³⁺. Thermodynamically, Tl⁺ is significantly more stable and typically represents the dominant form of thallium in environmental systems. However, in this chemical form, thallium remains highly toxic. This study focuses on the modification of a glassy carbon electrode (GCE) with silver nanostructures stabilised by potato starch derivatives. The modified electrode (GCE/AgNPs-E1451) was used for the determination of trace amounts of thallium ions using anodic stripping voltammetry. Emphasis was placed on assessing the effect of surface modification on key electrochemical performance parameters of the electrode. Measurements were carried out in a base electrolyte (EDTA) and in a real soil sample collected from Bali. The stripping peak current of thallium exhibited linearity over the concentration range from 19 to 410 ppb (9.31 × 10⁻⁸ to 2.009 × 10⁻⁶ mol/dm³). The calculated limit of detection (LOD) was 18.8 ppb (9.21 × 10⁻⁸ mol/dm³), while the limit of quantification (LOQ), corresponded to 56.4 ppb (2.76 × 10⁻⁷ mol/dm³). The GCE/AgNPs-E1451 electrode demonstrates several significant advantages, including a wide detection range, reduced analysis time due to the elimination of time-consuming pre-concentration steps, and non-toxic operation compared to mercury-based electrodes. Full article

To investigate the failure mechanisms of surrounding rock in deep mine tunnels and its spatio-temporal evolution patterns, a true triaxial disturbance unloading rock testing system, the acoustic emission (AE) system, and the miniature camera monitoring system were employed to conduct true triaxial graded loading tests on sandstone containing circular holes at burial depths of 800 m, 1000 m, 1200 m, 1400 m, and 1600 m. The study investigated the patterns of mechanical properties and failure characteristics of porous sandstone at different burial depths. The results showed that the peak strength of the specimens increased quadratically with increasing burial depth; the failure process of porous sandstone could be divided into four stages: the calm period, the particle ejection period, the stable failure period, and the complete collapse period; as burial depth increases, the failure mode transitions from a composite tensile–shear crack type to a shear crack-dominated type, with the ratio of shear cracks to tensile cracks exhibiting quadratic growth and reduction, respectively; the particle ejection stage is characterised by low-frequency, low-amplitude signals, corresponding to the microcrack initiation stage, while the stable failure stage exhibits a sharp increase in low-frequency, high-amplitude signals, reflecting macrocrack propagation characteristics, with the spatial evolution of their locations ultimately forming a penetrating oblique shear failure zone; and peak stress analysis indicates that as burial depth increases, peak stress during the particle ejection phase first increases and then decreases, while peak stress during the stable failure phase first decreases and then stabilises. The duration of the pre-instability calm phase shows a significant negative correlation with burial depth. The research findings provide a theoretical basis for controlling tunnel rock mass stability and disaster warning. Full article

In digital pathology, accurate diagnosis and prognosis critically depend on robust feature representation of Whole Slide Images (WSIs). While deep learning offers powerful solutions, its “black box” nature presents significant challenges to clinical interpretability and widespread adoption. Handcrafted features offer interpretability, yet orthogonal moments, particularly Tchebichef moments (TMs), remain underexplored for WSI analysis. This study introduces TMs as interpretable, efficient, and scalable handcrafted descriptors for WSIs, alongside a novel two-dimensional digital filter architecture designed to enhance numerical stability and hardware compatibility during TM computation. We conducted a comprehensive reconstruction analysis using H&E-stained WSIs from the MIDOG++ dataset to evaluate TM effectiveness. Our results demonstrate that lower-order TMs accurately reconstruct both square and rectangular WSI patches, with performance stabilising beyond a threshold moment order, confirmed by SNIRE, SSIM, and BRISQUE metrics, highlighting their capacity to retain structural fidelity. Furthermore, our analysis reveals significant computational efficiency gains through the use of pre-computed polynomials. These findings establish TMs as highly promising, interpretable, and scalable feature descriptors, offering a robust alternative for computational pathology applications that prioritise both accuracy and transparency. Full article

This study investigates long-term land surface temperature (LST) trends along the shoreline of Lake Drūkšiai, a transboundary lake in eastern Lithuania that formerly served as a cooling reservoir for the Ignalina Nuclear Power Plant (INPP). Although the INPP was decommissioned in 2009, its legacy continues to influence the lake’s thermal regime. Using Landsat 8 thermal infrared imagery and NDVI-based methods, we analysed spatial and temporal LST variations from 2013 to 2024. The results indicate persistent temperature anomalies and elevated LST values, particularly in zones previously affected by thermal discharges. The years 2020 and 2024 exhibited the highest average LST values; some years (e.g., 2018) showed lower readings due to localised environmental factors such as river inflow and seasonal variability. Despite a slight stabilisation observed in 2024, temperatures remain higher than those recorded in 2013, suggesting that pre-industrial thermal conditions have not yet been restored. These findings underscore the long-term environmental impacts of industrial activity and highlight the importance of satellite-based monitoring for the sustainable management of land, water resources, and coastal zones. Full article

Background: The active (remote) loading of drugs into nanoparticulate systems via the pH gradient technique has been proven highly successful in liposomes, as numerous formulations have reached the market. However, this is not the case for niosomes, as the full potential of this area remains largely undiscovered. The purpose of this research is to study the effect of different co-surfactants (Cremophor RH 40, Cremophor ELP and Solutol HS-15) on stabilising the niosomal membrane to enable the creation of a pH gradient. Methods: For visualisation of pH gradients, pH indicator bromocresol green (BCG) was used as a novel encapsulated model molecule to visually investigate the ability of niosomes to entrap drugs through active loading. Thereafter, the optimised BCG niosomal formulation was applied to encapsulate a therapeutic drug molecule, doxorubicin, via pH gradient active loading. Niosomes were formulated via thin-film hydration using Span 60, cholesterol, with or without co-surfactants. Thin films were hydrated with either Trizma buffer or HEPES buffer for BCG, or ammonium sulfate for doxorubicin. The niosomes’ outer membrane pH was adjusted via either the addition of HCl or citric acid in the case of BCG, or by passing the niosomes through a Sephadex G50 gel column, pre-equilibrated with PBS or Trizma buffer, in the case of doxorubicin. Results: Niosomes formulated with Span 60 and cholesterol could not be formed at acidic pH and thus could not create a pH gradient. All three co-surfactants, when added to Span 60 and cholesterol, stabilised the niosomes and enabled them to form a pH gradient. Niosomes (after size reduction) containing Solutol HS-15 showed significantly higher entrapment efficiency of BCG when compared to Cremophor RH 40 and Cremophor ELP (67.86% vs. 15.57% vs. 17.81%, respectively, with sizes of 159.6 nm, 177.9 nm and 219.1 nm, respectively). The use of HEPES buffer resulted in a higher EE of BCG compared to Trizma buffer (72.85% vs. 67.86%) and achieved a size of 283.4 nm. The Solutol HS-15 containing formulation has exhibited 68.28% EE of doxorubicin with ammonium sulfate as the inner buffer, while the external buffer was Trizma with a size of 241.1 nm after extrusion. Conclusions: Niosomal formulations containing Solutol HS-15 are highly promising for remote drug loading. The novel use of BCG for studying pH gradient and drug loading into niosomes has proved beneficial and successful. Full article

The United Kingdom seeks to achieve net-zero emissions by 2050, mostly via the shift to an electrical system exclusively powered by zero-carbon sources. Microgrids (MGs) can be seen as an effective system for integrating renewables into the energy portfolio. Nonetheless, MGs face the acknowledged obstacle of backup power generation due to the intermittent nature of renewable energy sources, necessitating the establishment of backup power generation capacity. This paper contrasts selfish power generation, where the MG pursues complete energy autonomy, with an alternative influenced by lean principles (Heijunka production), which seeks to stabilise power transactions within the national electricity supply chain, reduce emissions, and tackle the backup generation challenge. This study proposes a pre-contractual order update (COU) strategy for the operation of hybrid collaborative MG where a forward order update to the utility grid is placed, in contrast to selfish MG, which uses a spot order update strategy. The COU strategy was defined, and two simulation models (for selfish and collaborative MG) were developed, each incorporating four backup generation scenarios to illustrate the method’s efficacy by assessing the system’s critical performance metrics. It has been found that the collaborative MG model reduced the carbon emissions by 62% and the volatility of unplanned orders to the grid by 61% compared to the selfish model in the first scenario (grid-dependent MG). Furthermore, the MG achieved zero volatility and a 33% reduction in carbon content in the collaborative MG when using the H₂ burner as backup generation compared to the first scenario. Indicating that sustainability encompasses not only the use of renewable resources but also the stability of their outputs through the implementation of collaborative MGs. Full article

To enhance and stabilise the edible quality of coated tofu, this study explored the changes in the microstructure and intermolecular forces of coated tofu gel and sol under different heat treatments. It elucidated the phase transformation mechanism of coated tofu gel and sol under heat treatment. The results showed that the protein structure unfolded, the fluorescence intensity decreased, and the protein solubility, surface hydrophobicity, and free sulfhydryl group content increased as the coated tofu gel transformed to sol. Disulfide bonding and hydrophobic interactions were the primary intermolecular forces in the heat-induced gel–sol transition. FTIR showed that the content of β-sheets decreased significantly during gel–sol transformation, while the content of β-turns, α-helices and random coils increased significantly. Most remained relatively stable during the gel–sol transformation process, with only the A and B subunits of the 11S protein decreasing slightly. Their reduction became significant when the temperature reached 200 °C. Additionally, the high-temperature heat treatment promoted the gel–sol transition of the coated tofu, with its cross-section gradually transforming from a porous network structure to a more uniform and smooth texture during heat treatment process. The findings of this study provide a theoretical basis for improving the quality of coated tofu by optimising heat treatment parameters, laying the groundwork for future advancements in the development of pre-heat-treated coated tofu. Full article

When controlling difficult industrial processes characterised by open-loop instability and/or poor damping, predictive functional control (PFC) practitioners often face two critical design challenges. The first one arises due to the intrinsic simplicity of the PFC control algorithm that, instead of optimising the future control trajectory in real time like other predictive controllers, simply assumes constant control action, thereby producing unreliable model predictions in the long range and thus inconsistent closed-loop performance. The second issue is related to the controller tuning, which may become ambiguous and unsystematic due to the existence of an inconsistent relationship between the controller parameters and closed-loop behaviour. This paper presents a dual-loop control strategy that aims at mitigating both weaknesses simultaneously by combining the concepts of pre-stabilisation and relative tuning within the framework of predictive functional control. Two challenging industrial case studies have been analysed through computer simulations that successfully validate the efficacy of the proposal under various real world scenarios. Full article

Corpectomy is the surgical procedure of resecting a vertebral body or a part of it in order to decompress neural structures. Corpectomy is performed in patients with degenerative disease or cancer and following injury to the spine. We present a case of multilevel corpectomy in a female patient with massive degenerative disease associated with rheumatoid arthritis, combined with cervical myelopathy and osteoporosis. We present the case of a female patient who underwent C4-C5-C6 corpectomy and spinal stabilisation with a Cervical 3D Expandable cage and a cervical plate attached to the C3-C7 bodies. The rheumatoid arthritis caused degenerative changes, which, combined with the impact of environmental conditions and the patient’s postural defects, led to a pathological profile of the spine along the vertical and transverse axis, manifesting clinically as a cervical myelopathy with its characteristic neurological symptoms. Pre-operative imaging studies revealed a critical stenosis of the spinal canal. This report showcases an effective surgical technique for severe degenerative disease bearing an increased risk of tetraplegia that could be brought on by even a minor injury to the cervical spine in the presence of this kind of pathology. Multilevel cervical corpectomy can be an effective method for treating spinal canal stenosis to prevent the onset of neurological deficits. This procedure requires careful diagnostic work-up, surgical planning and an interdisciplinary approach, especially in patients with co-morbidities. Full article