Search Results (5,040)

Background/Aims: While pathogenic germline variants play a critical role in pediatric cancer susceptibility, traditional clinical genetics primarily focuses on single-gene interpretations. Transitioning to a systems-level analysis of inherited variation can uncover shared biological vulnerabilities, informing genetic counseling, surveillance, and targeted therapeutics. This study aims to implement an unsupervised machine learning framework to identify and characterize Germline Mutation Signatures (GMS) across diverse pediatric malignancies, elucidating latent genomic patterns that reveal shared oncogenic mechanisms. Methods: We analyzed germline whole-exome and whole-genome sequencing (WES/WGS) data from a retrospective cohort of 420 pediatric cancer patients and matched non-cancer controls. Variants were deeply annotated to capture multi-dimensional features, including predicted pathogenicity, splice-site disruption, regulatory impact, population frequency, and sequence context. To enable robust modeling, we integrated an augmented feature set encompassing evolutionary constraint, loss-of-function intolerance, and compositionally normalized substitution spectra. These high-dimensional annotations were processed using a deep autoencoder for non-linear representation learning, followed by Gaussian Mixture Modeling (GMM) of the latent space. Results: The framework delineated 13 signatures (GMS1–GMS13), yielding an optimal Davies–Bouldin index of 1.051. These signatures map to fundamental biological processes, including DNA repair deficiencies, transcription-coupled damage, replication stress, and aberrant RNA regulation. Crucially, these GMSs transcend traditional tissue-of-origin classifications, manifesting across multiple distinct cancer types. This observation indicates convergent germline etiologies and suggests potential shared susceptibilities to pathway-directed therapies. Conclusions: The discovery of these cross-cancer signatures provides a scalable, biologically interpretable framework for decoding inherited pediatric cancer risk. While the therapeutic mapping networks identified are currently exploratory and serve as a hypothesis-generating foundation, this deep learning-driven paradigm establishes a robust basis for stratified precision medicine. Pending prospective clinical validation, this approach holds significant translational potential to move beyond single-gene paradigms toward unified, systems-level precision oncology strategies. Full article

This study investigates the spatiotemporal dynamics of peri-urban expansion and land use transformation in Izmir, Türkiye, over 36 years (1986–2022) using an integrated GIS-based Multi-Criteria Decision Analysis (MCDA) framework. Multi-source datasets, including Landsat imagery, CORINE land cover (CLC) data, demographic statistics, and spatial variables (slope, transportation proximity, and distance to the city center), were combined to delineate urban, peri-urban, and rural zones. Results reveal a substantial percentage increase in urban areas from 2.8% in 1986 to 10.48% in 2022, corresponding to an expansion of approximately 7.6% (≈908.56 km²). In contrast, agricultural land declined by 5.8%, while forest areas experienced a more severe reduction of 19.1%, indicating significant environmental degradation. Population dynamics further support this transformation, with peri-urban districts exhibiting growth rates exceeding the metropolitan core average of 1.8% (1986–2010), followed by a relative slowdown to 0.5% after 2010, accompanied by outward migration-driven expansion. Spatial analysis demonstrates that peri-urban growth is strongly influenced by accessibility and topography, with development concentrated within 30–50 km of the city center and along major transportation corridors (500–1000 m buffers). Land Surface Temperature (LST) analysis indicates increasing urban heat island intensity, with surface temperatures ranging from 12 °C to 46 °C, particularly in densely built inner peri-urban zones. The MCDA-based classification identifies distinct inner and outer peri-urban belts, characterized by contrasting density, land use patterns, and environmental pressures. Overall, the findings highlight that Izmir’s peri-urbanization is a heterogeneous and rapidly evolving process driven by demographic, spatial, and policy-related factors. The study provides a replicable methodological framework and emphasizes the urgent need for integrated, sustainability-oriented planning strategies to mitigate ecological loss and uncontrolled urban sprawl. Full article

The COVID-19 pandemic highlighted the urgent need to develop effective and broad-spectrum antiviral therapies against coronaviruses. One strategy to address this concern is a combination therapy using repurposed drugs against zoonotic viruses with pandemic potential. We previously demonstrated that the combination of Remdesivir and Ivermectin is highly potent and synergistic in inhibiting the replication of murine hepatitis virus (MHV) in RAW264.7 macrophages. This study investigated the interactions between the drug combination, coronavirus and host by proteomics and RNA sequencing of MHV-infected H2.35 murine liver epithelial cells. Time-of-addition and time-of-removal assays suggested that the drug combination likely affected the synthesis of viral RNA and viral protein. This combination drastically diminished the live virus titer greater than the respective monotherapies in MHV-infected H2.35 cells (by ~4 log₁₀), as well as in SARS-CoV-2-infected VeroE6 cells and human nasal epithelial cells. Proteomic and transcriptomic analyses revealed that viral protein and RNA levels were significantly depressed upon combination treatment. The drug combination exhibited considerable negative effects upon host RNA processes and resulted in the upregulation of host protein processes (e.g., response to unfolded protein; protein insertion into ER membrane). Molecular pathways affected by the combination treatment were markedly distinct from the monotherapies and indicated that Ivermectin enhances Remdesivir by modulating critical host processes to synergistically exert its inhibitory effect on the coronavirus replication cycle. Full article

Advances in imaging and fabrication technologies offer new opportunities to develop tools that support the visualization and understanding of complex biological materials. This contribution presents a comprehensive methodological framework for generating anatomically representative, species-specific 3D models of wood microstructure, intended to enhance student comprehension in wood science and related fields. The workflow integrates micro-X-ray computed tomography (micro-CT) scanning, image segmentation, STL model preparation, and additive manufacturing. Using micro-CT, we captured high-resolution, non-destructive 3D datasets of four wood species—European beech (Fagus sylvatica), oak (Quercus robur L.), Norway spruce (Picea abies), and Scots pine (Pinus sylvestris). The resulting volumetric data were processed with dedicated software to isolate and reconstruct key anatomical features, which were subsequently converted into printable STL models. These models were fabricated at a 1:400 scale using filaments composed of 40% wood particles and 60% biodegradable polylactic acid (PLA), underscoring the relevance of sustainable materials in educational tool development. The primary aim of this work is to document and justify each stage of the technological process, thereby providing a replicable pathway for producing detailed, pedagogically useful representations of wood microstructure. The resulting models are publicly available on the Sketchfab platform as part of the “3D Wood Micro Structure Collection.” Full article

Field-Programmable Gate Array (FPGA) technology allows for the creation of unique hardware implementations based on mass-produced chips. The process of project prototyping for such systems using Hardware Description Languages (HDLs) remains complex, even with modern tools. The comparison of HDL coding styles, for example, a behavioral case statement against a structural binary-tree decomposition, shows that the choice is capable of affecting post-implementation timing and area. The performed study, using the open-source yosys/nextpnr toolchain, shows that the validity of such a comparison is decided by the fabric domain. Logic that falls through to generic Look-Up Table (LUT) mapping is governed by the mapper’s heuristic fixed point rather than by source intent: on the crossbar, the behavioral and structural netlists become identical in cell composition; on the priority encoder, the verdict reverses; and on the barrel shifter, the LUT area collapses, so the comparison does not isolate the coding-style variable. It was measured that the keep_hierarchy attribute restores a meaningful comparison at ~17% LUT cost (N = 8) and provides a structural invariant to the ABC mapper variant, but the behavioral result is mapper-sensitive and the N = 4 verdict reverses under the legacy -noabc9 mapper (Cohen’s d from +2.4 to −1.6). By contrast, logic that involves a dedicated primitive before LUT mapping—an adder bound to the carry chain or a multiplier bound to a DSP block—yields source-meaningful verdicts that do not reverse with a mapper. Replication on a second fabric (Lattice iCE40) confirms that this behavior is fabric- rather than vendor-specific. The main contribution of this work is the proposed first fabric-domain characterization of synthesis canonicalization as a methodological hazard for cross-HDL FPGA studies on open-source toolchains, which identifies the two-phase synthesis mechanism that delimits it and supplies a decision rule (inspect post-synthesis composition) to identify whether a given comparison is susceptible. Full article

Background/Objectives: The genes encoding HSPA1A, HSPA1B, and HSPA1L, located in the MHC class III region at 6p21.3–22.1, a region implicated in susceptibility to schizophrenia, are critical regulators of neurodevelopmental processes and contribute to synaptic neuroprotection. This study investigated whether the HSPA1A, HSPA1B, and HSPA1L genes are associated with schizophrenia. Methods: We sequenced the coding regions of HSPA1A, HSPA1B, and HSPA1L from 100 patients with schizophrenia to identify genetic variants. Further, we conducted a genetic association analysis of three SNPs (rs9469057, rs142416335, and rs2075800) in the HSPA1L gene in 519 patients with schizophrenia and 1492 healthy controls from the Taiwan Biobank. We analyzed the function of the HSPA1L protein via immunoblotting. Results: We identified 17 coding variants, including 8 missense and 9 synonymous mutations, in 100 patients with schizophrenia. Three variants (HSPA1L^p.Ala8Pro, HSPA1L^p.Ala8Thr, and HSPA1L^p.Glu602Lys) in the HSPA1L gene did not exhibit any significant differences in allele or genotype frequencies between patients and control subjects. Notably, one ultra-rare missense mutation, HSPA1L^p.Val262Met, was not documented in the control sample in Taiwan BioBank. Immunoblotting revealed HSPA1L^p.Val262Met mutant with decreased protein expression in SH-SY5Y cells compared with the wild type. Conclusions: While common variants in the HSPA1A, HSPA1B, and HSPA1L genes do not seem to be significant genetic risk factors for schizophrenia in this cohort, the ultra-rare mutation, HSPA1L^p.Val262Met, significantly reduces protein expression. These preliminary findings suggest that a potential loss-of-function or reduced expression of the HSPA1L gene may be a predisposing factor contributing to schizophrenia vulnerability in certain individuals. However, the finding should be replicated in other independent samples. The in vitro and in vivo impacts of the associated mutation at the HSPA1L gene on the pathophysiology of schizophrenia are worthy of future investigation. Full article

Precision glass molding is an economical and resource-efficient method for manufacturing precision optics in a replicative way, offering advantages over conventional manufacturing methods, particularly for complex geometries. However, challenges arise due to different thermal expansion coefficients between the mold and the glass, which lead to shape deviations during the cooling process and require high compensation efforts. This study investigates the machining behavior during ultra-precision grinding of an innovative MAX phase composite whose coefficient of thermal expansion can be specifically adapted to that of glass. The aim is to evaluate the influences of varying process parameters and material configurations on surface integrity and the suitability of ultra-precision grinding for mold manufacturing in the context of precision glass molding. Systematic grinding tests were carried out and complemented by force measurements. The resulting surfaces were characterized using optical measurement technology and atomic force microscopy; in addition, the edge zone was analyzed using transmission electron microscopy. The results confirm the basic suitability of ultra-precision grinding for the MAX phase composite but point to potential subsurface damage that could limit its usability in precision glass molding. Full article

Phosphorus (P) is a vital non-renewable macronutrient that is frequently immobilized by chemical fixation in acidic and calcareous soils. However, the specific transformation processes of different P sources across these different soil types remain poorly understood. A 120-day incubation experiment was conducted in a completely randomized design with three replicates using acidic and calcareous soils from Myanmar to evaluate six treatments: single superphosphate (SSP), diammonium phosphate (DAP), triple superphosphate (TSP), ammonium polyphosphate (APP), calcium phytate (CP), and an unfertilized control (CK). The modified Hedley fractionation method was employed to investigate the dynamic transformation of soil P fractions, the rate of available P transformation, and the relationship between soil transformation and soil P availability under different P-fertilizer sources. In both soils, SSP, DAP, and TSP provided high initial P release (249.7%, 239.9%, and 234.1%) in acidic soil and (159.5%, 170.8%, and 161.4%) calcareous soil, which peaked on day 10 compared to CK (p < 0.001) before rapidly declining. P transformation in calcareous soil declined more sharply than in acidic soil from the 10th day to the 15th day (especially in SSP and TSP, −11.3 and −16.9 mg kg⁻¹), indicating a higher rate of P immobilization in calcareous soil. Conversely, the delayed peak of APP (day 60) and the stability of CP indicate resistance to immediate soil fixation. Notably, overall effectiveness depended on soil type: SSP performed best in acidic soil and DAP in calcareous soil. Full article

Façades play a decisive role in shaping the visual and symbolic character of historic urban environments. Recent European funding schemes promoting energy-efficient retrofitting have accelerated interventions on building envelopes. Although aligned with decarbonization objectives, these processes are generating significant chromatic and material transformations that risk eroding the visual coherence and cultural sustainability of consolidated urban areas. In the historic Ensanches of San Sebastián, the replacement of traditional envelope systems with new cladding solutions is leading to the loss of the architectural style of some facades and altering their materials, textures, and colors. A progressive “contagion effect” has been identified, whereby dissonant chromatic schemes—often associated with the proliferation of so-called “zebra blocks”, residential buildings with façades clad in alternating black and white stripes that have proliferated in recent urban developments—are replicated across adjacent buildings, gradually weakening spatial continuity and the genius loci of the neighborhood. In response to this phenomenon, this research develops a systematic methodology to analyze, quantify, and anticipate chromatic transformation in consolidated urban fabrics. The study combines historical morphological analysis, classification of architectural periods, and chromatic mapping of recent façade interventions. Based on this framework, a CARI, Chromatic Alteration Risk Index is proposed to evaluate the potential impact of façade alterations on urban chromatic coherence. Drawing on an epidemiological framework, the methodology enables the identification of critical transformation clusters, the assessment of contagion dynamics, and the definition of regulatory thresholds for color and material interventions. By integrating perceptual criteria, urban morphology, and spatial distribution patterns, the study moves beyond descriptive diagnosis and offers a transferable tool for municipal planning. The proposed approach supports the proactive regulation of façade rehabilitation processes, balancing energy efficiency objectives with the preservation of collective memory, material identity, and urban sensory quality. This study proposes a quantitative model of “urban chromatic contagion” to assess how façade color interventions propagate within a neighborhood. We define the Chromatic Integration Percentage (CIP) and the Chromatic Alteration Risk Index (CARI) of the analyzed area. Results indicate that poorly regulated façades show higher chromatic dissonance (low CIP) and act as contagion hotspots, while a clear risk gradient emerges: highly protected buildings present lower risk, whereas mixed typologies and recent rehabilitations concentrate higher CARI values. The model supports preventive urban color management by identifying areas at risk before visible alteration. Full article

Micro-structured SAE H13 tool steel inserts for polymer injection molding require accurate replication of sub-millimeter features while retaining adequate densification and heat-treatment response. This study compared two powder-based routes on the same hemispherical insert containing pyramidal features of approximately 0.145 mm base width: hot embossing (HE) of water-atomized SAE H13 powder (supplier d50 = 5.7 µm, irregular morphology) compounded with a commercial M1 binder, and material extrusion (MEX) of a commercial gas-atomized SAE H13 filament processed on a Markforged Metal X. Rheological screening selected a 57:43 vol% powder-to-binder ratio for the in-house HE feedstock, and DSC/TGA measurements defined two-step debinding windows. The best HE conditions were 220 °C, 8 MPa, and 45 min for the in-house mixture, and 210 °C, 8 MPa, and 30 min for the granulated commercial filament; the latter showed a 0.15% linear deviation from the silicone replica diameter among the best-rated samples. Under the tested commercial MEX configuration, the pyramidal features were not resolved because the 0.40 mm deposition line width exceeded the target feature base width, causing the slicer to omit the sub-line-width geometry. The defect populations differed qualitatively: HE specimens showed porosity and local cracking associated with powder morphology and pressureless sintering, whereas MEX specimens showed build-direction-aligned inter-raster voids associated with the toolpath. Microhardness and tensile data are therefore interpreted as process-history-specific results rather than as a direct route ranking, because sintering conditions were not uniform across all specimens. The study defines an experimentally bound process-selection limit for SAE H13 micro-tooling: HE remains preferable for sub-nozzle surface features, whereas MEX remains attractive for macro-scale geometric freedom, if resolution, densification, and post-sintering consolidation are addressed. Full article

Background/Objectives: Patient experience is increasingly recognised as a key dimension of healthcare quality, yet most tools fail to capture its temporal and processual nature, limiting its contribution to system improvement. This study aimed to demonstrate how a biographical approach to patient experience can generate actionable insights for improving care pathways. Specifically, we sought to: (i) identify and characterise distinct types of prehospital care pathways among patients hospitalised for COVID-19; (ii) identify patient-perceived significant events and safety issues; and (iii) generate structured variables to inform a subsequent quantitative phase. Methods: We conducted semi-structured biographical interviews with 31 patients hospitalised for COVID-19 in two French university hospitals. Data were collected using a life-events calendar (LEC), enabling day-by-day reconstruction of symptoms, healthcare contacts, and decision-making processes. Thematic analysis was performed with multidisciplinary triangulation. The qualitative phase identified three pathway types and the key mechanisms underlying each; these patterns were subsequently confirmed in a separate quantitative follow-up study (n = 312) using state sequence analysis. Results: Three distinct pathway types emerged: short (≤3 days), intermediate (4–9 days), and long (≥10 days). Delayed pathways were associated with repeated false-negative tests, underestimation of severity, and silent hypoxaemia. Across all pathways, patient experience suggested critical system-level failures, including diagnostic delays and inadequate escalation of care. Notably, in many cases, hospitalisation was triggered by a relative rather than a healthcare professional. These findings highlight the role of patient and social context as key components of care pathways. Conclusions: When captured longitudinally, patient experience may provide actionable insights into healthcare system functioning, suggesting structural mismatches between clinical trajectories and care responses. The life-events calendar method offers a replicable framework for transforming patient experience data into clinically and organisationally relevant knowledge. Integrating such approaches into healthcare evaluation could enhance patient safety, improve care coordination, and support more responsive care systems beyond COVID-19. Full article

Background/Objectives: DNA-targeting small molecules that induce replication stress represent a promising strategy in anticancer drug development. 1,8-Naphthalimide (NI) derivatives are well-established DNA-intercalating agents, and heterocyclic annulation offers a rational approach to enhancing their potency and tumor selectivity. Here, we report the synthesis and biological evaluation of a novel series of benzofuran-containing naphthalimide derivatives, with particular focus on the lead dinitro-substituted compound 5d. Methods: Cytotoxic activity was assessed using the MTT assay in A549 (p53 wild-type), H1299 (p53-null), and MRC-5 cells. Long-term antiproliferative effects were evaluated by clonogenic survival assay. Cell cycle distribution was analyzed by propidium iodide staining and flow cytometry. Replication stress and DNA damage were quantified by EdU incorporation and γH2AX immunofluorescence, respectively. Apoptosis was assessed by Annexin V/PI staining and caspase-3/7 activation assay. p53 nuclear accumulation and autophagy induction were evaluated by immunofluorescence and Western blot, using LC3 as an autophagic marker. Results: All compounds exhibited cytotoxic activity in the nanomolar range, with 5d emerging as the most potent and selective. Clonogenic survival was significantly reduced, indicating durable suppression of proliferative capacity. Treatment with 5d induced G₁ arrest in A549 cells and the accumulation of H1299 cells in G₂/M, consistent with p53-dependent and p53-independent checkpoint activation, respectively. EdU incorporation was markedly reduced, while γH2AX intensity increased, collectively supporting a replication stress-driven mechanism of DNA damage. Apoptosis was confirmed by increased Annexin V-positive populations and caspase-3/7 activation. LC3 puncta formation and LC3-I/LC3-II conversion were increased, indicating LC3 processing and autophagosome accumulation consistent with the activation of autophagy-related processes. Conclusions: 5d induces a cellular phenotype consistent with replication stress, including reduced EdU incorporation, γH2AX accumulation, cell cycle arrest, and apoptotic cell death in a p53 status-dependent manner. These findings establish benzofuran-annulated naphthalimides as a promising scaffold for the development of anticancer agents that exploit replication stress vulnerabilities in tumor cells. Full article

Purple basil (Ocimum basilicum L.) is a medicinal plant widely recognized for its richness in bioactive compounds; however, its production in semi-arid regions is often constrained by soil and/or irrigation water salinity. Micronutrient fertilization may contribute to plant stress alleviation under salinity, since elements such as Mn, Mo, and Zn are involved in essential processes related to photosynthetic metabolism and physiological adjustment. This study aimed to evaluate the short-term effects of Mn, Mo, Zn, and their combinations on growth, gas exchange, and relative chlorophyll indices of purple basil plants subjected to severe NaCl stress under greenhouse conditions. The experiment was conducted under greenhouse conditions for 30 days in a randomized block design with nine treatments and four replicates: a non-saline control without micronutrients, a saline control without micronutrients, and plants exposed to 100 mM NaCl with substrate application of Mn, Mo, Zn, MoMn, ZnMo, ZnMn, or ZnMoMn. Micronutrient sources were applied to the substrate at 3.5 g kg⁻¹ according to each treatment. Fertilization with Mn, Mo, Zn, and their combinations enhanced plant stress alleviation under salinity compared with the saline control without micronutrients, with positive responses in growth and physiological performance, including increases in chlorophyll indices. The double combinations MoMn, ZnMo, and ZnMn attenuated the effects of NaCl, especially by increasing leaf area. Mn stood out for increasing net photosynthesis and water-use efficiency, whereas Mo and ZnMo were associated with higher relative chlorophyll indices. Although the triple combination ZnMoMn improved some traits compared with the saline control, its lower efficacy relative to selected single or double applications may indicate that the simultaneous supply of the three elements reduced specific synergistic effects, possibly due to nutritional imbalance or antagonistic interactions among micronutrients under severe salinity. Overall, micronutrient fertilization, particularly through specific double combinations, may contribute to short-term mitigation of NaCl-induced stress responses under controlled greenhouse conditions. Full article

High-Mobility Group Box (HMGB) proteins belong to the family of high-mobility proteins characterized by two DNA-binding domains and an unstructured, negatively charged C-terminal domain that modulates DNA–protein and protein–protein interactions. These proteins participate in multiple cellular processes, including DNA replication, transcription, recombination, and repair. The functional activity of HMGB proteins is associated with various physiological and pathological conditions, including malignant tumors and cardiovascular diseases, highlighting the need for strict regulation of their levels and activity to maintain cellular homeostasis. Such regulation can occur at multiple levels, including proteolytic degradation. In recent years, a number of E3 ubiquitin ligases that promote the degradation of HMGB proteins, as well as deubiquitinases (DUBs) that stabilize them by removing ubiquitin tags, have been identified. This review summarizes these enzymes and their proposed roles in controlling the functions of the HMGB family proteins, both through direct interaction with these proteins and via mediator proteins. Full article

The paper proposes a Digital Twin (DTw) framework, constructing a circuit model replicating the pulse transmission and reception processes for devices with high sensitivity to noises, such as wearable ultrasound transducers. The model is suitable to train supervised AI algorithms denoising the noisy ultrasound signal received. The DTw combines the circuit simulations with the AI data processing by training the model with the cleaned pulsed signals and by correcting the noises modeled by ‘white-noise’ voltage generators. Specifically, the voltage outputs of the circuit simulations are used to train the AI models and to test noisy signals for reconstruction. The DTw model is based on the transmission line theory combined with the perturbation impedance approach, supporting human body tissue discrimination based on noises. Two open-source tools are used for the DTw construction, the LTSpice and the Orange Mining tool, which are used for the circuit simulation and for the AI data processing, respectively. The theoretical work proves that the methodology is able to reconstruct correctly, with a good performance in the time domain and the frequency domain, noisy voltage signals, by addressing the analysis on cancer detection by combining circuit, AI and Monte Carlo approaches. Full article