Search Results (48,032)

With the wide application of Ni-Al high-temperature materials, the research on their performance has increasingly attracted attention. To further advance the development of Ni-Al high-temperature materials, it is necessary to conduct an in-depth analysis of the brittleness mechanism of Ni-Al intermetallic compounds and elucidate the fundamental nature of their brittleness. In this study, the tensile mechanical behavior and microscopic mechanism of single crystals NiAl (B2) and Ni₃Al (L1₂) at different temperatures were systematically studied by molecular dynamics simulations. It is revealed that although the mechanical properties of both NiAl and Ni₃Al degrade with increasing temperature, their deformation mechanisms exhibit fundamental differences. The high-temperature strength of NiAl is attributed to stable plastic flow dominated by 1/2 <111> screw dislocation. The early softening of Ni₃Al is associated with the formation of stacking fault formation, the phase transition to the HCP, and the slip of various incomplete dislocations (e.g., 1/6 <112> Shockley dislocation). Atomic strain analysis shows that regions of high strain exhibit a strong spatial correlation with the phase-transformed domains. This study reveals the distinct deformation mechanism of the two alloy phases at the atomic scale, providing a key theoretical basis for the rational selection of Ni-Al alloy in specific high-temperature applications. Full article

Background/Objectives: Pyrazole carboxamides are widely used as adaptable medicinal-chemistry scaffolds and have been explored as cholinesterase (ChE) inhibitor chemotypes. In this work, we prepared a new series of 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamides 5(a–m) and evaluated their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), supported by structure-based computational analyses. Methods: Thirteen derivatives 5(a–m) were synthesized, fully characterized with analytical techniques (FT-IR, H NMR, and C NMR), and tested in vitro against AChE and BChE, with tacrine (THA) used as the reference inhibitor. Docking calculations were used to examine plausible binding modes. The top-ranked complexes (7XN1–5e and 4BDS–5i) were further examined by 100 ns explicit-solvent molecular dynamics (MD) simulations in Cresset Flare, followed by RMSD/RMSF analysis and contact-persistence profiling. Predicted ADME/Tox. properties were also assessed to identify potential developability issues. Results: The series showed strong ChE inhibition, and several compounds were more potent than THA. Compound 5e (4-nitro) was the most active AChE inhibitor (K_I = 20.86 ± 1.61 nM) compared with THA (K_I = 164.40 ± 20.84 nM). For BChE, the K_I values ranged from 31.21 to 87.07 nM and exceeded the reference compound’s activity. MD trajectories supported stable binding in both systems (10–100 ns mean backbone RMSD: 2.21 ± 0.17 Å for 7XN1–5e; 1.89 ± 0.11 Å for 4BDS–5i). Most fluctuations were confined to flexible regions, while key contacts remained in place, consistent with the docking models. ADME/Tox. predictions suggested moderate lipophilicity but generally low aqueous solubility; all compounds were predicted as non-BBB permeant, and selected liabilities were flagged (e.g., carcinogenicity for 5e/5g/5h/5i; nephrotoxicity for 5f/5g). Conclusions: The 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamide scaffold delivers low-nanomolar ChE inhibition, with docking and MD supporting stable binding modes. Future optimization should prioritize solubility improvement and mitigation of predicted toxicities and metabolic liabilities, especially given the predicted lack of BBB permeability for CNS-directed applications. Full article

In recent years, digital technologies have become increasingly prevalent in the field of heritage protection. In addition to geomatic techniques like laser scanning (LiDAR) and Structure-from-Motion (SfM), geophysical methods, especially Ground-Penetrating Radar (GPR), offer added value for investigating protected buildings and objects. Additionally, chemical analysis (e.g., X-ray fluorescence, XRF) and mineral magnetic methods can be utilized to investigate specific research topics. All these methods are completely non-invasive and leave the heritage site untouched. Furthermore, they are cost-efficient and fast to use. Within this paper, we want to present an integrated study of a medieval sarcophagus in Bamberg Cathedral. The geophysical surveys via GPR and magnetic susceptibility (MS) measurements should answer open questions regarding the construction and internal layout of the sandstone sarcophagus, dated to the Early or High Middle Ages. The susceptibility data indicated an inner lead coffin in the lower part behind the stone slabs due to an unusual diamagnetic response in these parts. In contrast, the GPR data gave no such indication and revealed that the interior is too small for a direct burial of the bishop. Hence, an additional XRF survey was conducted to help solve this contradiction. The latter data indicate that the lead could be due to remains of a former painting on the sarcophagus with colours containing lead white pigments. Due to the porous sandstone, the moist environmental conditions, and the high weight of the lead elements, these could have accumulated at the bottom of the sarcophagus, creating the diamagnetism detected by the magnetic susceptibility measurements. Full article

Background/Objectives: From birth, infants learn how to interact with the world through exploration. It has been proposed that this early learning phase is driven by motor babbling: the spontaneous generation of exploratory movements that are progressively consolidated through associative mechanisms. This process leads to the acquisition of a repertoire of hand movements such as single- or multi-finger flexion, extension, touching, and pushing. Later, in a second phase, some of these movements (e.g., those that happen to enable access to biologically salient stimuli, such as grasping food) are further reinforced and consolidated through rewards obtained from the environment. However, the neural mechanisms underlying these processes remain unclear. Here, we used a fully neuroanatomically and neurophysiologically constrained neural network model to investigate the brain correlates of these processes. Methods: The model consists of six neural maps simulating six human brain areas, including three pre-central (motor-related) and three post-central (sensory-related) regions. Each map is composed of excitatory and inhibitory spiking neurons, with biologically constrained within- and between-area connectivity forming recurrent circuits. Hand action execution and corresponding haptic perception are simulated simply as activity in primary motor and somatosensory model areas, respectively. During an initial “exploratory” phase, the network learned, via Hebbian mechanisms, associations—as emerging distributed cell assembly (CA) circuits—linking “motor” to corresponding “haptic feedback” patterns. As a result of this initial training, the model began to exhibit spontaneous ignitions of these CA circuits, an emergent phenomenon taken to represent internally generated, non-stimulus-driven attempts at hand action exploitation. In a second phase, a global reward signal, simulating dopamine-mediated reward encoding, was applied to only a subset of “successful” actions upon their noise-driven ignition. Results: During the first exploratory phase, the neural architecture autonomously developed “action-perception” circuits corresponding to multiple possible hand actions. During the subsequent exploitation phase, positively reinforced circuits increased in size and, consequently, in frequency of spontaneous ignition, when compared to non-rewarded “actions”. Conclusions: These results provide a mechanistic account, at the cortical-circuit level, of the early acquisition of hand actions, of their subsequent consolidation, and of the spontaneous transition of an agent’s behavior from exploration to reward-seeking, as typically observed in humans and animals during development. Full article

Hemostasis and thrombosis reflect a delicate balance, regulated by the interplay between procoagulant and anticoagulant mechanisms. Hemophilia is traditionally viewed as a bleeding disorder, but emerging evidence highlights the paradoxical risks of thrombosis in hemophilia patients. We explore the landscape of hemophilia management, emphasizing challenges of balancing hemostasis in the context of aging, novel non-factor replacement therapies (NRTs), and comorbidity-driven thrombotic complications. Therapeutic approaches, including innovative NRTs, such as emicizumab, or rebalancing agents (e.g., concizumab, marstacimab, fitusiran), offer promising advancements in bleeding prophylaxis but may increase thrombotic risks. Conversely, novel anticoagulants, such as FXI inhibitors, offer potential thrombosis protection with minimal bleeding risk. Our review examines the impact of aging-related comorbidities, including cardiovascular disease, atrial fibrillation, HIV-associated complications, and acute coronary syndromes, on thrombotic risk in hemophilia patients. Evidence-based strategies for balancing hemostasis and thrombosis are outlined alongside experimental models, thrombin generation assays, and advancements in rebalancing coagulation through natural anticoagulant modulation. FXI inhibition emerges as a paradigm shift in thrombosis management, offering reduced bleeding risks while preserving vascular health. Finally, this review highlights the need for global laboratory assays to personalize treatments, emphasizing strategies to optimize safety and efficacy, particularly as hemophilia patients live longer with complex comorbidity profiles. Full article

This study systematically investigates cadmium (Cd) accumulation and translocation mechanisms in woody plants through integrated analysis of 16 species. Roots consistently exhibited the highest Cd concentrations (0.26 ± 0.13 mg/kg), serving as primary accumulation sites, while bark functioned as a critical secondary storage organ (0.22 ± 0.09 mg/kg) with strong physiological coordination to roots (r = 0.72, p < 0.001). Leaves demonstrated strict Cd restriction (0.09 ± 0.05 mg/kg) and low variability (CV = 48.7%), indicating evolutionary adaptations to minimize phytotoxicity in photosynthetic tissues. Three functional groups were identified: hyperaccumulators (e.g., Ulmus pumila, root/leaf ratio = 6.37), excluders (e.g., Malus spectabilis, root/leaf ratio = 1.12), and intermediate species (e.g., Syringa oblata) with balanced translocation patterns. Strong root-bark correlations (r = 0.68) and negative stem-leaf associations (r = −0.42) revealed complex interorgan translocation dynamics. Cd speciation analysis showed dominant residual fractions in soils (60–80%) and elevated water-soluble or weakly bound Cd in roots (35–52%). These findings provide a mechanistic basis for designing species-specific phytoremediation strategies, including phytoextraction and ecological stabilization. It will identify suitable tree species for effectively stabilizing or containing the metal pollution within a defined area, thereby preventing its lateral spread or leaching. Full article

The global construction industry faces persistent challenges of low productivity and labor shortages, positioning Off-Site Construction (OSC) as a critical solution. However, standardized industrialization indices for objectively evaluating OSC adoption remain underdeveloped, particularly in emerging markets. This study aims to identify a benchmark policy model and derive design principles for future indices. Specifically, this study focuses on ‘policy-driven markets’ where strong government intervention is essential for initial ecosystem formation, excluding mature market-driven economies where the ecosystem is already established (e.g., USA, Sweden, Japan). To identify an optimal benchmark, a comparative assessment was conducted on five institutional frameworks across four countries (UK, Malaysia, Singapore, and China). Notably, within China, Hong Kong SAR was analyzed as a distinct regulatory jurisdiction separate from Mainland China due to its unique construction governance system. This assessment was based on five key policy dimensions: Legal Mandate, Scope, Indicator Composition, Enforcement Mechanism, and Sustainability. The analysis identified Singapore’s ‘Buildability Score’ as the most comprehensive model in terms of systemic completeness and practical efficacy. A virtual project simulation demonstrated that the scoring system functions as a powerful regulatory mechanism, effectively driving the adoption of standardized, dry-process, and modularized high-productivity methods from the earliest design stages. While Singapore’s system serves as an effective policy tool for OSC proliferation, it exhibits clear limitations regarding reduced architectural design flexibility and insufficient sustainability integration. Consequently, future industrialization indices must evolve to balance productivity with architectural design diversity and integrate sustainability criteria while reflecting specific regional construction ecosystems. Full article

Metastatic urothelial carcinoma (mUC) is a lethal cancer with limited therapeutic options. Advances in genomic and transcriptomic research have deepened the understanding of mUC biology, leading to the identification of clinically relevant molecular alterations that represent potential actionable targets. This has broadened the treatment landscape of the disease to include novel agents, such as antibody–drug conjugates (e.g., enfortumab vedotin) and targeted therapies, including the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib. Genomic alterations in FGFR3 are well-established oncogenic drivers in bladder cancer and represent predictive biomarkers of response to FGFR-targeted therapies. The phase III THOR trial demonstrated the clinical benefit of erdafitinib in previously treated mUC patients harboring FGFR3 alterations and supported its subsequent approval by the European Medicines Agency. In this context, accurate molecular profiling is essential to guide patient selection for FGFR inhibitor therapy. Equally important is the standardization and timely implementation of FGFR3 testing in clinical practice to optimize treatment planning. This review addresses key considerations in FGFR3 testing in mUC and discusses how it can be routinely incorporated into clinical practice. Full article

Osteosarcoma (OS), a highly aggressive bone malignancy, is hard to treat due to complex molecular mechanisms. This study aimed to identify key bioactive compounds from medicine–food homologous (MFH) substances for OS intervention. We analyzed GEO transcriptomic data to get 317 differentially expressed genes (DEGs), screened bioactive compounds from 106 MFH via dual databases, predicted compound–DEG protein interactions with GraphBAN, and filtered 11 core compounds through drug-likeness/toxicity evaluations. Regulatory networks identified 5 key target genes (SOST, ACACB, TACR1, GRIN2B, MPO), 10 key compounds (e.g., ellagic acid dihydrate) and 8 MFHs (e.g., Daidaihua). Molecular docking/MD confirmed stable complexes. GSEA/GSVA revealed pathway dysregulation (e.g., upregulated WNT signaling), and immune analysis showed altered infiltration of 5 cell subsets. 143B cell experiments and qRT-PCR validated findings. MFH-derived compounds, especially ellagic acid dihydrate, have multi-target anti-OS potential, laying a foundation for novel OS therapeutics. Full article

In the “culture of digitality”, new (digital) spaces of opportunity in the contested field of formal and informal learning contexts are constantly emerging, forcing students to orient themselves and take responsibility for selecting information. To deal with the associated challenges (e.g., cognitive overload) this brings, digital skills are required, which can be acquired through various learning and usage practices. The aim of this study is to examine the interplay between students’ individual (digital) learning environments and their (digital) learning and usage practices, which are shaped by the culture of digitality, to derive actionable recommendations for the promotion of digital competencies. Thus, the multivariate results of a quantitative 10-day diary study with 70 students from a German University demonstrate that merely owning digital media is not sufficient to stimulate processes for developing digital competencies. Instead, students need to be encouraged to use these media in a way that actively promotes learning and reflection. Against the backdrop of these findings, there is a discussion about how learning environments can be designed to support and accompany students’ individual digital learning practices. Full article

Free-roaming cats may contribute to zoonotic risk via parasites and other eukaryotic taxa, yet surveillance in protected island settings is limited and conventional coprology can miss low-intensity or degraded signals. We conducted a cross-sectional 18S rRNA metabarcoding survey to establish a baseline profile of potentially pathogenic eukaryotes in community cats from La Graciosa (Natura 2000, Canary Islands, Spain) prior to large-scale antiparasitic interventions. We analysed 152 faecal samples, including fresh samples collected during a high-throughput TNR campaign (n = 37) and dry environmental deposits (n = 115). Host amplification was reduced using a feline 18S blocking primer; libraries were sequenced with Oxford Nanopore technology; and taxonomy was assigned using SILVA-based classifiers with downstream filtering for veterinary/zoonotic relevance. After quality control, 72 eukaryotic taxa were retained and DNA from at least 24 potentially pathogenic taxa was detected. Dipylidium caninum was most frequent (74.3%; 113/152), and opportunistic fungi/yeasts were common (e.g., Pichia kudriavzevii 42.4%, Diutina catenulata 31.5%). Zoonotic protozoa showed low-to-moderate detection frequency (Acanthamoeba castellanii 13.3%, Toxoplasma gondii 7.9%, Balamuthia mandrillaris 4.6%). Overall richness did not differ between fresh and dry samples (p > 0.05), but fresh samples contained higher richness of potentially pathogenic taxa (p < 0.01). Full article

Melatonin, an indolic neuromodulator with putative oncostatic and proposed anti-inflammatory properties, primarily demonstrated in preclinical models, is produced at extrapineal sites—most notably in the gut. Its canonical actions are mediated by high-affinity GPCRs (MT1/MT2) and by NQO2, a cytosolic enzyme with a melatonin-binding site (historically termed “MT3”). A growing body of work highlights a bidirectional interaction between the gut microbiota and host melatonin. We integrated two lines of work: (i) three clinical cohorts—cardiac arrhythmias (n = 111; 46–75 y), epilepsy (n = 77; 20–59 y), and stage III–IV solid cancers (25–79 y)—profiled with stool 16S rRNA sequencing, SCFA measurements, and circulating melatonin/urinary 6-sulfatoxymelatonin and (ii) an age-spanning cognitive cohort with melatonin phenotyping, microbiome analyses, and exploratory immune/metabolite readouts, including a novel observation of melatonin binding on bacterial membranes. Across all three disease cohorts, we observed moderate-to-severe dysbiosis, with reduced alpha-diversity and shifted beta-structure. The core dysbiosis implicated tryptophan-active taxa (Bacteroides/Clostridiales proteolysis and indolic conversions) and depletion of SCFA-forward commensals (e.g., Faecalibacterium, Blautia, Akkermansia, and several Lactobacillus/Bifidobacterium spp.). Synthesised literature indicates that typical human gut commensals rarely secrete measurable melatonin in vitro; rather, their metabolites (SCFAs, lactate, and tryptophan derivatives) regulate host enterochromaffin serotonin/melatonin production. In arrhythmia models, dysbiosis, bile-acid remodelling, and autonomic/inflammatory tone align with melatonin-sensitive antiarrhythmic effects. Epilepsy exhibits circadian seizure patterns and tryptophan–metabolite signatures, with modest and heterogeneous responses to add-on melatonin. Cancer cohorts show broader dysbiosis consistent with melatonin’s oncostatic actions. In the cognitive cohort, the absence of dysbiosis tracked with preserved learning across ages, and exploratory immunohistochemistry suggested melatonin-binding sites on bacterial membranes in ~15–17% of samples. A unifying microbiota–tryptophan–melatonin axis plausibly integrates circadian, electrophysiologic, and immune–oncologic phenotypes. Practical levers include fiber-rich diets (to drive SCFAs), light hygiene, and time-aware therapy, with indication-specific use of melatonin. Our conclusions regarding microbiota–melatonin crosstalk rely primarily on local paracrine effects within the gut mucosa (where melatonin concentrations are 10–400× plasma levels), whereas systemic chronotherapy conclusions depend on circulating melatonin amplitude and phase. This original research article presents primary data from four prospectively enrolled clinical cohorts (total n = 577). Full article

This study investigates the challenge of affordable housing in Riyadh, a city undergoing rapid transformation aligned with Saudi Arabia’s Vision 2030. It aims to bridge the structural gap in the housing market by developing a comprehensive analytical framework that measures housing suitability for emerging middle-income families, linking it to economic, spatial, and behavioral dimensions. The research employs a sequential mixed-methods design. The first phase involved a Multi-Criteria Decision Analysis (MCDA) of 106 residential neighborhoods, constructing a Housing Suitability Index (HSI) based on financing cost (≤SAR 880,000), quality of urban life, and geographical accessibility. The second phase utilized focus groups with 16 participants from real estate developers and new families to explore behavioral drivers and subjective trade-offs. Quantitative results identified “convenience clusters” primarily in the city’s southeastern and southwestern sectors, offering an optimal balance between price and accessibility. Qualitative analysis revealed a significant trust gap and a misalignment of priorities: new families are increasingly willing to sacrifice unit size for central location and construction quality, a preference that conflicts with developers’ strategies focused on luxury units or peripheral projects for higher margins. The study concludes that achieving the 70% homeownership target requires a hybrid policy model, combining supply-side stimuli (e.g., subsidized land) with demand-side management (e.g., progressive mortgages). It recommends integrating the HSI into urban planning to direct investment towards logistically connected areas, fostering sustainable communities. Full article

Background: Superficial venous thrombosis (SVT) is an inflammatory and thrombotic disorder affecting superficial veins. While varicose veins (VVs) are the primary risk factor, SVT occurring in non-varicose veins (NVVs) is a critical clinical finding, often acting as a sentinel marker for severe systemic pathologies. Aims: This review aims at examining incidence, mechanisms, underlying causes, and clinical outcomes of SVT within the NVV population. Materials and Methods: We conducted a comprehensive narrative review of the existing medical literature. Results: SVT in NVVs is frequently associated with systemic conditions, including inherited or acquired thrombophilia, visceral or hematologic malignancies (notably Trousseau’s syndrome), vasculitis (e.g., Behçet’s syndrome), and connective tissue disorders. Specific manifestations like migratory SVT or Mondor’s disease provide crucial diagnostic clues. Notably, NVV-SVT carries a significantly higher risk of recurrence and venous thromboembolic events compared to VV-associated cases. Conclusions: A thorough diagnostic work-up is essential for patients with NVV-SVT to ensure early detection of underlying systemic diseases. Although current management does not differentiate between VV and NVV cases, the increased thromboembolic risk in the latter suggests a need for tailored therapeutic approaches. Further prospective studies are required to evaluate differentiated anticoagulant strategies regarding dosage and duration for this high-risk population. Full article

The rapid rise in atmospheric CO₂ necessitates strategies for mitigation and valorization. Microalgae offer potential through simultaneous CO₂ capture and production of high-value biomolecules. Five Chlorophyta strains (A–E: Micractinium sp., Chlamydomonas sp., Micractinium sp., Chlorococcum sp., and Chlorella vulgaris) were isolated from temperate waters and soils and tested for growth and biochemical responses under controlled nitrogen availability (low: 0.346 g L⁻¹ nitrate; high: 0.6 g L⁻¹ nitrate + ammonia), carbon supply (low: 0.04% CO₂; high: 4% CO₂), and cultivation systems (batch reactors, fermenters, and varied illumination). Over 14 days, maximum dry biomass was achieved in batch cultivation with CO₂ sparging, low nitrogen, and continuous light, ranging from 1.47 g L⁻¹ (strain A) to 2.67 g L⁻¹ (strain D). Biomass composition varied: proteins, 25–45%; carbohydrates, 20–35%; and lipids, 18–28%. Nitrogen limitation promoted lipid accumulation (e.g., strain D: +40%) with concurrent protein decline (−25%). Chlorophyll a/b displayed strain-specific plasticity; high CO₂ generally increased chlorophyll, while nitrogen stress reduced it up to 50%. Overall, this study demonstrates that locally adapted Chlorophyta strains can achieve high biomass productivity under CO₂ enrichment while allowing for flexible redirection of carbon flux toward lipids, carbohydrates, or pigments through nutrient management. Among the tested isolates, strains D and E emerged as the most promising candidates for integrated CO₂ sequestration and biomass production, while strains B, C, and D showed strong potential for biodiesel feedstock; strain A for carbohydrate valorization; and strain E for chlorophyll extraction. Future research should focus on scale-up validation in pilot photobioreactors under continuous operation, optimization of two-stage cultivation strategies for lipid production, integration with industrial CO₂ point sources, and strain improvement using modern genomics-assisted breeding and genome-editing technologies. These efforts will support the translation of regional microalgal resources into scalable carbon-capture and bioproduct platforms. Full article