Search Results (102,341)

Introduction: Brain metastases represent a major clinical challenge due to a distinct immunosuppressive microenvironment and limited, heterogeneous efficacy of PD-1/PD-L1 immune checkpoint inhibition. The adenosine pathway, mediated by the ectonucleotidases CD39 and CD73, has emerged as an alternative immune escape mechanism, yet its relevance in brain metastases across tumor entities remains insufficiently characterized. Methods: We conducted targeted panel sequencing of brain metastases from multiple primary tumor entities and evaluated compartment-resolved expression of CD39, CD73, and PD-L1 by immunohistochemistry, distinguishing tumor cell and immune cell expression. Tumor mutational burden (TMB), recurrent gene alterations, and gene fusions were analyzed and integrated with immune marker profiles to define immunogenomic subtypes. Results: Brain metastases displayed a heterogeneous mutational landscape with recurrent alterations including TP53, KRAS, PIK3CA, and APC. CD39 and CD73 expression was frequent and highly variable, occurring on both tumor cells and tumor-infiltrating immune cells, and only partially overlapping with PD-L1 expression. A substantial subset of cases exhibited an adenosine-high phenotype despite low or absent PD-L1. Marker-associated enrichment analyses identified distinct genetic correlates, including enrichment of KRAS alterations in tumors with CD39/CD73 positivity on malignant cells, and APC/PIK3CA-associated patterns linked to immune compartment marker expression. TMB did not significantly differ across major tumor entity groups. Gene fusions were detected in a subset of tumors but were largely independent of immune phenotypes. Conclusions: Adenosine pathway activation is a frequent, genetically associated immune escape feature of brain metastases that complements PD-L1-based stratification. Integrating CD39/CD73 with PD-L1 enables actionable immunogenomic subtyping and supports rational immunotherapy strategies targeting adenosine-mediated immunosuppression. Full article

Complex products and production processes are intertwined and demand expressive, lifecycle-wide digital representations. The Asset Administration Shell emerged as a standard for Digital Twins (DTs), structuring heterogeneous data across cloud-based Industrial Internet of Things (IIoT) infrastructures. However, today’s deployments predominantly realize passive or reactive DTs, while intelligent behavior remains underexploited. This paper addresses this gap, proposing an end-to-end architecture operationalizing the DT Reference Model through the integration of machine-interpretable granulated industrial skills, which are semantically accumulated into a knowledge graph enabling discovery and reasoning, while a multi-agent system provides autonomous, utility-based negotiation via machine-to-machine interactions within a federated marketplace. The approach is applied in a real smart manufacturing demonstrator, combining order processes, production orchestration, and lifecycle documentation into a unified execution pipeline spanning IIoT-connected shopfloor assets and cloud-based services. Quantitative experiments evaluating negotiation latency, renegotiation robustness, and utility variation demonstrate stable, predictable behavior even under concurrent demand and failure scenarios. The architecture lays a foundation for interoperable, sovereign collaboration across value chains to realize shared production. The results underline the effectiveness of the tightly coupled enabler technologies realizing proactive, reconfigurable, and semantically enriched intelligent DTs. Full article

Histone deacetylases (HDACs) 1–3 are key regulators of gene expression and represent important therapeutic targets in cancer, neurodegenerative, and immune disorders. Many potent class I HDAC inhibitors display slow- and tight-binding kinetics, which profoundly influence their efficacy and pharmacodynamics. In particular, their dissociation rate (off-kinetic) is critical, since prolonged target engagement greatly influences drug efficacy in vivo. However, the off-kinetics of HDAC inhibitors are often overlooked in the early stages of drug development. Here, we investigated the dissociation kinetics of tucidinostat, trapoxin A, and TNG260 in comparison to the pan-HDAC inhibitor vorinostat. Using biochemical 100-fold jump dilution assays, NanoBRET assays, and cellular washout experiments, we characterized the dissociation of these compounds from purified proteins and in a cellular context. Tucidinostat showed moderately slow off-kinetics, while the clinical candidate TNG260 demonstrated pronounced tight-binding properties. Trapoxin A displayed remarkable discrepancies between assays, as it showed fast dissociation kinetics in the biochemical assay, but tight-binding properties in a cellular setting. These findings not only address the previously unexplored dissociation kinetics of two clinically relevant inhibitors, but also underscore the importance of comprehensive kinetic profiling of novel HDAC inhibitors in cellular models. Full article

The interface between biomaterials and biological systems is crucial for medical implants and tissue engineering. Surface modifications are a key strategy for controlling interactions. Synthetic glycopolymers offer a versatile toolbox, mimicking the structure and function of natural glycoconjugates like mucins. This review highlights the significance of glycopolymers for targeted surface modifications of established biomaterials, such as silicones and poly(meth)acrylates. Controlled polymerization techniques, like the reversible-addition-fragmentation chain-transfer (RAFT) polymerization, enable the synthesis of well-defined glycopolymer architectures. Glycopolymeric surface functionalization creates tailored interfaces for different biological responses, from preventing protein and cell adhesion to promoting specific cell-type binding. The focus lies on using single, well-characterized polymeric base materials and tuning their surface properties through glycopolymer coatings to achieve various and specific functions. This approach opens new dimensions in the development of advanced biomaterials for applications like contact lenses, drug delivery systems, and biosensors and also possesses potential regulatory advantages by leveraging the safety profiles of existing materials. Full article

Currently, a standardized process reference model specifically tailored for the business continuity management system (BCMS) is absent. Moreover, BCMS processes have not been a primary focus of ongoing research endeavors. This paper aims to fill this research gap by presenting findings from a process mapping study concerning BCMS processes within the most prominent and widely acknowledged standards for business continuity management, alongside insights gleaned from expert interviews. The authors propose a collection of BCMS processes that should comprise a BCMS process reference model intended for implementation at a maturity level tailored to individual organizational needs. It aims to strengthen the resilience of organizations to cyber threats and to optimize the processes for effective management within the disaster management cycle. The study identifies and maps the necessary processes required to build a comprehensive BCMS model. These processes include, among others, risk assessment, business impact analysis, the development of BC strategies and solutions, the creation of BC plans and procedures, incident and emergency management, and periodic reviews and exercises. The relevance of these processes was validated through expert interviews, making a clear distinction between core, management, and support processes. Full article

Chronic kidney disease (CKD) is a major global health burden leading to a loss of kidney function via podocyte damage, a non-regenerative renal cell type. Early detection of podocyte injury is crucial but remains limited, highlighting the need for non-invasive biomarkers. Therefore, we analysed urinary exosomal microRNAs (miRNAs) in relation to podocyte morphology in biopsies from 65 CKD patients, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD) and healthy controls. Global profiling distinguished CKD patients from controls, with miR-606 consistently upregulated and miR-431 downregulated. In podocytopathies, MCD displayed a predominantly suppressed miRNA profile, with miR-141, miR-429, and miR-660 as key candidates, whereas FSGS exhibited elevated miR-181c, miR-3610, miR-663b, miR-4651, and miR-429. Super-resolution morphometry revealed diffuse foot process effacement in MCD and heterogeneous, focally disrupted architecture in FSGS, providing a structural context for the molecular findings. Regression analyses linked these miRNAs to filtration slit density and length, proteinuria, and 25-Hydroxy-vitamin-D3 levels, integrating molecular, structural, and clinical readouts. These results define a coherent miRNA signature of podocyte injury that distinguishes CKD entities and correlates molecular changes with disease severity. Combining urinary exosomal miRNAs with morphometric analysis facilitates early, non-invasive identification of podocyte damage, enabling earlier therapeutic intervention in podocytopathies. Full article

Phage-encoded Shiga toxin (Stx) released by Shiga toxin-producing E. coli (STEC) can kill multiple eukaryotic bacterial predators, including Acanthamoeba castellanii, Tetrahymena thermophila and Caenorhabditis elegans. However, the impact of Stx type, Stx amount, and the serogroup of the E. coli on the effectiveness of this exotoxin are poorly understood. These factors impact the severity of Stx-mediated disease in humans and therefore, by studying their role in modulating predator–prey interactions, we may gain insight into how these virulence factors evolved to contribute to human pathogenicity. Herein, we investigated the effects of these factors on predator killing by measuring the efficiency with which five different hemolytic uremic syndrome (HUS)-causing STEC strains consume and/or kill A. castellanii and C. elegans. These strains express various combinations of Stx types and amounts and O-antigens. We found that variations in Stx types and amounts significantly affect the ability of a given bacterial strain to kill predator A. castellanii and C. elegans, with higher Stx1 titers (HUSEC 31 vs. 19) and the presence of Stx2 alone (HUSEC 20) correlating with significantly greater predator killing. These attributes also affect STEC pathogenicity in humans, suggesting that ecological selective pressures for anti-predator defense inadvertently drive the evolution of strains with higher virulence potential in humans. Full article

Maintaining voltage stability and minimizing power losses for remote marine loads powered by long submarine cables is the challenging context of this paper. Flexible Alternating Current Transmission Systems (FACTS) are well-studied for terrestrial grids. However, their comparative performance and efficiency in the context of high-capacity submarine links remain a gap in the literature. This paper presents a rigorous analysis of the performance of a Unified Power Flow Controller (UPFC), Static Synchronous Series Compensator (SSSC), and Thyristor Controlled Series Capacitor (TCSC). A mathematical framework is developed to introduce the “solution circle” concept, which demonstrates that the series impedance values required to maintain a specific load voltage define a circle in the complex plane. A theoretical analysis is performed, revealing that the UPFC, with its two degrees of freedom, is significantly more efficient because it can select the minimum impedance magnitude on this circle. In contrast, SSSC and TCSC are limited to the reactive axis, which, under certain operating conditions, may not cross the solution circle; therefore, they may not meet the power quality objective. The results of a practical case study show that UPFC requires approximately half the rated power (22.4 MVA) compared to its counterparts (39.4 MVA) to achieve the same control objectives. Full article

Long-fiber thermoplastic (LFT) materials are a versatile category of composite materials that can be directly compounded (LFT-D) in twin screw extruders and compression molded. Originating in the automotive sector, the LFT-D process is becoming increasingly attractive for other industries where low cycle times, lightweight performance and recyclability are required. The purpose of this work is to summarize mechanical properties and findings from the investigations into LFT-D process–microstructure–property relationships and present a design of experiments (DoE) study based on the current state of the art. Primary parameters from LFT-D compounding, screw speed, fiber roving amount and polymer throughput m_p are chosen as DoE factors. Polyamide 6 (PA6) is reinforced with a glass fiber (GF) mass fraction w_f between w_f = 20% and w_f = 60%. Tensile, flexural and impact properties are chosen as DoE output parameters, characterized and discussed in relation to the state of the art. The unique microstructure of LFT-D materials, especially the existence of a charge and flow area as well as the fiber migration, is considered in the discussion. All mechanical properties characterized have a linear relation to w_f. This study demonstrates the interactive relationship between the main factors and w_f, which significantly influences the mechanical properties. This dependence of w_f on the DoE factors is accounted for in advanced response contour plots proposed in this work. Parameter recommendations for the screw speed are reported by ranges of w_f and polymer throughput for the goal of maximum mechanical properties or low coefficient of variations. At w_f < 30% a low screw speed is recommended to improve most mechanical properties as well as the coefficient of variation. Full article

Chronic histiocytic intervillositis (CHI) is a placental lesion characterized by an inflammatory response, significantly influencing maternal and fetal outcomes. This study aims to develop a comprehensive morphologic atlas detailing the localization of fetal and maternal macrophages within the context of CHI. We employed immunohistochemical and multiplexing techniques to analyze placental samples, identifying expression patterns and spatial distribution of key macrophage markers, including CD68, CD163, CD14, and HLA-DR. The results revealed a marked accumulation of activated macrophages in both the intervillous space and villous stroma, with distinct differences in morphology and immunophenotype of fetal Hofbauer cells versus maternal macrophages. Our findings contribute to a better understanding of the immune landscape in CHI and provide a valuable resource for further research into placental immune dynamics. By establishing this morphologic atlas, we aim to enhance diagnostic and therapeutic strategies for affected pregnancies, thereby improving the diagnostic approach and making it more straightforward to recognize CHI histologically. Full article

Intelligence test batteries are a common tool in psychological assessment. Their results can have a large impact on an individual’s life, especially for children and adolescents. Despite this, uncertainty remains as to what extent these results are dependent on the test battery used. Two commonly used intelligence test batteries for children and adolescents in German speaking countries are the WISC-V and the AID 3. This study aimed to investigate the degree of comparability between the two test batteries in terms of their resulting scores, subtest content and test profiles in a mathematically gifted sample. A total of 36 children and adolescents (aged M = 12.89 years, SD = 0.58) completed all subtests of both test batteries. Results revealed that most IQ measures did not differ significantly between the two test batteries for this sample. The correlations of the subtests revealed a structure with four main nodes that was in line with previous factor analytical studies. The standard deviations of the $\tau$-adjusted test scores within test profiles were not significantly different; however, significantly higher ranges were found in the AID 3. Results indicate higher IQ scores on the WISC-V, differential validity for factor structures, and methodological benefits of adaptive testing with the AID 3, particularly in gifted samples. Despite subtest overlaps, composite scores diverge and require individualized interpretation. Full article

Thoracoabdominal aortic aneurysms (TAAAs) are uncommon and usually silent until rupture, causing a substantial burden to the health care system. Aneurysm growth and rupture prediction is mainly based on aneurysm diameter measurement by imaging modalities, meaning that the biology of aneurysm growth is not part of a potentially more adequate surveillance of aortic aneurysm patients. Alternatives or complementary options for aortic aneurysm surveillance are an ongoing, non-addressed open issue of vascular medicine. The application of different biomarkers has been discussed, yet so far, an adequate candidate for aortic aneurysm surveillance, if it comes to the thoracic or thoracoabdominal aorta, preferably without radiation exposure, has not been named. Elastin breakdown, as a component of aortic wall degeneration primarily driven by matrix metalloproteinases (MMPs), is a core element of aneurysm development. Desmosine is an elastin-specific cross-link increasingly studied as a circulating or urinary biomarker of compromised aortic wall integrity and disease activity. Accordingly, this review investigated whether plasma desmosine (pDES), a highly specific marker of elastin degradation, could be used as a non-invasive biomarker for detecting aortic aneurysms and assessing their risk profile. The existing literature of desmosine in fields of aortic pathologies in the acute and chronic setting will be assessed based on the current literature; furthermore, future perspectives of desmosine as a biomarker of aortic pathologies, such as aortic aneurysm dynamics, will be discussed. Full article

Background: In an earlier murine model of myocardial infarction (MI), we showed that CD8 cells and myeloid dendritic cells (mDCs) infiltrate the infarcted myocardium within the first week. However, in humans, the spatial interplay between CD8⁺ T cells and dendritic cells in the spatial context of human myocardial infarction remains underexplored. Objective: In the present study, we applied spatial transcriptomics and functional assays to characterize immune–stromal dynamics in infarcted myocardium and peripheral blood. Methods & Results: Spatial transcriptomics analysis of infarcted human myocardium at days 2 and 6 post-MI, combined with peripheral blood flow cytometry and EPC colony-forming assays, was performed. Cell composition, pathway enrichment, and cell-to-cell communication analyses were conducted to map immune–stromal cells’ dynamics across time points. Spatial mapping identified dynamic shifts in immune, fibroblast, and endothelial populations, with fibroblasts and endothelial cells remaining abundant throughout. CD8⁺ T cells accumulated in ischemic regions while their circulating levels declined. Gene Ontology and pathway analyses of CD8A⁺ transcripts revealed enrichment of proinflammatory and NF-κB survival programs. ITGAX/CD33/THBD⁺ APCs progressively increased within infarct zones, activating antigen-presentation and leukocyte chemotaxis pathways. Early (day 2) APC–endothelial crosstalk showed the strongest predicted recruitment signals for CD8⁺ T cells, which diminished by day 6. Finally, EPC colony-forming capacity showed a tendency for reduction in MI patients and inversely correlated with coronary lesion burden, indicating impaired vascular repair potential. Conclusions: This integrative spatial and functional study demonstrates that APC-driven CD8⁺ recruitment and EPC dysfunction are key features of human MI. Immune–endothelial niches facilitate early cytotoxic T-cell infiltration, while progenitor depletion limits vascular regeneration. These findings provide mechanistic insight into immune–vascular imbalance during infarct healing and highlight potential therapeutic targets to modulate inflammation and restore vascular repair. Full article

Background/Objectives: Staphylococcus epidermidis (RP62A) and Staphylococcus aureus (UAMS-1) are clinically relevant pathogens frequently implicated in implant-associated infections due to their ability to form biofilms. RP62A is typically linked to persistent, chronic, low-grade infections, whereas UAMS-1 is associated with acute, invasive disease. Both strains serve as representative models for chronic and acute periprosthetic joint infections (PJIs). The objective of this study was to examine and compare in vitro biofilm formation by RP62A and UAMS-1 on orthopaedic materials/disc surfaces of defined composition. Methods: In vitro biofilm formation assays were performed using orthopaedic disc surfaces composed of cobalt–chromium alloy (CoCr), titanium alloy (Ti), and polyethylene (PE) after 72 h of incubation. Biofilm biomass was quantified using crystal violet staining, with absorbance measured at OD₅₇₀. A polystyrene (PS) surface served as a control. Additionally, retrieved orthopaedic explant components were used as substrates for in vitro biofilm assays, in which RP62A was incubated for 72 h on the explanted surfaces. Supporting assays on glass slides were conducted to examine strain-specific biofilm-related architecture. Results: In vitro biofilm mass quantification assays showed strong biofilm formation by RP62A across all tested surfaces, with the highest absorbance on CoCr (OD₅₇₀ = 5.80 ± 0.19). Notably, biofilm formation on CoCr was 76% higher compared to PS (p < 0.0001). No significant differences were observed among all three surface discs (p > 0.1). Biofilm formation was highest on PE for UAMS-1 (OD₅₇₀ = 1.29 ± 0.09) and was significantly greater than on Ti (178%, p < 0.001) and CoCr (196%, p < 0.0001). In the in vitro assays performed on retrieved explant components, RP62A showed pronounced biofilm accumulation on polyethylene tibial inserts, particularly in regions of mechanical wear and friction. Supporting assays on glass slides were performed to examine strain-specific surface microstructural, revealing dense network-like structures for RP62A and thinner, discontinuous layers for UAMS-1. Conclusions: RP62A formed dense biofilms in vitro on multiple orthopaedic implant materials and retrieved explant components, consistent with its association with chronic periprosthetic joint infections. Increased biofilm accumulation was observed on mechanically worn polyethylene surfaces. In contrast, UAMS-1 showed lower biofilm formation on metallic disc surfaces, indicating strain- and material-dependent differences. These findings highlight the relevance of implant material selection and surface integrity for strategies targeting biofilm-associated implant infections. Full article

Many biomedical applications rely on the accurate recovery of absorption and scattering properties of human tissue. These characteristics serve as useful diagnostic indicators, holding information regarding the health and physiological status of a human subject. Many experimental methods exist for the determination of these optical properties, though many, such as integrating sphere methods, are not easily used in an in vivo setting. We have constructed and validated a spatially resolved reflectance imaging system that can be used to measure the absolute optical properties of absorbing turbid media in a non-contact, non-invasive fashion. We present detailed calibration procedures that consider our unique incident beam profile and system response with quantitative comparisons between experimentally and computationally obtained reflectance using Monte Carlo methods. Using highly scattering sphere suspensions with added absorption by ink, we show the spatially resolved reflectance imaging system’s ability to recover absorption within 20% of reference collimated transmission measurements and reduced scatter within 6% of those obtained by an extensively tested integrating sphere system, validating our system in preparation for in vivo measurements of the optical properties of human skin. Full article