Integrating Formalin-Fixed, Paraffin-Embedded–Derived Whole-Genome Sequencing into Routine Molecular Pathology

Formalin-fixed, paraffin-embedded (FFPE) tumor tissue is the standard in pathology due to logistical and quality constraints of fresh-frozen samples. Although whole-genome sequencing (WGS) offers diagnostic promise, its validity and utility in FFPE samples remain underexplored. This study bridges the gap by comparing FFPE-derived tumor WGS with next-generation sequencing results from FoundationOneCDx (F1CDx) and a melanoma-specific panel (MelArray) in 78 metastatic melanoma samples from the Swiss Tumor Profiler Study. A diagnostic pipeline was developed for quality control, variant annotation, and clinical actionability using public and commercial databases. FFPE-derived WGS displayed robust analytical validity, detecting 95% of somatic single nucleotide variants, 98% of multinucleotide variants, 90% of insertions/deletions, 76% of amplifications, and 96% of homozygous deletions identified by F1CDx. Tumor mutational burden strongly correlated with F1CDx (R = 0.98), particularly at the clinical threshold of ≥10 mutations per megabase, crucial for treatment decisions. WGS detected complex biomarkers such as UV-associated mutational signatures and genome-wide copy number alterations, aiding melanoma subtype distinction. Clinically, WGS suggested treatments or trials for all cases, identifying additional markers in 38% and 71% compared with F1CDx and MelArray, respectively. Novel therapeutic opportunities were found in 18% and 56% of cases. FFPE-derived WGS closely matches targeted panels in performance while providing comprehensive insights, enhancing therapeutic options. With decreasing costs, WGS could become a powerful routine diagnostic tool.ISSN:1525-1578ISSN:1943-781

Segmentation and finite element analysis in orthopaedic trauma

Background: Finite Element Analysis (FEA) has evolved into a crucial tool in orthopaedic trauma research and clinical practice. This review explores the broad applications of FEA in orthopedic surgery. Main body: FEA involves several steps, including geometry representation, segmentation, 3D rendering, meshing, material property assignment, defining boundary conditions, and specifying contact conditions. The process utilizes patient-specific volumetric data—computed tomography (CT) scan, for example—and aims for a balance between computational efficiency and accuracy. FEA provides valuable outcome measures such as stress distribution, strain quantification, fracture gap motion, failure prediction, and implant stability. These measures aid in evaluating fracture fixation techniques, implant design, and the impact of different fixation strategies. FEA has found applications in femur and proximal humerus fracture fixation, distal femur fracture planning, tibial plateau fractures, and post-traumatic osteoarthritis. It plays a pivotal role in predicting fracture risk, assessing construct stability, and informing surgical decision-making. Additionally, FEA facilitates the development of custom surgical planning and personalized implants. To enhance accuracy, FEA is combined with cadaveric biomechanical analysis, providing a reference-standard representation of in vivo kinematics. Future research should focus on refining FEA models through increased validation using cadaveric models and clinical data. Conclusion: FEA has revolutionized orthopaedic trauma research by offering insights into biomechanics, fracture fixation, and implant design. Integration with cadaveric biomechanical analysis enhances accuracy. Further validation efforts and integration into regular clinical practice are essential for realizing FEA’s full potential in individualized patient care. The combination of FEA and cadaveric analysis contributes to a comprehensive understanding of in vivo kinematics, ultimately improving patient outcomes

Anode-electrolyte interface in lithium-ion batteries investigated by liquid phase transmission electron microcopy: Achievements, challenges, and future directions

The electrochemical performance of lithium-ion batteries (LIBs) is strongly influenced by the complex interactions at the anode-electrolyte interface, which directly affect the battery's efficiency, cycle life, and safety. Liquid-phase transmission electron microscopy (LP-TEM) has become a key technique for in situ observations of the dynamic processes occurring at this interface. Numerous studies have investigated these complex interfacial processes, often complementing each other, occasionally overlapping, and sometimes presenting contradictory findings. In this work, we provide an overview of the key processes occurring at the anode-electrolyte interface, the most widely used LP-TEM setup to study them, and the current state of knowledge derived from these studies. Furthermore, we discuss the existing challenges, highlight areas that require further investigation, and propose future research directions aimed at overcoming these limitations to deepen our understanding of electrochemical mechanisms at the anode-electrolyte interface in LIBs.ISSN:2211-285

Five key concepts linking vacancies, structure, and oxygen evolution reaction activity in cobalt-based electrocatalysts

Focusing on five key concepts, we review the roles of cation and oxygen vacancies in determining the surface reconstruction pathway, reaction mechanism, and ultimate activity of cobalt-based oxygen evolution reaction (OER) electrocatalysts. Cation and oxygen vacancies can initiate reactant adsorption, facilitating active surface reconstruction, and can switch the dominant mechanism from the adsorbate evolution mechanism (AEM) to the lattice oxygen evolution mechanism (LOEM). However, these effects are facet-dependent. Rigorous oxygen vacancy quantification promises to identify the OER mechanism steering thresholds and unlock the full potential of vacancy engineering. Finally, oxygen vacancy quantification strategies are critically examined to facilitate this goal.ISSN:1359-7345ISSN:1364-548

Population pharmacokinetic-pharmacodynamic modeling of co-administered N,N-dimethyltryptamine and harmine in healthy subjects

N,N-dimethyltryptamine (DMT) is a psychedelic compound commonly co-administered with the monoamine oxidase inhibitor harmine in ayahuasca-inspired formulations. However, the impact of harmine on DMT pharmacokinetics (PK) and pharmacodynamics (PD) remains insufficiently characterized. In this single-blind, randomized, two-arm, factorial, dose-finding study, 16 healthy participants (9 males, 7 females) received six combinations of buccal DMT (0–120 mg) and harmine (0–180 mg) via a microcarrier-based transmucosal delivery system. Plasma concentrations and subjective intensity ratings of psychedelic effects were collected and analyzed using nonlinear mixed-effects modeling in NONMEM. A one-compartment model with delayed absorption, incorporating three transit compartments, best described the PK of DMT. Allometric scaling based on body weight improved the model fit, revealing significant interindividual variability in clearance and bioavailability. Harmine markedly enhanced DMT bioavailability and prolonged its absorption, resulting in higher and more sustained plasma concentrations. The relationship between DMT plasma concentrations and subjective drug effect intensity was captured by a sigmoidal maximum effect model, which demonstrated considerable variability in individual sensitivity to psychedelic effects. Model-based simulations showed a clear dose-dependent increase in subjective intensity for both DMT and harmine, with a potentiating effect observed at higher DMT doses when combined with escalating harmine doses. These findings provide a comprehensive population PK/PD framework that elucidates how harmine influences DMT exposure and subjective effects. By quantifying key sources of variability, this work provides a proof-of-concept approach applied to a specific population and dosing regimen, which lays the foundation for more precise, personalized dosing strategies in psychedelic-assisted therapy.ISSN:0753-3322ISSN:1950-600

Quantification of Lower Limb Kinematics During Swimming in Individuals with Spinal Cord Injury

Spinal cord injuries (SCI) often result in impaired motor functions. To quantify these impairments, swimming patterns were analyzed in individuals with SCI. Water provides a unique rehabilitation environment where buoyancy supports weight-bearing activities and can reveal deficits that might otherwise go unnoticed. Data were collected of 30 individuals with chronic, motor-incomplete SCI and 20 healthy controls during breaststroke swimming on a kickboard. Using eight wearable inertial sensors attached to the lower limbs, we captured detailed kinematic data. Spatiotemporal parameters were then calculated and compared between the two groups to assess differences in swimming patterns. An analysis of the parameters revealed significant differences in velocity (p 2 = 0.476) and distance per stroke (p 2 = 0.516), indicating decreased swimming speeds in individuals with SCI compared to controls. Furthermore, individuals with SCI demonstrated a reduced range of motion (RoM) in the ankle (p = 0.003, ε2 = 0.516) and knee joints (p = 0.041, ε2 = 0.142). The limited RoM likely contributes to the shorter distance covered per stroke. These observations underscore the impact of SCI on functional capabilities. The developed algorithm holds promise for enhancing the assessment of motor deficits after neurological injuries.ISSN:1424-822

Impact of grassland management intensity on associations between bacterial, fungal and plant communities

Understanding co-occurrences of different taxa is of both fundamental and applied relevance, for example, to understand ecosystem processes and to design monitoring programs for above- and belowground biodiversity. Plants and microorganisms form complex, interdependent relationships, which are exposed to and may be compromised by agricultural management. Here we assessed the effect of grassland management intensities on bacterial, fungal and plant communities and their associations. We further analyzed the potential of inferring information from taxa of one community on structural changes of the other communities with the aim of potentially enhancing the efficiency of biodiversity assessments by finding common indicator taxa. For that, bacterial, fungal and plant communities as well as environmental factors were assessed in 89 grassland sites of either extensive type (no fertilization, late and infrequent cuttings) or intensive type (fertilization, early and frequent cuttings) of management in the Swiss lowlands. Bacterial, fungal and plant community structures as well as plant indicator values for soil nutrients and moisture differed between management types. Also, community homogeneity was significantly higher for all communities in the intensively managed grassland. For bacterial community structures, this was likely related to a smaller soil pH range in intensively managed grassland, while a lower fungal and plant richness may have caused more homogenous fungal and plant community structures in intensively managed grassland. Further, correlation strength among community structures dropped by 25–66 % from extensively to intensively managed grassland. Finally, indicator analysis suggested that future monitoring programs may use plant taxa to estimate expected effects on fungal communities and vice versa, but bacterial communities require additional assessment. Our results revealed a multifaceted and profound effect of management on bacterial, fungal and plant communities, which reinforces the conservation value of extensively managed grassland.ISSN:1164-5563ISSN:1778-361

Epigenetic priming of mammalian embryonic enhancer elements coordinates developmental gene networks

Background: Embryonic development requires the accurate spatiotemporal execution of cell lineage-specific gene expression programs, which are controlled by transcriptional enhancers. Developmental enhancers adopt a primed chromatin state prior to their activation. How this primed enhancer state is established and maintained and how it affects the regulation of developmental gene networks remains poorly understood. Results: Here, we use comparative multi-omic analyses of human and mouse early embryonic development to identify subsets of postgastrulation lineage-specific enhancers which are epigenetically primed ahead of their activation, marked by the histone modification H3K4me1 within the epiblast. We show that epigenetic priming occurs at lineage-specific enhancers for all three germ layers and that epigenetic priming of enhancers confers lineage-specific regulation of key developmental gene networks. Surprisingly in some cases, lineage-specific enhancers are epigenetically marked already in the zygote, weeks before their activation during lineage specification. Moreover, we outline a generalizable strategy to use naturally occurring human genetic variation to delineate important sequence determinants of primed enhancer function. Conclusions: Our findings identify an evolutionarily conserved program of enhancer priming and begin to dissect the temporal dynamics and mechanisms of its establishment and maintenance during early mammalian development.ISSN:1474-760

The Surface-Topography Challenge: A Multi-Laboratory Benchmark Study to Advance the Characterization of Topography

Surface performance is critically influenced by topography in virtually all real-world applications. The current standard practice is to describe topography using one of a few industry-standard parameters. The most commonly reported number is Ra, the average absolute deviation of the height from the mean line (at some, not necessarily known or specified, lateral length scale). However, other parameters, particularly those that are scale-dependent, influence surface and interfacial properties; for example the local surface slope is critical for visual appearance, friction, and wear. The present Surface-Topography Challenge was launched to raise awareness for the need of a multi-scale description, but also to assess the reliability of different metrology techniques. In the resulting international collaborative effort, 153 scientists and engineers from 64 research groups and companies across 20 countries characterized statistically equivalent samples from two different surfaces: a “rough” and a “smooth” surface. The results of the 2088 measurements constitute the most comprehensive surface description ever compiled. We find wide disagreement across measurements and techniques when the lateral scale of the measurement is ignored. Consensus is established through scale-dependent parameters while removing data that violates an established resolution criterion and deviates from the majority measurements at each length scale. Our findings suggest best practices for characterizing and specifying topography. The public release of the accumulated data and presented analyses enables global reuse for further scientific investigation and benchmarking.ISSN:1023-8883ISSN:1573-271

Differential responses of taxonomic, functional and phylogenetic multi-taxa diversity to environmental factors in temperate forest ecosystems

Accelerated global biodiversity loss critically threatens forest ecosystem multifunctionality and service provision. Understanding environmental drivers across taxonomic (TD), functional (FD), and phylogenetic (PD) biodiversity facets is essential for effective conservation. However, the multi-dimensional nature of biodiversity is difficult to assess, and many studies overlook the interplay between functional traits and evolutionary history within a community. Here, we use Hill numbers to integrate TD, FD, and PD across five ecologically distinct taxa (birds, butterflies, snails, vascular plants, and mosses) to better understand environmental factors driving forest biodiversity in Switzerland. We included micro- and macroclimatic conditions, soil properties, topography, and vegetation structure and diversity. Our results highlight the intricate, taxon-specific nature of environmental effects on biodiversity. Across taxa, vegetation structure and diversity, and climatic factors emerged as key drivers of biodiversity facets, while soil characteristics mostly influenced less-mobile taxa. Vegetation structure and diversity acted as strong ecological filters shaping species richness and traits, reflecting responsiveness to short-term dynamics like disturbance or management, but were weak predictors of PD. Conversely, more temporally stable abiotic factors such as climate and soil conditions were consistent drivers across all facets, highlighting their broad impact on biodiversity. We show that FD and PD metrics complement TD by revealing additional insights into ecosystem functionality and evolutionary history. Given the differential responses of biodiversity indicators to environmental drivers, especially climate, maintaining ecosystem functionality and resilience under climate change requires assessments that go beyond taxonomic diversity and include the functional and phylogenetic dimensions.ISSN:1470-160XISSN:1872-703