A comparative study of biostatistical pipelines for benchmark concentration modeling of screening assays.

New approach methods (NAMs) have been prioritized to reduce the use of animals for chemical safety assessment while continuing to protect human health and the environment. A key challenge of generating toxicity data is the implementation of a standardized analysis approach for transparent and reproducible benchmark concentration (BMC) estimation and uncertainty quantification for assay developers, regulators, and other stakeholders. In this study, we compared the bioactivity results of 321 chemical samples from four established BMC analysis pipelines used for evaluation of developmental neurotoxicity (DNT) NAMs data: the ToxCast pipeline (tcpl), CRStats, DNT DIVER (Curvep and Hill pipelines).

Neural processing of laughter in depression.

Laughter can convey social intent ranging from acceptance (friendly inclusive laughter) to rejection (malign taunting laughter). We investigated perception of auditory and visual laughter in patients with major depressive disorder (MDD) versus healthy controls (HC). 48 MDD patients and 52 HC rated 60 laughter recordings presented auditorily or visually regarding the expressed social intent during an fMRI experiment at 3T.

Developmental neurotoxicity (DNT): A call for implementation of new approach methodologies for regulatory purposes: Summary of the 5th International Conference on DNT Testing.

The 5th International Conference on Developmental Neurotoxicity (DNT) Testing (DNT5) took place in April 2024 in Konstanz, Germany, organized by CAAT-Europe, the University of Konstanz, and scientists from the US EPA, SCAHT, and CAAT at Johns Hopkins University Bloomberg School of Public Health. The conference convened experts from regulatory agencies, industry, and academia to explore the latest advancements in DNT testing and the integration of animal-free new approach methodologies (NAMs) into next-generation risk assessment (NGRA). The key topic was the appli-cation and further development of the recently established DNT in vitro test battery (DNT-IVB).

Nuclear hormone receptors control fundamental processes of human fetal neurodevelopment: Basis for endocrine disruption assessment.

Despite growing awareness of endocrine disrupting chemicals (EDCs), knowledge gaps remain regarding their effects on human brain development. EDC risk assessment focuses primarily on EATS modalities (estrogens, androgens, thyroid hormones, and steroidogenesis), overlooking the broader range of hormone receptors expressed in the developing brain. This limits the evaluation of chemicals for their potential to cause endocrine disruption-mediated developmental neurotoxicity (ED-DNT).

Bridging imaging-based in vitro methods from biomedical research to regulatory toxicology.

Imaging technologies are being increasingly used in biomedical research and experimental toxicology to gather morphological and functional information from cellular models. There is a concrete opportunity of incorporating imaging-based in vitro methods in international guidelines to respond to regulatory requirements with human relevant data. To translate these methods from R&D to international regulatory acceptance, the community needs to implement test methods under quality management systems, assess inter-laboratory transferability, and demonstrate data reliability and robustness.

Mapping out strategies to further develop human-relevant, new approach methodology (NAM)-based developmental neurotoxicity (DNT) testing.

On occasion of the DNT5 meeting in Konstanz, Germany (April 2024), participants brainstormed on future challenges concerning a regulatory implementation of the developmental neurotoxicity (DNT) in vitro test battery (DNT-IVB). The five discussion topics below outline some of the key issues, opportunities, and research directions for the next several years: (1) How to contextualize DNT hazard with information on potential maternal toxicity or other toxicity domains (non-DNT)? Several approaches on how to use cytotoxicity data from new approach methodologies (NAMs) were dis­cussed. (2) What opportunities exist for an immediate or near-future application of the DNT-IVB, e.

The long way from raw data to NAM-based information: Overview on data layers and processing steps.

Toxicological test methods generate raw data and provide instructions on how to use these to determine a final outcome such as a classification of test compounds as hits or non-hits. The data processing pipeline provided in the test method description is often highly complex. Usually, multiple layers of data, ranging from a machine-generated output to the final hit definition, are considered.

Transcriptomic characterization of 2D and 3D human induced pluripotent stem cell-based in vitro models as New Approach Methodologies for developmental neurotoxicity testing.

The safety and developmental neurotoxicity (DNT) potential of chemicals remain critically understudied due to limitations of current in vivo testing guidelines, which are low throughput, resource-intensive, and hindered by species differences that limit their relevance to human health. To address these issues, robust New Approach Methodologies (NAMs) using deeply characterized cell models are essential. This study presents the comprehensive transcriptomic characterization of two advanced human-induced pluripotent stem cell (hiPSC)-derived models: a 2D adherent and a 3D neurosphere model of human neural progenitor cells (hiNPCs) differentiated up to 21 days.

External Mechanical Stability Regulates Hematoma Vascularization in Bone Healing Rather than Endothelial YAP/TAZ Mechanotransduction.

Bone fracture healing is regulated by mechanobiological cues. Both, extracellular matrix (ECM) deposition and microvascular assembly determine the dynamics of the regenerative processes. Mechanical instability as by inter-fragmentary shear or compression is known to influence early ECM formation and wound healing.

Molecular and Functional Characterization of Different BrainSphere Models for Use in Neurotoxicity Testing on Microelectrode Arrays.

The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs.

20-year Results of a 3D Titanium Mesh Coating Stability of 31 Artificial Cups.

Background: The aim of this work was to demonstrate the bony bond strength and resilience of a three-dimensional titanium mesh coating of an artificial acetabulum produced using the diffusion bonding technique. Under the extreme conditions ranging from abrasion-related osteolysis to acetabular perforation, the degree of residual bone and the integrity of the coating were determined. The remaining zones of the (still) stable bone connection are inevitably exposed to a greater load of the layer adhesion between the titanium mesh and the core shell.

Identifying Challenges, Enabling Practices, and Reviewing Existing Policies Regarding Digital Equity and Digital Divide Toward Smart and Healthy Cities: Protocol for an Integrative Review.

Background: Digital equity denotes that all individuals and communities have equitable access to the information technology required to participate in digital life and can fully capitalize on this technology for their individual and community gain and benefits. Recent research highlighted that COVID-19 heightened the existing structural inequities and further exacerbated the technology-related social divide, especially for racialized communities, including new immigrants, refugees, and ethnic minorities. The intersection of challenges associated with racial identity (eg, racial discrimination and cultural differences), socioeconomic marginalization, and age- and gender-related barriers affects their access to health and social services, education, economic activity, and social life owing to digital inequity.

Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro.

Adverse outcome pathways (AOPs) are organized sequences of key events (KEs) that are triggered by a xenobiotic-induced molecular initiating event (MIE) and summit in an adverse outcome (AO) relevant to human or ecological health. The AOP framework causally connects toxicological mechanistic information with apical endpoints for application in regulatory sciences. AOPs are very useful to link endophenotypic, cellular endpoints in vitro to adverse health effects in vivo.

Corrigendum to TBBPA Targets Converging Key Events of Human Oligodendrocyte Development Resulting in Two Novel AOPs.

In this manuscript, which appeared in ALTEX 38, 215-234 (doi:10.14573/altex.2007201), there was an error in Figure 4.

Progenitor cells derived from gene-engineered human induced pluripotent stem cells as synthetic cancer cell alternatives for in vitro pharmacology.

Limitations in genetic stability and recapitulating accurate physiological disease properties challenge the utility of patient-derived (PD) cancer models for reproducible and translational research. A portfolio of isogenic human induced pluripotent stem cells (hiPSCs) with different pan-cancer relevant oncoprotein signatures followed by differentiation into lineage-committed progenitor cells was genetically engineered. Characterization on molecular and biological level validated successful stable genetic alterations in pluripotency state as well as upon differentiation to prove the functionality of our approach.

Scientific Validation of Human Neurosphere Assays for Developmental Neurotoxicity Evaluation.

There is a call for a paradigm shift in developmental neurotoxicity (DNT) evaluation, which demands the implementation of faster, more cost-efficient, and human-relevant test systems than current guideline studies. Under the umbrella of the Organisation for Economic Co-operation and Development (OECD), a guidance document is currently being prepared that instructs on the regulatory use of a DNT battery (DNT IVB) for fit-for-purpose applications. One crucial issue for OECD application of methods is validation, which for new approach methods (NAMs) requires novel approaches.

Local slow-wave activity over the right prefrontal cortex reveals individual risk preferences.

In everyday life, we have to make decisions under varying degrees of risk. Even though previous research has shown that the manipulation of sleep affects risky decision-making, it remains unknown whether individual, temporally stable neural sleep characteristics relate to individual differences in risk preferences. Here, we collected sleep data under normal conditions in fifty-four healthy adults using a portable high-density EEG at participants' home.

Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs).

Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu).

Different Behavioral Types of Distributional Preferences Are Characterized by Distinct Neural Signatures.

There are many situations where resources are distributed between two parties and where the deciding party has information about the initial distribution and can change its outcome, for example, the allocation of budget for funds or bonuses, where the deciding party might have self-interested motives. Although the neural underpinnings of distributional preferences of resources have been extensively studied, it remains unclear if there are different types of distributional preferences and if these types underlie different disposing neural signatures. We used source-localized resting EEG in combination with a data-driven clustering approach to participants' behavior in a distribution game in order to disentangle the neural sources of the different types of distributional preferences.

Age-related decline in murine heart and skeletal muscle performance is attenuated by reduced Ahnak1 expression.

Background: Aging is associated with a progressive reduction in cellular function leading to poor health and loss of physical performance. Mitochondrial dysfunction is one of the hallmarks of aging; hence, interventions targeting mitochondrial dysfunction have the potential to provide preventive and therapeutic benefits to elderly individuals. Meta-analyses of age-related gene expression profiles showed that the expression of Ahnak1, a protein regulating several signal-transduction pathways including metabolic homeostasis, is increased with age, which is associated with low VO and poor muscle fitness.

Advisory opinion of the AWMF Ad hoc Commission In-vitro Diagnostic Medical Devices regarding in-vitro diagnostic medical devices manufactured and used only within health institutions established in the Union according to Regulation (EU) 2017/746 (IVDR).

In view of the approaching application date of Regulation (EU) 2017/746 ("IVDR") and the resulting EU-wide, harmonized requirements for in-vitro diagnostic medical devices (IVD) manufactured and used within European health institutions, the Ad hoc Commission IVD of the German Association of the Scientific Medical Societies (AWMF) takes a national position on the details of the requirements and conditions related to the use of these IVD products. The Ad hoc Commission IVD emphasizes the relevance of examination procedures developed in medical laboratories, especially in the field of orphan diseases and new diagnostic markers. The IVDR sets an adequate regulatory framework for IVD manufactured and used within health institutions as long as these requirements are fulfilled with reliability and in accordance with the current state of the art in medical laboratory sciences.