Design of optimal concentrations for in vitro cytotoxicity experiments.

Concentration-dependent cytotoxicity experiments are frequently used in toxicology. Although it has been reported that an adequate choice of concentrations improves the quality of the statistical inference substantially, a recent literature review of three major toxicological journals has shown that the corresponding methods are rarely used in toxicological practice. In this study the performance of different sets of concentrations, also called designs, are analyzed, while the overall goal is to promote the advantages of optimal design procedures and to present a user-friendly guideline for planning new cytotoxicity concentration-response experiments.

Auditory distraction, time perception, and the role of age: ERP evidence from a large cohort study.

Cognitive aging is typically associated with a higher susceptibility to distraction by concurrent, but task-irrelevant stimuli. Here, we studied the cognitive sub-processes involved in a sample of 484 healthy adults aged 20-70 years from the Dortmund Vital Study (Clinicaltrials.gov NCT05155397).

Resting-state EEG data before and after cognitive activity across the adult lifespan and a 5-year follow-up.

This dataset consists of 64-channels resting-state EEG recordings of 608 participants aged between 20 and 70 years, 61.8% female, as well as follow-up measurements after approximately 5 years of 208 participants, starting 2021. The EEG was measured for three minutes with eyes open and eyes closed before and after a 2-hour block of cognitive experimental tasks.

A liver digital twin for in silico testing of cellular and inter-cellular mechanisms in regeneration after drug-induced damage.

This communication presents a mathematical mechanism-based model of the regenerating liver after drug-induced pericentral lobule damage resolving tissue microarchitecture. The consequence of alternative hypotheses about the interplay of different cell types on regeneration was simulated. Regeneration dynamics has been quantified by the size of the damage-induced dead cell area, the hepatocyte density and the spatial-temporal profile of the different cell types.

Mild Deficits in Fear Learning: Evidence from Humans and Mice with Cerebellar Cortical Degeneration.

Functional brain imaging studies in humans suggest involvement of the cerebellum in fear conditioning but do not allow conclusions about the functional significance. The main aim of the present study was to examine whether patients with cerebellar degeneration show impaired fear conditioning and whether this is accompanied by alterations in cerebellar cortical activations. To this end, a 2 d differential fear conditioning study was conducted in 20 cerebellar patients and 21 control subjects using a 7 tesla (7 T) MRI system.

Factors Influencing the Total Functional Capacity Score as a Critical Endpoint in Huntington's Disease Research.

: The Total Functional Capacity (TFC) score is commonly used in Huntington's disease (HD) research. The classification separates each disease stage (1-5), e.g.

Risk assessment of parabens in a transcriptomics-based in vitro test.

Parabens have been used for decades as preservatives in food, drugs and cosmetics. The majority however, were banned in 2009 and 2014 leaving only methyl-, ethyl-, propyl-, and butyl-derivates available for subsequent use. Methyl- and propylparaben have been extensively tested in vivo, with no resulting evidence for developmental and reproductive toxicity (DART).

Transcriptome-based prediction of drugs, inhibiting cardiomyogenesis in human induced pluripotent stem cells.

Animal studies for embryotoxicity evaluation of potential therapeutics and environmental factors are complex, costly, and time-consuming. Often, studies are not of human relevance because of species differences. In the present study, we recapitulated the process of cardiomyogenesis in human induced pluripotent stem cells (hiPSCs) by modulation of the Wnt signaling pathway to identify a key cardiomyogenesis gene signature that can be applied to identify compounds and/or stress factors compromising the cardiomyogenesis process.

Cognitive aging at work and in daily life-a narrative review on challenges due to age-related changes in central cognitive functions.

Demographic change is leading to an increasing proportion of older employees in the labor market. At the same time, work activities are becoming more and more complex and require a high degree of flexibility, adaptability, and cognitive performance. Cognitive control mechanism, which is subject to age-related changes and is important in numerous everyday and work activities, plays a special role.

Guidance for statistical design and analysis of toxicological dose-response experiments, based on a comprehensive literature review.

The analysis of dose-response, concentration-response, and time-response relationships is a central component of toxicological research. A major decision with respect to the statistical analysis is whether to consider only the actually measured concentrations or to assume an underlying (parametric) model that allows extrapolation. Recent research suggests the application of modelling approaches for various types of toxicological assays.

Metabolomics-based strategy to assess drug hepatotoxicity and uncover the mechanisms of hepatotoxicity involved.

Toxicity studies, among them hepatotoxicity, are key throughout preclinical stages of drug development to minimise undesired toxic effects that might eventually appear in the course of the clinical use of the new drug. Understanding the mechanism of injury of hepatotoxins is essential to efficiently anticipate their potential risk of toxicity in humans. The use of in vitro models and particularly cultured hepatocytes represents an easy and robust alternative to animal drug hepatotoxicity testing for predicting human risk.

Selective spatial attention in lateralized multi-talker speech perception: EEG correlates and the role of age.

Speech comprehension under dynamic cocktail party conditions requires auditory search for relevant speech content and focusing spatial attention on the target talker. Here, we investigated the development of these cognitive processes in a population of 329 participants aged 20-70 years. We used a multi-talker speech detection and perception task in which pairs of words (each consisting of a cue and a target word) were simultaneously presented from lateralized positions.

Proteome analysis of monocytes implicates altered mitochondrial biology in adults reporting adverse childhood experiences.

The experience of adversity in childhood has been associated with poor health outcomes in adulthood. In search of the biological mechanisms underlying these effects, research so far focused on alterations of DNA methylation or shifts in transcriptomic profiles. The level of protein, however, has been largely neglected.

Using visual speech at the cocktail-party: CNV evidence for early speech extraction in younger and older adults.

The comprehension of spoken language benefits from visual speech information. One reason for this is the temporal lead of mouth and lip movements over the onset of acoustic speech utterance. Here, we investigated EEG event-related potentials preceding acoustic speech, focusing on a fronto-central contingent negative variation (CNV) prior to the onset of acoustic speech.

In vitro/in silico prediction of drug induced steatosis in relation to oral doses and blood concentrations by the Nile Red assay.

The accumulation of lipid droplets in hepatocytes is a key feature of drug-induced liver injury (DILI) and can be induced by a subset of hepatotoxic compounds. In the present study, we optimized and evaluated an in vitro technique based on the fluorescent dye Nile Red, further named Nile Red assay to quantify lipid droplets induced by the exposure to chemicals. The Nile Red assay and a cytotoxicity test (CTB assay) were then performed on cells exposed concentration-dependently to 60 different compounds.

Classification of Developmental Toxicants in a Human iPSC Transcriptomics-Based Test.

Despite the progress made in developmental toxicology, there is a great need for in vitro tests that identify developmental toxicants in relation to human oral doses and blood concentrations. In the present study, we established the hiPSC-based UKK2 in vitro test and analyzed genome-wide expression profiles of 23 known teratogens and 16 non-teratogens. Compounds were analyzed at the maximal plasma concentration () and at 20-fold for a 24 h incubation period in three independent experiments.

Influence of bile acids on the cytotoxicity of chemicals in cultivated human hepatocytes.

Bile acids (BA) are known to influence the susceptibility of hepatocytes to chemicals. We investigated the cytotoxicity of 18 compounds with known hepatotoxicity status and pharmacokinetics in cultivated primary human hepatocytes with and without the addition of a BA mix to the cell culture medium. This BA mix consisted of physiological ratios of the most abundant human BA at a cholestatic sum concentration of 0.

The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds.

An in vitro/in silico method that determines the risk of human drug induced liver injury in relation to oral doses and blood concentrations of drugs was recently introduced. This method utilizes information on the maximal blood concentration (C) for a specific dose of a test compound, which can be estimated using physiologically-based pharmacokinetic modelling, and a cytotoxicity test in cultured human hepatocytes. In the present study, we analyzed if the addition of an assay that measures the inhibition of bile acid export carriers, like BSEP and/or MRP2, to the existing method improves the differentiation of hepatotoxic and non-hepatotoxic compounds.

COVID-19 Pandemic and Personality: Agreeable People Are More Stressed by the Feeling of Missing.

The COVID-19 pandemic and the measures taken to contain it have substantial consequences for many people, resulting in negative effects on individual well-being and mental health. In the current study, we examined whether individual changes in perceived stress relative to pre-pandemic levels depended on differences in behavior, appraisal, and experience of pandemic-related constraints. In addition, we tested whether this potential relationship was moderated by personality traits.

Frontal and parietal EEG alpha asymmetry: a large-scale investigation of short-term reliability on distinct EEG systems.

EEG resting-state alpha asymmetry is one of the most widely investigated forms of functional hemispheric asymmetries in both basic and clinical neuroscience. However, studies yield inconsistent results. One crucial prerequisite to obtain reproducible results is the reliability of the index of interest.

Prenatal exposure to endocrine disrupting chemicals is associated with altered DNA methylation in cord blood.

Prenatal exposure to endocrine disrupting chemicals can interfere with development, and has been associated with social-cognitive functioning and adverse health outcomes later in life. Exposure-associated changes of DNA methylation (DNAm) patterns have been suggested as a possible mediator of this relationship. This study investigated whether prenatal low-dose exposure to polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) is associated with altered DNAm patterns across the genome in a Western urban-industrial population.

Turning to the negative: attention allocation to emotional faces in adolescents with dysregulation profile-an event-related potential study.

Patients with irritability, temper outbursts, hyperactivity and mood swings often meet the dysregulation profile (DP) of the Child Behavior Checklist (CBCL) or the Strengths and Difficulties Questionnaire (SDQ), which have been investigated over the past few decades. While the DP has emerged as a transdiagnostic marker with a negative impact on therapeutic outcome and psychosocial functioning, little is known about its underlying mechanisms such as attention and emotion regulation processes. In this study, we tested whether adolescent psychiatric patients (n = 27) with the SDQ-DP show impaired emotional face processing for task-irrelevant stimuli compared to psychiatric patients without the SDQ-DP (n = 30) and non-clinical adolescents (n = 21).

Towards a systematic use of effect biomarkers in population and occupational biomonitoring.

Effect biomarkers can be used to elucidate relationships between exposure to environmental chemicals and their mixtures with associated health outcomes, but they are often underused, as underlying biological mechanisms are not understood. We aim to provide an overview of available effect biomarkers for monitoring chemical exposures in the general and occupational populations, and highlight their potential in monitoring humans exposed to chemical mixtures. We also discuss the role of the adverse outcome pathway (AOP) framework and physiologically based kinetic and dynamic (PBK/D) modelling to strengthen the understanding of the biological mechanism of effect biomarkers, and in particular for use in regulatory risk assessments.

Comparing in vitro human liver models to in vivo human liver using RNA-Seq.

The liver plays an important role in xenobiotic metabolism and represents a primary target for toxic substances. Many different in vitro cell models have been developed in the past decades. In this study, we used RNA-sequencing (RNA-Seq) to analyze the following human in vitro liver cell models in comparison to human liver tissue: cancer-derived cell lines (HepG2, HepaRG 3D), induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-HLCs), cancerous human liver-derived assays (hPCLiS, human precision cut liver slices), non-cancerous human liver-derived assays (PHH, primary human hepatocytes) and 3D liver microtissues.