Exploring experiences of the regulatory toxicology system: system-level promoters and inhibitors of new approach methodologies.

The transition from traditional animal-based approaches and assessments to New Approach Methodologies (NAMs) marks a scientific revolution in regulatory toxicology, with the potential of enhancing human and environmental protection. However, implementing the effective use of NAMs in regulatory toxicology has proven to be challenging, and so far, efforts to facilitate this change frequently focus on singular technical, psychological or economic inhibitors. This article takes a system-thinking approach to these challenges, a holistic framework for describing interactive relationships between the components of a system of interest.

[Area-level socioeconomic deprivation, socioeconomic status, and depressive symptoms: a multilevel analysis using data from the GEDA 2019/2020 study].

Background: The prevalence of mental disorders in Germany is associated with socioeconomic position. International studies further indicate area-level correlations linking higher levels of socioeconomic deprivation with increased mental health burdens. However, these area-level associations have not yet been systematically examined in Germany and it is unclear whether socioeconomic disparities in mental health outcomes are contingent upon area-level socioeconomic deprivation.

Dynamic association of H3K36me3 with pericentromeric heterochromatin regulates its replication time.

The flexibility of the spatio-temporal genome replication program during development and disease highlights the regulatory role of plastic epigenetic mechanisms over genetic determinants. Histone post-translational modifications are broadly implicated in replication timing control, yet the specific mechanisms through which individual histone marks influence replication dynamics, particularly in heterochromatin, remain unclear. Here, we demonstrate that H3K36me3 dynamically enriches at pericentromeric heterochromatin, composed of major satellite DNA repeats, prior to replication during mid S phase in mouse embryonic stem cells.

Streptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes.

The sensing of Gram-negative Extracellular Vesicles (EVs) by the innate immune system has been extensively studied in the past decade. In contrast, recognition of Gram-positive EVs by innate immune cells remains poorly understood. Comparative genome-wide transcriptional analysis in human monocytes uncovered that S.

Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer.

Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer.

Meconium obstruction of prematurity in tiny babies - towards developing an international consensus.

Intestinal perforation occurring in extremely low gestational age neonates is a devastating complication, associated with high mortality and morbidity. Multiple phenotypes of bowel perforation in premature infants have been described, with the most common being spontaneous, or isolated, intestinal perforation and perforated necrotizing enterocolitis. The purpose of this article is to summarize literature describing "meconium obstruction of prematurity", increasingly recognized as a distinct clinical phenotype in the smallest and most immature neonates.

Metatranscriptomics-based metabolic modeling of patient-specific urinary microbiome during infection.

Urinary tract infections (UTIs) are among the most common bacterial infections and are increasingly complicated by multidrug resistance (MDR). While Escherichia coli is frequently implicated, the contribution of broader microbial communities remains less understood. Here, we integrate metatranscriptomic sequencing with genome-scale metabolic modeling to characterize active metabolic functions of patient-specific urinary microbiomes during acute UTI.

Economic evaluation of antibody-drug conjugates (ADCs) in patients with breast cancer: systematic review.

Introduction: Metastatic breast cancer (mBC) is a major global health challenge. Antibody-drug conjugates (ADCs), including trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG), offer clinical benefits but are associated with high costs, making cost-effectiveness assessments essential for policy decisions.

Methods: This systematic review analyzed economic evaluations comparing T-DM1, T-DXd, and SG with conventional treatments in breast cancer.

Long-term microgravity experiments reveal a new mechanism for particle aggregation in suspension.

Microgravity experiments on board the International Space Station, combined with particle-resolved direct numerical simulations, were conducted to investigate the long-term flocculation behavior of clay suspensions in saline water in the absence of gravity. After an initial homogenization of the suspensions, different clay compositions were continuously monitored for 99 days, allowing a detailed analysis of aggregate growth through image processing. The results indicate that the onboard oscillations (g-jitter) may have accelerated the aggregation process.

DelGrad: exact event-based gradients for training delays and weights on spiking neuromorphic hardware.

Spiking neural networks (SNNs) inherently rely on the timing of signals for representing and processing information. Augmenting SNNs with trainable transmission delays, alongside synaptic weights, has recently shown to increase their accuracy and parameter efficiency. However, existing training methods to optimize such networks rely on discrete time, approximate gradients, and full access to internal variables such as membrane potentials.

Local activity alterations in individuals with autism correlate with neurotransmitter properties and ketamine-induced brain changes.

Autism is a neurodevelopmental condition associated with altered resting-state brain function. An increased excitation-inhibition ratio is discussed as a pathomechanism but in-vivo evidence of disturbed neurotransmission underlying functional alterations remains scarce. We compare local resting-state brain activity and neurotransmitter co-localizations between autism (N = 405, N = 395) and neurotypical controls (N = 473, N = 474) in two independent cohorts and correlate them with excitation-inhibition changes induced by glutamatergic (ketamine) and GABAergic (midazolam) medication.

Algae-dominated metaproteomes uncover cellular adaptations to life on the Greenland Ice Sheet.

Eukaryotic algae-dominated microbiomes thrive on the Greenland Ice Sheet (GrIS) in harsh environmental conditions, including low temperatures, high light, and low nutrient availability. Chlorophyte algae bloom on snow, while streptophyte algae dominate bare ice surfaces. Empirical data about the cellular mechanisms responsible for their survival in these extreme conditions are scarce.

Contrasting contribution of resident and repopulated brain macrophages in sustaining sleep-wake circuitry.

Sleep is a complex behavior regulated by various brain cell types. However, the roles of brain-resident macrophages, including microglia and CNS-associated macrophages (CAMs), particularly those derived postnatally, in sleep regulation remain poorly understood. Here, we investigated the effects of resident (embryo-derived) and repopulated (postnatally derived) brain-resident macrophages on the regulation of vigilance states in mice.

Anatomical circuits for flexible spatial mapping by single neurons in posterior parietal cortex.

Primate lateral intraparietal area (LIP) has been directly linked to perceptual categorization and decision-making. However, the intrinsic LIP circuitry that gives rise to the flexible generation of motor responses to sensory instruction remains unclear. Using retrograde tracers, we delineate two distinct operational compartments based on different intrinsic connectivity patterns of dorsal and ventral LIP.

The kinetics of nsp7-11 polyprotein processing and impact on complexation with nsp16 among human coronaviruses.

In coronavirus (CoV) infection, polyproteins (pp1a/pp1ab) are processed into non-structural proteins (nsps), which largely form the replication/transcription complex (RTC). The polyprotein processing and complex formation is critical and offers potential therapeutic targets. However, the interplay of polyprotein processing and RTC-assembly remains poorly understood.

A soft micron accuracy robot design and clinical validation for retinal surgery.

Retinal surgery is one of the most delicate and complex operations, which is close to or even beyond the physiological limitation of the human hand. Robots have demonstrated the ability to filter hand tremors and motion scaling which has a promising output in microsurgery. Here, we present a novel soft micron accuracy robot (SMAR) for retinal surgery and achieve a more precise and safer operation.

Flexible use of multimodal communicative strategies in adult chimpanzees.

Human communication is remarkable for its flexibility, a trait largely reflected in its multimodal nature and shared to some extent with nonhuman primates. Although individual differences in social behaviour are known to have evolutionary implications, their role in shaping primate communication remains largely unexplored. This study adopts a multimodal framework to partition variation in chimpanzees' use of multicomponent and multisensory communicative strategies into socio-environmental, between-individual, and within-individual sources.

Amazon forest resistance to drought is increased by diversity in hydraulic traits.

The unique biodiversity and vast carbon stocks of the Amazon rainforests are essential to the Earth System but are threatened by future water balance changes. Empirical evidence suggests that species and trait diversity may mediate forest drought responses, yet little evidence exists for tropical forest responses. In this simulation study, we identify key axes of trait variation and quantify the extent to which functional trait diversity increases tropical forests' drought resistance.

PPR596 Is Required for nad2 mRNA Splicing and Complex I Biogenesis in Mitochondria of Arabidopsis thaliana.

Several genes in the mitochondria of angiosperms are interrupted by introns, and their posttranscriptional excision involves numerous nucleus-encoded auxiliary factors. Most of these factors are of eukaryotic origin, among them members of the pentatricopeptide-repeat (PPR) family of RNA-binding proteins. This family divides into the PLS and P classes, with PLS-class proteins typically participating in C-to-U mRNA editing and P-class members contributing to transcript stabilization and intron splicing.

Effects of a Patient Decision Aid for Nonmetastatic Prostate Cancer Established in Routine Care: The Randomized Controlled EvEnt-PCA Trial.

Background And Objective: Since 2016, >21 000 patients with prostate cancer (PC) used our personalized online decision aid in routine care in Germany. We analyzed the effects of this online decision aid for men with nonmetastatic PC in a randomized controlled trial.

Methods: In the randomized controlled EvEnt-PCA trial, 116 centers performed 1:1 allocation of 1115 patients with nonmetastatic PC to use an online decision aid (intervention = I) or a printed brochure (control = C).