Search

In silico toxicology protocols are meant to support computationally-based assessments using principles that ensure that results can be generated, recorded, communicated, archived, and then evaluated in a uniform, consistent, and reproducible manner. We investigated the availability of in silico models to predict the carcinogenic potential of pregabalin using the ten key characteristics of carcinogens as a framework for organizing mechanistic studies. Pregabalin is a single-species carcinogen producing only one type of tumor, hemangiosarcomas in mice via a nongenotoxic mechanism. The overall goal of this exercise is to test the ability of in silico models to predict nongenotoxic carcinogenicity with pregabalin as a case study. The established mode of action (MOA) of pregabalin is triggered by tissue hypoxia, leading to oxidative stress (KC5), chronic inflammation (KC6), and increased cell proliferation (KC10) of endothelial cells. Of these KCs, in silico models are available only for selected endpoints in KC5, limiting the usefulness of computational tools in prediction of pregabalin carcinogenicity. KC1 (electrophilicity), KC2 (genotoxicity), and KC8 (receptor-mediated effects), for which predictive in silico models exist, do not play a role in this mode of action. Confidence in the overall assessments is considered to be medium to high for KCs 1, 2, 5, 6, 7 (immune system effects), 8, and 10 (cell proliferation), largely due to the high-quality experimental data. In order to move away from dependence on animal data, development of reliable in silico models for prediction of oxidative stress, chronic inflammation, immunosuppression, and cell proliferation will be critical for the ability to predict nongenotoxic compound carcinogenicity.

This research demonstrates a method for the repeatable passive fiber optic coupling of single-mode waveguides with a micron-scale accuracy for high-precision disposables. The aim is to broaden the application of photonic integrated circuits (PICs) from traditional fiber optic communication systems to include medical, life science, and environmental sensing applications. The proposed passive coupling system enables the straightforward and reliable interchange of disposable photonic chips without manual read-out unit adjustments. Robustness is attributed to the chip-side grating couplers with 3 dB coupling tolerances exceeding ± 25 µm and a mechanical three-groove kinematic method ensuring precise alignment. The system simplicity is highlighted by the simple manual insertion and fixation of silicon nitride (Si3N4) PICs on a carrier using magnetic force and passive alignment features. Testing on a batch of 99 identical yet independent units revealed a standard deviation (SD) of 5.1 dB in coupling loss, without realignment post-calibration. This eliminates the need for active alignment processes, showing its potential for enabling field use. A usability assessment with five untrained operators confirms the suitability for various end-users, with consistent performance in engaging and disengaging disposable PICs. The research significantly advances the integration of photonic sensor technology into practical applications, particularly for chemical and biological fluid analysis in point-of-care settings.

In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment framework including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches.

Objective Background Method Results Conclusion Implications The aim of this study was to uncover patterns of parental postseparation conflict and to investigate possible links to the personality factors of the Dark Triad (i.e., Machiavellianism, narcissism, and psychopathy).Studies revealed different postseparation coparenting patterns that explain why some parents face long‐lasting conflicts after separation. However, the role of legal disputes and links to parental personality traits have mostly been neglected so far.The analyses included 486 separated parents from the German Family Panel “pairfam” in year 2020–2021. We aimed to identify postseparation patterns of conflict, including coparenting and legal conflict, by using latent profile analysis. Possible links between latent profiles and the Dark Triad were assessed.Three postseparation conflict profiles were found: a cooperative, a parallel‐derogating, and a conflictual profile. Links between these profiles and the Dark Triad could be found for narcissism, with membership to the conflictual profile being more likely with higher narcissism values.The findings show that a significant proportion of separated families is affected by postseparation conflict and that parents' personality plays a role here.The results indicate that interventions targeting families affected by postseparation conflict should take parental personality traits into account. [ABSTRACT FROM AUTHOR]

Successful integrated management of the invasive predatory sea lamprey (Petromyzon marinus) in the Laurentian Great Lakes of North America is owed largely to the long history of beneficial use of two lampricides: 3-trifluoromethyl-4nitrophenol (TFM) and 2',5-dichloro-4'-nitrosalicylanilide (niclosamide). Ensuring continued successful sea lamprey control necessitates consideration of possible next-generation lampricides to supplement or replace current lampricides. This review identifies fifteen hallmarks of success for current lampricides to be used as design criteria in a search for nextgeneration lampricides. A three-stage research approach is outlined. Targeted research using omics, computer modelling, and high-throughput technology to define molecular mechanisms and high probability molecular targets for sea lamprey selective toxic action is crucial to prioritizing chemical candidates. Targeted delivery or identifying synergists to existing or new lampricides can provide increased efficiency and reduced environmental impact. Ultimate development of next-generation lampricides will rely on traditional toxicity testing methodologies to ensure safety and regulatory compliance. Le succes de la gestion integree dans les Grands Lacs laurentiens de l'Amerique du Nord de la lamproie (Petromyzon marinus), un predateur envahissant, est en bonne partie du a l'utilisation efficace et soutenue de deux lampricides, le 3-trifluoromethyl-4-nitrophenol (TFM) et le 2',5-dichloro-4'-nitrosalicylanilide (niclosamide). Le maintien de l'efficacite de la lutte contre la lamproie requiert l'examen d'eventuels lampricides de nouvelle generation comme complements ou en remplacement des lampricides actuels. La presente synthese cerne 15 aspects cles expliquant l'efficacite des lampricides actuels a utiliser comme criteres de conception dans la quete de lampricides de nouvelle generation. Une approche de recherche a trois volets est decrite. Des travaux cibles faisant appel aux sciences omiques, a la modelisation par ordinateur et a des techniques de haute capacite pour definir les mecanismes moleculaires et des cibles moleculaires presentant une forte probabilite d'action toxique selective sur les lamproies sont d'importance cle pour la priorisation de substances chimiques candidates. La livraison ciblee et l'identification d'activateurs pour les lampricides actuels et de nouveaux lampricides peuvent rehausser l'efficacite et reduire l'impact environnemental. A terme, la mise au point de lampricides de nouvelle generation devra avoir recours a des methodes traditionnelles d'essai de toxicite afin d'en assurer l'innocuite et la conformite a la reglementation. [Traduit par la Redaction], 1. Introduction Aquatic nuisance species are a continuing threat to ecosystems and the economic stability of regions centered around those ecosystems (https://www.anstaskforce.gov). One of the most significant invasive species control [...]

Human mesenchymal stem cells (hMSCs) are well-known for their immunomodulatory potential. In recent clinical trials and in vivo studies, hMSCs were used as therapeutic measures to dampen inflammation. In this context, their effect on macrophages in vivo has been described to induce a phenotype change shifting from a proinflammatory to an anti-inflammatory environment. Despite several in vitro studies that investigated the potential of hMSCs to inhibit the polarization of macrophages into the proinflammatory M1 subtype, it is still unclear if hMSCs affect polarized M1 macrophages or if they control the environment by inhibiting the M1 polarization of unpolarized macrophages. Here, a comparative in vitro investigation of hMSC immunomodulation via soluble factors concerning the influence on the polarization of macrophages to M1 and on polarized M1 macrophages is presented. Human primary monocyte-derived macrophages (hMDMs) as well as THP-1 cells were used for this investigation. The macrophage subtype was analyzed by gene expression as well as cytokine secretion. hMSCs affected cytokine secretion of polarizing macrophages, while changes in gene expression were evident in polarized M1 macrophages. These effects were observed in THP-1 and hMDM macrophages. In conclusion, we suggest that hMSCs implement their immunomodulatory effects on polarizing and polarized macrophages in different ways.