Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action

This read-across case study characterises thirteen, structurally similar carboxylic acids demonstrating the application of in vitro and in silico human-based new approach methods, to determine biological similarity. Based on data from in vivo animal studies, the read-across hypothesis is that all analogues are steatotic and so should be considered hazardous. Transcriptomic analysis to determine differentially expressed genes (DEGs) in hepatocytes served as first tier testing to confirm a common mode-of-action and identify differences in the potency of the analogues. An adverse outcome pathway (AOP) network for hepatic steatosis, informed the design of an in vitro testing battery, targeting AOP relevant MIEs and KEs, and Dempster-Shafer decision theory was used to systematically quantify uncertainty and to define the minimal testing scope. The case study shows that the read-across hypothesis is the critical core to designing a robust, NAM-based testing strategy. By summarising the current mechanistic understanding, an AOP enables the selection of NAMs covering MIEs, early KEs, and late KEs. Experimental coverage of the AOP in this way is vital since MIEs and early KEs alone are not confirmatory of progression to the AO. This strategy exemplifies the workflow previously published by the EUTOXRISK project driving a paradigm shift towards NAM-based NGRA.Toxicolog

The origins and spread of domestic horses from the Western Eurasian steppes

Domestication of horses fundamentally transformed long-range mobility and warfare. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling at Botai, Central Asia around 3500 bc. Other longstanding candidate regions for horse domestication, such as Iberia and Anatolia, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc driving the spread of Indo-European languages. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture

Construção do "Habitat-Ação" saudável por meio de fundamentação teórico-metodológica do campo da semiologia do ambiente construído The construction of the healthy "Habitat-Action" through a theoretical-methodological framework from the field of the semiotics of the built environment

O artigo apresenta o processo de como se dá a qualidade do ambiente construído e as inter-relações com o seu entorno. Inicia-se com a reflexão sobre o campo da promoção da saúde, habitação saudável e conceitos correlatos. Em seguida, são introduzidas questões fundamentais para o desenvolvimento de propostas sociais de habitats saudáveis. Um caminho possível de aprofundamento teórico-metodológico desse campo dá-se por meio da Semiologia do Ambiente Construído, como ferramenta para a análise dos aspectos da habitabilidade. Aspectos fundamentais para construção de espacialidades saudáveis. Construção que se torna possível por meio da elaboração de políticas públicas saudáveis e da utilização de uma linguagem analítica para o ambiente construído. Ambas importantes no processo de desenvolvimento local, integrado e sustentável, adicionadas e incorporadas ao conceito e à prática metodológica da habitação saudável, campo intersetorial da promoção da saúde, habitação e meio ambiente.<br>This article approaches how the quality of the built environment and the interrelationships to its surroundings occur. It begins with a reflection on the field of health promotion, healthy housing and related concepts. Then it introduces the key issues concerning the development of social proposals for healthy habitats. One possible way of furthering the theoretical and methodological framework in this field is by using the Semiotics of the Built Environment as a tool to examine aspects of habitability. Fundamental aspects for building healthy spatialities. A construction that is made possible through the development of healthy public policies and through the use of an analytic language for the built environment. Both are important in the local, integrated and sustainable process of development, added and incorporated into the concept and methodological practice of healthy housing, which is an intersectoral field of health promotion, housing and environment