Genome-scale metabolic modelling of extremophiles and its applications in astrobiological environments.

Metabolic modelling approaches have become the powerful tools in modern biology. These mathematical models are widely used to predict metabolic phenotypes of the organisms or communities of interest, and to identify metabolic targets in metabolic engineering. Apart from a broad range of industrial applications, the possibility of using metabolic modelling in the contexts of astrobiology are poorly explored. In this mini-review, we consolidated the concepts and related applications of applying metabolic modelling in studying organisms in space-related environments, specifically the extremophilic microbes. We recapitulated the current state of the art in metabolic modelling approaches and their advantages in the astrobiological context. Our review encompassed the applications of metabolic modelling in the theoretical investigation of the origin of life within prebiotic environments, as well as the compilation of existing uses of genome-scale metabolic models of extremophiles. Furthermore, we emphasize the current challenges associated with applying this technique in extreme environments, and conclude this review by discussing the potential implementation of metabolic models to explore theoretically optimal metabolic networks under various space conditions. Through this mini-review, our aim is to highlight the potential of metabolic modelling in advancing the study of astrobiology.

Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-ß1 Expression in Pleural Mesothelioma.

We previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A in PM using an siRNA approach in PM cell lines (ACC Meso-1 and Mero82) and primary culture. The knockdown of CUL4B and CUL4A resulted in significantly reduced colony formation, increased cell death, and delayed cell proliferation. Furthermore, similar to the effect of CUL4A knockdown, downregulation of CUL4B led to reduced expression of Hippo pathway genes including YAP1, CTGF, and survivin. Interestingly, CUL4B and not CUL4A knockdown reduced TGF-ß1 and MMP2 expression, suggesting a unique association of CUL4B with this pathway. However, the treatment of PM cells with exogenous TGF-ß1 following CUL4B knockdown did not rescue PM cell growth. We further analyzed ACC Meso-1 xenograft tumor tissues treated with the cullin inhibitor, pevonedistat, which targets protein neddylation, and observed the downregulation of human TGF-ß1 and MMP2. In summary, our data suggest that CUL4B overexpression is important for tumor cell growth and survival and may drive PM aggressiveness via the regulation of TGF-ß1 expression and, furthermore, reveal a new mechanism of action of pevonedistat.