Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts.

Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.

A gray box framework that optimizes a white box logical model using a black box optimizer for simulating cellular responses to perturbations.

Predicting cellular responses to perturbations requires interpretable insights into molecular regulatory dynamics to perform reliable cell fate control, despite the confounding non-linearity of the underlying interactions. There is a growing interest in developing machine learning-based perturbation response prediction models to handle the non-linearity of perturbation data, but their interpretation in terms of molecular regulatory dynamics remains a challenge. Alternatively, for meaningful biological interpretation, logical network models such as Boolean networks are widely used in systems biology to represent intracellular molecular regulation. However, determining the appropriate regulatory logic of large-scale networks remains an obstacle due to the high-dimensional and discontinuous search space. To tackle these challenges, we present a scalable derivative-free optimizer trained by meta-reinforcement learning for Boolean network models. The logical network model optimized by the trained optimizer successfully predicts anti-cancer drug responses of cancer cell lines, while simultaneously providing insight into their underlying molecular regulatory mechanisms.

A Study on the Relationship between Mental Well-Being and Cultural Tourism Guides Based on the Interview Methodology.

The purpose of this study was to find a way for modern tourists to enjoy increased well-being while being provided with high-quality information about cultural assets. In order for tourists to enjoy well-being, cultural tourism guides must provide quality services while using various storytelling techniques. As the number of tourists who are interested in cultural assets and use their leisure time for this purpose increases, quality cultural tourism commentary can be directly connected to the well-being of tourists. Modern tourists can experience richness of life and emotional stability while being provided with cultural tourism commentary services through various storytelling techniques rather than professional knowledge. In order for tourists to effectively experience well-being through cultural tourism commentary, cultural tourism guides need to implement the following effective commentary. First, culture tourism guides should try to have sense of unity with visitors. Second, they should encourage humanistic imagination through related information. Third, they should provide customized explanations for tourists' understanding because tourists consist of various classes and ages. Cultural tourism guides who attract tourists' interest, have appropriate wit, skillful responses to cope with unexpected situations, cheerful laughter, and a loud voice gained satisfaction from many tourists. In modern society, cultural tourism commentators are not limited to simply explaining tourist destinations, but play an important role in satisfying the well-being of modern tourists who seek leisure and emotional stability. The external environment that refers to outdoor atmospherics is also crucial as it influences visitor experiences. In museums, external physical environment factors such as architectural style, positioning of entrances, and exterior décor and signage can be a crucial facet of external ambiance affecting visitor experiences. The external environment (e.g., spacious design, pretty landscape design, outdoor natural surroundings) is a constituent of the tangibility aspect of museum performances. These external environment factors and internal factors together create perceived physical environments that visitors and staff cognitively/emotionally/physiologically respond to. The significance of this study is that various cultural storytelling activities performed by tour guides are examining the possibility of experiencing increased psychological well-being while making tourists as well as themselves aware of the happiness and joy of life.