Yes / The integrin family of cell surface extracellular matrix binding proteins are key to several physiological processes involved in tissue development, as well as cancer proliferation and dissemination. They are therefore attractive targets for drug discovery with cancer and non-cancer applications. We have developed a new integrin antagonist chemotype incorporating a functionalised cyclobutane ring as the central scaffold in an arginine–glycine–aspartic acid mimetic structure. Here, we report the synthesis of cyclobutanecarboxylic acids and cyclobutylamines with tetrahydronaphthyridine and aminopyridine arginine mimetic sidechains and masked carboxylic acid aspartic acid mimetic sidechains of varying length. Effective αvβ3 antagonists and new aspartic acid mimetics were identified in cell-based adhesion and invasion assays. A lead compound selected based on in vitro activity (IC50 < 1 μM), stability (t1/2 > 80 minutes) and synthetic tractability was well-tolerated in vivo. These results show the promise of this synthetic approach for developing αvβ3 antagonists and provide a firm foundation to progress into advanced preclinical evaluation prior to progression towards the clinic. Additionally, they highlight the use of functionalised cyclobutanes as metabolically stable core structures and a straightforward and robust method for their synthesis. This important contribution to the medicinal chemists' toolbox paves the way for increased use of cyclobutanes in drug discovery. / This work was funded by Yorkshire Cancer Research (Award reference number B002-PhD) and Prostate Cancer UK (Pilot Grant PA10-01).

Mass media play an important role in shaping public perceptions about differentthematics, including crime and justice. The consumption of mediatic contents indifferent forms, such as newspapers, television news and crime dramas, can affectthe way people perceive and interpret concepts as deviance and punishments, theattitude towards the criminal system and the level of concern for becoming a victim.In the last years, Streaming Videos On Demand platforms have made easier theaccess and the consumptions of contents as crime dramas; the changes in themodality of fruition have been followed by changes in the representation ofcharacters, with the introduction and the increasing diffusion of morally ambiguousfigures. This opens new possibilities of research, particularly regarding the modesof representation of criminals as antiheroes. The purpose of the article is then toinvestigate how the figure of the offender is constructed as antihero in four OriginalNetflix Productions (You, Narcos, Ozark, La Casa de Papel). A Critical DiscourseAnalysis of two narrative themes is conducted combining Marxist andPostmodernist interpretative approaches.

Soft System Approaches have been developed worldwide to help problem-solvers and decision-makers develop solutions to complex problems, such as aerospace systems. Soft System Approaches were designed to help lower the disorder of developing a complex system by increasing understanding of a situation. Four Soft System Approaches were investigated, two from the West and two from the East. Within the context of the paper, the West refers to thought patterns associated with thinkers and scientists in Europe and North America, and the East refers to those from and around China. The two from the West are Peter Checkland’s Soft Systems Methodology and Fran Ackerman and Colin Eden’s Strategic Options Development and Analysis, and from the East they are Qian Xuesen’s Meta-Synthetic Approach and Jifa Gu and Zhichang Zhu’s Wuli-Shili-Renli Approach. The four approaches were selected due to their prevalence and notoriety within the Soft System Approach research. The Western Soft System Approaches were created as a direct response to reductionism and are more holistic than Hard System Approaches; however, they are classified as systematic due to their structure. The approaches are tools that can be deployed for a specific task. Eastern Soft System Approaches rooted in Eastern philosophy went from holism to reductionism to a unity of the two. There is no one-size-fits-all approach; therefore, approaches that seek to balance reductionism and holism and give guidance and structure while inviting in other methods. The Eastern approaches are classified as framework Soft System Approaches, which provide structure and guidance but not a formula. Systematic approaches are better for determining a course of action, while framework approaches are better for guiding a whole program. The Eastern approaches covered can and do incorporate other methods, including each other. Depending on the problem and problem solver, the systematic or framework approach may be better suited. Overall, however, the framework approach will be able to solve the most varied problems due to the lack of prescriptiveness and the use of other approaches. Knowing the difference between the approaches and how they can be used helps manage the development of complex aerospace systems.