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Background: Erectile dysfunction has been associated with leisure sedentary behavior in several epidemiological and observational studies. However, the interpretation of these findings is difficult due to residual confounding or reverse causality. Objectives: To explore the causal association between leisure sedentary behavior and erectile dysfunction, and to explore the underlying mechanism using Mendelian randomization. Materials and methods: In the present study, publicly available large‐scale genome‐wide association studies of leisure sedentary behaviors (television watching, computer use, and driving), erectile dysfunction, sex hormones (total testosterone, bioactive testosterone, estradiol, follicle‐stimulating hormone, luteinizing hormone, prolactin, and sex hormone binding globulin), biomarkers of endothelial function (C reactive protein, E‐selectin, and matrix metalloproteinase 7), and psychiatric symptoms (depression and anxiety) were used to perform two‐sample Mendelian randomization analyses. The inverse variance weighting method was the main method used to estimate the association, and sensitivity analyses were also performed. Results: A greater risk of erectile dysfunction was significantly associated with a higher genetic susceptibility to leisure computer usage (odds ratio = 3.57; 95% confidence interval = 1.78–7.16; p < 0.001). No evidence was obtained to suggest that watching television or driving for leisure increased the risk of erectile dysfunction. No association was found between computer use and depression, anxiety, C reactive protein, E‐selectin, matrix metalloproteinase 7, or other sex hormones, with the exception of follicle‐stimulating hormone levels (odds ratio = 0.29; 95% confidence interval = 0.12–0.69; p = 0.01). No indication of heterogeneity or pleiotropy was identified by sensitivity analysis. Discussion: Extended computer usage for leisure raised the likelihood of developing erectile dysfunction, which may be associated to lower follicle‐stimulating hormone levels; however, the role of endothelial dysfunction and psychological disorders in the development of erectile dysfunction should not be underestimated. Moderate physical activity may help to correct the dysfunction. Conclusion: The present study offered substantial evidence for a positive causal association between computer use and the risk of erectile dysfunction. However, a definitive causal association needs to be established by further research. [ABSTRACT FROM AUTHOR]

Oncogenes and tumor suppressors are well‐known to orchestrate several signaling cascades, regulate extracellular and intracellular stimuli, and ultimately control the fate of cancer cells. Accumulating evidence has recently revealed that perturbation of these key modulators by mutations or abnormal protein expressions are closely associated with drug resistance in cancer therapy; however, the inherent drug resistance or compensatory mechanism remains to be clarified for targeted drug discovery. Thus, dual‐target drug development has been widely reported to be a promising therapeutic strategy for improving drug efficiency or overcoming resistance mechanisms. In this review, we provide an overview of the therapeutic strategies of dual‐target drugs, especially focusing on pharmacological small‐molecule compounds in cancer, including small molecules targeting mutation resistance, compensatory mechanisms, synthetic lethality, synergistic effects, and other new emerging strategies. Together, these therapeutic strategies of dual‐target drugs would shed light on discovering more novel candidate small‐molecule drugs for the future cancer treatment. [ABSTRACT FROM AUTHOR]

To overcome the difficulties of time-consuming and inefficient in the response calculations of the submerged cylindrical shell with internal substructures, this paper firstly presents a refined mode superposition method. In view of the necessity and difficulties of directly and quickly obtaining the frequencies and modes of structures submerged in fluid (named the wet modes), the wet modes are expanded by the modes in vacuum (dry modes) and solved by the energy method. The added kinetic energy of the fluid is calculated via boundary integration, and the Lagrange equations of the second kind is applied to the fluid-structure coupling equations. Then the wet modes are solved by eigenvalue calculation and the modal mass and stiffness of each order wet mode are obtained. Finally, they are used for establishing a mode superposition approach for response calculations. The accuracy of the present method is verified by ANSYS software. In this method, all the required data are obtained from the structural analysis and the traditional complicated fluid force modeling is no longer required. Thus it has the advantages of high computational efficiency and applicability. Compared to the traditional semi-analytic model, this modeling methodology has broad application potential for vibration problems of complex underwater structures since the structural dry modes can be solved efficiently by commercial software. It also has practical value as a theoretical reference for developing mode-superposition-based calculations for fluid-structure problems using commercial software. [ABSTRACT FROM AUTHOR]

This paper studies the instability of a non-ideal pipe system conveying fluid. Unlike ideal modeling, three types of possible non-ideal factors have been considered in the present analysis. The pipe has a crack and is subjected to boundary relaxation, and the fluid in the pipe is viscous. It is an interesting instability problem of a fluid-structure system with multiple forms of imperfections. It gains motivation from our previous study and aims at further essential results for comprehensively understanding the nature of such a problem. In order to incorporate multiple imperfections, a new data-driven approach is developed to model the non-ideal pipe-fluid system. Then the influences of the support stiffness, fluid–solid mass ratio, crack, and fluid viscosity on the pipe instability are systematically discussed. Results show that the pipe exhibits flutter-divergence conversion at low mass ratios and flutter-mode transition at high mass ratios. Due to the two types of instability transitions, the critical flow speed could experience multiple sudden jumps as the support stiffness changes. With the imperfections of crack and viscous flow, the pipe's instability behavior tends to be more complicated, but the inducing mechanisms for the sudden changes are straightforward. They are instability-type conversion, instability-mode transition, and laminar-turbulent flow transition. [ABSTRACT FROM AUTHOR]