Dynamic Response Analysis of a Bulk Carrier by Nonlinear Hydroelastic Method

With increasing demands for huge ship dimensions and the wide use of high-strength steel, the influence of slamming and elastic structure on structural strength cannot be ignored. Therefore, in this paper, a three-dimensional (3D) nonlinear hydroelastic theory is introduced, in which the nonlinear hydrostatic restoring force caused by instantaneous wetted surface as well as slamming force are taken into consideration, and the bending moments with/without slamming effects are calculated, respectively. Numerical simulations of the dynamic response of a flexible hull at different speeds are carried out using the finite element analysis software MSC/PATRAN. By comparison with the results of classical beam theory, the accuracy of the dynamic analysis method is studied. Finally, the dynamic response method is compared with the quasi-static method and classical beam theory. By analyzing and quantifying the influence of forward speed and nonlinear factors on structural responses, the reasonable applicable conditions for different methods are discussed, which can be used as reference in the structure design of bulk carriers

Mutation network-based understanding of pleiotropic and epistatic mutational behavior of Enterococcus faecalis FMN-dependent azoreductase

We previously identified a highly active homodimeric FMN-dependent NADH-preferred azoreductase (AzoA) from Enterococcus faecalis, which cleaves the azo bonds (R-N˭N-R) of diverse azo dyes, and determined its crystal structure. The preliminary network-based mutational analysis suggested that the two residues, Arg-21 and Asn-121, have an apparent mutational potential for fine-tuning of AzoA, based on their beneficial pleiotropic feedbacks. However, epistasis between the two promising mutational spots in AzoA has not been obtained in terms of substrate binding and azoreductase activity. In this study, we further quantified, visualized, and described the pleiotropic and/or epistatic behavior of six single or double mutations at the positions, Arg-21 and Asn-121, as a further research endeavor for beneficial fine-tuning of AzoA. Based on this network-based mutational analysis, we showed that pleiotropy and epistasis are common, sensitive, and complex mutational behaviors, depending mainly on the structural and functional responsibility and the physicochemical properties of the residue(s) in AzoA

Cancer CD39 drives metabolic adaption and mal-differentiation of CD4+ T cells in patients with non-small-cell lung cancer

Abstract While ectonucleotidase CD39 is a cancer therapeutic target in clinical trials, its direct effect on T-cell differentiation in human non-small-cell lung cancer (NSCLC) remains unclear. Herein, we demonstrate that human NSCLC cells, including tumor cell lines and primary tumor cells from clinical patients, efficiently drive the metabolic adaption of human CD4+ T cells, instructing differentiation of regulatory T cells while inhibiting effector T cells. Of importance, NSCLC-induced T-cell mal-differentiation primarily depends on cancer CD39, as this can be fundamentally blocked by genetic depletion of CD39 in NSCLC. Mechanistically, NSCLC cells package CD39 into their exosomes and transfer such CD39-containing exosomes into interacting T cells, resulting in ATP insufficiency and AMPK hyperactivation. Such CD39-dependent NSCLC-T cell interaction holds well in patients-derived primary tumor cells and patient-derived organoids (PDOs). Accordingly, genetic depletion of CD39 alone or in combination with the anti-PD-1 immunotherapy efficiently rescues effector T cell differentiation, instigates anti-tumor T cell immunity, and inhibits tumor growth of PDOs. Together, targeting cancer CD39 can correct the mal-differentiation of CD4+ T cells in human NSCLC, providing in-depth insight into therapeutic CD39 inhibitors