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In this paper we defend that elective ventilation (EV), even if conceived as the instrument to maximise the chances of organ recovery, is mainly the means to provide the patient who is dying with a dignified death in several ways, one of them being the possibility of becoming an organ donor. Because EV does not harm the patient and permits the medical team a better assessment of the patient's clinical trajectory and a better management of the dying process by the family, EV does not violate the principle of non-beneficence nor the principle of autonomy if we restrict the initiation of EV to those cases in which it is not known what the previous wishes of the patient were as regards to his or her care at the end of life. [ABSTRACT FROM AUTHOR]

The outer corona plays an essential role at the onset of mitosis by expanding to maximize microtubule attachment to kinetochores. 1,2 The low-density structure of the corona forms through the expansion of unattached kinetochores. It comprises the RZZ complex, the dynein adaptor Spindly, the plus-end directed microtubule motor centromere protein E (CENP-E), and the Mad1/Mad2 spindle-assembly checkpoint proteins. 3,4,5,6,7,8,9,10 CENP-E specifically associates with unattached kinetochores to facilitate chromosome congression, 11,12,13,14,15,16 interacting with BubR1 at the kinetochore through its C-terminal region (2091–2358). 17,18,19,20,21 We recently showed that CENP-E recruitment to BubR1 at the kinetochores is both rapid and essential for correct chromosome alignment. However, CENP-E is also recruited to the outer corona by a second, slower pathway that is currently undefined. 19 Here, we show that BubR1-independent localization of CENP-E is mediated by a conserved loop that is essential for outer-corona targeting. We provide a structural model of the entire CENP-E kinetochore-targeting domain combining X-ray crystallography and Alphafold2. We reveal that maximal recruitment of CENP-E to unattached kinetochores critically depends on BubR1 and the outer corona, including dynein. Ectopic expression of the CENP-E C-terminal domain recruits the RZZ complex, Mad1, and Spindly, and prevents kinetochore biorientation in cells. We propose that BubR1-recruited CENP-E, in addition to its essential role in chromosome alignment to the metaphase plate, contributes to the recruitment of outer corona proteins through interactions with the CENP-E corona-targeting domain to facilitate the rapid capture of microtubules for efficient chromosome alignment and mitotic progression. [Display omitted] • CENP-E targets to unattached kinetochores through BubR1 and the RZZ complex/Spindly • CENP-E recruits the RZZ complex, Spindly, and Mad1 • Dynein is essential for both CENP-E targeting and removal Weber et al. demonstrate that CENP-E recruitment to kinetochores is dependent on both the BubR1- and the outer corona-dependent pathways and on dynein. They provide a molecular model of the CENP-E kinetochore-targeting domain and propose that CENP-E stabilizes the outer corona by recruiting the RZZ complex, Spindly and Mad1 to accelerate microtubule attachment. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo. [Copyright &y& Elsevier]

Abstract: A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR. [Copyright &y& Elsevier]