Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation.

BACKGROUND:Evidence indicates that Bax functions as a "lipidic" pore to regulate mitochondrial outer membrane permeabilization (MOMP), the apoptosis commitment step, through unknown membrane elements. Here we show mitochondrial ceramide elevation facilitates MOMP-mediated cytochrome c release in HeLa cells by generating a previously-unrecognized mitochondrial ceramide-rich macrodomain (MCRM), which we visualize and isolate, into which Bax integrates. METHODOLOGY/PRINCIPAL FINDINGS:MCRMs, virtually non-existent in resting cells, form upon irradiation coupled to ceramide synthase-mediated ceramide elevation, optimizing Bax insertion/oligomerization and MOMP. MCRMs are detected by confocal microscopy in intact HeLa cells and isolated biophysically as a light membrane fraction from HeLa cell lysates. Inhibiting ceramide generation using a well-defined natural ceramide synthase inhibitor, Fumonisin B1, prevented radiation-induced Bax insertion, oligomerization and MOMP. MCRM deconstruction using purified mouse hepatic mitochondria revealed ceramide alone is non-apoptogenic. Rather Bax integrates into MCRMs, oligomerizing therein, conferring 1-2 log enhanced cytochrome c release. Consistent with this mechanism, MCRM Bax isolates as high molecular weight "pore-forming" oligomers, while non-MCRM membrane contains exclusively MOMP-incompatible monomeric Bax. CONCLUSIONS/SIGNIFICANCE:Our recent studies in the C. elegans germline indicate that mitochondrial ceramide generation is obligate for radiation-induced apoptosis, although a mechanism for ceramide action was not delineated. Here we demonstrate that ceramide, generated in the mitochondrial outer membrane of mammalian cells upon irradiation, forms a platform into which Bax inserts, oligomerizes and functionalizes as a pore. We posit conceptualization of ceramide as a membrane-based stress calibrator, driving membrane macrodomain organization, which in mitochondria regulates intensity of Bax-induced MOMP, and is pharmacologically tractable in vitro and in vivo

Structurally diverse pi-cyclopentadienyl complexes of the main group elements

Jutzi P, Burford N. Structurally diverse pi-cyclopentadienyl complexes of the main group elements. CHEMICAL REVIEWS. 1999;99(4):969-990

A comprehensive review of quay crane scheduling, yard operations and integrations thereof in container terminals

Over the past decades, container transportation has achieved considerable growth, and maritime trade now constitutes 80% of the global trade. The vessel sizes increased in parallel, up to 21,400 TEU (Twenty-foot-equivalent unit container). Accordingly, global containerized trade reached up to 150 million TEU in 2017 (UNCTAD 2018). This growth brings the need to use scientific methods to manage and operate container terminals more economically throughout the globe. In order to manage container transshipment and to use large vessels efficiently, the docking time at the container port for each vessel should be minimized. The decrease in the docking time enables the vessel to move to its next destination faster, decreasing turnover time and facilitating more containers to be transported. Container terminals can be divided into five main areas as the berth, the quay, the storage yard, the transport area, and the gate. The vessels must be berthed in suitable positions, after which many containers have to be unloaded or loaded via quay cranes, transshipped by vehicles inside the terminal, and stacked by yard cranes to suitable positions, all by using expensive equipment. With the invention of new technologies, the bottleneck at the berth side is almost overcome; however, the yard and the quayside operations have to be further perfected to obtain efficient plans. In this comprehensive literature review study, we aim to combine the literature on both yard and quayside operations, carefully examining independently studied problems as well as integrated ones. General information about port operations and relevant literature is provided. For the quayside, the literature on quay crane assignment and scheduling problems is investigated, whereas, for the yard side, yard crane scheduling, transport vehicle dispatching and scheduling, vehicle routing and traffic control, and storage location and space planning problems are reviewed in depth. In addition to these individual problems, their integrations are also analyzed, relevant publications and their respective contributions are explained in detail. Besides the milestone papers that lead the literature on container terminals, recent publications and advances are also reviewed, and managerial insights and future research directions are identified.Project Evaluation Commission of Yasar University [BAP038]The authors would like to thank the anonymous referees for their invaluable suggestions. This study was supported within the scope of the scientific research project, which was accepted by the Project Evaluation Commission of Yasar University under project number BAP038 and title Solution Approaches for Integrated Liner Shipping Network Design and Container Terminal Operations