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The regulation of cellular metabolism and survival by trophic factors is not completely understood. Here, we describe a signaling cascade activated by the developmental regulator Notch, which inhibits apoptosis triggered by neglect in mammalian cells. In this pathway, the Notch intracellular domain (NIC), which is released after interaction with ligand, converges on the kinase mammalian target of rapamycin (mTOR) and the substrate-defining protein rapamycin independent companion of mTOR (Rictor), culminating in the activation of the kinase Akt/PKB. Biochemical and molecular approaches using site-directed mutants identified AktS473 as a key downstream target in the antiapoptotic pathway activated by NIC. Despite the demonstrated requirement for Notch processing and its predominant nuclear localization, NIC function was independent of CBF1/RBP-J, an essential DNA-binding component required for canonical signaling. In experiments that placed spatial constraints on NIC, enforced nuclear retention abrogated antiapoptotic activity and a membrane-anchored form of NIC-blocked apoptosis through mTOR, Rictor and Akt-dependent signaling. We show that the NIC-mTORC2-Akt cascade blocks the apoptotic response triggered by removal of medium or serum deprivation. Consistently, membrane-tethered NIC, and AktS473 inhibited apoptosis triggered by cytokine deprivation in activated T cells. Thus, this study identifies a non-canonical signaling cascade wherein NIC integrates with multiple pathways to regulate cell survival.

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Background With the decrease in the number of cerebral aneurysms treated surgically and the increase of complexity of those treated surgically, there is a need for simulation-based tools to teach future neurosurgeons the operative techniques of aneurysm clipping. Objective To develop and evaluate the usefulness of a new haptic-based virtual reality (VR) simulator in the training of neurosurgical residents. Methods A real-time sensory haptic feedback virtual reality aneurysm clipping simulator was developed using the Immersive Touch platform. A prototype middle cerebral artery aneurysm simulation was created from a computed tomography angiogram. Aneurysm and vessel volume deformation and haptic feedback are provided in a 3-D immersive VR environment. Intraoperative aneurysm rupture was also simulated. Seventeen neurosurgery residents from three residency programs tested the simulator and provided feedback on its usefulness and resemblance to real aneurysm clipping surgery. Results Residents felt that the simulation would be useful in preparing for real-life surgery. About two thirds of the residents felt that the 3-D immersive anatomical details provided a very close resemblance to real operative anatomy and accurate guidance for deciding surgical approaches. They believed the simulation is useful for preoperative surgical rehearsal and neurosurgical training. One third of the residents felt that the technology in its current form provided very realistic haptic feedback for aneurysm surgery. Conclusion Neurosurgical residents felt that the novel immersive VR simulator is helpful in their training especially since they do not get a chance to perform aneurysm clippings until very late in their residency programs.