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Summary Dopaminergic neurons provide value signals in mammals and insects [ 1–3 ]. During Drosophila olfactory learning, distinct subsets of dopaminergic neurons appear to assign either positive or negative value to odor representations in mushroom body neurons [ 4–9 ]. However, it is not known how flies evaluate substances that have mixed valence. Here we show that flies form short-lived aversive olfactory memories when trained with odors and sugars that are contaminated with the common insect repellent DEET. This DEET-aversive learning required the MB-MP1 dopaminergic neurons that are also required for shock learning [ 7 ]. Moreover, differential conditioning with DEET versus shock suggests that formation of these distinct aversive olfactory memories relies on a common negatively reinforcing dopaminergic mechanism. Surprisingly, as time passed after training, the behavior of DEET-sugar-trained flies reversed from conditioned odor avoidance into odor approach. In addition, flies that were compromised for reward learning exhibited a more robust and longer-lived aversive-DEET memory. These data demonstrate that flies independently process the DEET and sugar components to form parallel aversive and appetitive olfactory memories, with distinct kinetics, that compete to guide learned behavior. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most elusive subtype of breast cancer that encounters treatment dilemmas owing to the paucity of druggable targets. We found hyperactivation of c-MET and ephrin type-A receptor 2 (EphA2) in patients treated with 5FU driven chemotherapy which correlated with lower disease-free survival. However, silencing of both these genes resulted in a marked decrease in the invasive, migratory, and tumorigenic potential of TNBC cells, indicating that a dual target strategy is actionable. Lupeol is a phytochemical, with potent anticancer efficacy and minimal side effects in preclinical studies. A synergistic strategy with 5FU and Lupeol elicited promising anticancer responses in vitro , in vivo , and in patient-derived ex vivo tumor culture models. This synergistic regimen is effective, even in the presence of HGF, which mechanistically orchestrates the activation of c-MET and EphA2. These data lay the foundation for the clinical validation of this combination therapy for TNBC patients., Competing Interests: Authors have no conflict of interest to declare., (© 2023 The Authors.)

During olfactory learning in fruit flies, dopaminergic neurons assign value to odor representations in the mushroom body Kenyon cells. Here we identify a class of downstream glutamatergic mushroom body output neurons (MBONs) called M4/6, or MBON-β2β'2a, MBON-β'2mp, and MBON-γ5β'2a, whose dendritic fields overlap with dopaminergic neuron projections in the tips of the β, β', and γ lobes. This anatomy and their odor tuning suggests that M4/6 neurons pool odor-driven Kenyon cell synaptic outputs. Like that of mushroom body neurons, M4/6 output is required for expression of appetitive and aversive memory performance. Moreover, appetitive and aversive olfactory conditioning bidirectionally alters the relative odor-drive of M4β' neurons (MBON-β'2mp). Direct block of M4/6 neurons in naive flies mimics appetitive conditioning, being sufficient to convert odor-driven avoidance into approach, while optogenetically activating these neurons induces avoidance behavior. We therefore propose that drive to the M4/6 neurons reflects odor-directed behavioral choice., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)