Jones, C. D. | Search bioRxiv

bioRxiv2018

Combinations of DIPs and Dprs control organization of olfactory receptor neuron terminals in Drosophila

In Drosophila, 50 classes of olfactory receptor neurons (ORNs) connect to 50 class-specific and uniquely positioned glomeruli in the antennal lobe. Despite the identification of cell surface receptors regulating axon guidance, how ORN axons sort to form 50 stereotypical glomeruli remains unclear. Here we show that the heterophilic cell adhesion proteins, DIPs and Dprs, are expressed in ORNs during glomerular formation. Each ORN class expresses a unique combination of DIPs/dprs, with neurons of the same class expressing interacting partners, suggesting a role in class-specific self-adhesion ORN axons. Analysis of DIP/Dpr expression revealed that ORNS that target neighboring glomeruli have different combinations, and ORNs with very similar DIP/Dpr combinations can project to distant glomeruli in the antennal lobe. Perturbations of DIP/dpr gene function result in local projection defects of ORN axons and glomerular positioning, without altering correct matching of ORNs with their target neurons. Our results suggest that context-dependent differential adhesion through DIP/Dpr combinations regulate self-adhesion and sort ORN axons into uniquely positioned glomeruli.

neuroscience↗

bioRxiv2018

The SMAC Mimetic AZD5582 is a Potent HIV Latency Reversing Agent

The leading strategy towards eradication of human immunodeficiency virus (HIV) infection is the depletion of viral reservoirs through reversal of viral latency, followed by clearance of persistently infected cells. To date, a latency reversing agent (LRA) that reactivates a majority of the quiescent provirus population, without significant off-target effects, has not been identified. We show here that molecules mimicking the active N-terminal tetrapeptide of the second mitochondrial-derived activator of caspases (SMACm) potently reverse HIV latency in vitro and ex vivo without the pleotropic cellular effects seen with other LRA. We verified that SMACm facilitate latency reversal through activation of the non-canonical NFkB pathway as exemplified by rapid degradation of cellular inhibitor of apoptosis protein 1 (cIAP1), followed by a slower conversion of the inactive p100 form of NF{kappa}B2 into the active p52 transcription factor. A potent representative of this class, AZD5582, increases cell-associated HIV RNA expression in resting CD4+ T cells from ART-suppressed, HIV-infected donors while altering the expression of a restricted number of human genes. These findings represent the first demonstration that SMACm have single agent latency reversal activity in patient-derived cells and support evaluation of this class of molecules in preclinical animal models.

microbiology↗