Chemical Modulation of Slit Proteolysis by Tolloid-like 1

Slits are large secreted proteins that repel growing axons during nervous system development, primarily by binding Roundabout (Robo) receptors. In addition to axon guidance, Slit-Robo signaling is linked to a wide range of biological processes including cell migration, angiogenesis, and cancer metastasis. The full-length Slit protein (Slit-FL) is proteolytically cleaved into two functionally distinct fragments, Slit-N and Slit-C. The Slit-N fragment has been identified for its therapeutic potential in multiple disease pathologies with diverse beneficial effects such as increasing vascular stability and promoting neuronal survival and outgrowth. Accurately identifying the Slit protease is paramount for understanding Slit processing and necessary for targeting the protease for modulation to therapeutically increase availability of Slit-N. Here we provide evidence to support that the metalloprotease Tolloid-like 1 (Tll1) is the direct protease of Slit, not prohormone convertases as other labs have previously proposed. Furthermore, we propose a pharmacological strategy to indirectly activate Tll1 as a mechanism for increasing Slit-N levels in microbially infected endothelial and lung cells. This therapeutic potential speaks to the critical need for effective strategies to treat SARS-CoV-2-related vascular and lung damage

NeuroCOPE: A novel intervention to increase professional fulfillment and reduce burnout by connecting Neuro-ICU healthcare workers to their post-recovery patients

Background: Healthcare workers (HCWs) caring for patients with acute neurologic injury in the ICU rarely receive detailed information on the recovery of their patients. The missing connection between the period of acute neurologic injury and long-term outcomes is a psychological burden that contributes to moral fatigue and burnout. We hypothesize that attending an Interprofessional conference series through which patients describe their acute brain injury and recovery to Neuro-ICU HCWs may ease moral fatigue, increasing professional fulfillment and reducing burnout.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2023/1014/thumbnail.jp

High ErbB3 activating activity in human blood is not due to circulating neuregulin-1 beta

Neuregulin-1β (NRG-1) is a membrane-bound or secreted growth and differentiation factor that mediates its action by binding to ErbB receptors. Circulating levels of NRG-1 are characterized by large inter-individual variability with the range of absolute values covering two orders of magnitude, from hundreds to tens of thousands of picograms per milliliter of blood. NRG-1 signaling via ErbB receptors contributes to the cell survival and downregulation of the inflammatory response. A higher level of circulating NRG-1 may indicate increased shedding of membrane-bound NRG-1, which in turn can contribute to better protection against cardiovascular stress or injury. However, it is unknown whether circulating NRG-1 can induce activation of ErbB receptors. In the current study, we performed an analysis of circulating NRG-1 functional activity using a cell-based ELISA measuring phosphorylation of ErbB3 induced by blood plasma obtained from healthy donors. We found high levels of ErbB3 activating activity in human plasma. No correlations were found between the levels of circulating NRG-1 and plasma ErbB3 activating activity. To determine the direct effect of circulating NRG-1, we incubated plasma with neutralizing antibody, which prevented the stimulatory effect of recombinant NRG-1 on activation of ErbB3. No effect of the neutralizing antibody was found on plasma-induced phosphorylation of ErbB3. We also found that a significant portion of circulating NRG-1 is comprised of full-length NRG-1 associated with large extracellular vesicles. Our results demonstrate that circulating NRG-1 does not contribute to plasma-induced ErbB3 activating activity and emphasizes the importance of functional testing of NRG-1 proteins in biological samples