Cross-presentation is a key function of dendritic cells (DCs), which present exogenous Ags on MHC class I molecules to prime CTL responses. The effects of TLR triggering on the cross-presentation of exogenous Ags by DCs remain unclear. In this study, we used synthetic dipalmitoylated peptides and TLR2 agonist–conjugated peptides as models to elucidate the mechanisms of TLR2-mediated cross-presentation. We observed that the internalization of dipalmitoylated peptides by bone marrow–derived DCs was facilitated by TLR2 via clathrin-mediated endocytosis. The administration of these dipalmitoylated peptide-pulsed bone marrow–derived DCs eliminated established tumors through TLR2 signaling. We further demonstrated that the induction of Ag-specific CTL responses and tumor regression by dipalmitoylated peptides was TAP independent. In addition, presentation of dipalmitoylated peptides by MHC class I molecules was blocked in the presence of an endosomal acidification inhibitor (chloroquine) or a lysosomal degradation inhibitor (Z-FL-COCHO). The endocytosed dipalmitoylated peptide also passed rapidly from early endosome Ag-1–positive endosomes to RAS-related GTP-binding protein 7 (Rab7)–associated late endosomes compared with their nonlipidated counterparts. Furthermore, we found that dipalmitoylated peptide–upregulated Rab7 expression correlated with Ag presentation via the TLR2/MyD88 pathway. Both JNK and ERK signaling pathways are required for upregulation of Rab7. In summary, our data suggest that TLR2-mediated cross-presentation occurs through the upregulation of Rab7 and a TAP-independent pathway that prime CTL responses.
The cullin-RING ubiquitin ligases (CRLs) are responsible for about 20% of cellular protein degradation and regulate diverse cellular processes, and the dysfunction of CRLs is implicated in human diseases. Targeting the CRLs has become an emerging strategy for the treatment of human diseases. Herein, we describe the discovery of a hit compound from our in-house library and further structure-based optimizations, which have enabled the identification of new triazolo[1,5a]pyrimidine-based inhibitors targeting the DCN1−UBC12 interaction. Compound WS-383 blocks the DCN1−UBC12 interaction (IC 50 = 11 nM) reversibly and shows selectivity over selected kinases. WS-383 exhibits cellular target engagement to DCN1 in MGC-803 cells. WS-383 inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27, and NRF2. Collectively, targeting the DCN1−UBC12 interaction would be a viable strategy for selective neddylation inhibition of Cul3/1 and may be of therapeutic potential for disease treatment in which Cul3/1 is dysregulated.
Prospective memory (PM) refers to the ability to remember to perform intended actions in the future. Although PM deficits are a prominent impairment in schizophrenia, little is still known about the nature of PM in symptomatically remitted patients with schizophrenia. To address this issue, event-related brain potentials (ERPs) were recorded from 20 symptomatically remitted patients with schizophrenia and 20 healthy controls during an event-based PM paradigm. Behavioral results showed that symptomatically remitted patients with schizophrenia performed poorly on the PM task compared with healthy controls. On the neural level, the N300, a component of the ERPs related to PM cue detection, was reliable across these two groups, suggesting a degree of functional recovery of processes supporting cue detection in patients with symptomatically remitted schizophrenia. By contrast, the amplitude of the prospective positivity, a component of the ERPs related to PM intention retrieval, was significantly attenuated in symptomatically remitted schizophrenia patients relative to healthy controls. Furthermore, a significant positive correlation between the amplitude of the prospective positivity and accuracy on the PM task was found in those patients, indicating that patients’ poor performance on this task may result from the failure to recover PM cue-induced intention from memory. These results provide evidence for the existence of altered PM processing in patients with symptomatically remitted schizophrenia, which is characterized by a selective deficit in retrospective component (intention retrieval) of PM. Therefore, these findings shed new light on the neurophysiological processes underlying PM in schizophrenia patients during clinical remission.
Background: To determine the effectiveness of text message reminders (TMR) on medication adherence (MA) and to investigate the effects of TMR on clinical outcomes. Methods: The PubMed, Cochrane library, EMbase, and China Biology Medicine databases were searched for randomized-controlled trials with TMR as the intervention for patients with coronary heart disease. Two reviewers independently extracted data and assessed the risk of bias. Meta-analysis was conducted using Stata 15.0 software. Results: In total, 1678 patients in 6 trials were included. Compared with the control group, the MA was 2.85 times greater among the intervention group (RR [relative risk] 2.85; 95% confidence interval [CI] 1.07–7.58). TMR reduced systolic blood pressure (BP) (weighted mean difference) = −6.51; 95% CI −9.79 to -3.23), cholesterol (standard mean difference = −0.26; 95% CI −0.4 to -0.12) and increased the number of patients with BP <140/90 mm Hg (RR 1.39; 95% CI 1.26–1.54). Conclusion: TMR significantly promoted MA and reduced systolic BP, cholesterol level, and body mass index, but had no effect on mortality, diastolic BP, or lipoproteins. However, substantial heterogeneity existed in our analyses.
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