Disturbance of endoplasmic reticulum (ER) homoeostasis induces ER stress and leads to activation of the unfolded protein response (UPR), which is an adaptive reaction that promotes cell survival or triggers apoptosis, when homoeostasis is not restored. DDRGK1 is an ER membrane protein and a critical component of the ubiquitin-fold modifier 1 (Ufm1) system. However, the functions and mechanisms of DDRGK1 in ER homoeostasis are largely unknown. Here, we show that depletion of DDRGK1 induces ER stress and enhances ER stress-induced apoptosis in both cancer cells and hematopoietic stem cells (HSCs). Depletion of DDRGK1 represses IRE1α-XBP1 signalling and activates the PERK-eIF2α-CHOP apoptotic pathway by targeting the ER-stress sensor IRE1α. We further demonstrate that DDRGK1 regulates IRE1α protein stability via its interaction with the kinase domain of IRE1α, which is dependent on its ufmylation modification. Altogether, our results provide evidence that DDRGK1 is essential for ER homoeostasis regulation.

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Myocardial infarction (MI) is primarily caused by ischemic heart or coronary artery disease and is a major cause of mortality worldwide. Thus, it is necessary to establish reliable biochemical markers for the early diagnosis of MI. MicroRNAs (miRNAs or miR) have been demonstrated to circulate in biological fluids and are enclosed in extracellular vesicles, including exosomes. The current study assessed the differential expression of exosomal miRNAs in the plasma of patients with MI and healthy individuals, and the possible mechanism involved. Plasma-derived exosomes were isolated from patients with MI and healthy control individuals, and vesicles with a membrane were observed using transmission electron microscopy. Furthermore, an exosomal miRNA expression profile was compared between patients with MI and healthy individuals using a miRNA microarray. Significantly differentially expressed miRNAs were validated using reverse transcription-quantitative polymerase chain reaction. To the best of our knowledge, the present study was the first to demonstrate that miR-183 was markedly upregulated in patients with MI compared with healthy individuals. In addition, the relative exosomal miR-183 level increased with the degree of myocardial ischemic injury. Additionally, GO and KEGG analyses demonstrated that miR-183 is primarily involved in cell communication, protein kinase activity regulation and adrenergic signaling in cardiomyocytes. Furthermore, a protein-protein interaction network of all the miR-183 target genes was constructed. The results demonstrated that five core genes ( PPP2CB, PPP2CA, PRKCA, PPP2CA, PPP2R5C and PPP2R2A ) in the PPI network were also associated with protein kinase activity regulation and adrenergic signaling in cardiomyocytes. Taken together, these data demonstrate that exosomal miR-183 derived from the serum of patients with MI may be a novel diagnostic biomarker involved in the regulation of protein kinase activity. miR-183 may therefore be further developed for clinical use to benefit patients with coronary artery diseases.

We consider the variable‐coefficient fractional diffusion equations with two‐sided fractional derivative. By introducing an intermediate variable, we propose a mixed‐type Galerkin variational formulation and prove the existence and uniqueness of the variational solution over H01(normalΩ)×H1−β2(normalΩ). On the basis of the formulation, we develop a mixed‐type finite element procedure on commonly used finite element spaces and derive the solvability of the finite element solution and the error bounds for the unknown and the intermediate variable. For the Toeplitz‐like linear system generated by discretization, we design a fast conjugate gradient normal residual method to reduce the storage from O(N2) to O(N) and the computing cost from O(N3) to O(NlogN). Numerical experiments are included to verify our theoretical findings. Copyright © 2017 John Wiley & Sons, Ltd.

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