Myocardial damage caused by myocardial ischemia-reperfusion injury (MIRI) is difficult to be alleviated because cardiomyocyte necrosis is an irreversible and unregulated death form. Recently, necroptosis, a necrosis form caused by tumor necrosis factor-α (TNF-α) and Fas ligand (FasL), was found to be regulated by receptor interacting protein 3 (RIP3) and RIP3-receptor interacting protein 1 (RIP1)-mixed lineage kinase domain like protein (MLKL) pathway. But it is unclear whether they also play a regulatory role in MIRI-induced necroptosis. Our previous results showed that in rat MIRI, RIP3 could translocate and express highly in mitochondria. Therefore, it is important to explore proteins that interact with RIP3 which was translocated to mitochondria. The aim of this study was to explore the role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of hypoxia/reoxygenation (H/R). Our results showed that H/R could cause RIP3-depended mitochondrial fragmentation and necrosis-based death; and RIP3-promoted H/R-induced necroptosis in H9c2 cells through increasing lactate dehydrogenase release and inhibiting cell viability. This process did not require RIP1 or MLKL but dynamin-related protein 1 (Drp1), which was related to Drp1 activation, reactive oxygen species elevation, and ΔΨm decline. This study provides novel insights into the role of RIP3 in cardiomyocyte injury during H/R. RIP3 may serve as a potential target for the treatment of MIRI.

Triple-negative breast cancer (TNBC) accounts for ~15% of all breast cancer diagnoses each year. Patients with TNBC tend to have a higher risk for early relapse and a worse prognosis. TNBC is characterized by extensive somatic copy number alterations (CNAs). However, the DNA CNA profile of TNBC remains to be extensively investigated. The present study assessed the genomic profile of CNAs in 201 TNBC samples, aiming to identify recurrent CNAs that may drive the pathogenesis of TNBC. In total, 123 regions of significant amplification and deletion were detected using the Genomic Identification of Significant Targets in Cancer algorithm, and potential driver genes for TNBC were identified. A total of 31 samples exhibited signs of chromothripsis and revealed chromosome pulverization hotspot regions. The present study further determined 199 genomic locations that were significantly enriched for breakpoints, which indicated TNBC-specific genomic instability regions. Unsupervised hierarchical clustering of tumors resulted in three main subgroups that exhibited distinct CNA profiles, which may reveal the heterogeneity of molecular mechanisms in TNBC subgroups. These results will extend the molecular understanding of TNBC and will facilitate the discovery of therapeutic and diagnostic target candidates.

Background: α 2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α 2A-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α 2A-AR subtype of traditional drugs greatly limits their clinic usage. Methods: A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α 2-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism. Results: Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α 2A-AR over α 2B-and α 2C-ARs. Besides, the affinities are of similar linker lengthdependence for each α 2-AR subtype. Among all the compounds tested, C10 has the highest affinity for α 2A-AR (pKi=−7.45±0.62), which is 12-fold and 60-fold selective over α 2B-AR and α 2C-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and "allosteric" sites of the α 2A-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99. Conclusion: The specificity of C10 for the α 2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α 2A-AR subtype selective compounds.

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In order improve the performance of Strapdown Inertial Navigation System (SINS) alignment in moorage, a novel alignment method is proposed. With the aid of a cascade low-pass FIR filter, the gravity vector is separated from the measurements of accelerometers due to the high frequency characteristic of the disturbance accelerations and the low frequency characteristic of the gravity vector. Two non collinear velocities both in the inertial frame and in the concretionary are integrated by the gravity vector and the cosin matrix between the two frames is calculated. With the other matrix which can be calculated easily, the alignment is accomplished. Results of experiment show that the accuracy of the alignment method proposed in this paper converges much faster than the traditional alignment methods. However, the new method is a open-loop method, thus the precision is not significantly improved.