Triple negative breast cancer (TNBC) is a heterogeneous disease and has a higher rate of recurrence and distant metastasis. African-American (AA) women have a higher frequency of BRCA1 mutations and TNBC compared to other populations. Basal-like tumors have a higher rate of brain, lung and distant nodal metastasis more than other TNBC subtypes, contributing to higher mortality rate. Our previous work suggested Ubc9, a SUMO E2-conjugating enzyme to induce proliferation and migration of BRCA1-incompetent TNBC cells and TNBC cell lines established from the pleural effusion metastasis of a woman with TNBC. To understand the downstream signaling axis involved in distant metastasis we have used clinically relevant BRCA1 mutant and lung metastatic TNBC cell lines and our results show deregulated expression of caveolin-1, VEGF and SIRT1 in these cells compared to normal mammary epithelial cells by immunofluorescence analysis. We observed SIRT1 to be induced by wild type BRCA1a and BRCA1a I26A mutant unlike the disease associated Ubc9 binding mutants in TNBC cells. Knock down of Ubc9 induced SIRT1 expression in TNBC and ER-α expression in breast cancer cells. This is the first report demonstrating a role for Ubc9 in repressing both SIRT1 and ER-α expression in BRCA1 associated TNBC cells. It also suggests that the BARD-dependent E3 Ubiquitin ligase and HR (homologous recombination) activity of BRCA1 may not be required for inducing SIRT1 expression. Our results suggest for the first time that in BRCA1 mutant TNBC Ubc9-mediated induction of VEGF, inhibition of caveolin-1, SIRT1 and ER-α expression as a novel molecular mechanism underlying TNBC EMT (epithelial mesenchymal transition) leading to lung metastasis with pleural effusion. Drugs that target Ubc9 to both induce SIRT1 and ER-α or using SIRT1 agonists in combination with chemotherapy can be used as a promising targeted therapeutic approach for treating basal-like metastatic BRCA1-linked TNBC thus reducing the mortality in patients with TNBC.
The paper designed a small rapid power reduction system (SRPRS) based on gray control rods for pressurized nuclear power plants, and technical scheme of SRPRS was proposed in the paper. Different to current RPRS for turbine trip, SRPRS was designed for feed water pump trip. When one FWP happened, partial of gray banks dropped into the reactor core to reduce the core power, and reactor trip due to power mismatch between primary and secondary sides would be avoided. The paper researched the basic principles of SRPRS, and demonstrated the feasibility of using SRPRS in pressurized nuclear power plants with gray control rods. The small rapid power reduction system designed in the paper includes three stages: activation, recovery and normal operation. Each stage can automatically complete control actions with a few human intervention. The small rapid power reduction system makes full use of the gray control rod characteristics: low reactivity worth and small disturbance to core power distribution, so it can achieve rapid reduction of core power while maintaining a flat power distribution. Meanwhile, since the control rod insertion limit set in the technical specification does not limit the insertion of gray control rods, the operation of small rapid power reduction system will not exceed the requirements of the technical specification for normal operation. The paper designed a “slope factor” in small rapid power reduction system. By calculating the slope factor in advance and judging the rods to be dropped in real time, the small rapid power reduction system can perform its function at any initial gray control rod position.
Drug-resistant cases of human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitors (NRTI) are constantly accumulating due to the frequent mutations of the reverse transcriptase (RT). Predicting the potential drug resistance of HIV-1 NRTIs could provide instructions for the proper clinical use of available drugs. In this study, a novel proteochemometric (PCM) model was constructed to predict the drug resistance between six NRTIs against different variants of RT. Forty-seven dominant mutation sites were screened using the whole protein of HIV-1 RT. Thereafter, the physicochemical properties of the dominant mutation sites can be derived to generate the protein descriptors of RT. Furthermore, by combining the molecular descriptors of NRTIs, PCM modeling can be constructed to predict the inhibition ability between RT variants and NRTIs. The results indicated that our PCM model could achieve a mean AUC value of 0.946 and a mean accuracy of 0.873 on the external validation set. Finally, based on PCM modeling, the importance of features was calculated to reveal the dominant amino acid distribution and mutation patterns on RT, to reflect the characteristics of drug-resistant sequences.
The Sichuan–Yunnan block is located in the eastern of Tibetan Plateau and exhibits strong tectonic and earthquake activity. The Maisu fault is an E–W-trending fault within this block. Via interpretations of remote-sensing imagery and field surveys, we identified a earthquake surface rupture zone that has developed along the Maisu fault; we then estimated its Holocene activity. The surface rupture extends westward from the town of Puma, Sichuan Province, to the village of Worilong, Xizang Province, and has a length of approximately 45 km. According to a fault outcrop and carbon-14 dating of a profile near the village of Yongqu, Xizang Province, the most recent earthquake along this rupture may have occurred after 1850 ± 30 BP. The Maisu fault extends eastward and may intersect the Garzê–Yushu fault. Accordingly, as a secondary fault, the Maisu fault likely accommodates the partitioned horizontal slip deformation of the Garzê–Yushu fault.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.