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East China Sea and its adjacent areas are an important part of the circum-Pacific tectonic belt, and its fluctuation characteristics of Moho can provide an important basis for the study of the deep structure of the western Pacific. At present, the inversion of Moho depth based on potential field data is an important task. Meanwhile, its inversion accuracy is closely related to the gravity anomaly data quality, and to the density contrasts and inversion algorithm. We use the fast solution algorithm of forward problem for gravity field in a dual interface model to eliminate the gravity influence of terrain and sediments, and adopt the minimum curvature potential field separation method to remove the effect of residual geological bodies. Then we try to identify the Moho gravity anomaly as the regional field which has the strongest correlation with depths estimations from seismic data. Regression analysis and the "3σ" principle are used to delete the constraint points of Moho depth with large deviations, and the Bouguer plate formula is used to estimate the laterally variable density contrasts of Moho. Finally, the Moho depth in East China Sea and its adjacent areas is obtained by the dual-interface fast inversion algorithm, and the inversion deviations are mostly concentrated within 2 km. The inversion result shows that there is an obvious local uplift zone of Moho in East China Sea Basin, while the Okinawa Trough basin is located on a whole Moho uplift. The strike of the two uplift belts has the same change from NE to NNE.

Aiming at the difficulty of numerical simulation of the DDT process during the detonation combustion of aviation kerosene, this paper has presented a single-component simplified mechanism of aviation kerosene to carry out the numerical simulation of the DDT detonation process. By simplifying the detailed mechanism of n-decane, the simplified mechanism of RP-3 aviation kerosene single-component alternative fuel was obtained, and the DDT process of aviation kerosene was numerically simulated, and the influence law of the obstacle blocking ratio and arrangement mode on the DDT process was analyzed. The results show that the simplified mechanism model for the single-component alternative fuel can better fit the combustion characteristics of aviation kerosene under high temperature and pressure. The numerical simulation results of the DDT process are analyzed, and it is found that the DDT time will increase with the increasing of blocking ratio. The DDT time at the same blocking ratio is shorter when the obstacles are symmetrically distributed.

Figure S4. Sensitivity to AZD1775 in ATRX WT and KO PLC/PRF/5 cells after adjusting for differences in growth rates.

The tumor suppressor gene ATRX is frequently mutated in a variety of tumors including gliomas and liver cancers, which are highly unresponsive to current therapies. Here, we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for ATRX-mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase WEE1, uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines in vitro, as well as xenografts in vivo. The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage–induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring ATRX mutations, indicating that the synthetic lethal relationship between WEE1 and ATRX could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in ATRX.Significance:ATRX-mutant cancer cells depend on WEE1, which provides a basis for therapeutically targeting WEE1 in ATRX-deficient cancers.See related commentary by Cole, p. 375

Treatment of AZD1775 activated CDK pathway, which leads to S-phase arrest and DNA damage, and finally apoptosis of cells.

An efficient, robust, and cost-effective synthetic process of fasudil hydrochloride 1 was developed. Starting from readily available ethylenediamine and 5-isoquinoline sulfonyl chloride, the target...

Diabetic retinopathy (DR) has been regarded as a sight-threatening vascular complication of diabetes mellitus. Accumulating evidence has identified the involvement of long non-coding RNAs (lncRNAs) in DR pathogenesis. We aim to investigate the role and underlying mechanism of linc00174 in the DR process. Samples of human vitreous humour from proliferative DR and non-diabetic individuals were collected to examine the levels of linc00174. Human retinal microvascular endothelial cells (HRMECs) exposed with high glucose (HG) were employed to simulate the pathological statues of DR. Short hairpin RNA specifically targeting linc00174 was applied. CCK-8, transwell, and matrigel tube formation were performed to evaluate cell proliferation, migration, and angiogenesis. Bioinformatics analysis and luciferase reporter assay were conducted to verify the linc00174/miR-150-5p/vascular endothelial growth factor A (VEGFA) regulatory network. Western blotting was employed to determine the expression of VEGFA. Linc00174 was significantly elevated in patients with DR, as well as HG-stimulated HRMECs, of which knockdown repressed HG-induced proliferation, migration, and angiogenesis. miR-150-5p was identified as a downstream effector to be involved in linc00174-mediated protective effects. miR-150-5p directly bound to the 3′ untranslated region of VEGFA. The linc00174/miR-150-5p/VEGFA axis was confirmed in retinal vascular dysfunction. The linc00174 deteriorates diabetic retinal microangiopathy via regulating miR-150-5p/VEGFA pathway, indicating a novel therapeutic target for DR treatment.

Intraoperative cholangiography (IOC) has always been the gold standard for diagnosing biliary atresia (BA). Our study attempted to diagnose BA using laparoscopic fluorescein cholangiography (LFC).We retrospectively included 18 patients with preoperative suspected BA as the case group and 4 without extrahepatic biliary obstruction requiring laparoscopic surgery as the control group. All patients received indocyanine green (ICG) intravenously at 0.05 mg/Kg. The first 6 patients in the case group underwent IOC and LFC simultaneously, and the control group completed LFC. The imaging characteristics of LFC were recorded and summarized by the conventional and fluorescence mode of the endoscopic fluorescence imaging system (DPM-ENDOCAM-03). On this basis, 12 patients in the case group were diagnosed as BA according to LFC without IOC, and all 18 patients completed open Kasai surgery to confirm the diagnosis.Laparoscopic fluorescence mode in BA detected liver fluorescence but no visualization of the extrahepatic bile ducts. However, the extrahepatic bile ducts in the control group were visible. Based on the imaging characteristics summarized from the LFC of the first 6 cases with BA in the case group, the remaining 12 cases who only underwent LFC were also successfully diagnosed with BA. Furthermore, the formation of hepatic hilar fibrous mass was found in all the patients during the open Kasai procedure, which confirmed the BA diagnosis.LFC appears as a specific pattern in BA and can be used for intraoperative diagnosis of BA. It has the advantages of simplicity, short time-consuming, and no radiation damage.

Gravity and magnetic data have unique advantages for studying the lateral extents of geologic bodies. There is a class of methods for edge recognition called maximum-edge-recognition methods (MERMs) that use their extreme values to locate the edges of geologic bodies. These methods include the total horizontal derivative (THDR), the analytic signal amplitude, the theta map, and the normalized standard deviation. These are all first-order derivative-based techniques. There are also higher-order derivative-based methods that are derived from the first-order filters, for example, the THDR of the tilt angle. We have developed an edge-recognition filter that is based on the idea of the normalized vertical derivatives (VDRs) of existing methods. For each MERM, we first calculate its nth-order VDR and then use thresholding to locate its peaks. The peak values are subsequently normalized by the values of the original MERM. Testing on synthetic and real data indicates that the normalized VDRs of the MERMs have higher accuracy and better lateral resolution and they are more interpretable than existing techniques; thus, they are a worthwhile addition to the set of edge-detection tools for potential-field data.

We aim to share our experience of esophageal elongation by bougienage and delayed primary thoracoscopic anastomosis for pure esophageal atresia (EA) without tracheoesophageal fistula (TEF).Fifteen patients with pure EA treated with delayed primary thoracoscopic anastomosis combined with or without esophageal elongation by bougienage were retrospectively analyzed.Four patients were managed without bougienage, and their surgical repair was performed thoracoscopically after natural esophageal growth. Among the remaining 11 patients, the average tension-free distance before elongation was 5 (4.5-6) vertebral bodies, and the mean age at the start and end of the bougienage period was 123 (63-280) days and 173 (106-350) days, respectively, with an average duration of 50 (29-82) days. The average age at the definitive operation in this series was 184 (107-385) days, with a mean operative duration of 186 (95-300) min. Neither anastomotic leakage nor TEF occurred, and oral feeding was partially or completely established in 13 patients during hospitalization. Among all patients, one was lost to follow-up, and others were followed up with an average duration of 47.7 (9.8-97.1) months. All patients had different degrees of anastomosis stricture, and 8 patients had gastroesophageal reflux. Oral feeding was completely established in 12 patients; however, tube feeding was required in 2 patients.The management of pure EA is complicated and inconclusive. Esophageal elongation by bougienage and delayed primary thoracoscopic anastomosis for long-gap pure EA without TEF is safe and effective.