Hypermethylation of BMPR2 and TGF-ß Promoter Regions in Tibetan Patients with High-Altitude Polycythemia at Extreme Altitude.

Although the expression of many genes is associated with adaptation to high-altitude hypoxic environments, the role of epigenetics in the response to this harsh environmental stress is currently unclear. We explored whether abnormal DNA promoter methylation levels of six genes, namely, ABCA1, SOD2, AKT1, VEGFR2, TGF-ß, and BMPR2, affect the occurrence and development of high-altitude polycythemia (HAPC) in Tibetans. The methylation levels of HAPC and the control group of 130 Tibetans from very high altitudes (> 4500 m) were examined using quantitative methylation-specific real-time PCR (QMSP). Depending on the type of data, the Pearson chi-square test, Wilcoxon rank-sum test, and Fisher exact test were used to assess the differences between the two groups. The correlation between the methylation levels of each gene and the hemoglobin content was explored using a linear mixed model. Our experiment revealed that the methylation levels of the TGF-ß and BMPR2 genes differed significantly in the two groups (p < 0.05) and linear mixed model analysis showed that the correlation between the hemoglobin and methylation of ABCA1, TGF-ß, and BMPR2 was statistically significant (p < 0.05). Our study suggests that levels of TGF-ß and BMPR2 methylation are associated with the occurrence of HAPC in extreme-altitude Tibetan populations among 6 selected genes. Epigenetics may be involved in the pathogenesis of HAPC, and future experiments could combine gene and protein levels to verify the diagnostic value of TGF-ß and BMPR2 methylation levels in HAPC.

[Detection and Significance of Molecular Markers in Immunotherapy and Targeted Therapy of Colorectal Cancer in Tibet].

Objective To study the expression of SWI/SNF-related,matrix-associated,actin-dependent regulator of chromatin,subfamily A,member 4(SMARCA4)/Brahma-related gene 1,V-raf murine sarcoma viral oncogene homolog B(BRAF),P53,programmed cell death protein-1(PD-1),and programmed death-ligand 1(PD-L1),and changes in the expression of BRAF and neurotrophic tyrosine receptor kinase(NTRK) in the patients with colorectal cancer in Tibet,thereby providing a basis for targeted therapy and immunotherapy for this disease in Tibet. Methods A total of 64 patients with colorectal cancer resected in the Tibet Autonomous Region People's Hospital from January 2015 to July 2021 were enrolled in this study.The expression of SMARCA4,BRAF,P53,PD-1,and PD-L1 was detected by immunohistochemical staining.The gene fusion involving NTRK1,NTRK2,and NTRK3 was detected by fluorescence in situ hybridization,and the BRAF V600E gene mutation by polymerase chain reaction. Results The 64 patients with colorectal cancer were at a male-to-female ratio of 1.21∶1,with the mean age of (56.59±13.27) years.The tumors were located in the colon in 46(71.88%) patients and in the rectum in 18(28.12%) patients.Sixty(93.75%) patients presented adenocarcinoma,and 4(6.25%) patients presented other types of tumors.The patients in T1/T2 and T3/T4 phases accounted for 17.19%(n=11) and 82.81%(n=53),respectively.Lymph node metastasis occurred in 24(37.50%) patients.The immunohistochemical staining results showed partially down-regulated or absent expression of SMARCA4 in 1(1.56%) patient,positive BRAF expression in 4(6.25%) patients,and mutant expression of P53 in 35(54.69%) patients.The PD-1-expressing tumor associated immune cell was proportion score<10% in 45(70.31%) patients and≥10% in 19(29.69%) patients.The PD-L1 combined positive score was<10 in 52(81.25%) patients and≥10 in 12(18.75%) patients.The gene fusion of NTRK1,NTRK2,and NTRK3 was negative in all the patients,and BRAF V600E gene mutation was positive in 4(6.25%) patients.The SMARCA4 gene alteration was not detected in the patient with partial expression missing of SMARCA4.The PD-L1 combine positive score was correlated with the deficient mismatch repair(dMMR)/microsatellite instability-high (MSI-H) and the PD-1 expression (χ2=10.223,P=0.001;χ2=11.979,P=0.001). Conclusions The down-regulated or absent SMARCA4 expression and NTRK gene fusion are rare in the patients with colorectal cancer in Tibet.A few patients present BRAF V600E gene mutations,and Pan-TRK and BRAF expression can be used for the primary screening of NTRK gene fusion and BRAF gene mutation.The patients with dMMR/MSI-H are prone to high expression of PD-L1 and expected to benefit from immunotherapy.No significant correlation exists between P53 mutation and PD-L1 expression.The high expression of PD-1 is positively correlated with the high expression of PD-L1.

Structure Performance Correlation of N-Heterocyclic Oligomer Leveler for Acid Copper Plating of Advanced Interconnects.

Levelers, as an essential part of organic additives in copper electroplating, play a crucial role in the fabrication of sophisticated interconnects in integrated circuits, packaging substrates, and printed circuit boards. In this work, four N-heterocyclic oligomers were synthesized and characterized, along with investigations of their electrochemical behaviors and their synergism with other bath components. The corresponding effects of the oligomers on the deposited copper films were analyzed by morphological and compositional characterizations. The leveling mechanism of the oligomers was further discussed with the aid of quantum chemical calculations. The results exhibit that each of these N-heterocyclic oligomers holds a particular degree of leveling ability. The oligomer of 1,3-bis(1-imidazolyl)propane and 1,3-dichloro-2-propanol (IPIEP) is the best leveler for THs plating compared with the other three oligomers. It was found that the hydroxyl group in IPIEP enhances the hydrophilicity of the modified molecule and triggers a more stable complexation between IPIEP and H2O-Cu(I)-MPS. Moreover, imidazole demonstrates a better practicality than piperazine. This work recommends the combination of N-heterocycles in planar conformation with modification by the hydroxyl group to synthesize high-performance straight-chain levelers.

Electroless deposition of Ni-P/Au coating on Cu substrate with improved corrosion resistance from Au(iii)-DMH based cyanide-free plating bath using hypophosphite as a reducing agent.

The green cyanide-free gold deposition is an important development direction in electroless gold plating. However, the commonly Au(i) based cyanide-free gold plating bath always suffers from severe corrosion to the Ni-P layer and unsatisfactory service life of the bath. In this work, a green and environmentally friendly cyanide-free gold plating bath was developed with hypophosphite added as a reducing agent into the Au(iii)-DMH (5,5-dimethylhydantoin) based plating bath to retard the corrosion of the Ni-P layer. SEM micrographs combined with XRD and XPS analysis indicated that the electroless deposited gold was pure and compact. And XRD also revealed that the oriented deposition of gold was growing preferentially on Au (111). Corrosion tests, including salt spray tests, potentiodynamic polarization tests, and electrochemical impedance spectroscopy tests, indicated that the obtained Cu/Ni-P/Au coatings had significantly improved corrosion resistance performance with the loading of hypophosphite as the reducing agent. The baths remained transparent and no turbidity or precipitates were detected for 210 days, reflecting good stability. The detection for the Ni2+ concentration in the bath showed that adding hypophosphite could retard the replacement reaction between Au3+ and the Ni-P layer in part and this is important for decreasing the severe corrosion of the Ni-P layer. Moreover, Au was inactive for catalyzing the oxidation of hypophosphite during the deposition process which was confirmed furthermore via quantum chemical calculations. Therefore, our developed green cyanide-free electroless gold deposition process can beneficially provide research value and application prospects in microelectronic industry.