Ripretinib inhibits HIV-1 transcription through modulation of PI3K-AKT-mTOR.

Despite the effectiveness of antiretroviral therapy (ART) in prolonging the lifespan of individuals infected with HIV-1, it does not offer a cure for acquired immunodeficiency syndrome (AIDS). The "block and lock" approach aims to maintain the provirus in a state of extended transcriptional arrest. By employing the "block and lock" strategy, researchers endeavor to impede disease progression by preventing viral rebound for an extended duration following patient stops receiving ART. The crux of this strategy lies in the utilization of latency-promoting agents (LPAs) that are suitable for impeding HIV-1 provirus transcription. However, previously documented LPAs exhibited limited efficacy in primary cells or samples obtained from patients, underscoring the significance of identifying novel LPAs that yield substantial outcomes. In this study, we performed high-throughput screening of FDA-approved compound library in the J-Lat A2 cell line to discover more efficacious LPAs. We discovered ripretinib being an LPA candidate, which was validated and observed to hinder proviral activation in cell models harboring latent infections, as well as CD4+ T cells derived from infected patients. We demonstrated that ripretinib effectively impeded proviral activation through inhibition of the PI3K-AKT-mTOR signaling pathway in the HIV-1 latent cells, thereby suppressing the opening states of cellular chromatin. The results of this research offer a promising drug candidate for the implementation of the "block and lock" strategy in the pursuit of an HIV-1 cure.

[Responses of tree growth and intrinsic water-use efficiency of Robinia pseudoacacia to climate factors]. / åˆºæ§ç”Ÿé•¿å’Œå† åœ¨æ°´åˆ†åˆ©ç”¨æ•ˆçŽ‡å¯¹æ°”å€™å› å­çš„å“åº”.

We investigated tree growth in Robinia pseudoacacia plantations at Ansai in Shaanxi Province and at Ji-xian in Shanxi Province by comparing the tree-ring width, basal area increase (BAI), δ13C value, intrinsic water-use efficiency (iWUE), and stomatal regulation. We quantified the responses of tree growth and iWUE to climatic factors at each site. The tree-ring width at Ansai and Jixian decreased with stand age, whereas the BAI at Ansai increased, and that at Jixian decreased after the BAI peaked. The δ13C value and iWUE of trees at Jixian were higher than those at Ansai. The iWUE of trees at both sites was similar to the constant intercellular CO2 concentration/atmospheric CO2 concentration (Ci/Ca) scenario, indicating that the Ci of trees was elevated with increasing Ca, while the stomata remained open. The BAI at Ansai was significantly positively correlated with highest temperature in May, relative humidity in June, precipitation in August, relative humidity in September, and standardized precipitation evapotranspiration index (SPEI) in September and October of current year, but negatively correlated with temperature in June. The BAI at Jixian was significantly positively correlated with SPEI in June and July, and lowest temperature in October of current year. The iWUE of trees at Ansai was significantly positively correlated with relative humidity and precipitation in June of the current year, but negatively correlated with minimum temperature in May, relative humidity in June, and temperature and maximum temperature in July of current year. A significant positive correlation between iWUE of trees at Jixian and lowest temperature in June of current year was detected. At the annual scale, the BAI of trees at Ansai was positively correlated with precipitation and SPEI, but no significant relationship was observed for trees at Jixian. However, the iWUE of trees at both sites was significantly affected by precipitation. Path analysis showed that SPEI and minimum temperature had a direct effect on BAI and iWUE of trees at Ansai, whereas precipitation and average temperature indirectly affected BAI and iWUE through SPEI. The highest temperature had a direct effect on tree growth at Jixian, whereas precipitation, minimum temperature, and average temperature had direct effects on iWUE. These results suggested that SPEI was the main climatic factor that affected the growth of R. pseudoacacia, while Ci was an important physiological factor. Our results could provide reference for the protection and management of R. pseudoacacia plantations under climate change.

[A 1:2 matched case-control study on the interaction of HPV16E6 and HLA-DR9 allele to esophageal cancer in Kazakh ethnicity, Xinjiang].

OBJECTIVE: To evaluate the role and the association between HPV16E6 infection and HLA-DR9 immune-associated gene to esophageal cancer (EC) in Kazakh of Xinjiang, China. METHODS: A 1:2 matched case-control study was conducted with 63 cases of EC and 126 controls involved. The controls were matched by sex, nationality, area of residence and age within 5-year difference. HPV16E6 and HLA-DR9 allele were identified by PCR-SSP. Interaction was performed to identify risk factors. RESULTS: HPV16E6 infection and HLA-DR9 allele positive status were the risk factors for EC, with OR values as 2.67 (95%CI: 1.38 - 5.17) and 3.83 (95%CI: 1.48 - 9.96) respectively. The rate of HPV16E6 infection in individuals with HLA-DR9 allele was different from the ones who were HLA-DR9 allele free (chi(2) = 7.57, P = 0.006), with OR value as 5.79 (95%CI: 1.53 - 21.87). In the controls, the rates of HPV16E6 infection were 22.2% and 16.2% among individuals with HLA-DR9 allele atatus as positive or negative, and without statistically significant difference. Interaction analysis showed there was an interaction of HPV16E6 with HLA-DR9 and were higher than the sum of the two factors presented individually. CONCLUSION: In our study, we found that the HLA-DR9 allele and HPV16E6 infection had a function of synergy in the process of malignant transformation of esophageal epithelial cells, and jointly promoting the occurrence and development of EC.

[Clinical observation on treatment of Stein-Leventhal syndrome caused sterility by combined use of clomiphene and Chinese nourishing shen and activating blood circulation drugs].

OBJECTIVE: To observe the efficacy of combination therapy of clomiphene and Chinese drugs for nourishing Shen and activating blood circulation (NSABC) in treating Stein-Leventhal syndrome caused sterility. METHODS: Sixty-two patients with anovulation caused sterility were randomly divided into the treated group (n = 32) and the control group (n = 30). The treated grop was treated with the combination therapy and the control group treated by the same dosage of clomiphene alone. RESULTS: After treatment, when comparing with that before treatment, the endocrine hormones in the treated group improved significantly, showing a markedly decrease of androgen and luteotropic hormone, and increase of estrogen (P < 0.001). The periodic ovulation rate in the treated group reached 87%, the total pregnancy rate being 65.6%, with no occurrence of ovarian hyperstimulation syndrome (OHSS) and luteinized unruptured follicle syndrome (LUFS), while in the control group, the periodic ovulation rate was 66%, the total pregnancy rate 36.6%, with LUFS occurred in 4 patients. Comparison of the therapeutic effects between the two groups showed significant difference (P < 0.05). CONCLUSION: The combination therapy of clomiphene and NSABC has a better therapeutic effect in treating Stein-Leventhal syndrome caused sterility than that of using clomiphene alone.