Machine learning assesses drivers of PM2.5 air pollution trend in the Tibetan Plateau from 2015 to 2022.

The Tibetan Plateau (known as the Earth's Third Pole) has significant impact on climate. Fine particulate matter (PM2.5) is an important air pollutant in this region and has significant impact on health and climate. To mitigate PM2.5 air pollution over China, a series of clean air actions has been implemented. However, interannual trends in particulate air pollution and its response to anthropogenic emissions in the Tibetan Plateau are poorly understood. Here, we applied a random forest (RF) algorithm to quantify drivers of PM2.5 trends in six cities of the Tibetan Plateau from 2015 to 2022. The decreasing trends (-5.31 to -0.73 µg m-3 a-1) in PM2.5 during 2015-2022 were observed in all cities. The RF weather-normalized PM2.5 trends - which were driven by anthropogenic emissions - were -4.19 to -0.56 µg m-3 a-1, resulting in dominant contributions (65 %-83 %) to the observed PM2.5 trends. Relative to 2015, such anthropogenic emission driver was estimated to contribute -27.12 to -3.16 µg m-3 to declines in PM2.5 concentrations in 2022. However, the interannual changes in meteorological conditions only made a small contribution to the trends in PM2.5 concentrations. Potential source analysis suggested biomass burning from local residential sector and/or long-range transports originated from South Asia could significantly promote PM2.5 air pollution in this region. Based on health-risk air quality index (HAQI) assessment, the HAQI value was decreased by 15 %-76 % between 2015 and 2022 in these cities, with significant contributions (47 %-93 %) from anthropogenic emission abatements. Indeed, relative contribution of PM2.5 to the HAQI was decreased from 16 %-30 % to 11 %-18 %, while increasing and significant contribution from ozone was observed, highlighting that further effective mitigation of both PM2.5 and ozone air pollution could obtain more substantial health benefits in the Tibetan Plateau.

MEIS-mediated suppression of human prostate cancer growth and metastasis through HOXB13-dependent regulation of proteoglycans.

The molecular roles of HOX transcriptional activity in human prostate epithelial cells remain unclear, impeding the implementation of new treatment strategies for cancer prevention and therapy. MEIS proteins are transcription factors that bind and direct HOX protein activity. MEIS proteins are putative tumor suppressors that are frequently silenced in aggressive forms of prostate cancer. Here we show that MEIS1 expression is sufficient to decrease proliferation and metastasis of prostate cancer cells in vitro and in vivo murine xenograft models. HOXB13 deletion demonstrates that the tumor-suppressive activity of MEIS1 is dependent on HOXB13. Integration of ChIP-seq and RNA-seq data revealed direct and HOXB13-dependent regulation of proteoglycans including decorin (DCN) as a mechanism of MEIS1-driven tumor suppression. These results define and underscore the importance of MEIS1-HOXB13 transcriptional regulation in suppressing prostate cancer progression and provide a mechanistic framework for the investigation of HOXB13 mutants and oncogenic cofactors when MEIS1/2 are silenced.

Decisions regarding the treatment of patients with early-stage prostate cancer are often based on the risk that the cancer could grow and spread quickly. However, it is not always straightforward to predict how the cancer will behave. Studies from 2017 and 2018 found that samples of less aggressive prostate cancer have higher levels of a group of proteins called MEIS proteins. MEIS proteins help control the production of numerous other proteins, which could affect the behavior of prostate cancer cells in many ways. VanOpstall et al. ­ including some of the researchers that performed the 2017 and 2018 studies ­ have investigated how MEIS proteins affect prostate cancer. When prostate cancer cells are implanted into mice, they result in tumors. VanOpstall et al. found that tumors that produced MEIS proteins grew more slowly. Next, MEIS proteins were extracted from the prostate cancer cells and were found to interact with another protein called HOXB13, which regulates the activity of numerous genes. When the cells were genetically modified to prevent HOXB13 being produced, the protective effect of MEIS proteins was lost. MEIS proteins work with HOXB13 to regulate the production of several other proteins, in particular a protein called Decorin that can suppress tumors. When MEIS proteins and HOXB13 are present, the cell produces more Decorin and the tumors grow more slowly and are less likely to spread. VanOpstall et al. found that blocking Decorin production rendered MEIS proteins less able to slow the spread of prostate cancer. These results suggest that MEIS proteins and HOXB13 are needed to stop tumors from growing and spreading, and some of this ability is by prompting production of Decorin. This study explains how MEIS proteins can reduce prostate cancer growth, providing greater confidence in using them to determine whether aggressive treatment is needed. A greater understanding of this pathway for tumor suppression could also provide an opportunity for developing anti-cancer drugs.

Indole-core-based novel antibacterial agent targeting FtsZ.

BACKGROUND: The prevalence of drug-resistant bacterial infections urges the development of new antibacterial agents that possess a mechanism of action different from traditional antibiotics. FtsZ has been recognized as a key functional protein in bacterial cell division and it is currently believed to be a potential target for the development of novel antibacterial agents. PURPOSE: The primary aim of the study is to screen out an inhibitor targeting at FtsZ and followed to investigate its antibacterial activity and mode of action. METHODS: Cell-based cell division inhibitory screening assay, antimicrobial susceptibility test, minimum bactericidal concentration assay, time-killing curve determination, FtsZ polymerization assay, GTPase activity assay, and molecular modeling were performed in the present study. RESULTS: The screening study from a small library consisting of benzimidazole and indole derivatives discovered a compound (CZ74) with an indole-core structure. The compound exhibited strong cell division inhibitory effect. In addition, CZ74 shows high antibacterial potency against a number of tested Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. The minimum inhibitory concentration values obtained were within the range of 2-4 µg/mL. The results of biological study revealed that CZ74 at 2 µg/mL is able to disrupt FtsZ polymerization and inhibit GTPase activity and cell division. From molecular modeling study, CZ74 is found possibly binding into the interdomain cleft of FtsZ protein and then leads to inhibitory effects. CONCLUSION: This indole-cored molecule CZ74 could be a potential lead compound and could be further developed as a new generation of antibacterial agents targeting FtsZ to combat against multidrug-resistant bacteria.