The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability.

Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5+ intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.

An evolving assessment model for environmental carrying capacity: A case study of coral reef islands.

Environmental carrying capacity (ECC) provides an insight into measuring sustainability of the vulnerable coral reef islands. However, an integrated assessment of ECC on the social-ecological system of reef islands is rarely existence. And conventional approaches miss addressing the difference of social development, which would lead to a misinterpretation of sustainable development of reef island system. This study develops an evolving model of RI-ECC which incorporates five specific development phases, and the assessment involves (1) identification and measurement of carrying components, (2) supply/demand surplus analysis of indicators and (3) ECC states determination. A case study is conducted in Zhaoshu Island of China, indicating the efficiency of RI-ECC model and serving as a reference for adaptive management.

The contribution of toll-like receptor 2 on Helicobacter pylori activation of the nuclear factor-kappa B signaling pathway in gastric epithelial cells.

Helicobacter pylori (H. pylori) is a spiral shaped gram-negative bacterium that induces immune responses in the gastric mucosa. Toll-like receptors (TLRs) play important roles in mediating inflammatory cytokines by recognition of conserved molecular patterns on bacteria. Changes in the expression of toll-like receptor (TLR) 2, TLR4 and the relative inflammatory cytokines were analyzed in normal gastric epithelial GES-1 cells following treatment with H. pylori or Escherichia coli lipopolysaccharide (E. coli LPS) in order to investigate the contribution of TLRs in recognizing and mediating the inflammatory response to H. pylori, and study the differences in TLRs' performance between H. pylori and E. coli. Specific inhibitors for the declines in TLR2 and TLR4 were also employed. The results showed that H. pylori infection increased TLR2 expression in GES-1 cells, but TLR4 remained unchanged regardless of H. pylori or TLR2 small interfering RNA treatment. Furthermore, the secretion of cyclooxygenase-2 (COX-2) induced by H. pylori was inhibited by declines in TLR2, but not in TLR4. In conclusion, TLR2 plays an even more important role than TLR4 not only in recognizing H. pylori, but also in the induction of inflammatory cytokines initiated by H. pylori. However, both TLR2 and TLR4 are necessary in mediating the inflammatory response to E. coli LPS.

Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer.

Lineage plasticity causes therapeutic resistance; however, it remains unclear how the fate conversion and phenotype switching of cancer-associated fibroblasts (CAFs) are implicated in disease relapse. Here, we show that androgen deprivation therapy (ADT)-induced SPP1+ myofibroblastic CAFs (myCAFs) are critical stromal constituents that drive the development of castration-resistant prostate cancer (CRPC). Our results reveal that SPP1+ myCAFs arise from the inflammatory CAFs in hormone-sensitive PCa; therefore, they represent two functional states of an otherwise ontogenically identical cell type. Antiandrogen treatment unleashes TGF-ß signaling, resulting in SOX4-SWI/SNF-dependent CAF phenotype switching. SPP1+ myCAFs in turn render PCa refractory to ADT via an SPP1-ERK paracrine mechanism. Importantly, these sub-myCAFs are associated with inferior therapeutic outcomes, providing the rationale for inhibiting polarization or paracrine mechanisms to circumvent castration resistance. Collectively, our results highlight that therapy-induced phenotypic switching of CAFs is coupled with disease progression and that targeting this stromal component may restrain CRPC.

Analysis of the Electricity Consumption in Municipal Wastewater Treatment Plants in Northeast China in Terms of Wastewater Characteristics.

A municipal wastewater treatment plant plays an important role in treating urban sewage and reducing the quantity of pollutants discharged into rivers. However, the energy consumption of the municipal wastewater treatment industry is large. High energy consumption indirectly produces ecological damage, accelerates the energy crisis, and increases carbon emissions. For energy conservation and emission reduction in wastewater treatment plants, it is first necessary to identify the main factors influencing energy consumption. Electricity consumption accounts for more than 80% of the energy consumption of wastewater treatment plants. Wastewater quantity and wastewater quality have become the key influencing factors of energy conservation and consumption reduction in wastewater treatment plants. In this study, a municipal wastewater treatment plant in Northeast China was selected as the research object, and the measured data, such as air temperature, wastewater quantity, wastewater quality, and electricity consumption of the plant from 2017 to 2020 were statistically analyzed to explore the influences of temperature and wastewater quantity and wastewater quality indicators of influent and effluent on energy consumption. Firstly, the range of influent quantity in the wastewater treatment plant was large. The influent quantity in summer was high because some rainwater entered the sewage treatment plant. In winter, average daily electricity consumption (ADEC) was higher than that in summer. The relationship between ADEC and the wastewater quantity showed a positive correlation, and ADEC slowly increased with the increase in wastewater quantity. Electricity consumption per unit of wastewater (UEC) was negatively correlated with the wastewater quantity, but the correction coefficient in winter was larger than that in summer. Secondly, the ranges of chemical oxygen demand (CODCr) and ammonia nitrogen in influent were large, and the ranges of CODCr and ammonia nitrogen in effluent were small. Influent CODCr concentration was negatively correlated with influent ammonia nitrogen concentration. ADEC increased slightly with the increase in influent CODCr concentration. In winter, the increasing trend of ADEC with the influent CODCr concentration was higher than that in the summer. The increasing trend of UEC with the increase in influent COD concentration in summer was more significant than that in winter. Thirdly, influent CODCr in 11.6% of the samples exceeded the corresponding designed value, and influent ammonia nitrogen concentration in 41.4% of the samples exceeded the corresponding designed value. Effluent CODCr in 10.6% of the samples exceeded the First Level Class B standard in "Discharge Standard of Pollutants for Municipal Wastewater Treatment Plants (GB18918-2002)", and unqualified CODCr in 94% of the effluent samples was ascribed to the unqualified ammonia nitrogen concentration in the influent samples. The electricity consumption level under abnormal conditions was higher than that under normal conditions. Fourthly, ADEC was positively correlated with the average daily CODCr reduction. The correction coefficient of ADEC with average daily CODCr reduction was greater in winter than that in summer. Fifthly, the average electricity consumption per unit of wastewater was close to the national average energy consumption, displaying the characteristics of high energy consumption in winter and low energy consumption in summer. The correlation analysis results of unit electricity consumption and temperature showed that when it was below 0 °C, the lower the temperature, the higher the electricity consumption. In Northeast China, the influences of seasons and temperatures on the electricity consumption of sewage plants were obvious. Accordingly, it is necessary to implement the diversion of rainwater and sewage, reduce the discharge of unqualified wastewater from enterprises, and take thermal insulation measures in winter. In addition, activated sludge microorganisms suitable for a low temperature area and the optimal scheduling of sewage pipe networks can also improve the operation and management of sewage treatment plants.

Histone methyltransferase WHSC1 loss dampens MHC-I antigen presentation pathway to impair IFN-γ-stimulated antitumor immunity.

IFN-γ-stimulated MHC class I (MHC-I) antigen presentation underlies the core of antitumor immunity. However, sustained IFN-γ signaling also enhances the programmed death ligand 1 (PD-L1) checkpoint pathway to dampen antitumor immunity. It remains unclear how these opposing effects of IFN-γ are regulated. Here, we report that loss of the histone dimethyltransferase WHSC1 impaired the antitumor effect of IFN-γ signaling by transcriptional downregulation of the MHC-I machinery without affecting PD-L1 expression in colorectal cancer (CRC) cells. Whsc1 loss promoted tumorigenesis via a non-cell-autonomous mechanism in an Apcmin/+ mouse model, CRC organoids, and xenografts. Mechanistically, we found that the IFN-γ/STAT1 signaling axis stimulated WHSC1 expression and, in turn, that WHSC1 directly interacted with NLRC5 to promote MHC-I gene expression, but not that of PD-L1. Concordantly, silencing Whsc1 diminished MHC-I levels, impaired antitumor immunity, and blunted the effect of immune checkpoint blockade. Patient cohort analysis revealed that WHSC1 expression positively correlated with enhanced MHC-I expression, tumor-infiltrating T cells, and favorable disease outcomes. Together, our findings establish a tumor-suppressive function of WHSC1 that relays IFN-γ signaling to promote antigen presentation on CRC cells and provide a rationale for boosting WHSC1 activity in immunotherapy.

ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression.

Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKß activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression of Arid1a-deficient tumors. Mechanistically, inflammatory cues activate IKKß to phosphorylate ARID1A, leading to its degradation via ß-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKß/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression.

Development of a comprehensive assessment model for coral reef island carrying capacity(CORE-CC).

Coral reef islands provide precious living space and valuable ecological services for human beings, and its sustainability cannot be ignored under the pressure of human activities. Carrying capacity (CC) assessment has gradually become an important means to measure sustainability of islands. However, there is little comprehensive evaluation of the carrying capacity of coral reef islands, and traditional evaluation methods are difficult to express the social-ecological characteristics of coral reef islands. The present paper proposes a comprehensive assessment model for coral reef island carrying capacity (CORE-CC) which comprises dimensions of resources supply, environmental assimilative, ecosystem services, and socio-economic supporting. According to the characteristics of the coral reef islands, the core factors and indicators of each dimension are selected and the corresponding assessment index system of "pressure-support" is constructed. The assessment involves (1) identification of carrying dimensions and core factors, (2) pressure/support measurement and (3) assessment of carrying state. A case study is conducted in Zhaoshu Island of China, demonstrating the applicability of CORE-CC model and serving as a reference for adaptive management.

Drug repurposing for cancer treatment through global propagation with a greedy algorithm in a multilayer network.

OBJECTIVE: Drug repurposing, the application of existing therapeutics to new indications, holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development. The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases, particularly cancers. METHODS: Here, by targeting 4,096 human diseases, including 384 cancers, we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in DrugBank. We performed additional experimental validation for the dominant repurposed drugs in cancer. RESULTS: The overall performance of the model was well supported by cross-validation and literature mining. Focusing on the top-ranked repurposed drugs in cancers, we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments. Because of the distinctive antitumor effects of nifedipine (an antihypertensive agent) and nortriptyline (an antidepressant drug) in prostate cancer, we further explored their underlying mechanisms by using quantitative proteomics. Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication, the cell cycle, and RNA transport. Moreover, in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model. CONCLUSIONS: Our predicted results, which have been released in a public database named The Predictive Database for Drug Repurposing (PAD), provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.

SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways.

The level of SETD2-mediated H3K36me3 is inversely correlated with that of EZH2-catalyzed H3K27me3. Nevertheless, it remains unclear whether these two enzymatic activities are molecularly intertwined. Here, we report that SETD2 delays prostate cancer (PCa) metastasis via its substrate EZH2. We show that SETD2 methylates EZH2 which promotes EZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state that enables cells to acquire metastatic traits. Conversely, mice harboring nonmethylated EZH2 mutant or SETD2 mutant defective in binding to EZH2 develop metastatic PCa. Furthermore, we identify that metformin-stimulated AMPK signaling converges at FOXO3 to stimulate SETD2 expression. Together, our results demonstrate that the SETD2-EZH2 axis integrates metabolic and epigenetic signaling to restrict PCa metastasis.

Analysis of the land use structure changes based on Lorenz curves.

Land use change has become a new field in global change research, and it is closely related to land resource security and sustainable development. The environmental simulation model was mostly used to study the land-use change before. In this paper, we use the Economic Lorenz curve and Gini coefficient of economic model to study the land use structure changes in the western plain of Jilin Province, China. The results showed that the Lorenz curve has the phenomenon of "two near and two far" and Gini coefficient "two increased and two decreased". That is to say, during the 15 years from 1989 to 2004, the areas of cultivated land and unused land had increased, Lorenz curves were near to the perfect equality line, and the distribution tended to be uniform; the areas of grassland and water body were reduced, the Lorenz curves were away from the perfect equality line, and the distribution tended to be increasingly uneven, which reflects the main process of the land use structure changes. Studying on the land use changes based on Economic model is simpler and more intuitionistic, and had the generalization values.

Chromatin remodeling ATPase BRG1 and PTEN are synthetic lethal in prostate cancer.

Loss of phosphatase and tensin homolog (PTEN) represents one hallmark of prostate cancer (PCa). However, restoration of PTEN or inhibition of the activated PI3K/AKT pathway has shown limited success, prompting us to identify obligate targets for disease intervention. We hypothesized that PTEN loss might expose cells to unique epigenetic vulnerabilities. Here, we identified a synthetic lethal relationship between PTEN and Brahma-related gene 1 (BRG1), an ATPase subunit of the SWI/SNF chromatin remodeling complex. Higher BRG1 expression in tumors with low PTEN expression was associated with a worse clinical outcome. Genetically engineered mice (GEMs) and organoid assays confirmed that ablation of PTEN sensitized the cells to BRG1 depletion. Mechanistically, PTEN loss stabilized BRG1 protein through the inhibition of the AKT/GSK3ß/FBXW7 axis. Increased BRG1 expression in PTEN-deficient PCa cells led to chromatin remodeling into configurations that drove a protumorigenic transcriptome, causing cells to become further addicted to BRG1. Furthermore, we showed in preclinical models that BRG1 antagonist selectively inhibited the progression of PTEN-deficient prostate tumors. Together, our results highlight the synthetic lethal relationship between PTEN and BRG1 and support targeting BRG1 as an effective approach to the treatment of PTEN-deficient PCa.

A Vector-Based Short Hairpin RNA Targeting Aurora B Suppresses Human Prostatic Carcinoma Growth.

Aurora kinase B, playing a vital, important role in mitosis, is frequently detected to be overexpressed in many cancer cell lines and various tumor tissues, including prostatic carcinoma. Given the essential function of Aurora kinase B in mitosis and its association with tumorigenesis, it might be a drug target for prostatic carcinoma treatment. In our study, short hairpin RNA targeting Aurora kinase B was cloned into a pGPU6 plasmid vector and then transfected into human prostatic carcinoma cells. The expression level of Aurora kinase B was verified by reverse transcription-polymerase chain reaction and Western blot. At the same time, cell apoptosis was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, fluorescent staining, and flow cytometric analysis. Furthermore, prostate carcinoma cells were injected into mice to establish a tumor xenograft model. Previous studies have shown the effect of pGPU6-shAURKB plasmid on tumor growth in a prostate carcinoma xenogenic implantation model. From the study, we knew that the Aurora kinase B was significantly downregulated in prostate carcinoma cells, and cell apoptosis was also detected higher in treated groups than that in control groups. Moreover, in the prostate carcinoma xenogenic implantation model, compared with the control groups, the tumor growth was inhibited about 78.7% in the pGPU6-shAURKB plasmid-treated group, and cell apoptosis in the experimental group was notably higher than that in control groups. The average duration of tumor-bearing mice was prolonged to about 35 days. The results of experiment indicated that specific knockdown of Aurora kinase B led to prostate carcinoma cells apoptosis and inhibited tumor growth. Our data clearly confirmed that specific knockdown of Aurora kinase B expression by vector-based short hairpin RNA/liposome may be a potential new approach to treat human prostatic carcinoma.

The effect of trimethylamine N-oxide on Helicobacter pylori-induced changes of immunoinflammatory genes expression in gastric epithelial cells.

Colonization of Helicobacter pylori (H. pylori) induces immune and inflammatory response in gastric mucosa. Trimethylamine N-oxide (TMAO), from diet and metabolite through the action of gut microbiota, has been linked to inflammatory diseases. To investigate the effects of TMAO and H. pylori infection on gene expression in gastric epithelial cells, Human gene chip Affymetrix HTA 2.0 was used in this study. 1312 genes were identified as differentially expressed genes in GES-1 cells with H. pylori and TMAO co-treatment compared to the control. GO and KEGG analyses indicated that the functions of these differentially expressed genes were related closely with immune inflammation. GO-network showed that Toll-like receptor signaling pathway was the most important biological processes and 49 up-regulated genes related to immune inflammation were obtained. The synergistic effects of H. pylori and TMAO enhanced the genes expression of IL-6, CXCL1, CXCL2, FOS and C3 related to immune inflammation in comparison with those of non-infected control cells, H. pylori-infected cells, and TMAO-stimulated cells. RT-PCR verified the expression levels of IL-6, CXCL1. Additionally, expression levels of 2053 genes were altered and 52 immunoinflammatory genes were upregulated in comparison with H. pylori-infected cells. This study suggested that TMAO altered the expression levels of immunoinflammatory genes induced by H. pylori infection, and the synergistic effects of H. pylori and TMAO provided novel insights into the development of chronic gastritis, gastric ulcer and gastric cancer.

Antibacterial activity of Pyrrosia petiolosa ethyl acetate extract against Staphylococcus aureus by decreasing hla and sea virulence genes.

The aim of this study was to explore the antibacterial activity of Pyrrosia petiolosa ethyl acetate extract (PPEAE) against Staphylococcus aureus in vitro and analyse its chemical components by gas chromatograph-mass spectrometry. The results of anti-microbial assay revealed that PPEAE had strong inhibitory activity against S .aureus, with MIC and MBC of 7.8 and 15.6 mg/mL, respectively. The transcriptional levels of hla and sea were reduced to 14.33 and 46.39% at the MIC compared to the control. Analysing test result exhibited that eugenol made a great contribution to antibacterial activity. This experiment indicated that PPEAE had prominent antibacterial activity against S. aureus.