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U-tube steam generators (UTSGs) are crucial in nuclear power plants, serving as the interface between the primary and secondary coolant loops. UTSGs ensure efficient heat exchange, operational stability, and safety, directly impacting the plant's efficiency and reliability. Existing UTSG models have fixed structures, which can only be used when certain parameters are given as model input. Such constraints hinder their ability to accommodate the diverse operating conditions, where input and output parameters can vary significantly. To address this challenge, we propose a machine learning-based method for developing a high-degree-of-freedom UTSG thermal model. The most notable feature of this approach is its capacity to flexibly interchange input and output parameters. By adopting comprehensive parameter sensitivity analysis, the most efficient method for training dataset generation is determined. Leveraging a lightweight machine learning method, the prediction accuracy for all UTSG parameters is improved to within 2.1%. The flexibility of the proposed machine learning approach ensures that the UTSG model can accommodate any type of parameter input without extensive reconfiguration of the model structure, thereby enhancing its applicability and robustness in real-world applications. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is a non-fermentative Gram-negative bacterium that can cause nosocomial infections in critically ill patients. Carbapenem-resistant A. baumannii (CRAB) has spread rapidly in clinical settings and has become a key concern. The main objective of this study was to identify the distribution of integrons and biofilm-formation-related virulence genes in CRAB isolates. A total of 269 A. baumannii isolates (219 isolates of CRAB and 50 isolates of carbapenem-sensitive A. baumannii (CSAB)) were collected. Carbapenemase genes (blaKPC, blaVIM, blaIMP, blaNDM, and blaOXA-23-like) and biofilm-formation-related virulence genes (abal, bfms, bap, and cusE) were screened with PCR. Class 1 integron was screened with PCR, and common promoters and gene cassette arrays were determined with restriction pattern analysis combined with primer walking sequencing. Whole-genome sequencing was conducted, and data were analyzed for a blaOXA-23-like-negative isolate. All 219 CRAB isolates were negative for blaKPC, blaVIM, blaIMP, and blaNDM, while blaOXA-23-like was detected in 218 isolates. The detection rates for abal, bfms, bap, and cusE in 219 CRAB were 93.15%, 63.93%, 88.13%, and 77.63%, respectively. Class 1 integron was detected in 75 CRAB (34.25%) and in 3 CSAB. The single gene cassette array aacA4-catB8-aadA1 with relatively strong PcH2 promoter was detected in class 1 integrons. The blaOXA-23-like-negative CRAB isolate was revealed to be a new sequence type (Oxford 3272, Pasteur 2520) carrying blaOXA-72, blaOXA-259, and blaADC-26. In conclusion, blaOXA-23-like was the main reason for CRAB's resistance to carbapenems. A new (Oxford 3272, Pasteur 2520) CRAB sequence type carrying the blaOXA-72, blaOXA-259, and blaADC-26 was reported. [ABSTRACT FROM AUTHOR]

Direct contact condensation (DCC) is a phenomenon observed when steam interacts with subcooled water, exhibiting higher heat and mass transfer rates compared to wall condensation. It has garnered significant interest across industries such as nuclear, chemical, and power due to its advantageous characteristics. In the context of pressure-relief tanks, understanding and optimizing the DCC process are critical for safety and efficiency. The efficiency of pressure-relief tanks depends on the amount of steam condensed per unit of time, which directly affects their operational parameters and design. This study focuses on investigating the direct gas–liquid contact condensation process in pressure-relief tanks using computational fluid dynamics (CFD). Through experimental validation and a sensitivity analysis, the study provides insights into the influence of inlet steam parameters and basin temperature on the steam plume characteristics. Furthermore, steady-state and transient calculation models are developed to simulate the behaviour of the pressure-relief tank, providing valuable data for safety analysis and design optimization. There is a relatively high-pressure area in the upper part of the bubble hole of the pressure-relief tube, and the value increases as it is closer to the holes. The steam velocity in the bubbling hole near the 90° elbow position is higher. This study contributes to the understanding of steam condensation dynamics in pressure-relief tanks. When the steam emission and pressure are fixed, the equilibrium temperature increases linearly as the initial temperature increases (where a = 1, b = 20 in y = a x+ b correlation), the equilibrium pressure increases nearly exponentially, and the equilibrium gas volume decreases. When the steam emission and initial temperature are fixed, the equilibrium temperature does not change as the steam discharge pressure increases. The correlations between the predicted equilibrium parameters and the inlet steam parameters and tank temperature provide valuable insights for optimizing a pressure-relief tank design and improving the operational safety in diverse industrial contexts. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 5 (PRMT5) catalyzes mono-methylation and symmetric di-methylation on arginine residues and has emerged as a potential antitumor target with inhibitors being tested in clinical trials. However, it remains unknown how the efficacy of PRMT5 inhibitors is regulated. Here we report that autophagy blockage enhances cellular sensitivity to PRMT5 inhibitor in triple negative breast cancer cells. Genetic ablation or pharmacological inhibition of PRMT5 triggers cytoprotective autophagy. Mechanistically, PRMT5 catalyzes monomethylation of ULK1 at R532 to suppress ULK1 activation, leading to attenuation of autophagy. As a result, ULK1 inhibition blocks PRMT5 deficiency-induced autophagy and sensitizes cells to PRMT5 inhibitor. Our study not only identifies autophagy as an inducible factor that dictates cellular sensitivity to PRMT5 inhibitor, but also unearths a critical molecular mechanism by which PRMT5 regulates autophagy through methylating ULK1, providing a rationale for the combination of PRMT5 and autophagy inhibitors in cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: PRMT5 is overexpressed and activated in various human cancers, including breast cancer. This study aims to dissect the mechanism underlying how PRMT5 is dysregulated in cancers. Our results demonstrate that TRAF6-mediated ubiquitination plays an important role in the regulation of PRMT5 activity and cell proliferation. Thus, inhibition of TRAF6 is a possible strategy for improving PRMT5 targeted therapy. Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme generating symmetric dimethylarginine (sDMA) on numerous substrates, through which it regulates many cellular processes, such as transcription and DNA repair. Aberrant expression and activation of PRMT5 is frequently observed in various human cancers and associated with poor prognosis and survival. However, the regulatory mechanisms of PRMT5 remain poorly understood. Here, we report that TRAF6 serves as an upstream E3 ubiquitin ligase to promote PRMT5 ubiquitination and activation. We find that TRAF6 catalyzes K63-linked ubiquitination of PRMT5 and interacts with PRMT5 in a TRAF6-binding-motif-dependent manner. Moreover, we identify six lysine residues located at the N-terminus as the primarily ubiquitinated sites. Disruption of TRAF6-mediated ubiquitination decreases PRMT5 methyltransferase activity towards H4R3 in part by impairing PRMT5 interaction with its co-factor MEP50. As a result, mutating the TRAF6-binding motifs or the six lysine residues significantly suppresses cell proliferation and tumor growth. Lastly, we show that TRAF6 inhibitor enhances cellular sensitivity to PRMT5 inhibitor. Therefore, our study reveals a critical regulatory mechanism of PRMT5 in cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial carcinoma is one of the most threatening gynecological malignancies to women's health, with mortality linked to it increasing, and finding novel and effective methods to combat endometrial carcinoma is becoming a clinical challenge. The stimulator of interferon genes (STING) pathway plays a crucial role in antitumor immunity, and it is strictly regulated by many types of post-translational modifications. The aim of our study was to uncover the expression and the contribution of acetylation involved in the regulation of STING to endometrial cancer. We confirmed that STING expression was deregulated by both β-estradiol and HDAC3, and worked as an important regulator of proliferation and apoptosis. Inhibition of HDAC3 increased STING expression, thereby inhibiting tumorigenesis. Therefore, this study uncovers a novel molecular mechanism by which HDAC3 inhibits STING transcription via β-estradiol-ERα, and provides a promising therapy with a combination of HDAC and STING for combating endometrial cancer. Purpose: The stimulator of interferon genes (STING) pathway plays a crucial role in antitumor immunity, and it is strictly regulated by many types of post-translational modifications. However, the contribution of acetylation involved in the regulation of STING to endometrial tumorigenesis remains unclear. Methods: We attempted to identify the key role of STING in endometrial carcinoma (EC) tissue and cell lines and explore its epigenetic regulation mechanism by HDACs that are critically involved in EC. We used IHC and qRT-PCR to detect the protein level and mRNA level of STING expression in endometrial carcinoma tissues, then explored the potential role of STING in tumor proliferation and apoptosis by CCK8 and flow cytometry, and identified the STING effect in the tumorigenicity by a mouse xenograft assay. We explored the possible relationship of acetylation alteration in STING regulation by ChIP analysis and Co-IP, and we knocked out STING in ECC1 and Ishikawa cells using CRISPR-Cas9 to further confirm the critical role of STING restoration induced by HDAC3 inhibitor RGFP-966 in the proliferation and apoptosis. Results: We found that STING expression was largely decreased and worked as an important regulator of cell proliferation and apoptosis; either activated or overexpressed STING, with both pharmacological and genetic approaches, largely blocked cell proliferation and induced apoptosis in EC. Moreover, STING expression was deregulated by both β-estradiol and HDAC3. Mechanically, we determined that HDAC3 can interact with β-estradiol-ERα and induce deacetylation of histone 3 lysine 4 at the STING promoter, thereby decreasing STING expression. Inhibition of HDAC3 increased STING expression, thereby inhibiting tumorigenesis. Conclusion: This study reveals a novel molecular mechanism by which HDAC3 inhibits STING transcription via β-estradiol-ERα and provides a promising therapy (a combination of HDAC and STING) for combating endometrial cancer. [ABSTRACT FROM AUTHOR]

In response to DNA damage, cells have developed a sophisticated signaling pathway, consisting of DNA damage sensors, transducers, and effectors, to ensure efficient and proper repair of damaged DNA. During this process, posttranslational modifications (PTMs) are central events that modulate the recruitment, dissociation, and activation of DNA repair proteins at damage sites. Emerging evidence reveals that protein arginine methylation is one of the common PTMs and plays critical roles in DNA damage response. Protein arginine methyltransferases (PRMTs) either directly methylate DNA repair proteins or deposit methylation marks on histones to regulate their transcription, RNA splicing, protein stability, interaction with partners, enzymatic activities, and localization. In this review, we summarize the substrates and roles of each PRMTs in DNA damage response and discuss the synergistic anticancer effects of PRMTs and DNA damage pathway inhibitors, providing insight into the significance of arginine methylation in the maintenance of genome integrity and cancer therapies. [ABSTRACT FROM AUTHOR]

Embryonic stem cells (ESCs) are a type of cells capable of self-renewal and multi-directional differentiation. The self-renewal of ESCs is regulated by factors including signaling pathway proteins, transcription factors, epigenetic regulators, cytokines, and small molecular compounds. Similarly, non-coding RNAs, small RNAs, and microRNAs (miRNAs) also play an important role in the process. Functionally, the core transcription factors interact with helper transcription factors to activate the expression of genes that contribute to maintaining pluripotency, while suppressing the expression of differentiation-related genes. Additionally, cytokines such as leukemia suppressor factor (LIF) stimulate downstream signaling pathways and promote self-renewal of ESCs. Particularly, LIF binds to its receptor (LIFR/gp130) to trigger the downstream Jak-Stat3 signaling pathway. BMP4 activates the downstream pathway and acts in combination with Jak-Stat3 to promote pluripotency of ESCs in the absence of serum. In addition, activation of the Wnt-FDZ signaling pathway has been observed to facilitate the self-renewal of ESCs. Small molecule modulator proteins of the pathway mentioned above are widely used in in vitro culture of stem cells. Multiple epigenetic regulators are involved in the maintenance of ESCs self-renewal, making the epigenetic status of ESCs a crucial factor in this process. Similarly, non-coding RNAs and cellular energetics have been described to promote the maintenance of the ESC's self-renewal. These factors regulate the self-renewal and differentiation of ESCs by forming signaling networks. This review focused on the role of major transcription factors, signaling pathways, small molecular compounds, epigenetic regulators, non-coding RNAs, and cellular energetics in ESC's self-renewal. [ABSTRACT FROM AUTHOR]

A full AKT activation event requires phosphorylation of AKT at Thr SP 308 sp (AKT-pThr SP 308 sp ) in the activation loop by PDK1 and Ser SP 473 sp (AKT-pSer SP 473 sp ) in the hydrophobic motif in a manner mediated by mTORC2 ([20]). Sin1-4A mutant inhibits AKT-pSer 473 in response to DNA damage.(A) MCF7- Sin1 KO cells were reconstituted with Sin1-WT or Sin1-4A. EV was a negative control. I ECT2 i -depleted cells exhibited similar reduction of AKT-pSer SP 473 sp as cells expressing Sin1-4A, and depletion of I ECT2 i in Sin1-4A-expressing cells had no additive effects in AKT-pSer SP 473 sp reduction (Fig. To investigate whether Sin1-pSQ governs mTORC2 activation in response to DNA damage, we reconstituted Sin1-WT or Sin1-4A mutant at comparable levels in I Sin1 i -knockout MCF7 cells ( I Sin1 i SP KO sp ) and I Sin1 i SP -/- sp MEFs. [Extracted from the article]

The implementation of strict emission control during the 11th National Minority Games (NMG) in September 2019 provided a valuable opportunity to assess the impact of such emission controls on the characteristics of VOCs and other air pollutants. Here, we investigated the characteristics of VOCs and the O3 – NOx –VOC sensitivity comprehensively in Zhengzhou before, during, and after the NMG by delivering field measurements combined with WRF-CMAQ (Weather Research and Forecasting Community Multiscale Air Quality) model simulations. The average mixing ratios of VOCs during the control periods were 121 ± 55 µgm-3 and decreased by about 19 % and 11 % before and after emission reduction. The ozone precursors (NOx) also decreased significantly during the control period; however, the ozone pollution was severe during the entire observation period. Positive matrix factorization analysis indicated seven major sources of ambient VOCs, including coal combustion, biomass burning, vehicle exhausts, industrial processes, biogenic emissions, solvent utilization, and liquefied petroleum gas (LPG). The results show that the major source emissions, such as coal combustion and solvent utilization, were significantly reduced during the control period. As for ozone formation potential (OFP), the value during the control period was 183 ± 115 µgm-3 , which was 0.23 and 0.17 times lower than before and after the control period, respectively. Solvent utilization and combustion controls were the most important measures taken to reduce OFP during the NMG period. Control policies can effectively reduce carcinogenic risk. However, non-cancer risks of ambient VOC exposures were all exceeding the safe level (hazard quotient = 1) during the sampling periods, and emphasis on the reduction of acrolein emissions was needed. In addition, the WRF-CMAQ model simulation indicated that O3 formation was controlled by VOCs in Zhengzhou. The results of the Empirical Kinetic Modeling Approach showed that the NOx reduction in Zhengzhou might lead to higher ozone pollution. It is suggested that reduction ratios of the precursors (VOCs : NOx) should be more than 2, which can effectively alleviate ozone pollution. [ABSTRACT FROM AUTHOR]

AKT is involved in a number of key cellular processes including cell proliferation, apoptosis and metabolism. Hyperactivation of AKT is associated with many pathological conditions, particularly cancers. Emerging evidence indicates that arginine methylation is involved in modulating AKT signaling pathway. However, whether and how arginine methylation directly regulates AKT kinase activity remain unknown. Here we report that protein arginine methyltransferase 5 (PRMT5), but not other PRMTs, promotes AKT activation by catalyzing symmetric dimethylation of AKT1 at arginine 391 (R391). Mechanistically, AKT1-R391 methylation cooperates with phosphatidylinositol 3,4,5 trisphosphate (PIP3) to relieve the pleckstrin homology (PH)-in conformation, leading to AKT1 membrane translocation and subsequent activation by phosphoinositide-dependent kinase-1 (PDK1) and the mechanistic target of rapamycin complex 2 (mTORC2). As a result, deficiency in AKT1-R391 methylation significantly suppresses AKT1 kinase activity and tumorigenesis. Lastly, we show that PRMT5 inhibitor synergizes with AKT inhibitor or chemotherapeutic drugs to enhance cell death. Altogether, our study suggests that R391 methylation is an important step for AKT activation and its oncogenic function. Arginine methylation has been reported to regulate AKT-associated signalling. Here, the authors show that PRMT5-mediated arginine methylation promotes AKT activity and induces tumourigenesis. [ABSTRACT FROM AUTHOR]

The implementation of strict emission control during the 1lth National Minority Games (NMG) in September 2019 provided a valuable opportunity to assess the impact of such emission controls on the characteristics of VOCs and other air pollutants. Here, we investigated the characteristics of VOCs and the O3-NOx-VOCs sensitivity comprehensively in Zhengzhou before, during, and after the NMG by delivering field measurements combined with the WRF (Weather Research and Forecasting)-CMAQ (Community Multi-scale Air Quality) model simulations. The average mixing ratios of VOCs during the control periods were 34 ppbv, and cut down by about 16% before and after emission reduction. The ozone precursors (NOx) also decreased significantly during the control period; however, the ozone pollution was severe during the entire observation period. Positive Matrix Factorization analysis indicated seven major sources of ambient VOCs, including coal combustion, biomass burning, vehicle exhausts, industrial processes, biogenic emissions, solvent utilization and liquefied petroleum gas (LPG). The results show that the major source emissions, such as coal combustion and solvent utilization, were significantly reduced during the control period. As for ozone formation potential (OFP), the value during the control period was 183 μg/m3, which was 0.23 and 0.17 times lower than those before and after control period, respectively. Solvent utilization and combustion controls were the most important measures taken to reduce OFP during NMG period. Through control policies, it can effectively reduce carcinogenic risk. However, non-cancer risks of ambient VOC exposures were all exceeding the safe level (hazard quotient = 1) during the sampling periods, and emphasis on the reduction of acrolein emissions was needed. In addition, the WRF/CMAQ model simulation indicated that 03 formation was controlled by VOCs in Zhengzhou. The results of the Empirical Kinetic Modelling Approach showed that the NOx reduction in Zhengzhou might led to higher ozone pollution. It is suggested that reduction ratios of the precursors (VOCs:NOx) is more than 2, which can effectively alleviate ozone pollution. [ABSTRACT FROM AUTHOR]

Particle acidity is a fundamental property that affects atmospheric particulate chemistry. Synchronous online monitoring was performed at two urban sites, Zhengzhou (U-ZZ) and Anyang (U-AY), and three rural sites, Anyang (R-AY), Xinxiang (R-XX), and Puyang (R-PY) in Henan Province, during a haze episode to investigate the pH value and its driving factors in the agricultural regions of China. The pH values of particles calculated by ISORROPIA-II model at rural sites were slightly higher than those at urban sites, with the median (min–max) values of 5.2 (4.8–6.9, R-PY), 5.1 (4.7–6.5, R-AY), 4.9 (4.1–6.8, R-XX), 4.8 (3.9–5.9, U-AY), and 4.5 (3.8–5.2, U-ZZ). Sensitivity tests show that TNHx (total ammonium, gas + aerosol) followed by total sulfate were the most important factors that influenced the predicted pH. Generally, particle pH increased with a cation increase and decreases in anions, temperature, and relative humidity. Similar pH values (∼3.0) at the required NHx concentrations for the five sites indicated that the presence of excess NHx was likely important for the lower acidity of PM2.5 during the severe haze episodes in this region. Moreover, the concentrations of excess NHx may drive the higher pH values at rural sites, because of the higher excess NHx concentrations at rural sites than those at urban sites. The underlying influence of regional transport on local particle pH cannot be neglected, as it differs the chemical components of PM2.5 and meteorological conditions. Air masses transported from rural and agricultural regions may enhance the particle pH value in urban aerosols given the high pH of particles and high ammonia levels. These results suggest that ammonia is urgently needed to be involved in the regional strategy for the improvement of air quality in China. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a common histomorphological feature of renal aging and chronic kidney diseases of all etiologies, and its initiation and progression are substantially influenced by aberrant epigenetic modifications of fibrosis-susceptible genes, yet without effective therapy. "Epigenetic diets" exhibit tissue-protective and epigenetic-modulating properties; however, their anti-renal fibrosis functions and the underlying mechanisms are less understood. In this study, we show that genistein, a phytoestrogenic isoflavone enriched in dietary soy products, exhibits impressive anti-renal fibrosis activities by recovering epigenetic loss of Klotho, a kidney-enriched anti-aging and fibrosis-suppressing protein. Mouse fibrotic kidneys induced by UUO (unilateral ureteral occlusion) displayed severer Klotho suppression and adverse expression of renal fibrosis-associated proteins, but genistein administration markedly recovered the Klotho loss and attenuated renal fibrosis and the protein expression abnormalities. The examination of possible causes of the Klotho recovery revealed that genistein simultaneously inhibited histone 3 deacetylation of Klotho promoter and normalized the promoter DNA hypermethylation by suppressing elevated DNA methyltransferase DNMT1 and DNMT3a. More importantly, genistein's anti-renal fibrosis effects on the renal fibrotic lesions and the abnormal expressions of fibrosis-associated proteins were abrogated when Klotho is knockdown by RNA interferences in UUO mice. Thus, our results identify Klotho restoration via epigenetic histone acetylation and DNA demethylation as a critical mechanism of genistein's anti-fibrosis function and shed new lights on the potentials of epigenetic diets in preventing or treating aging or renal fibrosis-associated kidney diseases. Key messages: Genistein prevents renal fibrosis and the associated Klotho suppression in UUO mice. Genistein upregulates Klotho in part by reversing the promoter histone 3 hypoacetylation. Genistein also preserves Klotho via relieving Klotho promoter hypermethylation. Genistein demethylates Klotho promoter by inhibiting aberrant DNMT1/3a expression. Genistein restoration of Klotho is essential for its anti-renal fibrosis function. [ABSTRACT FROM AUTHOR]

Bubble departure diameter has a significant effect on nucleate boiling heat transfer characteristics, so it is necessary to study it in depth. The existing models are usually developed emperically and the bubble departure diameter model established based on dimensionless numbers is not clear in the physical significance. In this paper, a theoretical prediction model of bubble departure diameter is established based on the force anywise. Chen's experiment data is used to validate the model, the averaged relative deviation between the predict results of the model and the experimental data is less than 22. 29%. [ABSTRACT FROM AUTHOR]

TIMAP (TGFβ-inhibited membrane-associated protein) is an endothelium-enriched TGFβ downstream protein and structurally belongs to the targeting subunit of myosin phosphatase; however, the mechanism of TGFβ repressing TIMAP and its functional relevance to TGFβ bioactivity remain largely unknown. Here, we report that TIMAP is reduced in TGFβ-elevated mouse fibrotic kidney and highly expressed in macrophages. TGFβ repression of TIMAP is associated with HDAC3 upregulation and its recruitment by Smad2/3 at the Smad binding element on TIMAP promoter, whereas specific HDAC3 inhibition reversed the TIMAP repression, suggesting that TGFβ transcriptionally downregulates TIMAP through HDAC3-associated Smad signaling. Further investigation showed that TIMAP over-expression interrupted TGFβ-associated Smad signaling and TIMAP repression by TGFβ correlated with TGFβ-induced macrophage M2 polarization markers, migration, and phagocytosis-the processes promoted by phosphorylation of the putative TIMAP substrate myosin light chain (MLC). Consistently, TIMAP dephosphorylated MLC in macrophages and TGFβ induced macrophage migration and phagocytosis in TIMAP- and MLC phosphorylation-dependent manners, suggesting that TIMAP dephosphorylation of MLC constitutes an essential regulatory loop mitigating TGFβ-associated macrophage M2 phenotypic activities. Given that hyperactive TGFβ often causes excessive macrophage phagocytic activities potentially leading to various chronic disorders, the strategies targeting HDAC3/TIMAP axis might improve TGFβ-associated pathological processes. Key message: [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin complex1 (mTORC1) is a central regulator of metabolism and cell growth by sensing diverse environmental signals, including amino acids. The GATOR2 complex is a key component linking amino acid signals to mTORC1. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical regulator of GATOR2. In response to amino acids, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote PRMT1 translocation from nucleus to cytoplasm and lysosome, which in turn methylates WDR24, an essential component of GATOR2, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses hepatocellular carcinoma (HCC) cell proliferation and xenograft tumor growth. High PRMT1 protein expression is associated with elevated mTORC1 signaling in patients with HCC. Thus, our study dissects a phosphorylation- and arginine methylation-dependent regulatory mechanism of mTORC1 activation and tumor growth and provides a molecular basis to target this pathway for cancer therapy. [Display omitted] • PRMT1 is required for amino-acid-induced mTORC1 activation • CDK5 phosphorylates PRMT1 to promote its cytoplasmic localization and activity • PRMT1 methylates WDR24 to promote mTORC1 activation by amino acids • The CDK5-PRMT1-WDR24 axis is critical for cell proliferation and tumor growth Yin et al. find that CDK5 serves as an upstream kinase and WDR24 acts as a downstream target of PRMT1 to promote mTORC1 pathway activation in response to amino acids. They further show that disruption of CDK5, PRMT1, and WDR24 suppresses tumor growth, implicating their therapeutic potential. [ABSTRACT FROM AUTHOR]

Introduction: Carbon monoxide (CO) released from CORM-2 has anti-inflammatory function, but the critical molecule mediating the inflammation inhibition has not been elucidated. Previous studies indicate that CORM-2 can activate Nrf2, a key transcription factor regulating host defense against oxidative stress and inflammation-related disorders. In this study we use Nrf2 knockout mice to determine the role of Nrf2 in mediating the CO anti-inflammatory action. Methods: We compared CORM-2's inhibiting effect on pro-inflammatory cytokine expressions (TNF-α, IL-1β and IL-6 and iNOS) in primary peritoneal macrophages, mouse liver and brain tissues from Nrf2 and Nrf2 mice. We further assayed the inflammatory cell infiltration in both liver and brain tissues of the Nrf2 and Nrf2 mice. Finally, we examined CORM's influence on mouse mortality in a mouse sepsis model. Results: Our results showed that CORM-2 dramatically inhibited the expression of pro-inflammatory cytokines in Nrf2 mice, but not in Nrf2 mice. Furthermore CORM-2 substantially decreased LPS-induced mouse mortality of Nrf2 mice, but not of Nrf2 mice. Conclusion: We conclude that Nrf2 is indispensable for CORM-2 inhibition of LPS-induced inflammation. [ABSTRACT FROM AUTHOR]

To assess the exposure doses of PM and to investigate its chemical components for the subpopulation (i.e., school children and industrial downwind residents), simultaneous sampling of indoor and outdoor PM was conducted at an elementary school close to traffic arteries and a residence located in the downwind area of a steel plant in metropolitan Guangzhou in 2010. Chemical components, i.e., organic carbon, elemental carbon and 6 water soluble ions were analyzed in PM. A survey was also conducted to investigate the time-activity patterns of the school children and the industrial downwind residents. Indoor and outdoor PM were 63.2 ± 20.1 and (76.7 ± 35.8) μg/m at the school, and 118.8 ± 44.7 and 125.7 ± 57.1 μg/m in the community, respectively. Indoor PM was found to be highly related to outdoor sources, and stationary sources were the significant contributors to PM at both sites. The daily average doses of PM for the school children at the school ( D) and the industrial downwind residents in the community ( D) were (7.6 ± 1.9) and (36.1 ± 36.8) μg/kg-day, respectively. The daily average doses of particulate organic mass and SO were the two most abundant chemical components in PM. PM exposure for the school children was contributed by indoor and outdoor environments by 48.8 and 51.2 %, respectively; for the industrial downwind residents, the contributions were 66.0 and 34.0 %, respectively. Age and body weight were significantly and negatively correlated with D, while age, body weight and education level were significantly and negatively correlated with D; gender was not a significant factor at both cases. [ABSTRACT FROM AUTHOR]

With the rapid development of the social economy in China, numerous Chinese cities are facing high levels of particulate matter (PM) pollution problems. In this study, high-resolution ZY-3 images and GIS techniques were used to establish the emission inventory of total suspended particle (TSP), particulate matter 10 (PM10) and particulate matter 2.5 (PM2.5) from fugitive dust sources in May 2016, and a spatial grid of 3 km × 3 km resolution was established to demonstrate the spatial distribution of PM emission. Results showed that the total emissions of TSP, PM10 and PM2.5 in Zhengzhou city were 237.5 kt·a−1, 103.7 kt·a−1 and 22.4 kt·a−1, respectively. Construction dust source was the main fugitive dust emission source in Zhengzhou city—the TSP, PM10 and PM2.5 emission of which account for 76.42%, 89.68% and 88.39%, respectively, of the total emission, followed by road dust source and soil dust source. PM emission was higher in Zhongyuan, Huiji, Jinshui and Zhengdong New District, while Zhongmou, Xingyang, Dengfeng and other remote areas had low PM emissions. Compared to other Chinese cities or regions, the PM emission from the construction dust source was at a high level in Zhengzhou city, while the PM emissions from the soil dust source and road dust source were at moderate levels. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, proliferation, and metabolism by integrating various environmental inputs including growth factors, nutrients, and energy, among others. mTOR signaling has been demonstrated to control almost all fundamental cellular processes, such as nucleotide, protein and lipid synthesis, autophagy, and apoptosis. Over the past fifteen years, mapping the network of the mTOR pathway has dramatically advanced our understanding of its upstream and downstream signaling. Dysregulation of the mTOR pathway is frequently associated with a variety of human diseases, such as cancers, metabolic diseases, and cardiovascular and neurodegenerative disorders. Besides genetic alterations, aberrancies in post-translational modifications (PTMs) of the mTOR components are the major causes of the aberrant mTOR signaling in a number of pathologies. In this review, we summarize current understanding of PTMs-mediated regulation of mTOR signaling, and also update the progress on targeting the mTOR pathway and PTM-related enzymes for treatment of human diseases. [ABSTRACT FROM AUTHOR]

Bone loss and increased fracture are the devastating outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD) resulting from Klotho deficit-related mineral disturbance and hyperparathyroidism. Because Klotho down-regulation after renal injury is presumably affected by aberrant histone deacetylase (HDAC) activities, here we assess whether HDAC inhibition prevents Klotho loss and attenuates the CKD-associated bone complication in a mouse model of CKD-MBD. Mice fed adenine-containing diet developed the expected renal damage, a substantial Klotho loss and the deregulated key factors causally affecting bone remodeling, which were accompanied by a marked reduction of bone mineral density. Intriguingly, administration of a potent HDAC inhibitor trichostatin A (TSA) impressively alleviated the Klotho deficit and the observed alterations of serum, kidney and bone. TSA prevented Klotho loss by increasing the promoter-associated histone acetylation, therefore increasing Klotho transcription. More importantly the mice lacking Klotho by siRNA interference largely abolished the TSA protections against the serum and renal abnormalities, and the deranged bone micro-architectures. Thus, our study identified Klotho loss as a key event linking HDAC deregulation to the renal and bone injuries in CKD-MBD mice and demonstrated the therapeutic potentials of endogenous Klotho restoration by HDAC inhibition in treating CKD and the associated extrarenal complications. [ABSTRACT FROM AUTHOR]