Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis.

Osteoarthritis (OA) is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA. These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium. In this study, we found that phosphoglycerate mutase 5 (PGAM5) significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models. To address the role of PGAM5 in macrophages in OA, we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo. Mechanistically, we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways, whereas inhibited M2 polarization via STAT6-PPARγ pathway in murine bone marrow-derived macrophages. Furthermore, we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2 (DVL2) which resulted in the inhibition of ß-catenin and repolarization of M2 macrophages into M1 macrophages. Conditional knockout of both PGAM5 and ß-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice. Motivated by these findings, we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection, which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis. Collectively, these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.

Identification and functional analysis of Toll-like receptor 2 from razor clam Sinonovacula constricta.

Toll-like receptor 2 (TLR2) is a member of TLR family that plays important roles in the innate immune system, such as pathogen recognition and inflammation regulation. In this study, the TLR2 homologue was cloned from razor clam Sinonovacula constricta (denoted as ScTLR2) and its immune function was explored. The full-length cDNA of ScTLR2 comprised 2890 nucleotides with a 5'-UTR of 218 bp, an open reading frame of 2169 bp encoding 722 amino acids and a 3'-UTR of 503 bp. The deduced amino acid of ScTLR2 showed similar structure to TLR2 homologue with a conserved signal peptide, four LRR domains, one LRR-TYP domain, one LRR-CT domain, one transmembrane domain and a conserved TIR domain. ScTLR2 mRNA was detected in all examined tissues with the highest expression in the gill. After Vibrio parahaemolyticus challenge, the mRNA expression of ScTLR2 was significantly induced both in gill and haemocytes. The recombinant ScTLR2-LRR protein could bind all tested PAMPs including LPS, PGN and MAN. Bacterial agglutination assay showed that rScTLR2 could agglutinate the six tested bacteria with a calcium dependent manner. More importantly, ScTLR2 silencing by siRNA transfection could significantly depress the mRNA expression of Myd88, NF-κB, Tollip, IRF1, and IRF8. The survival rate of S. constricta was markedly decreased after V. parahaemolyticus challenge under this condition. Our current study demonstrated that ScTLR2 served as a pattern recognition receptor to induce immune response against invasive pathogen.

Deubiquitinating enzyme OTUD4 stabilizes RBM47 to induce ATF3 transcription: a novel mechanism underlying the restrained malignant properties of ccRCC cells.

Dysregulation of deubiquitination contributes to various diseases, including cancer, and aberrant expression of deubiquitinating enzymes is involved in carcinoma progression. As a member of the ovarian tumor (OTU) deubiquitinases, OTUD4 is considered a tumor suppressor in many kinds of malignancies. The biological characteristics and mechanisms of OTUD4 in clear cell renal cell carcinoma (ccRCC) remain unclear. The downregulation of OTUD4 in ccRCC was confirmed based on the TCGA database and a validation cohort of 30-paired ccRCC and para-carcinoma samples. Moreover, OTUD4 expression was detected by immunohistochemistry in 50 cases of ccRCC tissues, and patients with lower levels of OTUD4 showed larger tumor size (p = 0.015). TCGA data revealed that patients with high expression of OTUD4 had a longer overall survival rate. In vitro and in vivo studies revealed that downregulation of OTUD4 was essential for tumor cell growth and metastasis in ccRCC, and OTUD4 overexpression inhibited these malignant phenotypes. We further found that OTUD4 sensitized ccRCC cells to Erastin-induced ferroptosis, and ferrostain-1 inhibited OTUD4-induced ferroptotic cell death. Mechanistic studies indicated that OTUD4 functioned as an anti-proliferative and anti-metastasic factor through the regulation of RNA-binding protein 47 (RBM47)-mediated activating transcription factor 3 (ATF3). OTUD4 directly interacted with RBM47 and promoted its stability via deubiquitination events. RBM47 was critical in ccRCC progression by regulating ATF3 mRNA stability, thereby promoting ATF3-mediated ferroptosis. RBM47 interference abolished the suppressive role of OTUD4 overexpression in ccRCC. Our findings provide mechanistic insight into OTUD4 of ccRCC progression and indicate a novel critical pathway OTUD4/RBM47/ATF3 may serve as a potential therapeutic pathway for ccRCC.

Strategies to Promote the Journey of Nanoparticles Against Biofilm-Associated Infections.

Biofilm-associated infections are one of the most challenging healthcare threats for humans, accounting for 80% of bacterial infections, leading to persistent and chronic infections. The conventional antibiotics still face their dilemma of poor therapeutic effects due to the high tolerance and resistance led by bacterial biofilm barriers. Nanotechnology-based antimicrobials, nanoparticles (NPs), are paid attention extensively and considered as promising alternative. This review focuses on the whole journey of NPs against biofilm-associated infections, and to clarify it clearly, the journey is divided into four processes in sequence as 1) Targeting biofilms, 2) Penetrating biofilm barrier, 3) Attaching to bacterial cells, and 4) Translocating through bacterial cell envelope. Through outlining the compositions and properties of biofilms and bacteria cells, recent advances and present the strategies of each process are comprehensively discussed to combat biofilm-associated infections, as well as the combined strategies against these infections with drug resistance, aiming to guide the rational design and facilitate wide application of NPs in biofilm-associated infections.

Lipid-like gemcitabine diester-loaded liposomes for improved chemotherapy of pancreatic cancer.

Gemcitabine (GEM) is a non-selective chemotherapeutic agent used in the treatment of pancreatic cancer. Its antitumor efficacy is limited by a short plasma half-life and severe adverse reactions. To overcome these shortcomings, four novel lipid-like GEM diesters were synthesized and encapsulated into liposomes. Through optimization, dimyristoyl GEM (dmGEM)-loaded liposomes (LipodmGEM) were successfully obtained with an almost complete encapsulation efficiency. Compared to free GEM, LipodmGEM showed enhanced cellular uptake and cell apoptosis, improved inhibition of cell migration on AsPC-1 cells and a greatly extended half-life (7.22 vs. 1.78 h). LipodmGEM succeeded in enriching the drug in the tumor (5.28 vs. 0.03 µmol/g at 8 h), overcoming a major shortcoming of GEM, showed excellent anticancer efficacy in vivo and negligible systemic toxicity, superior to GEM. Attractive as well, suspensions of LipodmGEM remained stable at 2-10 °C away from light for no <2 years. Our results suggest that LipodmGEM might become of high interest for treating pancreatic cancer while the simple strategy we reported might be explored as well for converting other antitumor drugs with high water-solubility and short plasma half-life into attractive nanomedicines.

Altered NCR3 Splice Variants May Result in Deficient NK Cell Function in Renal Cell Carcinoma Patients.

BACKGROUND/AIM: The natural killer (NK) cell function of patients with malignant tumours may be suppressed by deficiency, and the poor prognosis of renal cell carcinoma (RCC) patients may be due to escape from NK cell cytotoxicity, especially with respect to natural cytotoxicity receptors (NCRs) on the NK cell surface. However, the specific mechanism remains unclear. Therefore, in this study, we sought to explore the role of NCR, especially NCR3 splice variants, in the process of NK cell deficiency in RCC patients. MATERIALS AND METHODS: We used flow cytometry to analyse the phenotype of NK cells from the peripheral blood and kidney tumour tissue of RCC patients. The NKp30-mediated NK cell killing function was measured by antibody-dependent cell-mediated cytotoxicity (ADCC) in NK and RCC cell coincubation. We extracted RNA from the peripheral blood mononuclear cells (PBMCs) of RCC patients and renal carcinoma tissue and carried out real-time quantitative PCR to detect the mRNA levels of NKp30a, NKp30b and NKp30c. mRNA expression levels of cytokines (IL-6, IL-8, IL-10, IL-18 and TGF-ß) based on RNA extracted from renal carcinoma tissue and adjacent normal kidney tissues were also measured by real-time quantitative PCR. RESULTS: Regarding the phenotype of NK cells in RCC patients, the proportion of NK cells in tumour tissue was significantly reduced, with changes in the NK cell proportion being most obvious in NKp30+ NK cells. Furthermore, the results of the ADCC function assay showed limited NKp30+ NK cell-mediated cytotoxicity in RCC patients. Through real-time quantitative PCR, we found lower expression of NKp30a and NKp30b, the immunostimulatory splice variants of NCR3 encoding NKp30, in RCC patients. Moreover, expression of activating cytokines (IL-6 and IL-8) in renal cancer tissue was decreased, though inhibitory cytokine (TGF-ß) expression remained unchanged, which may result in an immunosuppressive cytokine microenvironment. CONCLUSION: Decreased expression of immunostimulatory NCR3 splice variants and the inhibitory cytokine microenvironment in RCC patients may contribute to deficient NK cell cytotoxicity and renal carcinoma cell immune escape from NK cell killing, which may provide a theoretical basis for finding new immunotherapeutic targets for RCC.

Research progress in arthritis treatment with the active components of Herba siegesbeckiae.

Arthritis is a group of diseases characterized by joint pain, swelling, stiffness, and limited movement. Osteoarthritis, rheumatoid arthritis, and gouty arthritis are the most common types of arthritis. Arthritis severely affects the quality of life of patients and imposes a heavy financial and medical burden on their families and society at large. As a widely used traditional Chinese medicine, Herba siegesbeckiae has many pharmacological effects such as anti-inflammatory and analgesic, anti-ischemic injury, cardiovascular protection, and hypoglycemic. In addition, it has significant therapeutic effects on arthritis. The rich chemical compositions of H. siegesbeckiae primarily include diterpenoids, sesquiterpenoids, and flavonoids. As one of the main active components of H. siegesbeckiae, kirenol and quercetin play a vital role in reducing arthritis symptoms. In the present study, the research progress in arthritis treatment with the active components of H. siegesbeckiae is reviewed.

Dietary Bacillus cereus LS2 protects juvenile sea cucumber Apostichopus japonicus against Vibrio splendidus infection.

This study aimed to investigate the effects of Bacillus cereus LS2 on the growth performance, innate immunity, intestinal microbiota, and disease resistance of sea cucumber Apostichopus japonicus. After feeding with LS2 for 30 days, results showed that dietary with LS2 had a significant improvement in the growth rate and immune parameters (including total coelomocytes counts, phagocytosis, respiratory burst, and immune-related enzymes) of juvenile sea cucumbers. Subsequently, transcriptome sequencing and qRT-PCR verification were performed to analyze the potential mechanism of LS2 diet and thus improve the immune response of A. japonicus. GO and KEGG pathway analysis indicated that LS2 can primarily activate the "Lectins" and "complement and coagulation cascades" pathways to modulate the innate immunity of the sea cucumbers. Furthermore, 16S rRNA sequencing was used to analyze the intestinal microbial composition of sea cucumbers after dietary with LS2. Results showed that Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes were the most prevalent phyla in A. japonicus intestinal microbiota. The abundance of Actinobacteria (46.20%) and Bacteroidetes (12.80%) were significantly higher in the LS2 group, whereas the relative abundance of Proteobacteria (49.98%) and Firmicutes (14.97%) were higher in the control group. The LDA scores of Nocardiaceae and Rhodococcus were also the highest taxa after the dietary administration of LS2, indicating that Actinobacteria phylum played a pivotal role in the intestinal microbial function of A. japonicus. Overall, these results suggested that feeding with Bacillus LS2 may be beneficial for A. japonicus farming.

Assessing the long-term impact of cascade hydropower development on the inundation patterns of floodplain wetlands.

The inundation process of floodplain wetlands plays a crucial role in maintaining the balance of river ecosystems, which are highly sensitive to hydrological alteration. Nevertheless, the specific mechanisms through which these hydrological changes affect the inundation patterns of floodplain wetlands are still unclear. This study aimed to investigate the impact mechanism of cascade hydropower development on the inundation process of floodplain wetlands. Multitemporal remote sensing datasets and long-term hydrometeorological data series were utilized in this study. By employing the water appearance frequency (WAF) index, wetland hydrological stability assessment, and wavelet analysis, the inundation changes in floodplain wetlands and the underlying hydrological driving mechanisms were examined. The results revealed significant alterations in the inundation frequency of floodplain wetlands due to the construction of upstream dams. Specifically, the construction of the Danjiangkou and Wangfuzhou dams led to an increase in the total inundated area of Part A (16.09 km2) and Part B (76.93 km2), respectively. Conversely, the moderate frequency inundation zone in Part C decreased (26.7 km2) after the construction of the Cuijiaying Dam. The typical floodplain wetland 7 shifted from high to low (8.94 km2) stability after the construction of the Cuijiaying Dam. Furthermore, the cascade hydropower dam construction resulted in increased fluctuations in downstream water discharge. This study provides an effective approach to understanding the impact of cascade hydropower dams on the inundation process of floodplain wetlands.

Aboveground biomass estimation of wetland vegetation at the species level using unoccupied aerial vehicle RGB imagery.

Wetland vegetation biomass is an essential indicator of wetland health, and its estimation has become an active area of research. Zizania latifolia (Z. latifolia) is the dominant species of emergent vegetation in Honghu Wetland, and monitoring its aboveground biomass (AGB) can provide a scientific basis for the protection and restoration of this and other wetlands along the Yangtze River. This study aimed to develop a method for the AGB estimation of Z. latifolia in Honghu Wetland using high-resolution RGB imagery acquired from an unoccupied aerial vehicle (UAV). The spatial distribution of Z. latifolia was first extracted through an object-based classification method using the field survey data and UAV RGB imagery. Linear, quadratic, exponential and back propagation neural network (BPNN) models were constructed based on 17 vegetation indices calculated from RGB images to invert the AGB. The results showed that: (1) The visible vegetation indices were significantly correlated with the AGB of Z. latifolia. The absolute value of the correlation coefficient between the AGB and CIVE was 0.87, followed by ExG (0.866) and COM2 (0.837). (2) Among the linear, quadratic, and exponential models, the quadric model based on CIVE had the highest inversion accuracy, with a validation R2 of 0.37, RMSE and MAE of 853.76 g/m2 and 671.28 g/m2, respectively. (3) The BPNN model constructed with eight factors correlated with the AGB had the best inversion effect, with a validation R2 of 0.68, RMSE and MAE of 732.88 g/m2 and 583.18 g/m2, respectively. ​Compared to the quadratic model constructed by CIVE, the BPNN model achieved better results, with a reduction of 120.88 g/m2 in RMSE and 88.10 g/m2 in MAE. This study indicates that using UAV-based RGB images and the BPNN model provides an effective and accurate technique for the AGB estimation of dominant wetland species, making it possible to efficiently and dynamically monitor wetland vegetation cost-effectively.

Optimizing 129Xe and 131Xe relaxation in an NMR gyroscope using buffer gas pressure and wall coating.

The accuracy of inertial measurement performed by the nuclear magnetic resonance gyroscope (NMRG) with two isotopes depends on the duration of transverse relaxation. Extending the relaxation of the xenon isotopes at the same time plays a very important role in the accuracy of gyro. The relaxation time of 129Xe and 131Xe can be increased to about 15-20 s by optimizing the buffer gas pressure of N2 at about 0.57 amg and coating RbH, respectively. According to the results of theoretical analysis and experimentation, the gyro stability reaches 0.6°/h, and the active measurement volume is 3 × 3 × 3 âˆ¼ mm3.

Dispersal and transport of microplastic particles under different flow conditions in riverine ecosystem.

Microplastic (MP) pollution is a global issue owing to its potential threats to ecosystems and human health. MP pollution in river ecosystems is widely investigated, but the transport process under different hydrological conditions remain unclear. In this study, an approach of particle tracking in conjunction with hydrodynamic modeling was developed to investigate the dispersal and transport processes of microplastic particles in riverine ecosystem. The concentration and dispersal pattern of polyamide (PA), polyethylene (PE), polypropylene (PP), polystyrene (PS), and polyethylene terephthalate (PET) particles under base flow and flood events with recurrence intervals of 10-year, 20-year and 50-year were identified. Results indicated that rainfall intensity had a significant impact on the microplastic transport in rivers. Higher suspension concentration and lower sedimented concentration were observed in high flow periods, and the sedimented concentration showed a slow increasing trend in the flood recession stage. High water velocity facilitated the microplastic particles to be migrated for a longer distance, and high water flow was conducive to transport more microplastics from source points. Besides, microplastic particles with high density had worse mobility in water and more prone to deposition. PET were likely to be transported for a relatively shorter distance, while PP had higher mobility and took less time to reach the same simulation point. This study put forward an effective approach to understand the transport of MPs in the river. The results obtained are useful to identify pollution hotspots and track pollution paths.

Mediating role of perceived social support in the relationship between perceived stress and job burnout among midwives in the post-COVID-19 era.

AIM: The aim of this study was to explore the mediating role of perceived social support in the association between perceived stress and job burnout in midwives. DESIGN: A descriptive, cross-sectional online survey. METHODS: Using the stratified cluster sampling method, 329 midwives in 20 hospitals in China were selected as the participants. They completed self-report assessment measures of job burnout, perceived stress and perceived social support. RESULTS: 63.5% of the participants had job burnout. Perceived stress was negatively associated with social support (r = -.350, p < .01), while it was positively associated with job burnout (r = -.382, p < .01). Social support was negatively correlated with job burnout (r = -.569, p < .01). The total effect of perceived stress on job burnout was 0.474 (95% CI: 0.367 ~ 0.596, p < .01), the direct effect was 0.242 (95% CI: 0.142 ~ 0.355, p < .01), and the indirect effect was 0.232 (95% CI: 0.160 ~ 0.316, p < .01). Social support programmes for midwives should be implemented to control the impact of perceived stress on job burnout.

Novel 5-Fluorouracil Carbonate-Loaded Liposome: Preparation, In Vitro, and In Vivo Evaluation as an Antitumor Agent.

5-Fluorouracil (5-FU) is a chemotherapeutic drug against many types of cancers, especially colorectal cancer. However, its short plasma half-life and serious adverse reactions limit its wide clinical applications. To overcome these shortcomings, a novel lipophilic 5-FU carbonate [XL-01, (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl tetradecyl carbonate] was designed, synthesized, and encapsulated into liposome (LipoXL-01) by a thin-film dispersion method through formulation screening and optimization. LipoXL-01 was characterized by a particle size of around 100 nm, polydispersity index of 0.200, ζ-potential value of -41 mV, encapsulation efficiency of 93.9%, and drug-loading efficiency of 11.6%. The cellular uptake of LipoXL-01 was increased in a concentration-dependent manner on HCT15 cells. LipoXL-01 could enhance the induction of cell apoptosis and the inhibition of cell migration and arrest the ability of the cell cycle at the S-phase on HCT15 cells better than 5-FU. Additionally, LipoXL-01 exhibited a slow drug release profile with a cumulative release rate of 12% in 8 h. The results of pharmacokinetic and biodistribution studies revealed that LipoXL-01 had a long plasma half-life (7.21 h) and a high tumor accumulation (733 nmol/g at 8 h). The in vivo antitumor effect study also showed that LipoXL-01 had more potent efficacy than 5-FU (65 vs 48% of the tumor-inhibition rate). Simultaneously, negligible systemic toxicity was observed via analyzing the body weight as well as hematological and pathological parameters in the tested mice. The current study suggested that LipoXL-01 might be a promising nanocandidate for chemotherapy of colorectal cancer.

MicroRNA-185 modulates CYP7A1 mediated cholesterol-bile acid metabolism through post-transcriptional and post-translational regulation of FoxO1.

BACKGROUND AND AIMS: Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate limiting enzyme of the bile acid biosynthetic pathway to convert cholesterol to bile acids, which is a major output pathway for cholesterol catabolism. In this study, we aimed to assess the potential regulatory mechanisms of microRNA-185 (miR-185) in cholesterol and bile acid homeostasis. METHODS: Eight-week-old male ApoE KO mice fed a high-fat diet (HFD) were injected with lentiviruses encoding antisense miR-185 (miR-185-inh). Microarrays were applied to profile miR-185-regulated genes involved in bile acid metabolism. The expression of potential targets of miR-185 was validated using qPCR and Western blotting assay in human hepatoma HepG2 cells. RESULTS: The administration of miR-185-inh correlated with decreased serum total bile acids levels in ApoE KO mice. Microarray gene profiling revealed that inhibition of miR-185 upregulated hepatic CYP7A1 expression in vivo, which was further validated in HepG2 cells and primary hepatic cells in vitro by overexpression or inhibition of miR-185. Furthermore, it was revealed that miR-185 regulated CYP7A1 expression via a FoxO1-involved indirect pathway and that miR-185 directly modulated FoxO1 expression by binding to its mRNA 3'UTR in a traditional post-transcriptional manner. Besides, we also observed that miR-185 regulated CYP7A1 expression by increasing p-AKT/AKT level, which induced the phosphorylation of FoxO1 and promoted FoxO1 degradation at a post-translational level. CONCLUSIONS: This study provides convincing evidence on the critical role of miR-185 in FoxO1 modulation at both post-transcriptional and post-translational levels, which accounts for the effects on CYP7A1 gene and its mediated cholesterol-bile acid metabolism. These results suggest an important role of miR-185 as a novel atherosclerosis-protective target for drug discovery.

Recent Progress on Micro-Fabricated Alkali Metal Vapor Cells.

Alkali vapor cells are the core components of atomic sensing instruments such as atomic gyroscopes, atomic magnetometers, atomic clocks, etc. Emerging integrated atomic sensing devices require high-performance miniaturized alkali vapor cells, especially micro-fabricated vapor cells. In this review, bonding methods for vapor cells of this kind are summarized in detail, including anodic bonding, sacrificial micro-channel bonding, and metal thermocompression bonding. Compared with traditional through-lighting schemes, researchers have developed novel methods for micro-fabricated vapor cells under both single- and double-beam schemes. In addition, emerging packaging methods for alkali metals in micro-fabricated vapor cells can be categorized as physical or chemical approaches. Physical methods include liquid transfer and wax pack filling. Chemical methods include the reaction of barium azide with rubidium chloride, ultraviolet light decomposition (of rubidium azide), and the high-temperature electrolysis of rubidium-rich glass. Finally, the application trend of micro-fabricated alkali vapor cells in the field of micro-scale gyroscopes, micro-scale atomic clocks, and especially micro-scale biomagnetometers is reviewed. Currently, the sensing industry has become a major driving force for the miniaturization of atomic sensing devices, and in the near future, the micro-fabricated alkali vapor cell technology of atomic sensing devices may experience extensive developments.

Coupling with high-resolution remote sensing data to evaluate urban non-point source pollution in Tongzhou, China.

Urban non-point source (NPS) pollution has gradually become one of the important factors affecting the urban water environment. The quantitative evaluation of urban NPS pollution is the priority to identify key control area of urban NPS pollution. Current model applied in China is mainly focused on small-scale area, large-scale spatial continuous simulation is lacking. In this study A spatial continuous evaluation method coupled with high-resolution remote sensing data has been established and the method was applied to Tongzhou, China. With the spatial distribution of land-use type and built-up area which were been obtained by remote sensing technology, the accumulative and wash-off load of urban NPS nitrogen and phosphorus were estimated for the prominent problems of nitrogen and phosphorus nutrient pollution in the rivers in the study area. The main sources of urban NPS Nitrogen and phosphorus pollution are roof and road rainfall runoff respectively. Compared to other urban NPS pollution models, the method developed in this study can quickly realize spatial visualization assessment of urban NPS pollution and provide a means to estimate urban NPS loads in entire city or urban agglomeration, it is applicable for common urban NPS pollutants and also has advantages in areas without data.

Considering ecological flow in multi-objective operation of cascade reservoir systems under climate variability with different hydrological periods.

The trade-off between ecological and socioeconomic benefits in the reservoir operation has become a focus issue in the watershed water resource management. However, finding a suitable reservoir ecological operation scheme in the multi-objective cascade reservoir systems remains unclear. At present, most ecological operation models are designed on the basis of water quantity balance, neglecting the dynamic variability of the hydrological process. This study proposed a multi-objective ecological operation system, which coupled a two-dimensional hydrodynamic model with a rainfall-runoff model, and integrated the ecological operation scheme into the hydrodynamic simulation system considering ecological flow. Moreover, the applicability of the operation scheme under climate variability with different hydrological periods was evaluated. Results indicated that multi-reservoir joint operation had the largest effect in normal years; the variation in the monthly hydrological magnitude, extreme events and their duration, temporal change and frequency of streamflow were significantly reduced after reservoir ecological operation. The SAM0-UNICON model performed better than the two other climate models, the ecological deficit (ED) under the Representative Concentration Pathway (RCP) 8.5 climate change scenario was larger than other scenarios with different operation schemes. Future climate change will have a larger impact on discharge change in the wet season than in other hydrological periods. This study emphasises the comprehensive application of the hydrological and hydrodynamic methods, which is of considerable importance for decision-making in basin water resource management and reservoir regulation.

ZMYND8 mediated liquid condensates spatiotemporally decommission the latent super-enhancers during macrophage polarization.

Super-enhancers (SEs) govern macrophage polarization and function. However, the mechanism underlying the signal-dependent latent SEs remodeling in macrophages remains largely undefined. Here we show that the epigenetic reader ZMYND8 forms liquid compartments with NF-κB/p65 to silence latent SEs and restrict macrophage-mediated inflammation. Mechanistically, the fusion of ZMYND8 and p65 liquid condensates is reinforced by signal-induced acetylation of p65. Then acetylated p65 guides the ZMYND8 redistribution onto latent SEs de novo generated in polarized macrophages, and consequently, recruit LSD1 to decommission latent SEs. The liquidity characteristic of ZMYND8 is critical for its regulatory effect since mutations coagulating ZMYND8 into solid compartments disable the translocation of ZMYND8 and its suppressive function. Thereby, ZMYND8 serves as a molecular rheostat to switch off latent SEs and control the magnitude of the immune response. Meanwhile, we propose a phase separation model by which the latent SEs are fine-tuned in a spatiotemporal manner.

Genetics Responses to Hypoxia and Reoxygenation Stress in Larimichthys crocea Revealed via Transcriptome Analysis and Weighted Gene Co-Expression Network.

The large yellow croaker (Larimichthys crocea) is an important marine economic fish in China; however, its intolerance to hypoxia causes widespread mortality. To understand the molecular mechanisms underlying hypoxia tolerance in L. crocea, the transcriptome gene expression profiling of three different tissues (blood, gills, and liver) of L. crocea exposed to hypoxia and reoxygenation stress were performed. In parallel, the gene relationships were investigated based on weighted gene co-expression network analysis (WGCNA). Accordingly, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that several pathways (e.g., energy metabolism, signal transduction, oxygen transport, and osmotic regulation) may be involved in the response of L. crocea to hypoxia and reoxygenation stress. In addition, also, four key modules (darkorange, magenta, saddlebrown, and darkolivegreen) that were highly relevant to the samples were identified by WGCNA. Furthermore, some hub genes within the association module, including RPS16, EDRF1, KCNK5, SNAT2, PFKL, GSK-3ß, and PIK3CD, were found. This is the first study to report the co-expression patterns of a gene network after hypoxia stress in marine fish. The results provide new clues for further research on the molecular mechanisms underlying hypoxia tolerance in L. crocea.