Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor.

Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8+ T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8+ T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8+ T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8+ T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8+ T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8+ T cell exhaustion and could be targeted to potentiate cancer immunotherapy.

Plant extracellular self-DNA inhibits growth and induces immunity via the jasmonate signaling pathway.

Plants have evolved sophisticated mechanisms to detect various forms of danger. Damage-associated molecular patterns (DAMPs) are endogenous danger molecules that are released from damaged cells and activate the innate immunity. Recent evidence suggests that plant extracellular self-DNA (esDNA) can serve as a DAMP molecule. However, the mechanisms by which esDNA functions are largely unknown. In this study, we confirmed that esDNA inhibits root growth and triggers reactive oxygen species (ROS) production in a concentration- and species-specific manner in Arabidopsis (Arabidopsis thaliana) and tomato (Solanum lycopersicum L.). Furthermore, by combining RNA sequencing, hormone measurement, and genetic analysis, we found that esDNA-mediated growth inhibition and ROS production are achieved through the jasmonic acid (JA) signaling pathway. Specifically, esDNA induces JA production and the expression of JA-responsive genes. The esDNA-mediated growth inhibition, ROS production, and gene expression are impaired in the JA-related mutants. Finally, we found that the JA signaling pathway is required for the esDNA-elicited resistance against the pathogens Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000. This finding highlights the importance of JA signaling in esDNA-mediated biological effects, thereby providing insight into how esDNA functions as a DAMP.

Modulation of DOM-Induced Head-Twitch Response by mGluR2 Agonist/Inverse Agonist is Associated with 5-HT2AR-Mediated Gs Signaling Pathway.

Hallucinogenic 5-HT2A receptor (5-HT2AR) agonists-induced head-twitch response (HTR) is regulated by Gs signaling pathway. Formation of heterodimers between 5-HT2AR and metabotropic glutamate mGlu2 receptor (mGluR2) is essential for the hallucinogenic 5-HT2AR agonist-induced HTR. In order to investigate the effects of mGluR2 agonists and inverse agonists on hallucinogenic 5-HT2AR agonists DOM-induced HTR, C57BL/6 mice were pretreated with mGluR2 agonists (LY379268, LY354740, LY404039) or the inverse agonist LY341495, and the HTR was manually counted after administering DOM immediately. IP-One (IP1) HTRF assay and cAMP assay were performed to evaluate the effect of LY341495 or LY354740 on DOM-induced Gq and Gs activation in Human Embryonic Kidney-293 (HEK-293) T-type cells co-expressing 5-HT2AR and mGluR2. The results showed that DOM-induced HTR in mice was dose-dependently inhibited by LY379268, LY354740, and LY404039, while it was dose-dependently enhanced by LY341495. Moreover, LY341495 reversed the inhibitory effect of LY354740 on DOM-induced HTR. In HEK-293T cells co-expressing 5-HT2AR and mGluR2, DOM-induced cAMP level was decreased by LY354740 and increased by LY341495, but DOM-induced IP1 level was not regulated by LY354740 or LY341495. The regulation of DOM-induced HTR by mGluR2 agonists and inverse agonists is closely related to 5-HT2AR-mediated Gs signaling pathway. In HEK-293T cells co-expressing 5-HT2AR and mGluR2 A677S/A681P/A685G mutant (mGluR2 3 A mutant), DOM-induced cAMP level was not regulated by LY354740, but was significantly enhanced by LY341495. The 5-HT2AR/mGluR2 heterodimers is critical for DOM-induced HTR and cAMP level, both of which are inhibited by mGluR2 agonists and enhanced by mGluR2 inverse agonists.

Baseline prevalence and longitudinal assessment of autonomic dysfunction in early Parkinson's disease.

Autonomic dysfunction (AutD) is common and debilitating in Parkinson's disease (PD). Predictors of AutD are unclear, and data are limited on the biological relevance of AutD in PD. Here, we evaluated the baseline prevalence and 2-year longitudinal assessment of AutD in patients with de novo PD compared with healthy controls (HC). Moreover, we also assessed various variables that could predict longitudinal changes in AutD in early PD. Parkinson's Progression Markers Initiative (PPMI) was utilized to evaluate untreated PD participants at baseline and HC. Autonomic function was assessed using the 25-item Scale for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT) score at baseline and 2 years. Clinical and biological variables were measured for their correlations with AuD for up to 2 years. Two hundred and ninety PD subjects and 170 HC were enrolled and followed for 2 years. SCOPA-AUT mean (SD) scores increased from baseline 8.49 ± 5.23 to 10.12 ± 5.77 at year 2 in PD subjects (p < 0.001) versus from 4.98 ± 3.34 to 5.03 ± 374 in HC (p = 0.496), with a significant difference between the groups (p < 0.001). Among them, 242 PD participants and 151 HC completed the SCOPA-AUT assessment, including sexual function. In the multivariate analysis, a higher baseline SCOPA-AUT score was associated with higher baseline MDS-UPDRS Part I scores (p < 0.001). Moreover, a longitudinal increase in autonomic function severity was associated with the white race (p = 0.010) at baseline. In contrast, there was no association with the CSF biomarkers. MDS-UPDRS Part I score may predict AuD in patients with early PD, which is correlated with nonmotor symptoms and race.

Heteryunine A, an amidated tryptophan-catechin-spiroketal hybrid with antifibrotic activity from Heterosmilax yunnanensis.

An unprecedented spiro-C-glycoside adduct, heteryunine A (1), along with two uncommon alkaloids featuring a 2,3-diketopiperazine skeleton, heterpyrazines A (2) and B (3), were discovered in the roots of Heterosmilax yunnanensis. The detailed spectroscopic analysis helped to clarify the planar structures of these compounds. Compound 1, containing 7 chiral centers, features a catechin fused with a spiroketal and connects with a tryptophan derivative by a CC bond. Its complex absolute configuration was elucidated by rotating frame overhauser enhancement spectroscopy (ROESY), specific rotation, and the 13C nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculation. The possible biosynthetic routes for 1 were deduced. Compounds 1 and 2 showed significant antifibrotic effects and further research revealed that they inhibited the activation, migration and proliferation of hepatic stellate cells (HSCs) through suppressing the activity of Ras homolog family member A (RhoA).

Interactions between the gut bacterial community of Exopalaemon carinicauda and infection by Enterocytozoon hepatopenaei.

To explore the relationship between the intestinal flora of Exopalaemon Carinicauda and infection by Enterocytozoo Hepatopenaei (EHP), we analyzed the species and richness of gut microbiota in infected individuals in different EHP load groups [i.e., control (C), high load (H), and low load (L)] using gene sequencing after infection. The results showed that the abundance of intestinal flora in the high-load EHP group was significantly lower than that in the healthy group. Based on the UPGMA cluster tree and PCoA analysis, with comparisons to healthy shrimp, the gut microbiota of the EHP high load and low load groups were clustered into one branch, which indicated that EHP infection changed the composition of the gut microbiota of infected shrimps. The heat map analysis of species abundance clustering revealed that the dominant bacteria in the low EHP load group and the control group were beneficial genera such as Lactococcus, Ligilactobacillius, and Bifidobacterium, but the dominant bacteria in the high EHP load group were harmful genera such as Pseudomonas, Photobacterium, and Candidatus hepatincola. The functions of the intestinal flora predicted that most genes related to metabolism were more abundant in healthy shrimp, most genes related to metabolism and the organisms' system were more abundant in the low EHP load group, and most genes related to diseases and environmental information processing were more abundant in the high EHP load group. After separation and purification, the dominant bacteria (Bifidobacterium animalis in healthy shrimp and Lactococcus garvieae in the low EHP load group) and the non-dominant bacteria (Macrococus caseolyticus in the low EHP load group) were obtained. Each of these isolated strains were used together with EHP to infect E. carinicauda, and the results showed that Bifidobacterium animali and Lactococcus garvieae significantly reduced the EHP load in EHP-infected individuals. At the same time, the morphology and structure of the hepatopancreas and intestinal tissue of EHP-infected E. carinicauda were improved. No improvement was seen in tissue that was infected with Macrococus caseolyticus.

De novo transcriptional analysis of the response to starvation stress in the white ridgetail prawn, Exopalaemon carinicauda.

To study the mechanism of the biomolecular response in Exopalaemon carinicauda to starvation stress, we subjected muscle tissue RNA samples from four stress points, including 0 d(control group), 10 d, 20 d, and 30 d, to starvation stress on white ridgetail prawn with a body weight of 1.41 + 0.42 g, aquaculture water temperature of 23-25 °C, salinity of 26, dissolved oxygen ≥5 mg/L, and pH 8-8.5, Then performed de novo transcriptome assembly and gene expression analysis using BGISEQ-500 with a tag-based digital gene expression (DGE) system. By de novo assembling at the four times, we obtained 28,167, 21,115, 24,497, and 27,080 reads, respectively. The results showed that the stress at 10 d led to no significant difference in the expressed genes, while the stress at 20 d and 30 d showed a significant increase (or decrease) in the expression of 97 (276) and 143 (410) genes, respectively, which were involved in 8 different metabolic pathways. In addition, we detected 2647 unigene transcription factors. Eleven upregulated and sixteen downregulated genes from the different starvation stress groups were choose to verify the reliability of the transcriptome data, and the results showed that the expression trends of these genes were consistent with the results shown by the transcriptome. The analysis of the experimental data and our discussion of the response mechanism of white ridgetail prawn under starvation stress provides a foundation for further screening of the key genes of starvation stress and may help to elucidate their functions.

Six new iridoid glycosides from the whole plants of Hedyotis diffusa.

Six new iridoid glycosides were isolated from the ethyl acetate fraction of the whole plants of Hedyotis diffusa Willd. They were identified as E-6-O-p-methoxycinnamoyl-10-O-acetyl scandoside acid methyl ester (1), Z-6-O-p-methoxycinnamoyl-10-O-acetyl scandoside acid methyl ester (2), E-6-O-caffeoyl scandoside methyl ester (3), E-6-O-p-coumaroyl-6'-O-acetyl scandoside methyl ester (4), Z-6-O-p-coumaroyl-6'-O-acetyl scandoside methyl ester (5), and E-6-O-p-coumaroyl-4'-O-acetyl scandoside methyl ester (6). The structures of them were elucidated based on unambiguous spectroscopic data (UV, IR, HRESIMS, and NMR). They were screened for anti-inflammatory effect, antioxidant effect, antitumor effect, and neuroprotective effect and did not show potent activities.

Chromium Catalysts for Selective Ethylene Oligomerization Featuring Binuclear PNP Ligands.

A series of novel binuclear PNP ligands based on the cyclohexyldiamine scaffold were synthesized for this study. The experimental results showed that positioning the two PNP sites at the para-positions of the cyclohexyl framework led to a significant enhancement in the catalytic activity for selective tri/tetramerization of ethylene. The PNP/Cr(acac)3/MAO(methylaluminoxane) catalytic system exhibited relatively high catalytic activity (up to 3887.7 kg·g-1·h-1) in selective ethylene oligomerization with a total selectivity of 84.5% for 1-hexene and 1-octene at 40 °C and 50 bar. The relationship between the ligand structure and ethylene oligomerization performance was further explored using density functional theory calculations.

[Mechanisms of changes of active components in Chinese medicinal materials during drying: a review].

Drying is an indispensable processing step for Chinese medicinal materials after harvesting. It often leads to significant changes in the active components of these materials, thus impacting their medicinal values. Understanding the mechanisms behind the changes during the drying process is of great importance for regulating the transformation of key active components. Therefore, this paper reviews the available studies and comprehensively expounds the mechanisms underlying the changes in active components during the drying process. The aim is to offer insights for the development of regulatory strategies and the improvement of drying techniques for Chinese medicinal materials.

FGF4 protects the liver from nonalcoholic fatty liver disease by activating the AMP-activated protein kinase-Caspase 6 signal axis.

BACKGROUND AND AIMS: NAFLD represents an increasing health problem in association with obesity and diabetes with no effective pharmacotherapies. Growing evidence suggests that several FGFs play important roles in diverse aspects of liver pathophysiology. Here, we report a previously unappreciated role of FGF4 in the liver. APPROACH AND RESULTS: Expression of hepatic FGF4 is inversely associated with NAFLD pathological grades in both human patients and mouse models. Loss of hepatic Fgf4 aggravates hepatic steatosis and liver damage resulted from an obesogenic high-fat diet. By contrast, pharmacological administration of recombinant FGF4 mitigates hepatic steatosis, inflammation, liver damage, and fibrogenic markers in mouse livers induced to develop NAFLD and NASH under dietary challenges. Such beneficial effects of FGF4 are mediated predominantly by activating hepatic FGF receptor (FGFR) 4, which activates a downstream Ca2+ -Ca2+ /calmodulin-dependent protein kinase kinase beta-dependent AMP-activated protein kinase (AMPK)-Caspase 6 signal axis, leading to enhanced fatty acid oxidation, reduced hepatocellular apoptosis, and mitigation of liver damage. CONCLUSIONS: Our study identifies FGF4 as a stress-responsive regulator of liver pathophysiology that acts through an FGFR4-AMPK-Caspase 6 signal pathway, shedding light on strategies for treating NAFLD and associated liver pathologies.

Involvement of the SIRT1-NLRP3 pathway in the inflammatory response.

The silent information regulator 2 homolog 1-NACHT, LRR and PYD domains-containing protein 3 (SIRT1-NLRP3) pathway has a crucial role in regulation of the inflammatory response, and is closely related to the occurrence and development of several inflammation-related diseases. NLRP3 is activated to produce the NLRP3 inflammasome, which leads to activation of caspase-1 and cleavage of pro-interleukin (IL)-1ß and pro-IL-18 to their active forms: IL-1ß and IL-18, respectively. They are proinflammatory cytokines which then cause an inflammatory response.SIRT1 can inhibit this inflammatory response through nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B pathways. This review article focuses mainly on how the SIRT1-NLRP3 pathway influences the inflammatory response and its relationship with melatonin, traumatic brain injury, neuroinflammation, depression, atherosclerosis, and liver damage. Video Abstract.

Rongalite as C1 Synthon in the Synthesis of Divergent Pyridines and Quinolines.

Rongalite has been used as a cheap and efficient carbon synthon for the synthesis of divergent N-heteroaromatics, including different pyridines and quinolines. The selective synthesis of different products can be achieved by employing enaminones or enaminones/anilines as reaction partners. In addition, compared with the reaction using conventional aldehyde synthons, rongalite displays an evident advantage in providing products with considerably higher product yields under milder conditions. The GC-MS analysis of the reaction process has been performed to probe the possible reaction mechanism.

Unraveling the Positive Effect of Soil Moisture on the Bioaugmentation of Petroleum-Contaminated Soil Using Bioinformatics.

Petroleum contamination is a severe threat to the soil environment. Previous studies have demonstrated that petroleum degradation efficiency is promoted by enhancing soil moisture content (MC). However, the effects of MC on soil microbial ecological functions during bioremediation remain unclear. Here, we investigated the impacts of 5% and 15% of moisture contents on petroleum degradation, soil microbial structures and functions, and the related genes using high-throughput sequencing and gene function prediction. Results indicated that petroleum biodegradation efficiency was increased by 8.06% in the soils with 15% MC when compared to that with 5% of MC. The complexity and stability of soil microbial community structures with 15% MC were higher than those in the soils with 5% MC when hydrocarbon-degrading bacterial flora (HDBF) were inoculated into the soils. Fifteen percent of moisture content strengthened the interaction of the bacterial community network and reduced the loss of some key bacteria species including Mycobacterium, Sphingomonas, and Gemmatimonas. Some downregulated gene pathways relating to bioaugmentation were enhanced in the soils with 15% MC. The results suggested that the dynamic balances of microbial communities and the metabolic interactions by 15% MC treatment are the driving forces for the enhancement of bioremediation in petroleum-contaminated soil.

Characterization of a crustin-like peptide involved in shrimp immune response to bacteria and Enterocytozoon hepatopenaei (EHP) infection in Palaemon carinicauda.

Crustins represent one type of antimicrobial peptides (AMPs) that are key components of the innate immune process of crustaceans. This study successfully identified a novel crustin-like peptide, EcCrustin2, in ridgetail white prawn, Palaemon carinicauda (formerly Exopalaemon carinicauda). EcCrustin2 was found to be 1082 bp in length, with a 378 bp open reading frame (ORF) encoding 125 amino acids. The deduced amino acid sequence of EcCrustin2 exhibited characteristics of crustins in crustacean, including a Cys-rich region at the N-terminus as well as a whey acidic protein domain at the C-terminus. Phylogenetic analysis revealed that the EcCrustin2 was first clustered with Type I crustins, then with other crustins. Expression of EcCrustin2 was mainly detected in immune tissues, including hemocytes, gill and stomach. The expression level of EcCrustin2 was also significantly up-regulated after being exposed to lipopolysaccharide (LPS), lipoteichoic acid (LTA), Vibrio parahaemolyticus and Staphylococcus aureus. EHP infection could also induce EcCrustin2 expression in P. carinicauda. Knockdown of EcCrustin2 with siRNA increased the mortality of V. parahaemolyticus challenged shrimp. Finally, the recombinant EcCrustin2 protein was obtained and demonstrated a wide spectrum of antibacterial activity in vitro. These results indicated that EcCrustin2 takes part in the immune response against bacteria and EHP infection.

Lessons drawn from Shanghai for controlling highly transmissible SARS-CoV-2 variants: insights from a modelling study.

BACKGROUND: The continuous emergence of novel SARS-CoV-2 variants with markedly increased transmissibility presents major challenges to the zero-COVID policy in China. It is critical to adjust aspects of the policy about non-pharmaceutical interventions (NPIs) by searching for and implementing more effective ways. We use a mathematical model to mimic the epidemic pattern of the Omicron variant in Shanghai to quantitatively show the control challenges and investigate the feasibility of different control patterns in avoiding other epidemic waves. METHODS: We initially construct a dynamic model with a core step-by-step release strategy to reveal its role in controlling the spread of COVID-19, including the city-based pattern and the district-based pattern. We used the least squares method and real reported case data to fit the model for Shanghai and its 16 districts, respectively. Optimal control theory was utilized to explore the quantitative and optimal solutions of the time-varying control strength (i.e., contact rate) to suppress the highly transmissible SARS-CoV-2 variants. RESULTS: The necessary period for reaching the zero-COVID goal can be nearly 4 months, and the final epidemic size was 629,625 (95%CI: [608,049, 651,201]). By adopting the city-based pattern, 7 out of 16 strategies released the NPIs more or earlier than the baseline and ensured a zero-resurgence risk at the average cost of 10 to 129 more cases in June. By adopting the district-based pattern, a regional linked release can allow resumption of social activity to ~ 100% in the boundary-region group about 14 days earlier and allow people to flow between different districts without causing infection resurgence. Optimal solutions of the contact rate were obtained with various testing intensities, and higher diagnosis rate correlated with higher optimal contact rate while the number of daily reported cases remained almost unchanged. CONCLUSIONS: Shanghai could have been bolder and more flexible in unleashing social activity than they did. The boundary-region group should be relaxed earlier and more attention should be paid to the centre-region group. With a more intensive testing strategy, people could return to normal life as much as possible but still ensure the epidemic was maintained at a relatively low level.

Delta of Exopalaemon carinicauda: molecular characterization, expression in different tissues and developmental stages, and its SNPs association analysis with development.

BACKGROUND: The Notch signaling pathway plays a significant role in the gene regulatory network of development of vertebrate and invertebrate. However, as a ligand for the Notch signaling pathway, the mechanism of Delta in the development of Exopalaemon carinicauda is still unclear. METHODS AND RESULTS: The Delta's molecular characteristics, tissue distribution and their association with development in E. carinicauda were studied by RACE (rapid amplification of cDNA end), qRT-PCR (quantitative Real-time PCR) and SNP (single nucleotide polymorphism), respectively. The delta in E. carinicauda had a full-length cDNA of 2807 bp and its Delta of 808 amino-acid residue had the highest identity with the Delta of Homarus americanus (identity = 76.63%). Delta had the highest expression in the ovary, and its expression varied with different stages of embryonic, larval, and ovarian development. After delta RNA interference (with a highest interference efficiency of 66% at 24 h), the expression of Notch signaling pathway genes and developmental related genes was significantly reduced, and the ovarian development was significantly delayed. Further study found that there were 4 SNPs (ds1-4) in delta cDNA, of which two (ds2 T1521G caused a mutation Asn422Lys and ds3 G1674A caused a mutation Tyr473Cys in the EGF-like domain) were associated with the development of E. carinicauda. The Gonadosomatic Index (GSI) of the ds2 TT genotypes was 37.28% and 134.60% higher than E. carinicauda of GT and GG genotype respectively (P < 0.05). CONCLUSION: Our research indicated that delta was involved in the development of E. carinicauda and provided new insights for molecular breeding with SNP markers in E. carinicauda.

Dissolved oxygen benefits N-decanoyl-homoserine lactone regulated biological nitrogen removal system to resist acute ZnO nanoparticle exposure.

The beneficial effects of N-decanoyl-homoserine lactone (C10-HSL), one of the typical N-acyl-homoserine lactones on biological nitrogen removal (BNR) system to resist the acute exposure of zinc oxide nanoparticles (ZnO NPs) has attracted extensive attentions. Nevertheless, the potential impact of dissolved oxygen (DO) concentration on the regulatory capacity of C10-HSL in the BNR system has yet to be investigated. This study conducted a systematic investigation of the impact of DO concentration on the C10-HSL-regulated BNR system against short-term ZnO NP exposure. Based on the findings, sufficient DO played a crucial role to improve the BNR system's resistance capacity to ZnO NPs. Under the micro-aerobic condition (0.5 mg/L DO), the BNR system was more sensitive to ZnO NPs. The ZnO NPs induced increased intracellular reactive oxygen species (ROS) accumulation, reduced antioxidant enzyme activities, and decreased specific ammonia oxidation rates in the BNR system. Furthermore, the exogenous C10-HSL had a positive effect on the BNR system's resistance to ZnO NP-induced stress, primarily by decreasing ZnO NPs-induced ROS generation and improving ammonia monooxygenase activities, especially under low DO concentrations. The findings contributed to the theoretical foundation for regulation strategy development of wastewater treatment plants under NP shock threat.

Application of 15N tracing and bioinformatics for estimating microbial-mediated nitrogen cycle processes in oil-contaminated soils.

Crude oil pollution can profoundly alter the nitrogen (N) cycle in the soil. Here, a 30-day incubation with 15N tracer approach was performed to assess the impacts of crude oil concentrations (medium: 10,000 mg kg-1; heavy: 50,000 mg kg-1) on soil N cycling based on a numerical model. Results showed that crude oil pollution significantly increased the gross N-transformation rates, but the rates of oxidation of recalcitrant organic N, the immbolization of NO3- and the adsorption of NH4+ changed differently as a function of hydrocarbon concentrations. There was no significant difference of the oxidation rate of recalcitrant organic N between the medium and heavy oil-contaminated soils (medium: 0.1149 mmol N kg-1 d-1; heavy: 0.1299 mmol N kg-1 d-1), but the rates of NO3- immobilization (0.1135 mmol N kg-1 d-1) and NH4+ adsorption were the highest (0.1148 mmol N kg-1 d-1) in the moderately oil-contaminated soils than those in the heavy polluted soil (0.0849 mmol N kg-1 d-1 and 0.0034 mmol N kg-1 d-1, respectively). The NO3- immobilization rate was 2.5-fold higher than its reduction rate, indicating that NO3- immobilization played a more important role during the process of NO3- transformation. Microbial community structure analysis indicated that phyla of Actinobacteria and Ascomycota respectively promoted the immobilization of NO3- to recalcitrant organic N and the reduction of NO3- to NH4+. The genus of Aspergillus was related to net NH4+ production, and the genera of Penicillium and Acremonium were responsible for oxidation of recalcitrant organic N to NO3-.

Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis.

Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in cancer cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120ub1 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation, and this process is not affected by H2AK119 ubiquitination catalyzed by PRC1. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives cancer cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during tumor progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of tumor patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for cancer intervention.