USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus.

Effective treatment of systemic lupus erythematosus (SLE) remains an unmet need. Different subsets of macrophages play differential roles in SLE and the modulation of macrophage polarization away from M1 status is beneficial for SLE therapeutics. Given the pathogenic roles of type I interferons (IFN-I) in SLE, this study investigated the effects and mechanisms of a mitochondria localization molecule ubiquitin specific peptidase 18 (USP18) preserving anti-IFN effects and isopeptidase activity on macrophage polarization. After observing USP18 induction in monocytes from SLE patients, we studied mouse bone marrow-derived macrophages and showed that USP18 deficiency increased M1signal (LPS + IFN-γ treatment)-induced macrophage polarization, and the effects involved the induction of glycolysis and mitochondrial respiration and the expression of several glycolysis-associated enzymes and molecules, such as hypoxia-inducible factor-1α. Moreover, the effects on mitochondrial activities, such as mitochondrial DNA release and mitochondrial reactive oxygen species production were observed. In contrast, the overexpression of USP18 inhibited M1signal-mediated and enhanced interleukin-4 (IL-4)-mediated polarization of macrophages and the related cellular events. Moreover, the levels of USP18 mRNA expression showed tendency of correlation with the expression of metabolic enzymes in monocytes from patients with SLE. We thus concluded that by preserving anti-IFN effect and downregulating M1 signaling, promoting USP18 activity may serve as a useful approach for SLE therapeutics.

Risk Factors for Postoperative Cognitive Decline After Orthopedic Surgery in Elderly Chinese Patients: A Retrospective Cohort Study.

Purpose: We aimed to identify the risk factors for postoperative cognitive decline (POCD) by evaluating the outcomes from preoperative comprehensive geriatric assessment (CGA) and intraoperative anesthetic interventions. Patients and Methods: Data used in the study were obtained from the Aged Patient Perioperative Longitudinal Evaluation-Multidisciplinary Trial (APPLE-MDT) cohort recruited from the Department of Orthopedics in Xuanwu Hospital, Capital Medical University between March, 2019 and June, 2022. All patients accepted preoperative CGA by the multidisciplinary team using 13 common scales across 15 domains reflecting the multi-organ functions. The variables included demographic data, scales in CGA, comorbidities, laboratory tests and intraoperative anesthetic data. Cognitive function was assessed by Montreal Cognitive Assessment scale within 48 hours after admission and after surgery. Dropping of ≥1 point between the preoperative and postoperative scale was defined as POCD. Results: We enrolled 119 patients. The median age was 80.00 years [IQR, 77.00, 82.00] and 68 patients (57.1%) were female. Forty-two patients (35.3%) developed POCD. Three cognitive domains including calculation (P = 0.046), recall (P = 0.047) and attention (P = 0.007) were significantly worsened after surgery. Univariate analysis showed that disability of instrumental activity of daily living, incidence rate of postoperative respiratory failure (PRF) ≥4.2%, STOP-Bang scale score, Caprini risk scale score and Sufentanil for maintenance of anesthesia were different between the POCD and non-POCD patients. In the multivariable logistic regression analysis, PRF ≥ 4.2% (odds ratio [OR] = 2.343; 95% confidence interval [CI]: 1.028-5.551; P = 0.046) and Sufentanil for maintenance of anesthesia (OR = 0.260; 95% CI: 0.057-0.859; P = 0.044) was independently associated with POCD as risk and protective factors, respectively. Conclusion: Our study suggests that POCD is frequent among older patients undergoing elective orthopedic surgery, in which decline of calculation, recall and attention was predominant. Preoperative comprehensive geriatric assessments are important to identify the high-risk individuals of POCD.

USP18 enhances dengue virus replication by regulating mitochondrial DNA release.

Dengue virus (DENV) infection remains a challenging health threat worldwide. Ubiquitin-specific protease 18 (USP18), which preserves the anti-interferon (IFN) effect, is an ideal target through which DENV mediates its own immune evasion. However, much of the function and mechanism of USP18 in regulating DENV replication remains incompletely understood. In addition, whether USP18 regulates DENV replication merely by causing IFN hyporesponsiveness is not clear. In the present study, by using several different approaches to block IFN signaling, including IFN neutralizing antibodies (Abs), anti-IFN receptor Abs, Janus kinase inhibitors and IFN alpha and beta receptor subunit 1 (IFNAR1)knockout cells, we showed that USP18 may regulate DENV replication in IFN-associated and IFN-unassociated manners. Localized in mitochondria, USP18 regulated the release of mitochondrial DNA (mtDNA) to the cytosol to affect viral replication, and mechanisms such as mitochondrial reactive oxygen species (mtROS) production, changes in mitochondrial membrane potential, mobilization of calcium into mitochondria, 8-oxoguanine DNA glycosylase 1 (OGG1) expression, oxidation and fragmentation of mtDNA, and opening of the mitochondrial permeability transition pore (mPTP) were involved in USP18-regulated mtDNA release to the cytosol. We therefore identify mitochondrial machineries that are regulated by USP18 to affect DENV replication and its association with IFN effects.

A Visual Positioning Method of UAV in a Large-Scale Outdoor Environment.

Visual positioning is a basic component for UAV operation. The structure-based methods are, widely applied in most literature, based on local feature matching between a query image that needs to be localized and a reference image with a known pose and feature points. However, the existing methods still struggle with the different illumination and seasonal changes. In outdoor regions, the feature points and descriptors are similar, and the number of mismatches will increase rapidly, leading to the visual positioning becoming unreliable. Moreover, with the database growing, the image retrieval and feature matching are time-consuming. Therefore, in this paper, we propose a novel hierarchical visual positioning method, which includes map construction, landmark matching and pose calculation. First, we combine brain-inspired mechanisms and landmarks to construct a cognitive map, which can make image retrieval efficient. Second, the graph neural network is utilized to learn the inner relations of the feature points. To improve matching accuracy, the network uses the semantic confidence in matching score calculations. Besides, the system can eliminate the mismatches by analyzing all the matching results in the same landmark. Finally, we calculate the pose by using a PnP solver. Furthermore, we evaluate both the matching algorithm and the visual positioning method experimentally in the simulation datasets, where the matching algorithm performs better in some scenes. The results demonstrate that the retrieval time can be shortened by three-thirds with an average positioning error of 10.8 m.

Phase separation of the nuclear pore complex facilitates selective nuclear transport to regulate plant defense against pathogen and pest invasion.

The nuclear pore complex (NPC), the sole exchange channel between the nucleus and cytoplasm, is composed of several subcomplexes, among which the central barrier determines the permeability/selectivity of the NPC to dominate the nucleocytoplasmic trafficking essential for many important signaling events in yeast and mammals. How plant NPC central barrier controls selective transport is a crucial question remaining to be elucidated. In this study, we uncovered that phase separation of the central barrier is critical for the permeability and selectivity of plant NPC in the regulation of various biotic stresses. Phenotypic assays of nup62 mutants and complementary lines showed that NUP62 positively regulates plant defense against Botrytis cinerea, one of the world's most disastrous plant pathogens. Furthermore, in vivo imaging and in vitro biochemical evidence revealed that plant NPC central barrier undergoes phase separation to regulate selective nucleocytoplasmic transport of immune regulators, as exemplified by MPK3, essential for plant resistance to B. cinerea. Moreover, genetic analysis demonstrated that NPC phase separation plays an important role in plant defense against fungal and bacterial infection as well as insect attack. These findings reveal that phase separation of the NPC central barrier serves as an important mechanism to mediate nucleocytoplasmic transport of immune regulators and activate plant defense against a broad range of biotic stresses.

Tunable microwave-optical entanglement and conversion in multimode electro-opto-mechanics.

We study tunable double-channel microwave-optical (M-O) entanglement and coherent conversion by controlling the quantum interference effect. This is realized in a two-mechanical-mode electro-opto-mechanical (EOM) system, in which two mechanical resonators (MRs) are coupled with each other by phase-dependent phonon-phonon interaction, and link the interaction between the microwave and optical cavity. It's demonstrated that the mechanical coupling between two MRs leads to the interference of two pathways of electro-opto-mechanical interaction, which can generate the tunable double-channel phenomena in comparison with a typical three-mode EOM system. In particular, by tuning of phonon-phonon interaction and couplings between cavities with MRs, we can not only steer the switch from the M-O interaction with a single channel to that of the double-channel, but also modulate the entanglement and conversion characteristics in each channel. Moreover, our scheme can be extended to an N-mechanical-mode EOM system, in which N discrete channels will be observed and controlled. This study opens up prospects for quantum information transduction and storage with a wide bandwidth and multichannel quantum interface.

Subjective Changes of Taste and Smell in Conjunction With Anxiety and Depression Are Associated With Symptoms in Globus Patients Without Evidence of Pathologic Acid Reflux.

BACKGROUND/AIM: Patients suffering from globus often report decreased enjoyment when eating as well as a psychological abnormality. Some patients exhibit taste and smell changes (TSCs) when compared with the period before the diagnosis. The main aim of this study was to explore if TSCs and psychological abnormality are present in patients with globus, whether they are associated with the severity of throat symptoms, and the potential risk factors for globus. PATIENTS AND METHODS: A total of 116 included patients who met the Rome IV diagnostic criteria for globus had been performed 24-hour pH monitoring, and the results shown no evidence of pathologic acid reflux. Meanwhile, 125 healthy controls were enrolled in this prospective study. All subjects completed several questionnaires including the Taste and Smell Survey, the Glasgow Edinburgh Throat Scale, the Hamilton Anxiety Scale (HAMA), and the Hamilton Depression Scale (HAMD). Multiple logistic regression was performed to explore the potential risk factors for globus. The study protocol was registered on the Chinese Clinical Trial Registry (No. ChiCTR-2100044972). RESULTS: First, globus patients without evidence of pathologic acid reflux exhibited a 58.62% and 31.03% change in taste and smell, respectively, while their levels of anxiety and depression were 51.72% and 44.83%, respectively. Second, there was a significant difference in the taste score (Z=-4.954, P<0.001) and smell score (Z=-4.552, P<0.001) between globus group patients and healthy controls. Similarly, globus group patients had a higher HAMA score (9.52±2.437 vs. 3.12±1.059, t=6.867, P<0.001) and HAMD score (9.79±2.931 vs. 3.16±1.650, t=6.416, P<0.001) when compared with the healthy controls. Third, in globus group patients, the Glasgow Edinburgh Throat Scale was significantly correlated with the taste score (Spearman ρ=0.782; P<0.001), smell score (Spearman ρ=0.582; P=0.001), HAMA (Spearman ρ=0.676; P<0.001), and HAMD (Spearman ρ=0.672; P<0.001). In addition, the taste score was significantly correlated with HAMA (Spearman ρ=0.532; P=0.004) and HAMD (Spearman ρ=0.681; P<0.001), while the smell score was significantly correlated with HAMD (Spearman ρ=0.392; P=0.035). Finally, multivariate logistic regression revealed that TSCs, anxiety, and depression were significant independent risk factors for globus, with depression exhibiting the highest degree of association (odds ratio: 3.244). CONCLUSIONS: TSCs and psychological comorbidities are prominent in globus patients without evidence of pathologic acid reflux. The obtained results indicated that there is a strong relationship between TSCs, psychological comorbidities, and globus. Therefore, awareness of this high prevalence of TSCs and psychological disorder may help to better understand the severity of throat symptoms.

The feasibility and safety of "one-stop" left atrial appendage closure and percutaneous coronary intervention in atrial fibrillation patients with significant coronary artery disease (PCI-LAAC study).

BACKGROUND: The anti-thrombotic strategy for patients with atrial fibrillation (AF) who have undergone percutaneous coronary intervention (PCI) for coronary artery disease (CAD) is a common and difficult challenge. This pilot study aimed to assess the feasibility and safety of "one-stop" left atrial appendage closure (LAAC) combined with PCI as an alternative stroke prophylaxis strategy. METHODS: From March 2017 to October 2019, AF patients with elevated bleeding risk and significant stable CAD requiring PCI were recruited to undergo LAAC as alternative stroke prophylaxis in Fuwai Hospital, Beijing, China. LAAC was performed either in the same setting with PCI (i.e. "one-stop" LAAC/PCI), or as staged procedure after PCI. Dual antiplatelet therapy was given for all patients after LAAC. Peri-procedural and intermediate-term clinical outcomes were assessed through hospital clinical records review and standardized telephone interviews. RESULTS: A total of 24 patients were recruited including 13 (54.2%) underwent stage procedure and 11 (45.8%) underwent "one-stop" procedure respectively. The mean CHA2DS2-VASc and HAS-BLED scores were 4.5±1.4 and 3 (IQR 3,4) respectively. Six patients (46.1%) in the staged procedure cohort were treated with triple anti-thrombotic following PCI, with 2 developed minor bleeding before LAAC. One patient ("one-stop" cohort) had gastrointestinal bleeding 1 day after procedure. Otherwise, there was no device related complication or peri-procedural stroke/myocardial infarction. After a mean 19±5.4 months follow-up, there was no death, myocardial infarction, stroke and systemic embolization detected. CONCLUSIONS: In this pilot study, "one-stop" LAAC with PCI was shown to be efficacious with no stroke, MI, VARC-2 major bleeding or CV death reported over a mean follow-up of 19 months, and safe with no major peri-procedural bleeding or device related complications.

Characterization of a Secretory YML079-like Cupin Protein That Contributes to Sclerotinia sclerotiorum Pathogenicity.

Sclerotinia sclerotiorum causes devastating diseases in many agriculturally important crops, including oilseed rape and sunflower. However, the mechanisms of Sclerotinia sclerotiorum pathogenesis remain poorly understood. In this study, we characterized a YML079-like cupin protein (SsYCP1) from Sclerotinia sclerotiorum. We showed that SsYCP1 is strongly expressed and secreted during Sclerotinia sclerotiorum infection. Sclerotinia sclerotiorum infection was promoted by SsYCP1 overexpression and inhibited by silencing this gene with synthetic double-stranded RNA. These results collectively indicate SsYCP1 as a putative effector protein that contributes to Sclerotinia sclerotiorum pathogenicity. These findings extend our understanding of effector-mediated Sclerotinia sclerotiorum pathogenesis and suggest a novel role for YML079-like cupin proteins in plant-pathogen interactions.

Characterization of the molecular mechanism underlying the dwarfism of dsh mutant watermelon plants.

Developing dwarf watermelon is a major objective among breeders. The dsh dwarf watermelon germplasm developed in our laboratory is genetically stable. We previously produced preliminary evidence that Cla010726, which encodes a gibberellin 20-oxidase-like protein, is the primary gene controlling dwarfism in watermelon. However, the underlying genetic mechanism was unknown. In this study, we characterized the spontaneous recessive mutant dsh, which is a gibberellin (GA)-deficient mutant. Many of the phenotypic traits of dsh plants are similar to those of known GA-deficient mutants. The dsh plants were sensitive to exogenous bioactive GAs, which increased seedling height. Moreover, a quantitative analysis of endogenous GA3 proved that the bioactive GA3 content was substantially lower than normal in dsh. Additionally, the T5ClaGA20ox RNAi plants generally exhibited dwarfism, with short stems and internodes as well as small leaves and fruit. An examination of the transgenic plants carrying the ClaGA20ox1 promoter-GUS and mutant ClaGA20ox2 promoter-GUS constructs confirmed that two promoter sites are involved in the regulation of ClaGA20ox expression. Hence, mutations in the promoter of the GA20ox gene, which encodes a key enzyme involved in gibberellin biosynthesis, lead to the dwarfism of watermelon plants. The dsh mutant is a potentially useful germplasm resource for developing new watermelon varieties exhibiting dwarfism.

A Novel Effector Protein SsERP1 Inhibits Plant Ethylene Signaling to Promote Sclerotinia sclerotiorum Infection.

Sclerotinia sclerotiorum is one of the most devastating pathogens in Brassica napus and causes huge economic loss worldwide. Though around one hundred putative effectors have been predicted in Sclerotinia sclerotiorum genome, their functions are largely unknown. In this study, we cloned and characterized a novel effector, SsERP1 (ethylene pathway repressor protein 1), in Sclerotinia sclerotiorum. SsERP1 is a secretory protein highly expressed at the early stages of Sclerotinia sclerotiorum infection. Ectopic overexpression of SsERP1 in plant leaves promoted Sclerotinia sclerotiorum infection, and the knockout mutants of SsERP1 showed reduced pathogenicity but retained normal mycelial growth and sclerotium formation, suggesting that SsERP1 specifically contributes to the pathogenesis of Sclerotinia sclerotiorum. Transcriptome analysis indicated that SsERP1 promotes Sclerotinia sclerotiorum infection by inhibiting plant ethylene signaling pathway. Moreover, we showed that knocking down SsERP1 by in vitro synthesized double-strand RNAs was able to effectively inhibit Sclerotinia sclerotiorum infection, which verifies the function of SsERP1 in Sclerotinia sclerotiorum pathogenesis and further suggests a potential strategy for Sclerotinia disease control.

Mapping and Analysis of a Novel Genic Male Sterility Gene in Watermelon (Citrullus lanatus).

Seed production is critical for watermelon production, which mostly involves first-generation hybrid varieties. However, watermelon hybrid seed production currently requires complex procedures, including artificial isolation and pollination. Therefore, the development and use of a male-sterile system to generate watermelon hybrids can simplify the process. The scarcity of male-sterile watermelon germplasm resources necessitates the use of molecular breeding methods. Unfortunately, the genes responsible for male sterility in watermelon have not been cloned. Thus, the genetic basis of the male sterility remains unknown. In this study, two DNA pools derived from male-sterile and normal plants in the F2 population were used for whole-genome resequencing. The Illumina high-throughput sequencing resulted in 62.99 Gbp clean reads, with a Q30 of 80% after filtering. On the basis of the SNP index association algorithm, eight candidate regions (0.32 Mb) related to specific traits were detected on chromosome 6. Expression pattern analyses and watermelon transformation studies generated preliminary evidence that Cla006625 encodes a pollen-specific leucine-rich repeat protein (ClaPEX1) influencing the male sterility of watermelon. The identification and use of genic male sterility genes will promote watermelon male sterility research and lay the foundation for the efficient application of seed production technology.

Mitochondrial CMPK2 mediates immunomodulatory and antiviral activities through IFN-dependent and IFN-independent pathways.

Mitochondria regulate the immune response after dengue virus (DENV) infection. Microarray analysis of genes identified the upregulation of mitochondrial cytidine/uridine monophosphate kinase 2 (CMPK2) by DENV infection. We used small interfering RNA-mediated knockdown (KD) and CRISPR-Cas9 knockout (KO) approaches, to investigate the role of CMPK2 in mouse and human cells. The results showed that CMPK2 was critical in DENV-induced antiviral cytokine release and mitochondrial oxidative stress and mitochondrial DNA release to the cytosol. The DENV-induced activation of Toll-like receptor (TLR)-9, inflammasome pathway, and cell migration was suppressed by CMPK2 depletion; however, viral production increased under CMPK2 deficiency. Examining mouse bone marrow-derived dendritic cells from interferon-alpha (IFN-α) receptor-KO mice and signal transducer and activator of transcription 1 (STAT1)-KO mice, we confirmed that CMPK2-mediated antiviral activity occurred in IFN-dependent and IFN-independent manners. In sum, CMPK2 is a critical factor in DENV-induced immune responses to determine innate immunity.

Mitochondrial protein CMPK2 regulates IFN alpha-enhanced foam cell formation, potentially contributing to premature atherosclerosis in SLE.

BACKGROUND: Premature atherosclerosis occurs in patients with SLE; however, the mechanisms remain unclear. Both mitochondrial machinery and proinflammatory cytokine interferon alpha (IFN-α) potentially contribute to atherogenic processes in SLE. Here, we explore the roles of the mitochondrial protein cytidine/uridine monophosphate kinase 2 (CMPK2) in IFN-α-mediated pro-atherogenic events. METHODS: Foam cell measurements were performed by oil red O staining, Dil-oxLDL uptake and the BODIPY approach. The mRNA and protein levels were measured by qPCR and Western blotting, respectively. Isolation of CD4+ T cells and monocytes was performed with monoclonal antibodies conjugated with microbeads. Manipulation of protein expression was conducted by either small interference RNA (siRNA) knockdown or CRISPR/Cas9 knockout. The expression of mitochondrial reactive oxygen species (mtROS) was determined by flow cytometry and confocal microscopy. RESULTS: IFN-α enhanced oxLDL-induced foam cell formation and Dil-oxLDL uptake by macrophages. In addition to IFN-α, several triggers of atherosclerosis, including thrombin and IFN-γ, can induce CMPK2 expression, which was elevated in CD4+ T cells and CD14+ monocytes isolated from SLE patients compared to those isolated from controls. The analysis of cellular subfractions revealed that CMPK2 was present in both mitochondrial and cytosolic fractions. IFN-α-induced CMPK2 expression was inhibited by Janus kinase (JAK)1/2 and tyrosine kinase 2 (Tyk2) inhibitors. Both the knockdown and knockout of CMPK2 attenuated IFN-α-mediated foam cell formation, which involved the reduction of scavenger receptor class A (SR-A) expression. CMPK2 also regulated IFN-α-enhanced mtROS production and inflammasome activation. CONCLUSIONS: The study suggests that CMPK2 plays contributing roles in the pro-atherogenic effects of IFN-α.

Ameliorating Effects of Transcutaneous Electrical Acustimulation at Neiguan (PC6) and Zusanli (ST36) Acupoints Combined with Adaptive Biofeedback Training on Functional Outlet Obstruction Constipation.

BACKGROUND: Stimulant laxatives are still considered the most common treatment for functional outlet obstruction constipation (FOOC). However, the effectiveness of laxatives is unsatisfactory, and the long-term use of laxatives may cause certain adverse events. With this in mind, it is, however, paramount that novel complementary treatment(s) and/or other forms of alternative medicine are adequately investigated. AIMS: The study aims to explore the effects and potential mechanism(s) of transcutaneous electrical acustimulation (TEA) combined with adaptive biofeedback training (ABT) on FOOC. METHODS: A total of forty-five patients with FOOC were recruited and were randomly assigned to receive either Macrogol 4000 Powder (MAC, 10 g bid) (group A, n = 15) only, ABT + MAC + Sham-TEA (group B, n = 15), or TEA + ABT + MAC (group C, n = 15) in a six-week study. Individual patients' constipation-symptoms (PAC-SYM) and constipation-quality of life (PAC-QOL) were both assessed and scored. Serum acetylcholine (Ach) and nitric oxide (NO) were measured from drawn blood samples while individual patients' heart rate variability (HRV) was calculated at baseline and after each corresponding therapy. Anorectal manometry and balloon expulsion test were both performed before and after treatment. RESULTS: Firstly, participants in group C had significantly lower scores of PAC-SYM, PAC-QOL, and a decreased anal defecating pressure (ADP) as compared to participants in group B (all p < 0.050). These results, however, suggest the TEAs effect. Secondly, the low-frequency band (LF)/(LF + HF) ratio in groups B and C were decreased as compared to group A (p=0.037, p=0.010, respectively) regarding HRV. On the other hand, the high-frequency band (HF)/(LF + HF) ratio in groups B and C showed an opposite outcome. Finally, the serum Ach in groups B and C was significantly higher as compared to group A (p=0.023, p=0.012, respectively). Of significant importance, the serum NO in groups B and C were notably low as compared to group A (p=0.001, p < 0.001, respectively). CONCLUSIONS: TEA, combined with ABT, effectively improves constipation symptoms as well as QOL in FOOC patients. It is, however, achieved by decreasing ADP, which mechanisms are mediated via the autonomic and enteric mechanisms.

Author Correction: PAK1 confers chemoresistance and poor outcome in non-small cell lung cancer via ß-catenin-mediated stemness.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A Brain-Inspired Adaptive Space Representation Model Based on Grid Cells and Place Cells.

Grid cells and place cells are important neurons in the animal brain. The information transmission between them provides the basis for the spatial representation and navigation of animals and also provides reference for the research on the autonomous navigation mechanism of intelligent agents. Grid cells are important information source of place cells. The supervised learning and unsupervised learning models can be used to simulate the generation of place cells from grid cell inputs. However, the existing models preset the firing characteristics of grid cell. In this paper, we propose a united generation model of grid cells and place cells. First, the visual place cells with nonuniform distribution generate the visual grid cells with regional firing field through feedforward network. Second, the visual grid cells and the self-motion information generate the united grid cells whose firing fields extend to the whole space through genetic algorithm. Finally, the visual place cells and the united grid cells generate the united place cells with uniform distribution through supervised fuzzy adaptive resonance theory (ART) network. Simulation results show that this model has stronger environmental adaptability and can provide reference for the research on spatial representation model and brain-inspired navigation mechanism of intelligent agents under the condition of nonuniform environmental information.

Effect of icosapent ethyl on susceptibility to ventricular arrhythmias in postinfarcted rat hearts: Role of GPR120-mediated connexin43 phosphorylation.

The ω-3 fatty acids exert as an antioxidant via the G protein-coupled receptor 120 (GPR120). Icosapent ethyl, a purified eicosapentaenoic acid, showed a marked reduction in sudden cardiac death. Connexin43 is sensitive to redox status. We assessed whether icosapent ethyl attenuates fatal arrhythmias after myocardial infarction, a status of high oxidative stress, through increased connexin43 expression and whether the GPR120 signalling is involved in the protection. Male Wistar rats after ligating coronary artery were assigned to either vehicle or icosapent ethyl for 4 weeks. The postinfarction period was associated with increased oxidative-nitrosative stress. In concert, myocardial connexin43 levels revealed a significant decrease in vehicle-treated infarcted rats compared with sham. These changes of oxidative-nitrosative stress and connexin43 levels were blunted after icosapent ethyl administration. Provocative arrhythmias in the infarcted rats treated with icosapent ethyl were significantly improved than vehicle. Icosapent ethyl significantly increased GPR120 compared to vehicle after infarction. The effects of icosapent ethyl on superoxide and connexin43 were similar to GPR120 agonist GW9508. Besides, the effects of icosapent ethyl on oxidative-nitrosative stress and connexin43 phosphorylation were abolished by administering AH-7614, an inhibitor of GPR120. SIN-1 abolished the Cx43 phosphorylation of icosapent ethyl without affecting GPR120 levels. Taken together, chronic use of icosapent ethyl after infarction is associated with up-regulation of connexin43 phosphorylation through a GPR120-dependent antioxidant pathway and thus plays a beneficial effect on arrhythmogenic response to programmed electrical stimulation.

Hepatitis B virus X protein promotes tumor invasion and poor prognosis in hepatocellular carcinoma via phosphorylation of paxillin at Serine 178 by activation of the c-Jun NH2-terminal kinase.

Hepatitis B virus X protein (HBx) plays critical roles in hepatocellular tumorigenesis by activating different signaling pathways, including the c-Jun NH2-terminal kinase (JNK) pathway. Phosphorylation of paxillin (PXN) promotes cell migration via activation of the JNK signaling pathway, but PXN overexpression is not associated with poor outcome in patients with hepatocellular carcinoma (HCC). HBx gene manipulation and Western blotting indicated that phosphorylation of PXN at Serine 178 (pS178-PXN) by HBx may promote invasiveness in HCC cells via HBx-mediated JNK activation. Immunohistochemical analysis indicated a positive correlation between pS178-PXN and HBx expression levels in tumor specimens. The overall survival (OS) and relapse-free survival (RFS) were poorer in patients with high-pS178-PXN expressing or high-HBx expressing tumors than in patients with low-pS178-PXN expressing or low-HBx expressing tumors. In conclusion, phosphorylation of PXN at Serine 178 by HBx-mediated JNK activation may therefore play a critical role in tumor invasiveness and poor prognosis in patients with HBV-infected hepatocellular tumors. The expression levels of pS178-PXN may be a reliable prognostic biomarker to predict the clinical outcomes in patients with HBV-associated HCC.

The DELLA proteins interact with MYB21 and MYB24 to regulate filament elongation in Arabidopsis.

BACKGROUND: Gibberellin (GA) and jasmonate (JA) are two essential phytohormones for filament elongation in Arabidopsis. GA and JA trigger degradation of DELLAs and JASMONATE ZIM-domain (JAZ) proteins through SCFSLY1 and SCFCOI1 separately to activate filament elongation. In JA pathway, JAZs interact with MYB21 and MYB24 to control filament elongation. However, little is known how DELLAs regulate filament elongation. RESULTS: Here we showed that DELLAs interact with MYB21 and MYB24, and that R2R3 domains of MYB21 and MYB24 are responsible for interaction with DELLAs. Furthermore, we demonstrated that DELLA and JAZ proteins coordinately repress the transcriptional function of MYB21 and MYB24 to inhibit filament elongation. CONCLUSION: We discovered that DELLAs interact with MYB21 and MYB24, and that DELLAs and JAZs attenuate the transcriptional function of MYB21 and MYB24 to control filament elongation. This study reveals a novel cross-talk mechanism of GA and JA in the regulation of filament elongation in Arabidopsis.