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The quorum-sensing (QS) system between the phages and their hosts is important for the phage lysis-lysogeny decision. In Vibrio cholerae , the QS system consists of a LuxR-type receptor VqmA (VqmA Vc) and an autoinducer molecule 3,5-dimethylpyrazin-2-ol (DPO). A VqmA homolog encoded by vibriophage VP882 (VqmA Phage) can intervene the host QS system via binding to both the host-produced DPO and its cognate promoter (P qtip) to induce the phage lysogeny-to-lysis transition, whereas VqmA Vc cannot influence the VqmA Phage -induced pathway, suggesting an asymmetry regulation. In this study, we report the crystal structure of VqmA Phage -DPO complex at 2.65 Å and reveal that the mechanism of DPO recognition is conserved in VqmA homologs. Besides, we identify a non-classical palindrome sequence in P qtip , which can be effectively recognized by VqmA Phage but not VqmA Vc. The sequence contains an interval longer than that in the vqmR promoter recognized by VqmA Vc. In addition, the two DBD regions in the VqmA Phage dimer exhibit more relaxed architecture than that of the reported VqmA Vc , which is likely to be in the conformation that may easily bind to target promoter containing a longer interval. In summary, our findings provide a structural and biochemical basis for the DBD-dependent DNA recognition in different promoter regions in the phage lysogeny-to-lysis decision communication system, and provide clues for developing phage therapies against Vibrio cholerae infection. • The crystal structure of VqmA Phage -DPO complex was solved. • The molecular mechanism of DPO recognition is conserved in VqmA homologs. • DBD domain of VqmA Phage is important in qtip promoter recognition. • The target qtip promoter region of VqmA Phage was identified. • Demonstrates the difference of DNA sites recognized by VqmA Phage and VqmA Vc. [ABSTRACT FROM AUTHOR]

• LPS preconditioning prevents CSDS-induced behavioral abnormalities in mice. • 10-days interval abolishes the effect of LPS on behavioral abnormalities. • A second LPS injection produces prophylactic effect on behavioral abnormalities. • Repeated LPS injection prior to stress exposure prevents behavioral abnormalities. • Microglial inhibition blocks the effect of LPS on behavioral abnormalities. Over-activation of the innate immune system constitutes a risk factor for the development of nervous system disorders but may reduce the severity of these disorders by inducing tolerance effect. Here, we studied the tolerance-inducing effect and properties of innate immune stimulation on chronic social defeat stress (CSDS)-induced behavioral abnormalities in mice. A single injection of the innate immune enhancer lipopolysaccharide (LPS) one day before stress exposure prevented CSDS-induced impairment in social interaction and increased immobility time in the tail suspension test and forced swimming test. This effect was observed at varying doses (100, 500, and 1000 μg/kg) and peaked at 100 μg/kg. A single LPS injection (100 μg/kg) either one or five but not ten days before stress exposure prevented CSDS-induced behavioral abnormalities. A second LPS injection ten days after the first LPS injection, or a 2 × or 4 × LPS injections ten days before stress exposure also induced tolerance against stress-induced behavioral abnormalities. Our results furthermore showed that a single LPS injection one day before stress exposure skewed the neuroinflammatory response in the hippocampus and prefrontal cortex of CSDS-exposed mice toward an anti-inflammatory phenotype. Inhibiting the central innate immune response by pretreatment with minocycline or PLX3397 abrogated the tolerance-inducing effect of LPS preconditioning on CSDS-induced behavioral abnormalities and neuroinflammatory responses in the brain. These results provide evidence for a prophylactic effect of innate immune stimulation on stress-induced behavioral abnormalities via changes in microglial activation, which may help develop novel strategies for the prevention of stress-induced psychological disorders. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a diffuse pulmonary microvascular remodeling disease accompanied by malignant proliferation of pulmonary artery smooth muscle cells (PASMCs), which causes persistent pulmonary artery pressure elevation, right ventricular hypertrophy (RVH) and death. However, current therapies targeting pulmonary vascular remodeling and RVH remain poorly effective in reversing PAH. Overactivation of the protein tyrosine kinase Src plays an important role in tumor cell growth, proliferation and invasion; we thus hypothesized that inhibitors targeting Src activation could reverse experimental PAH. We demonstrated that Src was markedly activated in hypoxia-stimulated PASMCs from donors and PASMCs isolated from PAH patients. We investigated the effects of the Src-selective inhibitor 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4- d ]pyrimidin-4-amine (PP1) and berberine (BBR) on PAH-PASMC proliferation and migration by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2′-deoxyuridine (EdU) and wound-healing assays. Our in vitro results showed that inhibition of Src (Tyr416) phosphorylation repressed PAH-PASMC proliferation and migration by inhibiting hypoxia-inducible factor-1α (HIF-1α) expression through Akt/mTOR signal pathway. In vivo, PP1 and BBR significantly alleviated distal pulmonary vascular remodeling and decreased right ventricular systolic pressure (RVSP) and RVH in Sugen (SU) 5416/hypoxia (SU-PAH) mice. These findings demonstrate that pharmacological (PP1 or BBR) inhibition of Src activation could be a novel means of treating severe pulmonary vascular remodeling and RVH in PAH patients. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Environmental concern associated with excess fluoride has intrigued the unceasing exploration of new multifunctional hybrid materials to mitigate any undesirable consequence to human health. Herein, a novel hybrid monolith has been successfully fabricated via a facile in-situ growth strategy for highly efficient defluoridation from contaminated waters, in which homogeneously dispersed UiO-66 particles are perfectly anchored on three dimensional (3D) porous carbon foam (CF). Benefiting from fully exposed active sites, excellent pore accessibility and efficient mass transport, the integrated UiO-66/CF hybrid monolith exhibits fast adsorption kinetics, and outstanding uptake capacity toward fluoride as high as 295 mg g−1, which greatly outperforms the previously reported adsorbents. Furthermore, the fluoride removal efficiency of the spent monolith can reach up to 70% after four cycles, accompanied by facile separation nature and outstanding water stability. More significantly, the resulting UiO-66/CF packed column (0.36 g) can continuously treat 400 mL of F− solution with 6.2 mg L−1 before the breakthrough point occurs, highlight its potential feasibility for fluoride removal in the practical applicability. [ABSTRACT FROM AUTHOR]

Globally, microplastics (MPs) are highly prevalent, especially in coastal areas. Unfortunately, golden pompano as a major marine fish in China is typically raised in floating marine cages near coasts, facing these MPs sources. However, toxicological studies on Golden Pompano which farm in coastal areas and face actual microplastic exposure are rare. Therefore, golden pompano were exposed to 10.0 μg/L, 100.0 μg/L, and 1000.0 μg/L polystyrene MPs (PS-MPs) for 14 days to study the potential impact of the microplastics on the Golden Pompano. Fish show slowed growth after 14 days of exposure. Histopathology shows irregular shaped nuclei and nuclear and cytoplasmic vacuolation traits in liver. Oxidative stress-related enzyme activity and gene expression data show that oxidative damage occurs in the high-concentrations (100.0 μg/L and 1000.0 μg/L) of PS-MPs exposures. Up-regulation of Grp78 , Xbp-1 , Eif-2α and chop gene expression indicates the occurrence of endoplasmic reticulum stress, and the western blot results also confirmed this. Severe oxidative stress also caused ERS, which ultimately increased BAX/Bcl-2 ratios and induces apoptosis. Furthermore, up-regulated anaerobic respiration, altered lipid metabolism, and immune disturbance were exhibited during PS-MPs stress. Therefore, oxidative stress appeared to be the main toxicity issue caused by MPs, while ERS-mediated apoptosis, metabolic alterations, and immune responses were induced by this stress. Notably, endoplasmic reticulum stress and apoptosis are a self-protective mechanism, which may be an intermediate link in the toxicity of microplastics. This study highlights the role of endoplasmic reticulum stress in MPs toxicology and assesses the adverse effects of microplastics on Golden Pompano. • Microplastics will affect the physiological status of large cultured fishes. • Microplastics alter liver structure and function in golden pompano. • Oxidative stress induced by microplastics mediates endoplasmic reticulum stress leading to apoptosis of liver. [ABSTRACT FROM AUTHOR]

Cobalt is a transition element that abundantly exists in the environment. Besides direct hypoxia stress, cobalt ions indirectly induce hypoxia-reoxygenation injury (HRI), the main cause of acute kidney injury (AKI), a life-threatening clinical syndrome characterized by the necrosis of the proximal tubular epithelial cells (PTECs) and inflammation. Pyroptosis, a type of inflammatory programmed cell death, might play an essential role in HRI-AKI. However, whether pyroptosis is involved in cobalt chloride (CoCl 2)-induced HRI-AKI remains unknown. Autophagy is a cellular biological process maintaining cell homeostasis that is involved in cell damage in AKI, yet the underlying regulatory mechanism of autophagy on pyroptosis has not been fully understood. In this study, the in vitro and in vivo models of CoCl 2 -induced HRI-AKI were established with HK-2 cell line and C57BL/6J mouse. Pyroptosis-related markers were detected with western blotting and immunofluorescence assays, and results showed that gasdermin E (GSDME)-mediated pyroptosis was involved in the cell damage in HRI-AKI. Specific chemical inhibitors of caspase 3, caspase 8, and caspase 9 significantly inhibited GSDME-mediated pyroptosis, verifying that GSDME-mediated pyroptosis was induced via the activation of caspase 3/8/9. The western blotting and immunofluorescence assays were adopted to detect the accumulation of the autophagosomes, and results suggested that HRI increased the autophagic level. The effects of autophagy on apoptosis and pyroptosis were evaluated using lentivirus transfection assays to knock down autophagy-specific genes atg5 and fip200 , and results demonstrated that autophagy induced GSDME-mediated pyroptosis via apoptotic pathways in HRI-AKI. Our results revealed the involvement of GSDME-mediated pyroptosis in CoCl 2 -induced HRI-AKI and promoted the understanding of the regulatory mechanism of GSDME cleavage. Our study might provide a potential therapeutic target for HRI-AKI, and will be helpful for the risk evaluation of cobalt exposure. [Display omitted] • Cobalt ions induced more serious damage in the reoxygenation stage in HRI. • CoCl 2 induced GSDME-mediated pyroptosis in the HRI-AKI model. • CoCl 2 -activated GSDME was cleaved via the intrinsic and extrinsic apoptotic pathways in HRI-AKI. • CoCl 2 -elevated autophagy promoted the induction of apoptosis and GSDME-mediated pyroptosis in HRI-AKI. [ABSTRACT FROM AUTHOR]

In the food industry, the competition and reciprocity between lactic acid bacteria (LAB) and yeasts in co-culture and the interactions of their metabolites affect product quality. Quorum sensing (QS) is a communication mechanism between bacterial cells, which participates in multiple physiological behaviors. The effects of Saccharomyces cerevisiae YE4 cell-free supernatant (CFS) on LAB were explored from the aspects of growth and metabolism, QS, and protein expression. The results showed the CFS inhibited not only the growth of Enterococcus faecium 8–3 and Lactobacillus fermentum 2-1 but also their acid production and biofilm formation. The acid production and biofilm amount was significantly decreased by 18.4% and 12.8% in L. fermentum 2–1 and E. faecium 8–3, respectively. The effect of CFS on QS was shown in the changes of Autoinducer-2 (AI-2) activity, luxS and pfs genes expression. Moreover, a total of 136 proteins of E. faecium 8-3 differed significantly in co-cultured with CFS, which involved in metabolic pathways including oxidative phosphorylation, pyruvate metabolism, metabolic pathways, mismatch repair, QS system, two-component system, and ABC transporters. Therefore, S. cerevisiae YE4 CFS might affect the physiological metabolism of E. faecium 8-3 by affecting the energy metabolism and QS system. • S. cerevisiae YE4 CFS influenced E. faecium and L. fermentum physiological behaviors. • S. cerevisiae YE4 CFS caused changes in AI-2 activity and QS gene expression. • YE4 CFS might achieve inhibition by affecting energy metabolism and QS system. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that the brain functional modular organization, which is a fundamental feature of the human brain, would change along the adult lifespan. However, these studies assumed that each brain region belonged to a single functional module, although there has been convergent evidence supporting the existence of overlap among functional modules in the human brain. To reveal how age affects the overlapping functional modular organization, this study applied an overlapping module detection algorithm that requires no prior knowledge to the resting-state fMRI data of a healthy cohort (N = 570) aged from 18 to 88 years old. A series of measures were derived to delineate the characteristics of the overlapping modular structure and the set of overlapping nodes (brain regions participating in two or more modules) identified from each participant. Age-related regression analyses on these measures found linearly decreasing trends in the overlapping modularity and the modular similarity. The number of overlapping nodes was found increasing with age, but the increment was not even over the brain. In addition, across the adult lifespan and within each age group, the nodal overlapping probability consistently had positive correlations with both functional gradient and flexibility. Further, by correlation and mediation analyses, we showed that the influence of age on memory-related cognitive performance might be explained by the change in the overlapping functional modular organization. Together, our results revealed age-related decreased segregation from the brain functional overlapping modular organization perspective, which could provide new insight into the adult lifespan changes in brain function and the influence of such changes on cognitive performance. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the effect of the signal molecule AI-2 on biofilm formation in Lactobacillus sanfranciscensis. We found that the influence of signal molecule AI-2 on strains is related to a variety of physiological metabolic behaviors, such as bacterial growth, morphological characteristics, biofilm development, related gene expression, and bile salt stress tolerance. The survival rates of planktonic and biofilm forms of L. sanfranciscensis were measured after acid, bile salt, and in vitro digestion. The results showed that the biofilm strain had stronger stress resistance. Next, the effects of endogenous and synthetic AI-2 on L. sanfranciscensis growth were compared. The addition of synthetic AI-2 improved L. sanfranciscensis cell density and enhanced bacterial cohesion. Upregulated expression of ftsH was found to promote biofilm formation and growth. AI-2 intervention will improve bile salt tolerance in L. sanfranciscensis. In conclusion, the signal molecule AI-2 is involved in the regulation of biofilm formation and development in L. sanfranciscensis. • The biofilm of Lactobacillus sanfranciscensis had stronger stress resistance. • Effect of endogenous AI-2 on the growth and biofilm was studied for the first time. • The synthetic AI-2 increased the biofilm formation and enhanced bacterial cohesion. • AI-2 intervention will improve bile salt tolerance in L. sanfranciscensis. [ABSTRACT FROM AUTHOR]

The plant Sophora flavescens Ait. has been used in the clinical management of colorectal cancer (CRC). Its constituent compounds, notably the alkaloids matrine, oxymatrine, and sophoridine, have received considerable research attention in experimental models of CRC in vivo and in vitro. This review found that extracts of S. flavescens and/or its constituent compounds have been reported to inhibit CRC cell proliferation by inducing cell-cycle arrest at the G1 phase, inducing apoptosis via the intrinsic pathway, interfering in cancer metabolism, inhibiting metastasis and angiogenesis, regulating senescence and telomeres, regulating the tumour microenvironment and down-regulating cancer-related inflammation. In addition, matrine and oxymatrine reversed multi-drug resistance and enhanced the effects of chemotherapies. These anti-cancer effects were associated with regulation of several cellular signalling pathways including: MAPK/ERK, PI3K/AKT/mTOR, p38MAPK, NF-κB, Hippo/LATS2, TGF-β/Smad, JAK/STAT3, RhoA/ROC, and Wnt/ β-catenin pathways. These multiple actions in CRC suggest the alkaloids of S. flavescens may be therapeutic candidates for CRC management. Nevertheless, there remains considerable scope for future research into its flavonoid constituents, the effects of combinations of compounds, and the interaction between these compounds and anti-cancer drugs. In addition, more research is needed to investigate likely drug ligand-receptor interactions for each of the bioactive compounds. [Display omitted] • Suppressed CRC cell proliferation in vitro and in vivo. • Induced CRC cell cycle arrest at G1 phase and induced apoptosis. • Regulated CRC metabolism, metastasis, angiogenesis, senescence, tumour microenvironment, tumour-related inflammation and cachexia; and reversed multi-drug resistance. • These anti-cancer effects were associated with regulation of several cellular signalling pathways including: MAPK/ERK, PI3K/AKT/mTOR, p38MAPK, NF-κB, Hippo/LATS2, TGF-β/Smad, JAK/STAT3, RhoA/ROC, and Wnt/ β-catenin pathways. [ABSTRACT FROM AUTHOR]

Flagellar motility enables resource acquisition and noxious substance evasion, underpinning imperative ecological processes in aquatic environments. Yet the underlying mechanism that links flagellar motility with surface attachment and thereby biofilm formation, especially in conditions of limited resource availability, remains elusive. Here, we present experimental and modeling evidence to unveil bacterial motility and biofilm formation under nutrient-limited stresses with Pseudomonas aeruginosa (WT) and its nonflagellated isogenic mutant (Δ fliC) as model bacteria. Results revealed that boosted flagellar motility of WT strain promoted biofilm initialization to a peak value of 0.99 × 107 cells/cm2 at 1/50 dilution after 20 min incubation. We hypothesized that bacteria can invoke instant motility acceleration for survival confronting nutrient-limited stress, accompanied by optimized chemotactic foraging through sensing ambient chemical gradients. Accordingly, accelerated cell motility in oligotrophic environment created increased cell-cell and cell-surface interactions and thereof facilitated biofilm initialization. It was confirmed by the consistence of modeling predictions and experimental results of cell velocity and surface attachment. With the development of biofilm, promotion effect of flagellar motility responding to nutrient deprivation-stress faded out. Instead, loss of motility profiting increased growth rates and extracellular protein excretion, associated with an enhancement of biofilm development for the mutant in oligotrophic aquatic environment. For both strains, nutrient limitation evidently reduced planktonic cell propagation as expected. Our results offer new insights into the mechanical understanding of biofilm formation shaped by environmental stresses and associating biological responses. • Boosted flagellar motility promoted biofilm initialization in oligotrophic aquatic environment. • Instant stress response and chemotactic foraging contributed collectively to bacterial motility dynamics. • Loss of motility profited increased growth rates, PN excretion and biofilm development in oligotrophic aquatic environment. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated that Cryptocaryon irritans can efficiently propagate in golden pompano (Trachinotus blochii), especially under intensive high-density culture, which can lead to large-scale infection, bacterial invasion, and major economic losses. By contrast, Siganus oramin is less susceptible to C. irritans infection. Here, we artificially infected S. oramin and T. blochii with C. irritans. We then used RNA-seq to characterize the expression of genes in the gills of S. oramin and T. blochii at different times after infection, conducted bioinformatics analysis of relevant pathways, and compared the differentially expressed genes in the two species. The aim of this study was to enhance our understanding of host-parasite interactions to aid the development of effective prevention and treatment strategies for C. irritans. Infection with C. irritans induced the differential expression of a large number of genes in the gills of S. oramin , indicating that S. oramin may respond to C. irritans infection by modifying the expression of genes at the transcriptional level. Our research showed that the Toll-like receptor signaling pathway, Antigen processing and presentation, Complement and coagulation cascades, and Cytosolic DNA-sensing pathway are involved in the immune response of S. oramin and T. blochii to C. irritans infection. However, T. blochii has a weak ability to mobilize neutrophils to participate in defense against C. irritans infection and differs from S. oramin in its ability to induce specific immune responses. Because of gill tissue damage during infection, dissolved oxygen intake is reduced, which increases physiological and metabolic stress. The metabolic pathways of S. oramin and T. blochii significantly differed; specifically, the main pathways in S. oramin were related to glucose and lipid metabolism, and the main pathways in T. blochii were related to amino acid metabolism. This may reduce the efficiency of ATP biosynthesis in T. blochii and result in dysfunctional energy metabolism. Therefore, differential immune and metabolic responses underlie differences in the resistance of S. oramin and T. blochii to C. irritans. The figure includes experimental design and basic results, the red indicates the up-regulated, while the blue indicates the down-regulated. [Display omitted] • S. oramin respond infection by adjusting the expression of more genes at the transcriptional level. • T. blochii is weak in mobilizing neutrophils to participate in the fight against infection. • T. blochii and S. oramin differ in inducing specific immune responses. • Gill damage caused by infection may affect major metabolic pathways. [ABSTRACT FROM AUTHOR]

Abstract A wealth of research on resting-state functional MRI (R-fMRI) data has revealed modularity as a fundamental characteristic of the human brain functional network. The modular structure has recently been suggested to be overlapping, meaning that a brain region may engage in multiple modules. However, not only the overlapping modular structure remains inconclusive, the topological features and functional roles of overlapping regions are also poorly understood. To address these issues, the present work utilized the maximal-clique based multiobjective evolutionary algorithm to explore the overlapping modular structure of the R-fMRI data obtained from 57 young healthy adults. Without prior knowledge, brain regions were optimally grouped into eight modules with wide overlap. Based on the topological features captured by graph theory analyses, overlapping regions were classified into an integrated club and a dominant minority club through clustering. Functional flexibility analysis found that overlapping regions in both clubs were significantly more flexible than non-overlapping ones. Lesion simulations revealed that targeted attack at overlapping regions were more damaging than random failure or even targeted attack at hub regions. In particular, overlapping regions in the dominant minority club were more flexible and more crucial for information communication than the others were. Together, our findings demonstrated the highly organized overlapping modular architecture and revealed the importance as well as complexity of overlapping regions from both topological and functional aspects, which provides important implications for their roles in executing multiple tasks and maintaining information communication. Highlights • The human brain functional network had a widely overlapped modular organization. • The overlapping nodes were topological centre and functionally flexible. • The overlapping nodes had two clubs and one club was more dominant than the other. [ABSTRACT FROM AUTHOR]

Dissolved oxygen (DO) is essential for teleosts, and fluctuating environmental factors can result in hypoxic stress in the golden pompano (Trachinotus blochii). However, it is unknown whether different recovery speeds of DO concentration after hypoxia induce stress in T. blochii. In this study, T. blochii was subjected to hypoxic conditions (1.9 ± 0.2 mg/L) for 12 h followed by 12 h of reoxygenation at two different speeds (30 mg/L per hour and 1.7 mg/L per hour increasing). The gradual reoxygenation group (GRG), experienced DO recovery (1.9 ± 0.2 to 6.8 ± 0.2 mg/L) within 3 h, and the rapid reoxygenation group (RRG), experienced DO recovery (1.9 ± 0.2 to 6.8 ± 0.2 mg/L) within 10 min. Physiological and biochemical parameters of metabolism (glucose, glycegon, lactic acid (LD), lactate dehydrogenase (LDH), pyruvic acid (PA), phosphofructokinase (PFKA), and hexokinase (HK), triglyceride (TG), lipoprotein lipase (LPL), carnitine palmitoyltransferase 1 (CPT-1)) and transcriptome sequencing (RNA-seq of liver) were monitored to identify the effects of the two reoxygenation speeds. Increased LD content and increased activity of LDH, PA, PFKA, and HK suggested enhanced anaerobic glycolysis under hypoxic stress. LD and LDH levels remained significantly elevated during reoxygenation, indicating that the effects of hypoxia were not immediately alleviated during reoxygenation. The expressions of PGM2 , PFKA , GAPDH , and PK were increased in the RRG, which suggests that glycolysis was enhanced. The same pattern was not observed in the GRG. Additionally, In the RRG, reoxygenation may promote glycolysis to guarantee energy supply. However, the GRG may through the lipid metabolism such as steroid biosynthesis at the later stage of reoxygenation. In the aspect of apoptosis, differentially expressed genes (DEGs) in the RRG were enriched in the p53 signaling pathway, which promoted cell apoptosis, while DEGs in the GRG seem to activate cell apoptosis at early stage of reoxygenation but was restrained latterly. DEGs in both the RRG and the GRG were enriched in the NF-kappa B and JAK-STAT signaling pathways, the RRG may induce cell survival by regulating the expression of IL-12B , COX2 , and Bcl-XL , while in the GRG it may induce by regulating the expression of IL-8. Moreover, DEGs in the RRG were also enriched in the Toll-like receptor signaling pathway. This research revealed that at different velocity of reoxygenation after hypoxic stress, T. blochii would represent different metabolic, apoptotic and immune strategies, and this conclusion would provide new insight into the response to hypoxia and reoxygenation in teleosts. [Display omitted] • Glucose and lipid levels returned to normal during reoxygenation after hypoxia. • In the GRG, the expression of FDFT1 and HSD17B7 may guarantee the lipid metabolism. • In the RRG, the expression of Fas , CASP8 and CASP10 may promote apoptosis. • In the RRG, the expression of IL-12B , COX2 , and Bcl-XL may activate cell survival. [ABSTRACT FROM AUTHOR]

Epicardial adipose tissue (EAT) is a metabolically active organ which generates inflammatory cytokines. Thickness of EAT is associated with onset and development of heart failure with preserved ejection fraction (HFpEF). However, it is still unclear the specific mechanisms and pharmacological targets on EAT induced inflammation in HFpEF. A two-hit protocol with western diet and Nω-nitrol-arginine methyl ester (L-NAME) was used to establish HFpEF mouse model. In HFpEF mice, inflammatory biomarkers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and von willebrand factor (vWF) elevated in myocardium compared to control. Inflammatory cell infiltration in myocardium was increased. In HFpEF mice, inflammasome-mediated pyroptosis pathway was activated in the EAT. Suppression of pyroptosis-related protein gasdermin D (GSDMD) in cultured EAT could lower cardiomyocyte inflammation and autophagy. Furthermore, spironolactone and rosuvastatin, the two-hit anti-inflammatory agents, reduced NLR family pyrin domain containing 3 (NLRP3)/GSDMD pyroptosis in EAT and autophagy in myocardium of HFpEF mouse. The combination treatment also enhanced exercise tolerance and appeased inflammatory injuries in HFpEF mice. Pyroptosis signaling is involved in EAT-myocardium axis in mouse model of HFpEF. Targeting adipocyte-derived inflammation in EAT bears potential to treatment HFpEF. • Epicardial adipose tissue is a metabolically active organ which generates inflammatory cytokines. • In HFpEF mouse model, an epicardial adipose tissue-myocardium axis was established, and pyroptosis signaling mediate the effect of adipose tissue on myocardium. • Suppressing pyroptosis is a novel concept and strategy for the treatment of HFpEF. [ABSTRACT FROM AUTHOR]

• Infusion of anti-BDNF antibody into DG abolishes the antidepressant effect of LPS. • Antidepressant effects of LPS are blocked in BDNF Val66Met Knock-in mice. • Antidepressant effects of LPS are blocked by inhibition of BDNG-TrkB signaling. • The ERK1/2 signal mediates the LPS-induced synthesis of BDNF in DG. • ERK1/2 inhibition abolishes the antidepressant effect of LPS. Depressed mice have lower numbers of microglia in the dentate gyrus (DG). Reversal of this decline by a single low dose of lipopolysaccharide (LPS) may have antidepressant effects, but there is little information on the molecular mechanisms underlying this effect. It is known that impairment of brain-derived neurotrophic factor (BDNF) signaling is involved in the development of depression. Here, we used a combination of neutralizing antibodies, mutant mice, and pharmacological approaches to test the role of BDNF-tyrosine kinase receptor B (TrkB) signaling in the DG in the effect of microglial stimulation. Our results suggest that inhibition of BDNF signaling by infusion of an anti-BDNF antibody, the BDNF receptor antagonist K252a, or knock-in of the mutant BDNF Val68Met allele abolished the antidepressant effect of LPS in chronically stressed mice. Increased BDNF synthesis in DG, mediated by extracellular signal-regulated kinase1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling, was essential for the antidepressant effect of microglial stimulation. These results suggest that increased BDNF synthesis through activation of ERK1/2 caused by a single LPS injection and subsequent TrkB signaling are required for the antidepressant effect of hippocampal microglial stimulation. [ABSTRACT FROM AUTHOR]

• Adolescent LPS injection prevents CSDS-induced depression-like behavior in mice. • Adolescent LPS injection prevents CSDS-induced neuroinflammatory responses. • Microglia mediates the prevention of depression by adolescent LPS pre-injection. Our previous studies had reported that microglia activation one day before stress exposure prevented the behavioral abnormalities induced by chronic stress in adult mice, and a 10-day interval between microglia stimulation and stress exposure can abolish the prophylactic effect of LPS preinjection on the behavioral abnormalities induced by chronic stress, which, however, could be rescued by repeated LPS injection. This suggests that increased stimulation of microglia results in animals developing a strong ability to prevent deleterious stress stimuli. Because microglia in the adolescent brain exhibit flexible immunological plasticity, we hypothesize that a single low-dose LPS injection during adolescence may provide long-lasting protection against behavioral abnormalities induced by chronic stress in adult mice. As expected, our results showed that a single injection of LPS (100 μg/kg) at post-natal day 28 (PND 28) prevented the development of abnormal behaviors and shifted neuroinflammatory responses toward an anti-inflammatory phenotype in adult mice treated with CSDS at their different stages of the age (PND 56, 140, and 252). Moreover, pretreatment with minocycline or PLX3397 to inhibit microglial activation abolished the prophylactic effect of LPS preinjection after PND 28 on behavioral abnormalities and neuroinflammatory responses induced by CSDS in adult mice at their different stages of the age, PND 56, 140, and 252. These results indicate that stimulation of microglia in adolescence may confer long-lasting protection against neuroinflammatory responses and behavioral abnormalities induced by chronic stress in adult mice. This may offer the potential for the development of a "vaccine-like strategy" to prevent mental disorders. [ABSTRACT FROM AUTHOR]

As a recognized safe starter, lactic acid bacteria can improve the quality characteristics of fermented sausages and ensure the safety characteristics of sausages to a certain extent. The purpose of this study was to analyze the effects of Lactobacillus helveticus IMAUJBH1 on lipid profiles and volatile flavor compounds of Inner Mongolia mutton fermented sausage by lipidomics and GC-MS. The results showed that a total of 2024 lipid molecules were identified, and 1135 differential lipids were screened by multivariate analysis (P < 0.05, VIP>1). Pathway topology analysis showed that glycerophospholipid metabolism, glyceride metabolism and sphingolipid metabolism pathways were the three most active pathways. Furthermore, 21 key differential lipid molecules and 5 key volatile flavor compounds were selected as characteristic substances for correlation analysis. The results of correlation study indicated that the addition of Lactobacillus helveticus IMAUJBH1 would further affect the flavor of fermented mutton sausage by affecting the relative expression of lipid molecules LPC (17:0), LPC (22:6), LPC (18:1), LPC (18:3), LPC (22:4), Cer (d18:1/16:0), and Cer (d18: 1/22:0). The results provide a scientific theoretical basis for the application of IMAUJBH1 in mutton fermented sausage, and further promote the development of mutton processing industry in Inner Mongolia. • Lipidomics was used to evaluate the lipid metabolism of fermented sausages. • 21 Key differential lipid molecules were identified as characteristic substances. • 5 key volatile flavor substances (OAV>1) were used as characteristic substances. • IMAUJBH1 can reduce the content of related aldehydes and esters. [ABSTRACT FROM AUTHOR]

Pompano fishes have been widely farmed worldwide. As a representative commercial marine species of the Carangidae family, the golden pompano (Trachinotus blochii) has gained significant popularity in China and worldwide. However, because of rapid growth and high-density aquaculture, the golden pompano has become seriously threatened by various diseases. Cell lines are the most cost-effective resource for in vitro studies and are widely used for physiological and pathological research owing to their accessibility and convenience. In this study, we established a novel immortal cell line, GPF (Golden pompano fin cells). GPF has been passaged over 69 generations for 10 months. The morphology, adhesion and extension processes of GPF were evaluated using light and electron microscopy. GPF cells were passaged every 3 days with L-15 containing 20 % fetal bovine serum (FBS) at 1:3. The optimum conditions for GPF growth were 28 °C and a 20 % FBS concentration. DNA sequencing of 18S rRNA and mitochondrial 16S rRNA confirmed that GPF was derived from the golden pompano. Chromosomal analysis revealed that the number pattern of GPF was 48 chromosomes. Transfection experiments demonstrated that GPF could be utilized to express foreign genes. Furthermore, heavy metals (Cd, Cu, and Fe) exhibited dose-dependent cytotoxicity against GPF. After polyinosinic-polycytidylic acid (poly I:C) treatment, transcription of the retinoic acid-inducible gene I-like receptor (RLR) pathway genes, including mda5 , mita , tbk1 , irf3 , and irf7 increased, inducing the expression of interferon (IFN) and anti-viral proteins in GPF cells. In addition, lipopolysaccharide (LPS) stimulation up-regulated the expression of inflammation-related factors, including myd88 , irak1 , nfκb , il1β , il6 , and cxcl10 expression. To the best of our knowledge, this is the first study on the immune response signaling pathways of the golden pompano using an established fin cell line. In this study, we describe a preliminary investigation of the GPF cell line immune response to poly I:C and LPS, and provide a more rapid and efficient experimental material for research on marine fish immunology. • GPF was established and became a stable fin cell line of Trachinotus blochii. • GPF can be used to assess the cytotoxicity of heavy metals. • GPF can be utilized to express foreign genes with 32 % transfection efficiency. • GPF's immune response to LPS and poly I: C challenge proved it can be used for in vitro immunology study. [ABSTRACT FROM AUTHOR]

Image classification aims to automatically group a set of images into several categorizations, which is widely applied in scene categorization, image clustering. Lung cancer recognition can be achieved by using image classification technique, since there are distinct differences between healthy lung and sick lung images. In this paper, we propose lung cancer recognition based on image quality assessment, which can distinguish sick lung images from healthy lung images. First, our dataset is acquired using low-dose CT scan combined with full-mode iterative recombination (IMR). Then, we incorporate both low-level and high-level features to extract deep representation from obtained dataset. Specifically, our designed low-level features include color moment and texture feature, and CNN based method is leveraged for deep feature extraction. For reducing artifacts and noise of images, we assign quality score for each training image. And quality score and deep feature are fused to generate deep representation. Afterward, we propose a probabilistic model to learn the distribution of deep representation. Finally, lung cancer recognition can be achieved using learned model. We conduct comprehensive experiments and our proposed method is verified effective. [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang-II)-induced fibroblast differentiation plays an important role in the development of atrial fibrosis and atrial fibrillation (AF). Here, we show that the expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is increased in atrial muscle and atrial fibroblasts in patients with AF, accompanied by significant atrial fibrosis and atrial fibroblast differentiation. In addition, EZH2 is induced in murine models of atrial fibrosis. Furthermore, either pharmacological GSK126 inhibition or molecular silencing of EZH2 can inhibit the differentiation of atrial fibroblasts and the ability to produce ECM induced by Ang-II. Simultaneously, inhibition of EZH2 can block the Ang-II-induced migration of atrial fibroblasts. We found that EZH2 promotes fibroblast differentiation mainly through the Smad signaling pathway and can form a transcription complex with Smad2 to bind to the promoter region of the ACTA2 gene. Finally, our in vivo experiments demonstrated that the EZH2 inhibitor GSK126 significantly inhibited Ang-II-induced atrial enlargement and fibrosis and reduced AF vulnerability. Our results demonstrate that targeting EZH2 or EZH2-regulated genes might present therapeutic potential in AF. • EZH2 expression was significantly elevated in atrial muscle specimens of patients with atrial fibrillation. • EZH2 regulates the transformation and migration of atrial fibroblasts. • EZH2 regulates fibroblasts transformation mainly through Ang-II-TGF-β-Smads signaling pathway. • EZH2 inhibitor GSK126 significantly inhibits Ang-II-induced atrial enlargement, fibrosis, and reduced AF vulnerability. [ABSTRACT FROM AUTHOR]

Hyperglycemia-induced apoptosis plays a critical role in the pathogenesis of diabetic cardiomyopathy (DCM). Our previous study demonstrated that ivabradine, a selective I f current antagonist, significantly attenuated myocardial apoptosis in diabetic mice, but the underlying mechanisms remained unknown. This study investigated the underlying mechanisms by which ivabradine exerts anti-apoptotic effects in experimental DCM. Pretreatment with ivabradine, but not ZD7288 (an established I f current blocker), profoundly inhibited high glucose-induced apoptosis via inactivation of nuclear factor (NF)-κB signaling in neonatal rat cardiomyocytes. The effect was abolished by transfection of an siRNA targeting protein phosphatase 2A catalytic subunit (PP2Ac). In streptozotocin-induced diabetic mice, ivabradine treatment significantly inhibited left ventricular hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) and HCN4 (major components of the I f current), activated PP2Ac, and attenuated NF-κB signaling activation and apoptosis, in line with improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia. These effects were not observed in diabetic mice with virus-mediated knockdown of HCN2 or HCN4 after myocardial injection, but were alleviated by knockdown of PP2Acα. Molecular docking and phosphatase activity assay confirmed direct binding of ivabradine to, and activation of, PP2Ac. In conclusion, ivabradine may directly activate PP2Ac, leading to inhibition of NF-κB signaling activation, myocardial apoptosis, and fibrosis, and eventually improving cardiac function in experimental DCM. Taken together, the present findings suggest that ivabradine may be a promising drug for treatment of DCM. • PP2Ac phosphorylation is important in hyperglycemia-induced cardiomyocyte apoptosis. • Ivabradine, an I f current antagonist, binds and activates phosphorylated PP2Ac. • Ivabradine exerts cardioprotective effects on diabetic cardiomyopathy via PP2Ac. [ABSTRACT FROM AUTHOR]

Low shear stress (LSS)-induced endothelial inflammation is the basis for the development of atherosclerosis. However, the mechanism underlying LSS-induced inflammation is not well understood. The angiotensin II type 1 receptor (AT1R), a component of the renin-angiotensin system, participates in atherosclerotic plaque progression. The aim of this study was to investigate the role of AT1R in LSS-induced endothelial activation. Using immunohistochemistry, we noted significant increases in AT1R, vascular endothelial adhesion cell-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) expression in the inner curvature of the aortic arch in C57BL/6 mice compared to the descending aorta in these mice. Moreover, western blotting revealed that these LSS-induced increases in AT1R, ICAM1 and VCAM1 expression were time dependent. However, the expression of these proteins was significantly abolished by treatment with the AT1R antagonist Losartan (1 μM) or AT1R small interfering RNA (siRNA). AT1R inhibition significantly suppressed extracellular signal-regulated kinase 1/2 (ERK) upregulation, which also resulted in decreases in ICAM1 and VCAM1 protein expression. These findings demonstrate that LSS induces endothelial inflammation via AT1R/ERK signaling and that Losartan has beneficial effects on endothelial inflammation. [ABSTRACT FROM AUTHOR]

To explore the effects of different quorum sensing inhibitors (QSIs) on the biofilm formation of Lactobacillus fermentum , a high-production signal molecule AI-2 screened by the research group, was taken as the research object and subjected to various QSIs. Three QSIs, namely 100 μmol/L d -galactose, 200 μmol/L d -ribose, and furanone, could inhibit the AI-2 activity of L. fermentum and the biofilm formation in a certain concentration range but not significantly affect the growth of the strain. Scanning electron microscopy and fluorescence microscopy revealed that each QSI did not significantly affect the bacterial cell morphology in planktonic and biofilm states at the optimal inhibitory final concentration, although they reduced the adhesion of the strain. The expression of luxS , a key gene of quorum sensing, was downregulated. When biofilm production increased, QSIs were added, and the activity of the AI-2 was consistent with the change in biofilm production. Whole-genome technology revealed that QSIs inhibited the expression of the luxS , resulting in restriction of pyruvate synthesis and downregulation of the expression of genes such as gapA , pgmB , ribBA , and ribF , which in turn affected the transport and metabolism of carbohydrates and coenzymes in the strain and ultimately reduced the biofilm formation of L. fermentum. • The signal molecule AI-2 of Lactobacillus fermentum does not depend on cell density. • The effect of quorum sensing inhibitors on L. fermentum biofilm is strain-specific. • Different QSIs reduce biofilm formation by interfering with the transduction of AI-2. • QSIs may affect the transport and metabolism of carbohydrates and coenzymes in cell. [ABSTRACT FROM AUTHOR]

It has been revealed that intersubject variability (ISV) in intrinsic functional connectivity (FC) is associated with a wide variety of cognitive and behavioral performances. However, the underlying organizational principle of ISV in FC and its related gene transcriptional profiles remain unclear. Using resting-state fMRI data from the Human Connectome Project (299 adult participants) and microarray gene expression data from the Allen Human Brain Atlas, we conducted a transcription-neuroimaging association study to investigate the spatial configurations of ISV in intrinsic FC and their associations with spatial gene transcriptional profiles. We found that the multimodal association cortices showed the greatest ISV in FC, while the unimodal cortices and subcortical areas showed the least ISV. Importantly, partial least squares regression analysis revealed that the transcriptional profiles of genes associated with human accelerated regions (HARs) could explain 31.29% of the variation in the spatial distribution of ISV in FC. The top-related genes in the transcriptional profiles were enriched for the development of the central nervous system, neurogenesis and the cellular components of synapse. Moreover, we observed that the effect of gene expression profile on the heterogeneous distribution of ISV in FC was significantly mediated by the cerebral blood flow configuration. These findings highlighted the spatial arrangement of ISV in FC and their coupling with variations in transcriptional profiles and cerebral blood flow supply. [ABSTRACT FROM AUTHOR]

Increasingly attention has been paid to the active substances in grapefruit peel. In this study, insoluble bound phenolic compounds (BP) were released from grapefruit peel insoluble dietary fiber (GP-IDF) by microwave extraction (M-BP), enzymatic hydrolysis (E-BP) and combined microwave and enzymatic treatment (ME-BP). The results showed that the yield of ME-BP was the highest (148.856 ± 0.620 GAE mg/100 g), and conditions of microwave treatment (microwave power, temperature, time) were 600 W, 85 °C, and 37 min, while that of enzymatic treatment were 8% addition, 60 °C, and 2 h. Scanning electron microscopy displayed that GP-IDF became looser by ME. ME mainly resulted in the removal of lignin in IDF from X-ray diffraction, which was consistent with FT-IR. Twenty seven BP were identified by UPLC-ESI-QTOF-MS/MS. The high content of gallic acid (42.50 ± 3.21 μg/g DW), ferulic acid (18.46 ± 1.65 μg/g DW) and protocatechuic acid (6.16 ± 0.72 μg/g DW) was quantified by LC-ESI-QqQ-MS/MS. Furthermore, ME-BP showed stronger antioxidant capacities than that of others (ABTS, oxygen and DPPH free radical scavenging ability), and showed good inhibition of α-glucosidase. Our results demonstrated that combined microwave and enzymatic treatment was an effective treatment for improving the release of BP. • Combined microwave and enzymatic treatment (ME) released bound phenolic compounds. • Optimal condition was 600 W, 85 °C for 37 min and 8% enzyme dosage, 60 °C for 2 h. • ME-IDF (insoluble dietary fiber) was more seriously disintegrated than others. • Composition and content of ME-BP (bound phenolic compounds) was analyzed. • ME-BP exhibited higher antioxidant capacities and α-glucosidase inhibition. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is an early step in the development of atherosclerotic cardiovascular disease. Iron overload can lead to excessive mitochondrial reactive oxygen species (mtROS) production, resulting in mitochondrial dysfunction and vascular endothelial cell (EC) damage. Mitoferrin 2 (Mfrn2) is an iron transporter in the inner mitochondrial membrane. This study aimed to assess whether Mfrn2 and mitochondrial iron overload were involved in atherosclerosis progression and to explore the potential mechanism. We observed significant upregulation of Mfrn2 in the arteries of high-fat diet (HFD)-fed Apolipoprotein E−/- (ApoE−/-) mice and in TNF-α-induced mouse aortic endothelial cells (MAECs). Mfrn2 gene silencing inhibited mitochondrial iron overload, stabilized mitochondrial membrane potential and improved mitochondrial function in TNF-α-induced MAECs. Vascular EC-specific knockdown of Mfrn2 in ApoE−/- mice markedly decreased atherosclerotic lesion formation and the levels of ICAM-1 in aortas and reduced monocyte infiltration into the vascular wall. Furthermore, TNF-α increased the binding of 14-3-3 epsilon (ε) and Mfrn2, preventing Mfrn2 degradation and leading to mitochondrial iron overload in ECs, while 14-3-3ε overexpression increased Mfrn2 stability by inhibiting its ubiquitination. Together, our results reveal that Mfrn2 deficiency attenuates endothelial dysfunction by decreasing iron levels within the mitochondria and mitochondrial dysfunction. These findings may provide new insights into preventive and therapeutic strategies against vascular endothelial dysfunction in atherosclerotic disease. [ABSTRACT FROM AUTHOR]

• Fenoldopam, an FDA-approved drug, was identified as a novel LSD1 inhibitor for RCC treatment. • Fenoldopam displayed significant antiproliferative activity against ACHN cell line (IC 50 = 10.34 ± 1.35 μM). • Fenoldopam showed selective antiproliferative activity between renal adenocarcinoma cell and normal kidney cell line HK-2. Although targeted therapy for renal cell carcinoma (RCC) has achieved good therapeutic effects in clinic, a considerable number of patients develop drug resistance over time. So, there is still an urgent need to develop new drugs for RCC treatment. As LSD1 is considered as a promising drug target in diverse cancers, including RCC, we tried to find new LSD1 inhibitor using drug repurposing strategy from a compound library, and fenoldopam, an FDA-approved drug, was identified as a potent LSD1 inhibitor with IC 50 = 0.8974 μM in a reversible manner. Molecular docking predicted that fenoldopam occupied the FAD cavity of LSD1, forming hydrogen bonds with surrounding residues. Moreover, fenoldopam inactivated LSD1 and performed antiproliferative activity against ACHN cells and promoted cells apoptosis in vitro. Taken together, fenoldopam was identified as a novel LSD1 inhibitor firstly, and may serve as a new skeleton for RCC therapy. [ABSTRACT FROM AUTHOR]