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BACKGROUND: There are few isometric training systems based on upper limb rehabilitation robots. Its efficacy and neural mechanism are not well understood. OBJECTIVE: This study aims to investigate the cortex activation of dynamic resistance and static (isometric) training based on upper limb rehabilitation robot combined with virtual reality (VR) interaction by using functional near-infrared spectroscopy (fNIRS). METHODS: Twenty subjects were included in this study. The experiment adopts the block paradigm design. Experiment in dynamic and static conditions consisted of three trials, each consisting of task (60 s)-rest (40 s). The neural activities of the sensorimotor cortex (SMC), premotor cortex (PMC) and prefrontal cortex (PFC) were measured. The cortex activation and functional connectivity (FC) were analyzed. RESULTS: Both the dynamic and static training can activate SMC, PMC, and PFC. In SMC and PMC, the activation of static training was stronger than dynamic training, there were significant differences between the two modes of each region of interest (ROI) (p

Sucrose-based adhesives utilize renewable biomass material sucrose as the main ingredient, which are eco-friendly and non-toxic, making them attractive potential substitutes for formaldehyde-based wood adhesives. However, wood-based panel processing using sucrose-based adhesives requires extraordinary harsh conditions with high hot-pressing temperatures (≥170 ℃), limiting practical applications. In this study, the sucrose-based adhesive (SD adhesive) was modified by toluene-4-sulfonic acid (TsOH) and methylenediphenyl diisocyanate (MDI) in two steps. The sucrose-based solution (SS) of the optimal adhesive in the study (SDTM20 adhesive) was synthesized with 5%TsOH catalyst at 100 ℃ for 3h, and then 20%MDI curing agent was added, followed by mixing. After that, the curing behavior, curing mechanism and microscopic characterization was used to analyze the optimal prepared materials. The wet shear strength (0.80 MPa) of the prepared adhesive meets the GB/T 9846-2015 China National Standard (≥0.7 MPa).13C NMR showed that the TsOH catalyst promoted the formation of aromatic compounds, oligosaccharides and carbonyls, and the 5-HMF content of the SS in SDTM20 adhesive (44.0 g/L) was 158.8% higher than that of SD adhesive. In addition, the thermal curing behavior of SDTM20 adhesive was explained by changes in insoluble mass proportion (IMP) and TG-DSC thermal analysis. From the IMP measurement, SDTM20 adhesive (61.2%) increased by 141.9% compared with the SD adhesive. Additionally, in TG-DTG and DSC curves, the rapid weight loss temperature (145.1 ℃) corresponded to the endothermic reaction temperature (135.3 ℃), implying that the main curing reaction occurred at approximately 140 ℃, indicating that it is possible to improve curing efficiency of SD adhesive. ATR-FTIR was used to evaluate the curing mechanism of the SDTM20 adhesive. After adding TsOH/MDI, the dehydration reaction of sucrose, caramelization reaction, and Maillard reaction were accelerated to improve the curing efficiency. A complex polymeric cross-linking network structure with isocyanurate rings was generated, mainly connected by dimethyl ether bridges. SEM analysis of the microstructure of the adhesive revealed unknown crystal substances and small bubble pores on the fracture surface of the modified SDTM adhesive, showing that a novel cross-linking reaction had occurred.

There is increasing concern about the adverse impact of exposure to microplastic, as an emerging pollutant, on wild organisms, and particularly on organisms co-exposed to microplastic and other environmental contaminants. It has been widely reported that the combination of microplastics and heavy metals showed obvious toxicity to organisms in terms their growth and development. The present study was performed to determine the impact of binary metal mixtures of cadmium (Cd) and polystyrene microplastic (PS-microplastic) on Tigriopus japonicus, a typical marine model organism, using a titration design. Increasing concentrations of PS-microplastic (2 μg/L, 20 μg/L, and 200 μg/L) were titrated against a constant concentration of Cd (15.2 μg/L). The results showed no significant impact of exposure to this dose of Cd or co-exposure to Cd and the lowest dose of PS-microplastic examined (2 μg/L). However, the feeding rate, filtration rate, oxygen consumption rate, and hatching number declined significantly in T. japonicus co-exposed to Cd and higher concentrations of PS-microplastic (20 μg/L and 200 μg/L) (p < 0.05). Furthermore, the development of F1 larvae from nauplius stage (N) to adult stage (A) was markedly delayed when co-exposed to Cd and higher doses of PS-microplastic (20 and 200 μg/L), and the effects persisted to the F2 larval stage. Interestingly, the present titration design did not affect the sex ratio or number of oocysts in either the F1 or F2 generation. These results indicated that the current marine environmental concentrations of Cd and microplastic are safe for wild organisms. Further studies are required to address the knowledge gap regarding toxicological effects at the cellular and molecular levels.

Significant improvement in wastewater treatment is the most effective way for eutrophication control in semiarid regions. However, its effect on the nutrient status of the receiving water body has remained poorly considered and understood at broad temporal scales. Taking Guanting Reservoir (GR) in Hebei-Beijing (P. R. China) as an example, we present a study that links a continuous monitoring dataset for GR with corresponding estimates of human-induced nutrient discharges in its watershed from the year 2006 to 2019. We find that GR showed decreasing total nitrogen (TN), and total phosphorus (TP) concentrations and increasing TN/TP mass ratios, and the decreasing trend of TP was faster than that of TN. The improved municipal wastewater treatment capacity is mainly responsible for the decreasing TN, and TP concentrations and the increasing TN/TP ratios in GR, as phosphorus is easier to remove from wastewater than nitrogen. Although wastewater treatment capacity has improved, the observed TP of GR (93.7 μg L-1) is higher than the threshold value of harmful algae blooms occurring (50 μg L-1) in recent years (2016-2019). Given the potential ecological impact on aquatic biodiversity as well as ecosystem function of changes in TN/TP ratios and higher retention rate of TP (97.4%) compared with TN (93.1%) in GR, our findings highlight that future strategy for water pollution control should not only concentrate on more nutrient reduction efficiencies but attach importance to their stoichiometric balance to reduce the potential risk of eutrophication during the recovery of GR.

Evaluation of the river ecological environment can provide a basis for river management and ecological restoration. To conduct a comprehensive health assessment of the rivers in Tianjin, their biological, physical, and chemical indicators are investigated on the basis of 32 river monitoring sites from August to September 2018. The comprehensive pollution and ecological integrity indexes of the rivers are analyzed. Results of the two evaluations, compared to achieve the river ecological environment evaluation, are as follows. 1) Index of Ecological Integrity evaluation shows that among the sampling points, 18.8% are “healthy”, 28.1% are “sub-healthy”, 40.6% are “fair”, 6.3% are “poor”, and 6.3% are “very poor”. 2) The comprehensive evaluation of the chemical properties of the 32 river ecosystems in Tianjin shows severe overall river pollution and low standard water function area. Of the total sampling sites, 16 (50%) are heavily contaminated and 10 (31.3%) are moderately contaminated. Excessive chemical oxygen demand and ammonia nitrogen are the main causes of water pollution. 3) The Index of Ecological Integrity (IEI) has high correspondence with environmental factors. Pearson correlation analysis results show that the IEI index is significantly correlated with permanganate index (R = − 0.453; P = 0.023 < 0.05). Analysis results using BEST show that ammonia nitrogen is the best environmental parameter to explain the changes in IEI (Rho= 0.154; P = 0.02 < 0.05) and those using RELATE show significant correlation between the biotic index and the environmental parameter matrices (Rho= 0.154; P = 0.034 < 0.05).

Aiming for treating decentralized domestic wastewater in rural China, this study evaluates the effects of ceramsite size and structure, and water recirculation parameters, upon the performance of recirculating biofilter (RBF). RBF shows stable capability of chemical oxygen demand (COD) remediation and ammonia nitrification. In addition, the microbial flora and structures of the various layers in the system are analyzed via high-throughput sequencing in order to study the microbial diversity. The results indicate that while the ceramic particle size has no significant influence on the COD remediation capacity, the ceramics with smaller particle sizes exhibit better ammonia nitrogen (NH

Plastic pollution is a global crisis, especially in the marine environment. Excessive consumption and unsound disposal are responsible for the constant accumulation of plastic waste, resulting in plastic litter and microplastic contamination on a global scale. Establishing a new global framework is regarded as a promising tool to address plastic pollution, including marine plastic litter. However, there is a need to raise awareness of the role of consumers at individual and national levels in reducing the use of unnecessary plastics and increasing the recycling of plastic waste. The global framework should incorporate aspects of the importance of consumption responsibility in solutions addressing the issue of plastic pollution.

Pendrin is encoded by SLC26A4, which is expressed in the apical membrane of inner ear epithelial cells and drives chloride reabsorption in the apical septum. In the inner ear, pendrin dysfunction and hypofunctional mutations lead to vestibular aqueduct (EVA) enlargement and sensory neural hearing loss. Mutations in SLC26A4 are a common reason of deafness. However, the underlying mechanisms of SLC26A4 mutants in hearing loss remain unknown.In the present study, pEGFP-N1 carrying wild-type and mutant SLC26A4 (c.85GA, c.2006AT, and c.853GA) were transfected into HEK-293T cells. GFP fluorescence and GFP levels were determined. SLC26A4 mRNA levels were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Then, the expression of chloride intracellular channel 1 (CLIC1) and CLIC2 was measured by Immunofluorescence assay. Intracellular chloride concentration and apoptotic rate were analyzed by flow cytometry. The levels of membrane/cytoplasmic pendrin, apoptosis-associated proteins, and the PI3K/Akt/mTOR pathway members were determined by Western blot.Constructed SLC26A4 mutant 1 (c.85GA), SLC26A4 mutant 2 (c.2006AT), and SLC26A4 mutant 3 (c.853GA). The wild-type and 3 mutations were stably expressed in HEK-293T. SLC26A4 mRNA expression was significantly increased after transfection with wild-type SLC26A4 and mutant SLC26A4 compared with the untransfected vector group (After SLC26A4 mutation, pendrin was transferred from the membrane, the chloride intracellular channel function was reduced, and the excessive accumulation of chloride in the cytoplasm induced cell apoptosis by inhibited PI3K/Akt/mTOR pathway phosphorylation.

Heavy metal pollution has become a great concern due to its adverse effects on the ecological system and human health. The present study investigated the concentrations of six common heavy metals (Cr, Cu, Zn, As, Cd, and Pb) in the Tianjin coastal area to understand their distribution, enrichment, sources, and potential ecological risk levels, focusing on the main contributors. The results showed that the concentration of Cu was high in the surface seawater (6.89 µg/L for the average), while Cd was the main contaminating metal in the sediments, with an average concentration of 0.77 mg/kg. The potential ecological risk index (RI) implied that the heavy metals in the sediments could cause considerable ecological risk, and Cd was the major contributor to ecological risk in this area. In particular, the field investigation showed that Cd contamination occurred as a result of anthropogenic activities, including port transportation, mariculture, and metal fabrication along the coastal area. Therefore, it is necessary to control Cd contamination in the future to improve the quality of the marine environment in Bohai Bay.

Prevention of cardiomyocyte death is an important therapeutic strategy for heart failure. In this study, we focused on translationally controlled tumor protein (TCTP), a highly conserved protein that is expressed ubiquitously in mammalian tissues, including heart. TCTP plays pivotal roles in survival of certain cell types, but its function in cardiomyocytes has not been examined. We aimed to clarify the role of TCTP in cardiomyocyte survival and the underlying mechanism. Here, we demonstrated that downregulation of TCTP with siRNA induced cell death of cardiomyocytes with apoptotic and autophagic features, accompanied with mitochondrial permeability transition pore (mPTP) opening. TCTP loss did not induce cell death of cardiac fibroblasts. Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) was found to mediate the TCTP-loss-induced cardiomyocyte death. In exploring the clinical significance of the TCTP expression in the heart, we found that DOX treatment markedly downregulated the protein expression of TCTP in cultured cardiomyocytes and in mouse heart tissue. Exogenous rescue of TCTP expression attenuated DOX-induced cardiomyocyte death. In mice, cardiomyocyte-specific overexpression of TCTP resulted in decreased susceptibility to DOX-induced cardiac dysfunction, accompanied with attenuated induction of Bnip3. Dihydroartemisinin, a pharmacological TCTP inhibitor, induced development of heart failure and cardiomyocyte death in control mice, but not in mice with cardiomyocyte-specific TCTP overexpression. Our findings revealed TCTP has a pivotal role in cardiomyocyte survival, at least in part through a Bnip3-dependent mechanism. TCTP could be considered as a candidate therapeutic target to prevent DOX-induced heart failure.

The molecular mode of action underpinning the response of mollusks exposure to endocrine disrupting chemicals (EDCs) remains unclear due to a lack of available information regarding their genome. Single molecule real-time (SMRT) sequencing makes it possible to reveal molecular mechanisms by direct sequencing of full-length transcripts. In the present study, the transcriptome profile of the freshwater snail Parafossarulus striatulus after exposure to 17β-estradiol (E2) or 17α-methyltestosterone (MT) was evaluated using SMRT sequencing strategy. In total, 216,598 non-redundant and full-length gene isoforms were generated and 106,266 isoforms were predicted with a complete open reading frame (ORF). Moreover, 60.36% of the isoforms were matched to known proteins in at least one of six databases. Differential gene expression analyses showed significantly different patterns in paired samples with different treatments. The expression levels of several membrane receptor isoforms of P. striatulus including dopamine receptor (DR), FMRFamide receptor (FMRFaR), neuropeptide Y receptor (NYR) and neuropeptide FF receptor (NFFR), but not estrogen receptor (ER) or estrogen-related receptor (ERR), were significantly affected by E2 and MT. These findings suggest that activation of membrane receptors, as well as other signaling pathways, might be critical for mediating the effects of endocrine disruption in mollusks. The transcriptome information obtained from the SMRT sequencing provides a significant contribution to the investigation of the molecular mode of action of endocrine disrupting chemicals on P. striatulus.

Background Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The human G6PD gene is highly polymorphic, and over 200 mutations have been identified, many of which are associated with hemolytic anemia. Here, we analyzed the clinical genetics data of a Chinese girl with favism who developed acute hemolytic anemia after fava bean ingestion. Methods The clinical genetics data of the proband who developed acute hemolytic anemia were collected and analyzed, and G6PD gene exons were sequenced in the proband and her family. Results We reported for the first time a novel G6PD gene variant in a Chinese girl, which we named “G6PD Wuhan.” This variant is localized exon 3 of the G6PD gene at genomic position 141G > C, that is a change from p.Lys47 to Asn. The bioinformatics analysis and protein modeling study indicated this variant may have negative effects on the enzyme activity of G6PD. Conclusions Our results indicated that favism in the proband was caused by this novel heterozygous variant (c.141G > C) in G6PD. The variant in G6PD has implications for genetic counseling and could provide insights into the functional roles of G6PD mutations., A novel variant (c.141G > C) in the exons of the G6PD gene may have negative effects on the enzyme activity of G6PD.

Sympathetic activation causes clinically important arrhythmias including atrial fibrillation (AF) and ventricular tachyarrhythmia. Although the usefulness of β-adrenergic receptor blockade therapy is widely accepted, its multiple critical side effects often prevent its initiation or continuation. The aim of this study is to determine the advantages of vidarabine, an adenylyl cyclase (AC)-targeted anti-sympathetic agent, as an alternative treatment for arrhythmia. We found that vidarabine, which we identified as a cardiac AC inhibitor, consistently shortens AF duration and reduces the incidence of sympathetic activation-induced ventricular arrhythmias. In atrial and ventricular myocytes, vidarabine inhibits adrenergic receptor stimulation-induced RyR2 phosphorylation, sarcoplasmic reticulum (SR) Ca2+ leakage, and spontaneous Ca2+ release from SR, the last of which has been considered as a potential arrhythmogenic trigger. Moreover, vidarabine also inhibits sympathetic activation-induced reactive oxygen species (ROS) production in cardiac myocytes. The pivotal role of vidarabine's inhibitory effect on ROS production with regard to its anti-arrhythmic property has also been implied in animal studies. In addition, as expected, vidarabine exerts an inhibitory effect on AC function, which is more potent in the heart than elsewhere. Indexes of cardiac function including ejection fraction and heart rate were not affected by a dosage of vidarabine sufficient to exert an anti-arrhythmic effect. These findings suggest that vidarabine inhibits catecholamine-induced AF or ventricular arrhythmia without deteriorating cardiac function in mice.

To date, the foliar anthocyanin content was either determined via the pH differential or HPLC methods, both of which are slow and destructive. Here, a hyperspectral model was established to estimate the foliar anthocyanin content of purple corn (Zea mays L. var. Jingzi No. 1). The reflectivity (P) of the foliar hyperspectral was inverted to 1/P, lg P, 1/lg P, urn:x-wiley:20487177:media:fsn3588:fsn3588-math-0001, urn:x-wiley:20487177:media:fsn3588:fsn3588-math-0002, urn:x-wiley:20487177:media:fsn3588:fsn3588-math-0003, and urn:x-wiley:20487177:media:fsn3588:fsn3588-math-0004. The correlation coefficient between these inversions and the foliar anthocyanin content was plotted against the hyperspectral wavelength. The wavelength of inversions around 650 nm was sensitive to the foliar anthocyanin content. The hyperspectral model was fitted via linear, polynomial, power, exponential, and logarithmic functions with the sensitive band as independent variable and the anthocyanin content as function. The hyperspectral model (y = 3,000,000,000 × W6854.5896) fitted via inversion of urn:x-wiley:20487177:media:fsn3588:fsn3588-math-0005 showed the highest determination coefficients (0.768) among all models. The hyperspectral model was well validated with a determination coefficient of 0.932 and an RMSE of 0.0065. Moreover, the accuracy and stability of the hyperspectral model were further enhanced with a determination coefficient of 0.954 and RMSE of 0.0047 when the anthocyanin content of the sample was below 20 mg/g. Hence, the hyperspectral model estimated the foliar anthocyanin content of purple corn quickly and nondestructively.

Microplastic pollution is a growing global concern. Early evidences have suggested that microplastics ingestion occurs in various marine organisms. However, there is very limited information regarding the fate of microplastics after ingestion by marine mammals. The present study investigated the characteristics of microplastics identified in spotted seal cubs, Phoca largha. Microplastics were identified in the stomach, small intestine and large intestine of the seal cubs. Poly(ethylene terephthalate), polypropylene and poly(acrylonitrile:acrylic acid) were the main components of the total microplastic contents isolated, with fibers being the main morphological categorization. Importantly, the average size of microplastics detected in the stomach were larger than those in the small intestine (p 0.05), while the average abundance in stomach was lower than in the small intestine and large intestine (p > 0.05); these findings imply that microplastics that are ingested might be fragmented into smaller particles in the stomach during digestion before reaching the intestine. These data provide a novel signal for further understanding the fate of microplastics in marine mammals.

Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic stimulation leads to coupling of the β-adrenergic receptor/Gs/adenylyl cyclase, a membrane-bound enzyme that catalyzes the conversion of ATP to cAMP, thereby stimulating protein kinase A (PKA) and ultimately compensating for cardiac dysfunction. The mechanism of such compensation by catecholamine has been traditionally understood as PKA-mediated enforcement of cardiac contractility. We hypothesized that exchange protein activated by cyclic AMP (Epac), a new target of cAMP signaling that functions independently of protein kinase A, also plays a key role in protection against acute stresses or changes in hemodynamic overload. Lipopolysaccharide injection induced cytokine release and severe cardiac dysfunction in mouse. In mouse overexpressing Epac1 in the heart, however, the magnitude of such dysfunction was significantly smaller. Epac1 overexpression inhibited the Jak-STAT pathway, as indicated by decreased phosphorylation of STAT3 and increased SOCS3 expression, with subsequent inhibition of iNOS expression. In cultured cardiomyocytes treated with isoproterenol or forskolin, the increase of SOCS3 expression was blunted when Epac1 or PKCα was silenced with siRNA. Activation of the cAMP/Epac/PKCα pathway protected the heart against cytokine-induced cardiac dysfunction, suggesting a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac1 and its downstream pathways may be novel targets for treating cardiac dysfunction in endotoxemia.

INTRODUCTION: The periosteum has a bilayered structure that surrounds cortical bone. The outer layer is rich in connective tissue and fibroblasts, while the inner layer in contact with the cortical surface of the bone predominantly consists of osteoblasts and osteoblast progenitors. The identification of cell-specific surface markers of the bilayered structure of the periosteum is important for the purpose of tissue regeneration. MATERIALS AND METHODS: We investigated the expression of the discoidin domain tyrosine kinase receptor DDR2, fibroblast specific protein-1 (FSP-1) and alkaline phosphatase (ALP) in the periosteum of cortical bone by immunohistochemistry. Osteogenic differentiation was compared between DDR2- and FSP-1-expressing cells flow-sorted from the periosteum. RESULTS: We showed that DDR2 predominantly labeled osteogenic cells residing in the inner layer of the periosteum and that Pearson’s coefficient of colocalization indicated a significant correlation with the expression of ALP. The mineralization of DDR2-expressing osteogenic cells isolated from the periosteum was significantly induced. In contrast, FSP-1 predominantly labeled the outer layer of periosteal fibroblasts, and Pearson’s coefficient of colocalization indicated that FSP-1 was poorly correlated with the expression of DDR2 and ALP. FSP-1-expressing periosteal fibroblasts did not exhibit osteogenic differentiation for the induction of bone mineralization. CONCLUSION: DDR2 is a novel potential cell surface marker for identifying and isolating osteoblasts and osteoblast progenitors within the periosteum that can be used for musculoskeletal regenerative therapies.

Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine signaling has been traditionally understood to be cyclic AMP-dependent protein kinase (PKA)-mediated enforcement of cardiac contractility. We hypothesized that the exchange protein activated by cAMP (Epac), a newly identified target of cAMP signaling that functions independently of PKA, also plays a key role in this mechanism. In cultured cardiac myocytes, activation of Epac attenuated the inhibitory effect of interleukin-6 on the increase of intracellular Ca2+ concentration and contractility in response to isoproterenol, most likely through inhibition of the Jak-STAT pathway via SOCS3, with subsequent changes in inducible nitric oxide synthase expression. These findings suggest a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac and its downstream pathway may be a novel target for treating cardiac dysfunction in endotoxemia.

Type 5 adenylyl cyclase (AC5) plays an important role in the development of chronic catecholamine stress-induced heart failure and arrhythmia in mice. Epac (exchange protein activated by cAMP), which is directly activated by cAMP independent of protein kinase A, has been recently identified as a novel mediator of cAMP signaling in the heart. However, the role of Epac in AC5-mediated cardiac dysfunction and arrhythmias remains poorly understood. We therefore generated AC5 transgenic mice (AC5TG) with selective disruption of the Epac1 gene (AC5TG-Epac1KO), and compared their phenotypes with those of AC5TG after chronic isoproterenol (ISO) infusion. Decreased cardiac function as well as increased susceptibility to pacing-induced atrial fibrillation (AF) in response to ISO were significantly attenuated in AC5TG-Epac1KO mice, compared to AC5TG mice. Increased cardiac apoptosis and cardiac fibrosis were also concomitantly attenuated in AC5TG-Epac1KO mice compared to AC5TG mice. These findings indicate that Epac1 plays an important role in AC5-mediated cardiac dysfunction and AF susceptibility.

Background It has been suggested that protein directly activated by cAMP (Epac), one of the downstream signaling molecules of β-adrenergic receptor (β-AR), may be an effective target for the treatment of arrhythmia. However, there have been no reports on the anti-arrhythmic effects or cardiac side-effects of Epac1 inhibitors in vivo. Methods and Results: In this study, the roles of Epac1 in the development of atrial and ventricular arrhythmias are examined. In addition, we examined the usefulness of CE3F4, an Epac1-selective inhibitor, in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca2+ leak, a major trigger of arrhythmias, and spontaneous SR Ca2+ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca2+ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects. Conclusions These findings indicated that Epac1 is involved in the development of atrial and ventricular arrhythmias. CE3F4, an Epac1-selective inhibitor, prevented atrial and ventricular arrhythmias in mice.

Drip loss of fresh-cut watermelon has become a concern for both producers and consumers. The effect of visible light exposure on the drip loss of fresh-cut watermelon was evaluated. Visible light treatments of 3000 and 10 Lux were applied to fresh-cut watermelon at 4 °C during the shelf life for 5 days, with light exposure of 150 Lux as the control. The drip loss of the fresh-cut watermelon at 3000 Lux was 74.8% of that at 150 Lux on the fifth day, and the moisture evaporation at 3000 Lux was 1.89 times that at 150 Lux. Moreover, the light exposure of 3000 Lux reduced the activity of polygalacturonase, which is a key hydrolase related to cell wall degradation. The cell wall degradation ratio of the fresh-cut watermelon at 3000 Lux was 81.7% of that at 150 Lux on the fifth day. Overall, light exposure of 3000 Lux reduced drip loss by accelerating moisture evaporation in fresh-cut watermelon, as well as by reducing the activity of polygalacturonase and the ratio of cell wall degradation. Hence, exposing the fresh-cut watermelon to visible light of 3000 Lux during the shelf life was a feasible way of reducing drip loss.

The binding characteristics and protective capacity of cyanidin (Cy) and cyanidin-3-glucoside (C3G) to calf thymus DNA were explored for the first time. The Cy and C3G gave a bathochromic shift to the ultraviolet-visible spectra of the DNA, indicating the formation of the DNA-Cy and DNA-C3G complexes. The complexes were formed by an intercalative binding mode based on the results of the fluorescence spectra and competitive binding analysis. Meanwhile, the Cy and C3G protected the DNA from the damage induced by the hydroxyl radical. The binding capacity and protective capacity of the C3G were stronger than that of the Cy. Furthermore, the formation of the DNA-anthocyanin complexes was spontaneous when the hydrogen bond and hydrophobic force played a key role. Hence, the Cy and C3G could protect the DNA automatically from the damage induced by the hydroxyl radical.

Cyclic adenosine monophosphate (cAMP) and Ca(2+) levels may oscillate in harmony within excitable cells; a mathematical oscillation loop model, the Cooper model, of these oscillations was developed two decades ago. However, in that model all adenylyl cyclase (AC) isoforms were assumed to be inhibited by Ca(2+), and it is now known that the heart expresses multiple AC isoforms, among which the type 5/6 isoforms are Ca(2+)-inhibitable whereas the other five (AC2, 3, 4, 7, and 9) are not. We used a computational systems biology approach with CellDesigner simulation software to develop a comprehensive graphical map and oscillation loop model for cAMP and Ca(2+). This model indicated that Ca(2+)-mediated inhibition of AC is essential to create oscillations of Ca(2+) and cAMP, and the oscillations were not altered by incorporation of phosphodiesterase-mediated cAMP hydrolysis or PKA-mediated inhibition of AC into the model. More importantly, they were created but faded out immediately in the co-presence of Ca(2+)-noninhibitable AC isoforms. Because the subcellular locations of AC isoforms are different, spontaneous cAMP and Ca(2+) oscillations may occur within microdomains containing only Ca(2+)-inhibitable isoforms in cardiac myocytes, which might be necessary for fine tuning of excitation-contraction coupling.

PKA phosphorylates multiple molecules involved in calcium (Ca2+) handling in cardiac myocytes and is considered to be the predominant regulator of β-adrenergic receptor–mediated enhancement of cardiac contractility; however, recent identification of exchange protein activated by cAMP (EPAC), which is independently activated by cAMP, has challenged this paradigm. Mice lacking Epac1 (Epac1 KO) exhibited decreased cardiac contractility with reduced phospholamban (PLN) phosphorylation at serine-16, the major PKA-mediated phosphorylation site. In Epac1 KO mice, intracellular Ca2+ storage and the magnitude of Ca2+ movement were decreased; however, PKA expression remained unchanged, and activation of PKA with isoproterenol improved cardiac contractility. In contrast, direct activation of EPAC in cardiomyocytes led to increased PLN phosphorylation at serine-16, which was dependent on PLC and PKCε. Importantly, Epac1 deletion protected the heart from various stresses, while Epac2 deletion was not protective. Compared with WT mice, aortic banding induced a similar degree of cardiac hypertrophy in Epac1 KO; however, lack of Epac1 prevented subsequent cardiac dysfunction as a result of decreased cardiac myocyte apoptosis and fibrosis. Similarly, Epac1 KO animals showed resistance to isoproterenol- and aging-induced cardiomyopathy and attenuation of arrhythmogenic activity. These data support Epac1 as an important regulator of PKA-independent PLN phosphorylation and indicate that Epac1 regulates cardiac responsiveness to various stresses.

Based on biologic and environmental materials collected from coastal areas of Bohai Bay (China) in April, 2008, three biotic indices (AZTI’s Marine Biotic Index (AMBI), Shannon-Wiener Index and W-statistic) were applied together to evaluate the ecological status of the sampling area. The results showed a clear spatial gradient from a worse ecological status in the near-shore areas (especially around Haihe and Jiyun River Estuaries) to a better status in the offshore areas. While all the three indices could assist decision makers in visualizing spatial changes of organic pollutants in Bohai Bay, two indices, i. e., AMBI and Shannon-Wiener index, were effective in distinguishing sites from Haihe River Estuary, Jiyun River Estuary and other area. However, W-statistic can’t tell the differences between estuaries and other area. It would be explained that organic pollutants and/or other environmental stresses in Bohai Bay were not strong enough to reduce the size of macrozoobenthos, which may cause both of the abundance and biomass curves crossed. To our knowledge, this is the first time that several benthic indices were used to assess the benthic ecological status in Bohai Bay, which gave the similar results. Furthermore, there is indication that the ecological status is related to excess input of wastewater along main rivers and outlets. In a word, AMBI, Shannon-Wiener Index and W-statistic could be able to assess the benthic ecological status of Bohai Bay under the organic pollutants pressure.

Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine signaling has been traditionally understood to be cyclic AMP-dependent protein kinase (PKA)-mediated enforcement of cardiac contractility. We hypothesized that the exchange protein activated by cAMP (Epac), a newly identified target of cAMP signaling that functions independently of PKA, also plays a key role in this mechanism. In cultured cardiac myocytes, activation of Epac attenuated the inhibitory effect of interleukin-6 on the increase of intracellular Ca

The Changjiang (Yangtze) River estuary has been subject to a variety of anthropogenic pressures in recent decades. To assess the ecological health of the coastal benthic ecosystem adjacent to the estuary, three surveys were conducted in 2005, 2009, and 2010. The AZTI's Marine Biotic Index (AMBI) and multivariate-AMBI (M-AMBI) were used to analyse the benthic ecological status of this coast. The AMBI indicate that the ecological status of the coast adjacent to the Changjiang River estuary was only slightly degraded in all 3 years. In contrast, the M-AMBI indicated that the ecological status was seriously degraded, a result that is most likely due to pollution and eutrophication induced by human activities. The assessment of the coast's ecological status by the AMBI was not in agreement with that of the M-AMBI at some stations because of lower biodiversity values at those sites. The analysis of the two indices integrated with abiotic parameters showed that the M-AMBI could be used as a suitable bio-indicator index to assess the benthic ecological status of the coast adjacent to the Changjiang River estuary. The reference conditions proposed for the coast of the Changjiang River estuary should be further evaluated in future studies. Designation of local species could also provide an important reference for Chinese waters. To improve the reliability of AMBI and M-AMBI, further research into the ecology of local species is required to understand their arrangement in ecological groups.

Hashimoto's thyroiditis (HT) has long been epidemiologically associated with excess iodine levels. However, the underlying immunological mechanisms still remain largely unexplored. Th17 cells are commonly recognized as playing vital roles in various autoimmune diseases. Here we show that intra-thyroid infiltrating Th17 cells and serum IL-17 levels were significantly increased in HT patients. However, the concentration of serum IL-17 was inversely correlated with patients' residual thyroid function while the heterogeneously expressed thyroid IL-17 was directly correlated with local fibrosis. Administration of moderate high levels of iodine was found to facilitate the polarization of murine splenic naïve T cells into Th17 cells, whereas extreme high levels of iodine favored Th1 polarization and inhibited Treg development. These findings suggest that both Th1 and Th17 cells may be involved in the pathogenesis of HT and high levels of iodine may play a critical role in this process by modulating T cell differentiation.

Mechanisms by which tumor cells metastasize to distant organs still remain enigmatic. Immune cells have been assumed to be the root of metastasis by their fusing with tumor cells. This fusion theory, although interpreting tumor metastasis analogically and intriguingly, is arguable to date. We show in this study an alternative explanation by immune cell–derived microparticles (MPs). Upon stimulation by PMA or tumor cell–derived supernatants, immune cells released membrane-based MPs, which were taken up by H22 tumor cells, leading to tumor cell migration in vitro and metastasis in vivo. The underlying molecular basis was involved in integrin αMβ2 (CD11b/CD18), which could be effectively relayed from stimulated innate immune cells to MPs, then to tumor cells. Blocking either CD11b or CD18 led to significant decreases in MP-mediated tumor cell metastasis. This MP-mediated transfer of immune phenotype to tumor cells might also occur in vivo. These findings suggest that tumor cells may usurp innate immune cell phenotypes via MP pathway for their metastasis, providing new insight into tumor metastatic mechanism.

Despite various suspected causes, ranging from endocrine and genetic to infectious and immunological aspects, the molecular mechanisms of miscarriage still remain enigmatic. This work provides evidence that downregulation of 11β-hydroxysteroid dehydrogenase (HSD) type 2, the key enzyme inactivating glucocorticoid activities, insults the pregnant inflammatory milieu by inhibiting the biosynthesis of lipoxin A4 (LXA4), a metabolite of arachidonic acid, leading to an early loss of the pregnancy. Both LXA4 and its biosynthetic enzymes were found to be decreased in women with spontaneous miscarriages and in the murine miscarriage model. Replenishing LXA4 reversed LPS-induced miscarriages in mouse models, whereas blocking LXA4 signaling resulted in miscarriages in the pregnant mice. The protective effect of LXA4 might be explained by LXA4’s role in regulating uterine and placental inflammatory factors and mast cells. The underlying molecular mechanism involved miscarriage-inducing infections or stresses that downregulate the expression of 11β-HSD2, but not 11β-HSD1, resulting in increases in glucocorticoid activity and decreases in LXA4. Together, these findings suggest that the stress/glucocorticoid/LXA4 axis might be a common pathway through which miscarriages occur.

Rapid economic development in recent decades has resulted in environmental degradation of Liaodong Bay, North China, where eutrophication is becoming more evident because of excess nutrients inputs. To assess the benthic ecological status in Liaodong Bay, AZTI’s Marine Biotic Index (AMBI) and multivariate-AMBI (M-AMBI) were applied using both benthic macroinvertebrate density and biomass data collected from Liaodong Bay in July 2007. This first application of AMBI and M-AMBI in Liaodong Bay showed that the nearshore areas of the bay, especially near river estuaries, were severely disturbed, with a clear gradient of disturbance decreasing seaward. Ecological status assessed from density and biomass data was quite similar. Significant relationships were also found between both indices and environmental variables in Liaodong Bay. Moreover, the spatial distributions of both AMBI and M-AMBI matched those of plotted eutrophication indices (EI) in the surface water layer, and significant linear correlations were found between both benthic indices and EI. In general, both AMBI and M-AMBI worked well on assessing the ecological status of Liaodong Bay under eutrophication stress due to excess nutrients inputs.

Chronic administration of clenbuterol (CB), a lipophilic β2-adrenoceptor (β2-AR) agonist, induces skeletal muscle hypertrophy and slow-to-fast fiber–type transitions in mammalian species, but the mechanism and pathophysiological roles of these changes have not been explored. Here, we examined the effects of CB not only on masseter muscle mass, fiber diameter, and myosin heavy chain (MHC) composition, but also on daily muscle activity, a factor influencing muscle phenotype, by means of electromyogram analysis in rats. MHC transition towards faster isoforms was induced by 2-week CB treatment. In addition, daily duty time was increased at 1 day, 1 week, and 2 weeks after the start of CB treatment and its increase was greater at high activity level (6-fold) than at low activity level (2-fold). In order to examine whether these effects of CB were mediated through muscle or CNS β2-AR stimulation, we compared these effects of CB with those of salbutamol (SB), a hydrophilic β2-AR agonist. SB treatment induced masseter hypertrophy and MHC transition, like CB, but did not increase daily activity. These results suggest that CB-mediated slow-to-fast MHC transition with hypertrophy was induced through direct muscle β2-AR stimulation, but the increase of daily duty time was mediated through the CNS. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.12271FP] Keywords:: β2-adrenergic signaling, masseter muscle, electromyogram, myosin heavy chain, hypertrophy