Autoimmune Response Confers Decreased Cardiac Function in Patients with Rheumatic Mitral Lesion following Valve Replacement

Purpose: To explore the effect of autoimmune response on the decreased cardiac function in patients with rheumatic mitral lesion following valve replacement.Methods: In this case-controlled study, 29 patients who had undergone valve replacement as a result of mitral lesion were enrolled (mean age = 48.7 years). Twenty healthy volunteers were selected as control (mean age = 47.5 years). Plasma levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high –sensitivity C-reactive protein (hs-CRP) and echocardiographic indices of heart function in the two groups were investigated, respectively. Body mass index (BMI) was also calculated.Results: TNF-α, IL-6 and hs-CRP levels in plasma were significantly higher than those in controls (p < 0.05; 22.23 pg/mL vs. 13.24 pg/mL, 53.42 pg/mL vs. 9.57 pg/mL, and 2.12 μg/mL vs. 0.97 μg/mL, respectively). The indices of left atrial diameter (LAD), left ventricular end-diastolic diameter (LDD) and isovolumetric contraction time (ICT) were significantly higher (p < 0.05; 4.72 cm vs. 3.78 cm, 4.85 cm vs. 4.37 cm, and 76.38 ms vs. 66.24 ms, respectively), but those of early diastolic velocity (Ea), late diastolic velocities (Aa) and ejection time (ET) were significantly lower (p < 0.05; 7.65 cm/s vs. 16.8 cm/s, 5.56 cm/s vs. 12.9 cm/s, and 261.54 ms vs. 276.14 ms, respectively). Two-dimensional echocardiography obtained the same results.Conclusion: Valve replacement in patients with rheumatic heart disease (RHD) does not attenuate inflammatory response; rather, autoimmune response would keep affecting decreased heart function in RHD patients who have received mitral valve replacement.Keywords: Tumor necrosis factor-α, Interleukin-6, High sensitivity C reactive protein, Mitral lesion, Mitral valve replacemen

Activation of an AMP-activated protein kinase is involved in post-diapause development of Artemia franciscana encysted embryos

<p>Abstract</p> <p>Background</p> <p>Cysts of <it>Artemia </it>can remain in a dormant state for long periods with a very low metabolic rate, and only resume their development with the approach of favorable conditions. The post-diapause development is a very complicated process involving a variety of metabolic and biochemical events. However, the intrinsic mechanisms that regulate this process are unclear.</p> <p>Results</p> <p>Herein we report the specific activation of an AMP-activated protein kinase (AMPK) in the post-diapause developmental process of <it>Artemia</it>. Using a phospho-AMPKα antibody, AMPK was shown to be phosphorylated in the post-diapause developmental process. Results of kinase assay analysis showed that this phosphorylation is essential for AMPK activation. Using whole-mount immunohistochemistry, phosphorylated AMPK was shown to be predominantly located in the ectoderm of the early developed embryos in a ring shape; however, the location and shape of the activation region changed as development proceeded. Additionally, Western blotting analysis on different portions of the cyst extracts showed that phosphorylated AMPKα localized to the nuclei and this location was not affected by intracellular pH. Confocal microscopy analysis of immunofluorescent stained cyst nuclei further showed that AMPKα localized to the nuclei when activated. Moreover, cellular AMP, ADP, and ATP levels in developing cysts were determined by HPLC, and the results showed that the activation of <it>Artemia </it>AMPK may not be associated with cellular AMP:ATP ratios, suggesting other pathways for regulation of <it>Artemia </it>AMPK activity.</p> <p>Conclusion</p> <p>Together, we report evidence demonstrating the activation of AMPK in <it>Artemia </it>developing cysts and present an argument for its role in the development-related gene expression and energy control in certain cells during post-diapause development of <it>Artemia</it>.</p

Using customer service dialogues for satisfaction analysis with context-assisted multiple instance learning

Customers ask questions and customer service staffs answer their questions, which is the basic service model via multi-turn customer service (CS) dialogues on E-commerce platforms. Existing studies fail to provide comprehensive service satisfaction analysis, namely satisfaction polarity classification (e.g., well satisfied, met and unsatisfied) and sentimental utterance identification (e.g., positive, neutral and negative). In this paper, we conduct a pilot study on the task of service satisfaction analysis (SSA) based on multi-turn CS dialogues. We propose an extensible Context-Assisted Multiple Instance Learning (CAMIL) model to predict the sentiments of all the customer utterances and then aggregate those sentiments into service satisfaction polarity. After that, we propose a novel Context Clue Matching Mechanism (CCMM) to enhance the representations of all customer utterances with their matched context clues, i.e., sentiment and reasoning clues. We construct two CS dialogue datasets from a top E-commerce platform. Extensive experimental results are presented and contrasted against a few previous models to demonstrate the efficacy of our model

Carolignans from the Aerial Parts of Euphorbia sikkimensis and Their Anti-HIV Activity

Seven new carolignans, including two pairs of enantiomers (±)-erythro-7′-methylcarolignan E (1a/1b) and (±)-threo-7′-methylcarolignan E (2a/2b), (+)-threo-carolignan E (3a), (+)-erythro-carolignan E (4a), and (−)-erythro-carolignan Z (5), together with four known lignans (3b, 4b, 6, and 7) and six polyphenols (8–13) were isolated from the aerial parts of Euphorbia sikkimensis. The structures of the new compounds were elucidated by spectroscopic analysis, and their absolute configurations were determined by electronic circular dichroism calculations. Seven of the isolates were examined for anti-HIV effects, and compounds 1a and 1b showed moderate anti-HIV activity with EC50 values of 6.3 and 5.3 μM

Polyphyllin I Ameliorates Collagen-Induced Arthritis by Suppressing the Inflammation Response in Macrophages Through the NF-κB Pathway

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by an increased number of M1-like macrophages in the joints. Polyphyllin I (PPI), one of the main components in the Rhizoma of Paris polyphyllin, displays a selective inhibitory effect on various tumor cells. Here we sought to investigate the anti-rheumatoid arthritis effects and mechanisms of PPI on macrophages in vivo and in vitro.Materials and Methods:In vitro, primary bone marrow-derived macrophages (BMMs) and peritoneal elucidated macrophages (PEMs) were stimulated by lipopolysaccharide (LPS) and Interferon (IFN)-γ and then treated with PPI. We determined the degree of activation of IKKα/β and p65, two key mediators of the NF-κB-mediated inflammatory pathway, by measuring their phosphorylated forms by Western blot. The p65 nuclear localization was detected by immunofluorescent staining. Further, a NF-κB-linked luciferase reporter plasmid, as well as those expressing key mediators of the Toll-like receptor 4 pathway, such as myeloid differentiation primary response 88 (MYD88), interleukin-1 receptor (IL-1R) associated kinase (IRAK)-1, TNF receptor associated factors (TRAF)-6, Transforming growth factor-b–activated kinase 1 (TAK1) and p65, were used to identify the mechanism by which PPI achieves its inhibitory effects on macrophage-mediated inflammation. Moreover, a NF-κB inhibitor, p65-targeted siRNAs, and a p65 plasmid were further used to validate the anti-inflammatory mechanism of PPI. In vivo, PPI (1 mg/kg) was administered intragastrically one time a day for 7 weeks starting on the 42nd day after the first immunization with collagen in a collagen-induced arthritis (CIA) mouse model. Micro-computed Tomography scanning, histological examination, F4/80 and iNOS double immunofluorescent staining and CD4 immunohistochemical staining were performed to determine the effect of PPI treatment on joint structure and inflammation in this model.Results: PPI reduced the inflammatory cytokines production of PEMs stimulated by LPS/IFN-γ, inhibited the phosphorylation of IKKα/β and p65, and prevented p65 nuclear localization. The NF-κB luciferase assay showed that the target of PPI was closely related to the NF-κB pathway. Moreover, NF-κB inhibition, siRNA-mediated knockdown of p65, and p65 overexpression eliminated PPI's inhibitory effect. In addition, PPI attenuated the bone erosion and synovitis, as well as M1-like macrophage and T cell infiltration, in the ankle joint of the CIA model.Conclusion: PPI demonstrated effective amelioration of synovial inflammation in the ankle joint of CIA mice while suppressing NF-κB-mediated production of pro-inflammatory effectors in activated macrophages

Loss of PDZK1 expression activates PI3K/AKT signaling via PTEN phosphorylation in gastric cancer

Phosphorylation of PTEN plays an important role in carcinogenesis and progression of gastric cancer. However, the underlying mechanism of PTEN phosphorylation regulation remains largely elusive. In the present study, PDZK1 was identified as a novel binding protein of PTEN by association of PTEN through its carboxyl terminus and PDZ domains of PDZK1. By direct interaction with PTEN, PDZK1 inhibited the phosphorylation of PTEN at S380/T382/T383 cluster and further enhanced the capacity of PTEN to suppress PI3K/AKT activation. PDZK1 suppressed gastric cancer cell proliferation by diminishing PI3K/AKT activation via inhibition of PTEN phosphorylation in vitro and in vivo. The expression of PDZK1 was frequently downregulated in gastric cancer specimens and correlated with progression and poor prognosis of gastric cancer patients. Downregulation of PDZK1 was associated with PTEN inactivation, AKT signaling and cell proliferation activation in clinical specimens. Thus, low levels of PDZK1 in gastric cancer specimens lead to increase proliferation of gastric cancer cells via phosphorylation of PTEN at the S380/T382/T383 cluster and constitutively activation of PI3K/AKT signaling, which results in poor prognosis of gastric cancer patients

Bioinspired, self-powered, and highly sensitive electronic skin for sensing static and dynamic pressures

Flexible piezoresistive pressure sensors obtain global research interest owing to their potential applications in healthcare, human–robot interaction, and artificial nerves. However, an additional power supply is usually required to drive the sensors, which results in increased complexity of the pressure sensing system. Despite the great efforts in pursuing self-powered pressure sensors, most of the self-powered devices can merely detect the dynamic pressure and the reliable static pressure detection is still challenging. With the help of redox-induced electricity, a bioinspired graphite/polydimethylsiloxane piezoresistive composite film acting both as the cathode and pressure sensing layer, a neoteric electronic skin sensor is presented here to detect not only the dynamic forces but also the static forces without an external power supply. Additionally, the sensor exhibits a fascinating pressure sensitivity of ∼103 kPa–1 over a broad sensing range from 0.02 to 30 kPa. Benefiting from the advanced performance of the device, various potential applications including arterial pulse monitoring, human motion detecting, and Morse code generation are successfully demonstrated. This new strategy could pave a way for the development of next-generation self-powered wearable devices

A Refined Study of FCRL Genes from a Genome-Wide Association Study for Graves’ Disease

To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring FCRL1-5 and CD5L genes, we carried out a refined association study in the entire FCRL region in 1,536 patients with Graves’ disease (GD) and 1,516 sex-matched controls by imputation analysis, logistic regression, and cis-eQTL analysis. Among 516 SNPs with P<0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to FCRL3 expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on FCRL3 expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of FCRL3 whether in PBMCs or its subsets, especially in $CD19^+$ B cells and $CD8^+$ T subsets. Next, the combined analysis with 5,300 GD cases and 4,916 control individuals confirmed FCRL3 was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level ($P_{combined}$ = 2.27×$10^{−12}$ and 7.11×$10^{−13}$, respectively). Moreover, the haplotypes with the risk allele A of rs3761959 and risk allele C of rs7528684 were associated with GD risk. Finally, our epigenetic analysis suggested the disease-associated C allele of rs7528684 increased affinity for NF-KB transcription factor. Above data indicated that FCRL3 gene and its proxy SNP rs7528684 may be involved in the pathogenesis of GD by excessive inhibiting B cell receptor signaling and the impairment of suppressing function of Tregs