Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium.

IntroductionAcid-sensing ion channel 3 (ASIC3) is expressed in synoviocytes, activated by decreases in pH, and reduces inflammation in animal models of inflammatory arthritis. The purpose of the current study was to characterize potential mechanisms underlying the control of inflammation by ASIC3 in fibroblast-like synoviocytes (FLS).MethodsExperiments were performed in cultured FLS from wild-type (WT) and ASIC3-/- mice, ASIC1-/- mice, and people with rheumatoid arthritis. We assessed the effects of acidic pH with and without interleukin-1β on FLS and the role of ASICs in modulating intracellular calcium [Ca(2+)](i), mitogen activated kinase (MAP kinase) expression, and cell death. [Ca(2+)](i) was assessed by fluorescent calcium imaging, MAP kinases were measured by Western Blots; ASIC, cytokine and protease mRNA expression were measured by quantitative PCR and cell death was measured with a LIVE/DEAD assay.ResultsAcidic pH increased [Ca(2+)](i) and decreased p-ERK expression in WT FLS; these effects were significantly smaller in ASIC3-/- FLS and were prevented by blockade of [Ca(2+)]i. Blockade of protein phosphatase 2A (PP2A) prevented the pH-induced decreases in p-ERK. In WT FLS, IL-1β increases ASIC3 mRNA, and when combined with acidic pH enhances [Ca(2+)](i), p-ERK, IL-6 and metalloprotienase mRNA, and cell death. Inhibitors of [Ca(2+)](i) and ERK prevented cell death induced by pH 6.0 in combination with IL-1β in WT FLS.ConclusionsDecreased pH activates ASIC3 resulting in increased [Ca(2+)](i), and decreased p-ERK. Under inflammatory conditions, acidic pH results in enhanced [Ca(2+)](i) and phosphorylation of extracellular signal-regulated kinase that leads to cell death. Thus, activation of ASIC3 on FLS by acidic pH from an inflamed joint could limit synovial proliferation resulting in reduced accumulation of inflammatory mediators and subsequent joint damage

The Influence of Action Video Gaming Experience on the Perception of Emotional Faces and Emotional Word Meaning

Action video gaming (AVG) experience has been found related to sensorimotor and attentional development. However, the influence of AVG experience on the development of emotional perception skills is still unclear. Using behavioral and ERP measures, this study examined the relationship between AVG experience and the ability to decode emotional faces and emotional word meanings. AVG experts and amateurs completed an emotional word-face Stroop task prior to (the pregaming phase) and after (the postgaming phase) a 1 h AVG session. Within-group comparisons showed that after the 1 h AVG session, a more negative N400 was observed in both groups of participants, and a more negative N170 was observed in the experts. Between-group comparisons showed that the experts had a greater change of N170 and N400 amplitudes across phases than the amateurs. The results suggest that both the 1 h and long-term AVG experiences may be related to an increased difficulty of emotional perception. Furthermore, certain behavioral and ERP measures showed neither within- nor between-group differences, suggesting that the relationship between AVG experience and emotional perception skills still needs further research

Action Real-Time Strategy Gaming Experience Related to Increased Attentional Resources: An Attentional Blink Study

Action real-time strategy gaming (ARSG) is a cognitively demanding task which requires attention, sensorimotor skills, team cooperation, and strategy-making abilities. A recent study found that ARSG experts had superior visual selective attention (VSA) for detecting the location of a moving object that could appear in one of 24 different peripheral locations (Qiu et al., 2018), suggesting that ARSG experience is related to improvements in the spatial component of VSA. However, the influence of ARSG experience on the temporal component of VSA—the detection of an item among a sequence of items presented consecutively and quickly at a single location—still remains understudied. Using behavioral and electrophysiological measures, this study examined whether ARSG experts had superior temporal VSA performance compared to non-experts in an attentional blink (AB) task, which is typically used to examine temporal VSA. The results showed that the experts outperformed the non-experts in their detection rates of targets. Furthermore, compared to the non-experts, the experts had faster information processing as indicated by earlier P3 peak latencies in an AB period, more attentional resources distributed to targets as indicated by stronger P3 amplitudes, and a more flexible deployment of attentional resources. These findings suggest that experts were less prone to the AB effect. Thus, long-term ARSG experience is related to improvements in temporal VSA. The current findings support the benefit of video gaming experience on the development of VSA

Disentangling superconducting and magnetic orders in NaFe_1-xNi_xAs using muon spin rotation

Muon spin rotation and relaxation studies have been performed on a "111" family of iron-based superconductors NaFe_1-xNi_xAs. Static magnetic order was characterized by obtaining the temperature and doping dependences of the local ordered magnetic moment size and the volume fraction of the magnetically ordered regions. For x = 0 and 0.4 %, a transition to a nearly-homogeneous long range magnetically ordered state is observed, while for higher x than 0.4 % magnetic order becomes more disordered and is completely suppressed for x = 1.5 %. The magnetic volume fraction continuously decreases with increasing x. The combination of magnetic and superconducting volumes implies that a spatially-overlapping coexistence of magnetism and superconductivity spans a large region of the T-x phase diagram for NaFe_1-xNi_xAs . A strong reduction of both the ordered moment size and the volume fraction is observed below the superconducting T_C for x = 0.6, 1.0, and 1.3 %, in contrast to other iron pnictides in which one of these two parameters exhibits a reduction below TC, but not both. The suppression of magnetic order is further enhanced with increased Ni doping, leading to a reentrant non-magnetic state below T_C for x = 1.3 %. The reentrant behavior indicates an interplay between antiferromagnetism and superconductivity involving competition for the same electrons. These observations are consistent with the sign-changing s-wave superconducting state, which is expected to appear on the verge of microscopic coexistence and phase separation with magnetism. We also present a universal linear relationship between the local ordered moment size and the antiferromagnetic ordering temperature TN across a variety of iron-based superconductors. We argue that this linear relationship is consistent with an itinerant-electron approach, in which Fermi surface nesting drives antiferromagnetic ordering.Comment: 20 pages, 14 figures, Correspondence should be addressed to Prof. Yasutomo Uemura: [email protected]

Action Real-Time Strategy Gaming Experience Related to Enhanced Capacity of Visual Working Memory

Action real-time strategy gaming (ARSG)—a major genre of action video gaming (AVG)—has both action and strategy elements. ARSG requires attention, visual working memory (VWM), sensorimotor skills, team cooperation, and strategy-making abilities, thus offering promising insights into the learning-induced plasticity. However, it is yet unknown whether the ARSG experience is related to the development of VWM capacity. Using both behavioral and event-related potential (ERP) measurements, this study tested whether ARSG experts had larger VWM capacity than non-experts in a change detection task. The behavioral results showed that ARSG experts had higher accuracy and larger VWM capacity than non-experts. In addition, the ERP results revealed that the difference wave of the contralateral delay activity (CDA) component (size 4–size 2) elicited by experts was significantly larger than that of non-experts, suggesting that the VWM capacity was higher in experts than in non-experts. Thus, the findings suggested that prolonged ARSG experience is correlative with the enhancement of VWM

Targeting Tumor Microenvironment: Effects of Chinese Herbal Formulae on Macrophage-Mediated Lung Cancer in Mice

Our previous studies have shown that Qing-Re-Huo-Xue (QRHX) formulae had significant anti-inflammatory effects in chronic airway diseases such as asthma and chronic obstructive lung disease. Here, we examined the effects of QRHX on lung cancer cell invasion and the potential associated mechanism(s), mainly polarization of macrophages in the tumor microenvironment. In vivo, QRHX both inhibited tumor growth and decreased the number of tumor-associated macrophages (TAMs) in mice with lung cancer. Further study indicated that QRHX inhibited cancer-related inflammation in tumor by decreasing infiltration of TAMs and IL-6 and TNF-α production and meanwhile decreased arginase 1 (Arg-1) expression and increased inducible NO synthase (iNOS) expression. QRHX could markedly inhibit CD31 and VEGF protein expression. Additionally, CXCL12/CXCR4 expression and JAK2/STAT3 phosphorylation were reduced in QRHX treatment group. Thus, we draw that QRHX played a more important role in inhibiting tumor growth by regulating TAMs in mice, which was found to be associated with the inhibition of inflammation and the CXCL12/CXCR4/JAK2/STAT3 signaling pathway

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Advances in basic research of traditional Chinese medicine herbal formulae in the treatment of non-small cell lung cancer

Today, there is an increasing rate of morbidity and mortality in lung cancer worldwide. In China, lung cancer is also the leading cause of cancer-related death in China. The distinctive herbal therapy from traditional Chinese medicine (TCM) has shown good efficacy in treating lung cancer principally by inhibiting tumor growth or improving the anti-tumor immune response according to considerable experimental studies, which also justifies the concept of dispelling pathogenic qi and strengthening healthy qi in TCM