Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons.

ABSTRACT: Group I metabotropic glutamate receptors (group I mGluRs) have been implicated in several central nervous system diseases including chronic pain. It is known that activation of group I mGluRs results in the production of inositol triphosphate (IP3) and diacylglycerol that leads to activation of extracellular signal-regulated kinases (ERKs) and an increase in neuronal excitability, but how group I mGluRs mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that group I mGluRs recruit Orai1 as part of its downstream signaling pathway in dorsal horn neurons. We demonstrate that neurotransmitter glutamate induces STIM1 puncta formation, which is not mediated by N-Methyl-D-aspartate (NMDA) or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Glutamate-induced Ca2+ entry in the presence of NMDA or AMPA receptor antagonists is eliminated in Orai1-deficient neurons. Dihydroxyphenylglycine (DHPG) (an agonist of group I mGluRs)-induced Ca2+ entry is abolished by Orai1 deficiency, but not affected by knocking down of transient receptor potential cation channel 1 (TRPC1) or TRPC3. Dihydroxyphenylglycine-induced activation of ERKs and modulation of neuronal excitability are abolished in cultured Orai1-deficient neurons. Moreover, DHPG-induced nociceptive behavior is markedly reduced in Orai1-deficient mice. Our findings reveal previously unknown functional coupling between Orai1 and group I mGluRs and shed light on the mechanism underlying group I mGluRs-mediated neuronal plasticity.

A noninvasive and highly sensitive approach for the assessment of coronary collateral circulation by 192-slice third-generation dual-source computed tomography.

The coronary collateral circulation (CCC) is an alternative source of blood supply when the original vessels fail to provide sufficient blood. The accurate detection of CCC is critical for the treatment of ischemic heart disease, especially when the stent surgery is not an option. The assessment of minute vessels such as coronary collateral arteries is challenging. The objective of this study was to assess the feasibility of detection and classification of CCC using the192-slice third-generation dual-source computed tomography angiography (192-slice DSCT CTA).Eight hundred patients (450 men and 350 women, mean age: 56 ±â€Š11 years) with complete or subtotal occlusion of at least 1 major coronary artery were enrolled for our study. February 2016 and September 2018, the patient both 192-slice DSCT CTA and conventional coronary angiography (CAG) were performed in all enrolled patients. The interval between two approaches for a given patient was 6.1 ±â€Š3.7 days (Range: 1-15). The diagnostic accuracy of 192-slice DSCT CTA was evaluated by comparing it with that of CAG. The identified CCC was graded according to the Rentrop classification.The prevalence among patients of having at least 1 CCC was 43.8%. The sensitivity for detecting CCC by 192-slice DSCT was 91.7% (95% CI: 88.3% to 94.3%), specificity was 95.5% (95% CI: 93.1% to 97.2%), positive predictive value was 94.3% (95% CI: 91.5% to 96.2%), and negative predictive value was 93.3% (95% CI: 90.9% to 95.3%). Cohen-Kappa analysis showed that the consistency of the correct classification of CCC using CAG and 192-slice DSCT was very high with the kappa coefficient (κ) of 0.94 (95% CI: 0.91-0.96, P value = .01). Additionally, the radiation dose for 192-slice DSCT was as low as 0.42 ±â€Š0.04 mSv (range, 0.35-0.43 mSv).The 192-slice DSCT CTA is a reliable and sensitive non-invasive method for the evaluation of CCC with low radiation doses.

Surface Acting or Deep Acting, Who Need More Effortful? A Study on Emotional Labor Using Functional Near-Infrared Spectroscopy.

Emotional labor is characterized by two main regulation strategies: surface acting and deep acting. However, which strategy consumes more energy? To explore this, we used functional near-infrared spectroscopy (fNIRS) to measure changes in hemoglobin density while participants performed a task requiring them to make the opposite emotional facial expression of that presented in a picture. We found that (1) neither surface nor deep acting led to a significant change in hemoglobin concentration in the prefrontal cortex; (2) making negative and positive facial expressions activated the same left front and middle areas of the prefrontal cortex; and (3) making positive facial expressions activated the rear portion of the prefrontal cortex, but making negative facial expressions did not. Based on these findings and past work, we can infer that deep and surface acting may not significantly differ in terms of the activity in the prefrontal cortex energy consumed. Furthermore, engaging in positive and negative emotional labor appear to utilize some of the same neurological mechanisms, although they differ in others.

CD27 natural killer cell subsets play different roles during the pre-onset stage of experimental autoimmune encephalomyelitis.

NK cells participate in the development of human multiple sclerosis (MS) and mouse experimental autoimmune encephalomyelitis (EAE), but the roles of different NK cell subsets in disease onset remain poorly understood. In this study, murine NK cells were divided into CD27(high) and CD27(low/-) subsets. The CD27(high) subset was decreased and the CD27(low/-) subset was increased in lymphoid organs during the pre-onset stage of EAE. Compared with the counterpart in naïve mice, the CD27(high) subset showed lower expression of Ly49D, Ly49H and NKG2D, and less production of IFN-γ, whereas the CD27(low/-) subset showed similar expression of the above mentioned surface receptors but higher cytotoxic activity in EAE mice. Compared with the CD27(high) subset, the CD27(low/-) subset exhibited increased promotion of DC maturation and no significant inhibition of T cells proliferation and Th17 cells differentiation in vitro Additionally, adoptive transfer of the CD27(low/-) subset, but not the CD27(high) subset, exacerbated the severity of EAE. Collectively, our data suggest the CD27 NK cell subsets play different roles in controlling EAE onset, which provide a new understanding for the regulation of NK cell subsets in early autoimmune disease.

Basophil activation through ASGM1 stimulation triggers PAF release and anaphylaxis-like shock in mice.

Basophils have been shown to contribute to anaphylaxis through either an IgE-FcεRI-dependent pathway or an IgG-FcγR pathway. However, it remains largely unclear whether basophils can be activated to promote anaphylaxis via a non-FcR pathway as well. The glycolipid receptor ASGM1 (Asialoganglioside gangliotetraosylceramide), which has an exposed GalNAcß1-4Gal moiety and serves as a receptor for pathogen associated molecular patterns such as flagellin, was recently found to be expressed on basophils. Here, we demonstrate that stimulation of basophils with anti-ASGM1 antibodies promotes platelet-activating factor (PAF) secretion in vitro and in vivo. Moreover, we found that ASGM1 stimulation triggers basophil- and PAF-dependent anaphylactic shock in pertussis toxin (PTX)-pretreated mice. Thus, ASGM1 has a crucial role in basophil activation and basophil-mediated anaphylaxis-like shock in mice, especially when the vascular permeability is increased by PTX treatment. Our findings describe a novel anaphylaxis-associated pathway that is antigen-, antibody-, and FcR-independent.

Native soluble carcinoembryonic antigen is not involved in the impaired activity of CD56 natural killer cells in malignant pleural effusion.

BACKGROUND: Natural killer (NK) cells are lymphocytes of the innate immune system that play a crucial role in tumor immune surveillance. Accumulated data indicated that NK cells in the tumor microenvironment often display a suppressed function. However, the mechanism is not clear. OBJECTIVE: In this study, the effects and relative mechanisms of malignant pleural effusion (MPE) from patients with lung cancer on NK cells were researched. METHODS: MPE and peripheral blood (PB) samples were collected from patients with lung cancer. The cytotoxic activity of CD56(dim) NK cells in PB and MPE mononuclear cells was analyzed by flow cytometry. RESULTS: It was observed that the percentages of total NK cells and a CD56(dim) NK subset in MPE reduced accompanying impaired cytotoxic activity compared with that in paired PB. Cell-free MPE treatment reduced both the proportion and cytotoxic activity of CD56(dim) NK cells in PB from healthy donors. The suppression effects were not based on soluble carcinoembryonic antigen and the inhibitory cytokines interleukin-10 and transforming growth factor-ß1, but were dependent on the factor with a molecular weight >100 kDa. CONCLUSIONS: These results demonstrated that native soluble carcinoembryonic antigen does not suppress the activity of NK cells, and an unknown factor with a molecular weight >100 kDa plays a critical role in the impairment of CD56(dim) NK cells in MPE, which might lead to tumor progression.