Mental Tasks Modulate Motor-Units Above 10 Hz and are a Potential Control Signal for Movement Augmentation: a Preliminary Study.

Spinal motor neurons receive a wide range of input frequencies. However, only frequencies below ca. 10 Hz are directly translated into motor output. Frequency components above 10 Hz are filtered out by neural pathways and muscle dynamics. These higher frequency components may have an indirect effect on motor output, or may simply represent movement-independent oscillations that leak down from supraspinal areas such as the motor cortex. If movement-independent oscillations leak down from supraspinal areas, they could provide a potential control signal in movement augmentation applications. We analysed high-density electromyography (HD-EMG) signals from the tibialis anterior muscle while human subjects performed various mental tasks. The subjects performed an isometric dorsiflexion of the right foot at a low level of force while simultaneously (1) imagining a movement of the right foot, (2) imagining a movement of both hands, (3) performing a mathematical task, or (4) performing no additional task. We classified the channel-averaged HD-EMG signals and the cumulative spike train (CST) of motor-units using a filter bank and a linear classifier. We found that in some subjects, the mental task can be classified from the channel-averaged HD-EMG signals and the CST in oscillations above 10 Hz. Furthermore, we found that these oscillation modulations are incompatible with a systematic and task-dependent change in force level. Our preliminary findings from a limited number of subjects suggest that some mental task-induced oscillations from supraspinal areas leak down to spinal motor neurons and are discriminable via EMG or CST signals at the innervated muscle.

Airway epithelium IgE-FcεRI cross-link induces epithelial barrier disruption in severe T2-high asthma.

Although high-affinity immunoglobulin (Ig)E receptor (FcεRI) expression is upregulated in type 2 (T2)-high asthmatic airway epithelium, its functional role in airway epithelial dysfunction has not been elucidated. Here we report the upregulated expression of FcεRI and p-EGFR (Epidermal Growth Factor Receptor), associated with decreased expression of E-cadherin and claudin-18 in bronchial biopsies of severe T2-high asthmatics compared to mild allergic asthmatics and non-T2 asthmatics. Monomeric IgE (mIgE) decreased the expression of junction proteins, E-cadherin, claudin-18, and ZO-1, and increased alarmin messenger RNA and protein expression in cultured primary bronchial epithelial cells from T2-high asthmatics. Epithelial FcεRI ligation with mIgE decreased transepithelial electric resistance in air-liquid interface cultured epithelial cells. FcεRI ligation with mIgE or IgE- Dinitrophenyl or serum of high-level allergen-specific IgE activated EGFR and Akt via activation of Src family kinases, mediating alarmin expression, junctional protein loss, and increased epithelial permeability. Furthermore, tracheal instillation of mIgE in house dust mite-sensitized mice induced airway hyper-responsiveness, junction protein loss, epithelial cell shedding, and increased epithelial permeability. Thus, our results suggest that IgE-FcεRI cross-linking in the airway epithelium is a potential and unnoticed mechanism for impaired barrier function, increased mucosal permeability, and EGFR-mediated alarmin production in T2-high asthma.

Platelet Activation in High D-Dimer Plasma Plays a Role in Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Mutant Lung Adenocarcinoma.

Objective: Platelet activation and adhesion to cancer cells increase the release of multiple factors that contribute to EMT and chemoresistance. Elevated levels of D-dimer have been associated with poor clinical outcomes in lung cancer. Platelets in high D-dimer plasma may be activated and implicated in acquired resistance to EGFR TKI in advanced lung adenocarcinoma with mutant EGFR. Materials and Methods: Clinical responsive rate (RR), progression-free survival (PFS), and overall survival (OS) were prospectively measured in treatment-naïve lung adenocarcinoma patients with activation mutation. Plasma or platelets from patients with high or low D-dimer level were obtained to investigate the cytotoxic effects of TKIs on mutant cancer cells, and the mechanistic pathways were also explored. Results: Patients with high D-dimer had worse RR, PFS, and OS. High D-dimer plasma induced resistance to gefitinib, erlotinib, afatinib, or osimertinib in EGFR mutant lung cancer cells. Depletion of platelets in high D-dimer plasma reversed the resistance to TKI. Platelets of high D-dimer plasma had higher adherence capacity to cancer cells, and induced EGFR and Akt activation as well as EMT through Src activation. Inhibition of platelet adherence or activation of Src or Akt conquered the resistance to TKI. The acquired resistance to TKI by high D-dimer plasma was less attributed to secondary gene mutation. Conclusion: Increased platelet activation in the high D-dimer plasma may contribute to first-line acquired EGFR TKI resistance. Thus, therapeutic strategy against platelet activation in patients with high D-dimer levels may improve the efficacy of first-line treatment with EGFR TKI.

pcMSC Modulates Immune Dysregulation in Patients With COVID-19-Induced Refractory Acute Lung Injury.

Background and Objectives: The novel coronavirus disease 2019 (COVID-19) has been a pandemic health issue in 30 January 2020. The mortality rate is as high as 50% in critically ill patients. Stem cell therapy is effective for those who are refractory to standard treatments. However, the immune responses that underlie stem cell therapy have not been well reported, particularly, in patients associated with moderate to severe acute respiratory distress syndrome (ARDS). Methods: On Days 0 and 4, an intravenous infusion of 2 × 107 placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) were administered to five severe COVID-19 patients refractory to current standard therapies. Peripheral blood inflammatory markers and immune profiles were determined by multi-parameter flow cytometry and studied at Days 0, 4, and 8. Clinical outcomes were also observed. Results: None of the pc-MSC treated patients experienced 28-day mortality compared with the control group and showed a significant improvement in the PaO2/FiO2 ratio, Murray's lung injury scores, reduction in serum ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels. The cytokine profiles also showed a reduction in IL-1ß, IFN-γ, IL-2, and IL-6, and an increase in IL-13 and IL-5 type 2 cytokines within 7 days of therapy. Lymphopenia was also significantly improved after 7 days of treatment. Immune cell profiles showed an increase in the proportions of CD4+ T cells (namely, CD4+ naïve T cells and CD4+ memory T cell subtypes), Treg cells, CD19+ B cells (namely, CD19+ naïve B cells, CD27+ switched B cell subtypes) and dendritic cells, and a significant decrease in the proportion of CD14+ monocytes (namely, CD16- classical and CD16+ non-classical subtypes), and plasma/plasmablast cells. No adverse effects were seen at the serial follow-up visits for 2 months after initial therapy. Conclusion: pc-MSCs therapy suppressed hyper-inflammatory states of the innate immune response to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoting CD4+ T cells and CD19+ B cells toward adaptive immune responses in severely critically ill COVID-19 patients with moderate to severe ARDS, especially those who were refractory to current standard care and immunosuppressive therapies.

Anti-IgE therapy inhibits chemotaxis, proliferation and transformation of circulating fibrocytes in patients with severe allergic asthma.

BACKGROUND AND OBJECTIVE: Circulating fibrocytes act as precursors of myofibroblasts, contribute to airway remodelling in chronic asthma and migrate to injured tissues by expressing CXCR4 and CCR7. Anti-IgE therapy improves severe allergic asthma (SAA) control and airway remodelling in T2-high SAA. The effects of anti-IgE therapy on fibrocyte activities were investigated in this study. METHODS: The expression of CCR7, CXCR4, ST2 and α-SMA (α-smooth muscle actin) in both circulating and cultured fibrocytes from all patients with asthma was measured, and was repeated after omalizumab treatment in SAA. Fibrocytes recruitment, proliferation and transformation were also measured in response to anti-IgE therapy. RESULTS: Omalizumab effectively improved asthma control and pulmonary function in T2-high SAA, associated with a decline in serum levels of IL-33 and IL-13. Omalizumab down-regulates CXCR4 and CCR7 expression of fibrocytes, which could suppress fibrocyte recruitment into the lungs. Omalizumab also suppressed the increased number of fibrocytes and α-SMA+ fibrocytes within the cultured non-adherent non-T (NANT) cells after 3-7 days of culture. The decrease in serum levels of IL-33 by omalizumab contributed to the effectiveness in inhibiting fibrocyte recruitment, proliferation and myofibroblast transformation through IL-33/ST2 axis. The elevated IL-13 expression in SAA patients potentiated the effects of IL-33 by increasing ST2 expression. CONCLUSION: Omalizumab reduced the number of circulating fibrocytes, cell and number of fibrocytes as well as α-SMA+ fibrocytes after 3-7 days of culture in SAA patients. IL-33 and IL-13 may be implicated in the effectiveness of omalizumab in inhibiting fibrocyte activation contributing partly to the clinical benefits in reducing lamina propria and basement membrane thickening.

Discrimination of simple objects decoded from the output of retinal ganglion cells upon sinusoidal electrical stimulation.

Objective. Most neuroprosthetic implants employ pulsatile square-wave electrical stimuli, which are significantly different from physiological inter-neuronal communication. In case of retinal neuroprosthetics, which use a certain type of pulsatile stimuli, reliable object and contrast discrimination by implanted blind patients remained challenging. Here we investigated to what extent simple objects can be discriminated from the output of retinal ganglion cells (RGCs) upon sinusoidal stimulation.Approach. Spatially confined objects were formed by different combinations of 1024 stimulating microelectrodes. The RGC activity in theex vivoretina of photoreceptor-degenerated mouse, of healthy mouse or of primate was recorded simultaneously using an interleaved recording microelectrode array implemented in a CMOS-based chip.Main results. We report that application of sinusoidal electrical stimuli (40 Hz) in epiretinal configuration instantaneously and reliably modulates the RGC activity in spatially confined areas at low stimulation threshold charge densities (40 nC mm-2). Classification of overlapping but spatially displaced objects (1° separation) was achieved by distinct spiking activity of selected RGCs. A classifier (regularized logistic regression) discriminated spatially displaced objects (size: 5.5° or 3.5°) with high accuracy (90% or 62%). Stimulation with low artificial contrast (10%) encoded by different stimulus amplitudes generated RGC activity, which was classified with an accuracy of 80% for large objects (5.5°).Significance. We conclude that time-continuous smooth-wave stimulation provides robust, localized neuronal activation in photoreceptor-degenerated retina, which may enable future artificial vision at high temporal, spatial and contrast resolution.

Spatial and temporal resolution of optogenetically recovered vision in ChR2-transduced mouse retina.

Objective.Retinal ganglion cells (RGCs) represent an attractive target in vision restoration strategies, because they undergo little degeneration compared to other retinal neurons. Here we investigated the temporal and spatial resolution in adult photoreceptor-degenerated (rd10) mouse retinas, where RGCs have been transduced with the optogenetic actuator channelrhodopsin-2 (ChR2).Approach.The RGC spiking activity was recorded continuously with a CMOS-based microelectrode array during a variety of photostimulation protocols. The temporal resolution was assessed through Gaussian white noise stimuli and evaluated using a linear-nonlinear-Poisson model. Spatial sensitivity was assessed upon photostimulation with single rectangular pulses stepped across the retina and upon stimulation with alternating gratings of different spatial frequencies. Spatial sensitivity was estimated using logistic regression or by evaluating the spiking activity of independent RGCs.Main results.The temporal resolution after photostimulation displayed an about ten times faster kinetics as compared to physiological filters in wild-type RGCs. The optimal spatial resolution estimated using the logistic regression model was 10µm and 87µm based on the population response. These values correspond to an equivalent acuity of 1.7 or 0.2 cycles per degree, which is better than expected from the size of RGCs' optogenetic receptive fields.Significance.The high temporal and spatial resolution obtained by photostimulation of optogenetically transduced RGCs indicate that high acuity vision restoration may be obtained by photostimulation of appropriately modified RGCs in photoreceptor-degenerated retinas.

Electrical Imaging of Light-Induced Signals Across and Within Retinal Layers.

The mammalian retina processes sensory signals through two major pathways: a vertical excitatory pathway, which involves photoreceptors, bipolar cells, and ganglion cells, and a horizontal inhibitory pathway, which involves horizontal cells, and amacrine cells. This concept explains the generation of an excitatory center-inhibitory surround sensory receptive fields-but fails to explain the modulation of the retinal output by stimuli outside the receptive field. Electrical imaging of light-induced signal propagation at high spatial and temporal resolution across and within different retinal layers might reveal mechanisms and circuits involved in the remote modulation of the retinal output. Here we took advantage of a high-density complementary metal oxide semiconductor-based microelectrode array and investigated the light-induced propagation of local field potentials (LFPs) in vertical mouse retina slices. Surprisingly, the LFP propagation within the different retinal layers depends on stimulus duration and stimulus background. Application of the same spatially restricted light stimuli to flat-mounted retina induced ganglion cell activity at remote distances from the stimulus center. This effect disappeared if a global background was provided or if gap junctions were blocked. We hereby present a neurotechnological approach and demonstrated its application, in which electrical imaging evaluates stimulus-dependent signal processing across different neural layers.

Multiple Approaches for Enhancing Neural Activity to Promote Neurite Outgrowth of Retinal Explants.

Activity is important for neural development and regeneration. Enhancing neural activity can facilitate axon regrowth of retinal ganglion cells. Here, we describe various methods, including electrical stimulation, pharmacological manipulation, and optogenetics, to elevate neural activity of retinal explants in mice and to analyze their effects on promoting neurite outgrowth in organotypic culture.

Endotypes of severe allergic asthma patients who clinically benefit from anti-IgE therapy.

BACKGROUND: Omalizumab, a recombinant monoclonal anti-IgE antibody, was developed for the treatment of severe allergic asthma. Not all these patients respond to omalizumab. OBJECTIVE: This study aimed to evaluate whether the proinflammatory cytokine profiles in the severe allergic asthma patients were different between who responded and nonresponded to omalizumab therapy. METHODS: A prospective study was conducted to examine type 2 cytokines and epithelium-derived cytokines in the bronchial tissues by immunohistochemistry, Western blot and PCR analysis among patients with severe allergic asthma before and after omalizumab therapy. RESULTS: Fourteen of 23 patients with unstable severe allergic asthma improved their asthma control after 4 months of omalizumab treatment (Responders), while nine failed to improve (Non-Responders). Most of Responders were type 2-high endotype (12/14) with upregulated expression of IL-33, IL-25 and TSLP in their bronchial tissues, while most of Non-Responders were type 2-low endotype (8/9). Repeated bronchoscopic biopsy was done in nine responders after omalizumab treatment and showed a decline in IL-13, IL-33, IL-25 and TSLP expression in the bronchial tissues. Among 14 Responders who continued omalizuamb treatments to a total 12 months, six patients achieved a well control of asthma (ACT ≥ 23), while eight patients required additional treatment for asthma symptoms and had more rhinosinusitis comorbidities and a mixed eosinophilic and neutrophilic inflammation in their bronchial tissues. CONCLUSION: Most of the severe allergic asthma patients who benefited from omalizumab treatment were IL-33, IL-25 and TSLP aggravated type 2-high endotype. Rhinosinusitis or with a mixed eosinophilic and neutrophilic airway inflammation should be evaluated in patients who partially responded to omalizumab treatment.

Diesel exhaust particles up-regulate interleukin-17A expression via ROS/NF-κB in airway epithelium.

IL-17A is implicated in many aspects of pathogenesis of severe asthma, including inducing neutrophilic inflammation, airway hyperresponsiveness, steroid insensitivity and airway remodeling. Diesel exhaust particles (DEP) emission from vehicles has been shown to expand Th17 cells to increase IL-17A release that contributes to DEP-mediated exacerbation of asthma severity. It is not known whether non-immune cells in airways may also release IL-17A in response to DEP exposure. In this study, We found IL-17A expression was upregulated in the epithelium of severe allergic asthma patients from high road traffic pollution areas compared to those in low. Furthermore, we found DEP concentration-dependently increased IL-17A synthesis and release by 122.3 ±â€¯15.72% and 235.5 ±â€¯18.37%, respectively in primary bronchial epithelial cells (PBEC), accompanied with increased ROS production. Pretreatment of ROS scavenger (NAC) significantly inhibited DEP-induced IL-17A mRNA expression. DEP-induced IκBα degradation can be inhibited by NAC. We also found DEP increased p65 and RelB subunits expression, and pretreatment of NF-κB inhibitor (SN50) also inhibited DEP-induced IL-17A expression. We further found DEP increased NF-κB subunit RelB recruitment to IL-17A promoter in PBEC and airway tissue of severe allergic asthma patients from high road traffic pollution areas. These results indicate DEP stimulates IL-17A expression in airway epithelium through ROS/NF-κB pathway, and provide a possible link between traffic pollution exposure and IL-17A-related responses in severe allergic asthma patients.

Short-term Alteration of Developmental Neural Activity Enhances Neurite Outgrowth of Retinal Explants.

Purpose: It is well known that the gradual loss of axon growth ability of retinal ganglion cells (RGCs) during development is largely determined by extrinsic signals rather than being programmed intrinsically. Spontaneous retinal waves are the major neural activity during retinal development. Thus restoring the developmental environment by providing the proper neural activity may be able to help axon regeneration of RGCs. Methods: Retinal explants from P5 and P11 C57BL/6 mice were treated pharmacologically or stimulated electrically, and cultured with or without brain-derived neurotrophic factor (BDNF) on coverslips or a multielectrode array for 5 days to examine the neurite outgrowth capacity of RGCs. Results: Here we have demonstrated that neurite outgrowth of retinal explants was not affected when acetylcholine transmission was blocked pharmacologically in retinas that normally display stage II retinal waves. However, short-term induction of globally correlated neural activity at 1- to 2-minute intervals in retinas that normally display stage III retinal waves by blocking inhibitory neural transmission was found to greatly promote neurite outgrowth even in the absence of exogenous neurotrophic factors. Moreover, short-term electrical stimulation with a temporal pattern of 1- to 2-minute intervals rather than simply increasing the neural activity greatly enhanced neurite outgrowth of retinal explants of the same age. Conclusions: These results suggest that short-term alteration of neural activity with a specific temporal pattern in retinas of later developmental stages is sufficient to enhance neurite outgrowth of retinal explants. This finding could lead to a therapeutic strategy that is able to prevent the gradual loss of the axon growth ability of RGCs in more mature retinas.

Longitudinal Associations Between Immigrant Ethnic Density, Neighborhood Processes, and Latino Immigrant Youth Depression.

Depression rates rise in adolescence and the prevalence of depression is higher among Latino adolescents than other race/ethnic groups. Ethnic density among immigrant populations is associated with better health and mental health outcomes among adults, but little is known about its effects among adolescents or its mechanisms. This study examines the pathways by which immigrant density may affect mental health outcomes among Latino youth. Using data from the National Longitudinal Study of Adolescent Health (Add Health), we drew a sample of 2,678 Hispanic youth. Multivariate multilevel logistic regression analyses found that Latino immigrant density predicted lower odds of depression among both male and female immigrant but not non-immigrant Latino adolescents. No mediating effects of neighborhood efficacy, perceived safety or perceived contentment were observed in this study. Results reaffirm the need to further explore the mechanisms through which ethnic density exerts its salubrious effect on immigrant youth mental health.

Experimental demonstration of spinor slow light.

Slow light based on the effect of electromagnetically induced transparency is of great interest due to its applications in low-light-level nonlinear optics and quantum information manipulation. The previous experiments all dealt with the single-component slow light. Here, we report the experimental demonstration of two-component or spinor slow light using a double-tripod atom-light coupling scheme. The scheme involves three atomic ground states coupled to two excited states by six light fields. The oscillation due to the interaction between the two components was observed. On the basis of the stored light, our data showed that the double-tripod scheme behaves like the two outcomes of an interferometer enabling precision measurements of frequency detuning. We experimentally demonstrated a possible application of the double-tripod scheme as quantum memory/rotator for the two-colour qubit. Our study also suggests that the spinor slow light is a better method than a widely used scheme in the nonlinear frequency conversion.

Tumor-associated macrophages in stage IIIA pN2 non-small cell lung cancer after neoadjuvant chemotherapy and surgery.

PURPOSE: Most of the patients with stage IIIA pN2 non-small cell lung cancer (NSCLC) develop recurrence after surgery. It is not clear whether post neoadjuvant chemotherapy tumor-associated macrophages is associated with recurrence. PATIENTS AND METHODS: Stage IIIA pN2 NSCLC patients underwent cisplatin/docetaxel neoadjuvant chemotherapy and surgery were retrospectively enrolled. Immunohistochemical staining of CD68 was used to identify macrophages in surgical resected stored tissues. RESULTS: The objective response rate of cisplatin/docetaxel was 68%, overall median disease-free survival (DFS) was 13.1 months and median overall survival (OS) 36.8. months. Multiple Cox regression analysis showed low total macrophage numbers and mediastinal lymph nodes downstaging were independent factors for longer DFS, whereas high islet/stromal macrophages ratio was an independent facto for OS. In patients downstaged to pN0, low total macrophage numbers was also associated with longer DFS. CONCLUSIONS: Low total macrophage number is an independent factor for better DFS in pN2 stage IIIA NSCLC patients receiving neoadjuvant chemotherapy and surgical resection, which association was kept in those downstaged to pN0. Further studies are warrant to confirm the predictive role of TAMs and their potential causative role in tumor recurrence.

The forkhead transcription factor FOXO1 stimulates the expression of the adipocyte resistin gene.

Resistin is known as an adipocyte-specific hormone that can cause insulin resistance and decrease adipocyte differentiation. It can be regulated by transcriptional factors, but the possible role of forkhead transcription factor FOXO1 in regulating resistin gene expression is still unknown. Using 3T3 fibroblast and C3H10T1/2 and 3T3-L1 adipocytes, we found that transient overexpression of a non-phosphorylatable, constitutively active FOXO1, but not the wild type of FOXO1 or a DNA binding-deficient FOXO1, activated resistin promoter-directed luciferase expression. However, transient overexpression of a dominant-negative FOXO1 inactivated resistin promoter activity and reduced resistin mRNA expression. These observations indicate that the action of FOXO1 on resistin gene expression requires the activation of FOXO1 and that the effect of FOXO1 depends on the phosphorylation and dephosphorylation of FOXO1. The FOXO1 protein target sites on the resistin promoter were localized to the proximal -3545 to -787bp of 5'-flanking region of the resistin promoter. A chromatin immunoprecipitation assay also showed that FOXO1 bound the resistin promoter at nucleotide regions of -1539 to -1366bp and -1016 to -835bp, but not at the regions of -795 to -632bp. Results of this study suggest that FOXO1 transcription factor likely activates the expression of adipocyte resistin gene via direct association with the upstream resistin promoter.

Longitudinal predictors of dieting and disordered eating among young adults in the U.S.

OBJECTIVE: To assess longitudinal associations between cognitive and behavioral characteristics in adolescence and dieting and eating pathology in young adulthood. METHOD: Data from the National Longitudinal Study of Adolescent Health and multivariate logistic regressions were used to examine the unique and cumulative effects of adolescent behavior and cognition on four weight-related health indicators in young adulthood: dieting, extreme weight loss behaviors (EWLB), binge eating, and eating disorder (ED) diagnosis (N = 14,322). RESULTS: Early dieting, depression, and body image distortion (BID) prospectively predicted dieting or EWLB at Wave 3. In addition, early depression and dieting were associated with binge eating in young adulthood, and early BID was associated with ED diagnosis. Gender differences were observed. In the prospective models, the effect of depression on the onset of EWLB was stronger for women than men; while association between early depression and ED diagnosis was significantly stronger for men than women. Findings supported a cumulative risk effect. Among women, each additional correlate was associated with greater odds of eating pathology in young adulthood; among men, each additional correlate was associated with greater odds of ever reporting ED diagnosis. Overall prevalence of dieting and eating pathology among young adults was higher among women than men and increased over time for both sexes. DISCUSSION: Early weight control behavior and cognition affect long term eating patterns and are salient for both young adult men and women. Transition to young adulthood is a critical period for assessing and preventing weight and eating-related health problems.

The endothelin A receptor mediates fibrocyte differentiation in chronic obstructive asthma. The involvement of connective tissue growth factor.

RATIONALE: Fibrocytes possess increased differentiability into α-smooth muscle actin (α-SMA)(+) myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin-1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear. OBJECTIVES: To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA. METHODS: Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or α-SMA were identified by flow cytometry. MEASUREMENTS AND MAIN RESULTS: We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serum levels of ET-1 and the expression of the ETAR in fibrocytes were significantly higher in patients with COA compared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and α-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated α-SMA expression induced by ET-1 in fibrocytes from normal participants. CONCLUSIONS: Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.

Coherent optical memory with high storage efficiency and large fractional delay.

A high-storage efficiency and long-lived quantum memory for photons is an essential component in long-distance quantum communication and optical quantum computation. Here, we report a 78% storage efficiency of light pulses in a cold atomic medium based on the effect of electromagnetically induced transparency. At 50% storage efficiency, we obtain a fractional delay of 74, which is the best up-to-date record. The classical fidelity of the recalled pulse is better than 90% and nearly independent of the storage time, as confirmed by the direct measurement of phase evolution of the output light pulse with a beat-note interferometer. Such excellent phase coherence between the stored and recalled light pulses suggests that the current result may be readily applied to single photon wave packets. Our work significantly advances the technology of electromagnetically induced transparency-based optical memory and may find practical applications in long-distance quantum communication and optical quantum computation.