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Acupoint application inhibits nerve growth factor and attenuates allergic inflammation in allergic rhinitis model rats
Wenzhan Tu1,2 na1,
Xiaolong Chen1,2 na1,
Qiaoyun Wu1,2,
Xinwang Ying1,2,
Rong He1,2,
Xinfa Lou2,
Guanhu Yang1,2,
Kecheng Zhou1,2 &
Songhe Jiang1,2
Journal of Inflammation volume 17, Article number: 4 (2020) Cite this article
Acupoint application therapy (AAT) has been widely used to treat allergic inflammation induced by allergic rhinitis (AR). The therapeutic effect of acupoint application is obvious. But the underlying therapeutic mechanism is still indistinct. Nerve growth factor (NGF) expression showed a dramatic rise in nasal mucosa tissue after AR, and allergic inflammation also increased significantly. To demonstrate how AAT can improve allergic inflammation by down-regulating the expression of NGF, AR rat models were established by intraperitoneal injection of ovalbumin (OVA) and nasal drops in SD rats. The number of nasal rubbing, sneezing and the degree of runny nose were observed and the symptoms were scored by behavioral symptom scoring method within 3 min. The expression levels of NGF and its downstream key proteins, such as IL-4, IL-5, IL-13, IgE and IFN-γ were determined by q-PCR, Western blot analysis, ELISA and immunofluorescence staining. Furthermore, H&E staining and toluidine blue staining were used to observe the pathological structure of nasal mucosa and mast cells in nasal mucosa, and the ultrastructure of nasal mucosa was observed by electron microscopy.
Our data demonstrated that acupoint application significantly reduced the score of behavioral symptoms, and decreased the expression levels of NGF and its downstream key proteins, including IL-4, IL-5, IL-13, IgE, as well as promoting the expression level of IFN-γ in nasal mucosa tissue in AR rats. Thus, the activation of IgE and viability of mast cells was inhibited.
Our findings suggest that AAT can attenuate allergic inflammation by inhibiting the expression of NGF and its downstream pathway.
An increased incidence of allergic rhinitis (AR) has been manifested worldwide in recent years [1, 2]. AR, a chronic inflammatory disease of nasal mucosa, is mediated by immunoglobulin E (IgE) in T helper (TH) 2 type [3, 4]. AR, which stimulates the body by allergen, promotes the transformation of TH reaction from TH1 reaction to TH2 reaction evidenced by inhibiting the expression level of IFN-gamma secreted by TH1 cells, and promoting the expression levels of IL-4, IL-5 and IL-13 secreted by TH2 cells [5]. These cytokines attract mast cells, eosinophils and basophils to inflammatory sites. When the allergen stimulates the collective again, it binds to IgE on the surface of mast cells and produces an allergic reaction [6,7,8]. The main symptoms of AR were runny nose, itching and sneezing, seriously affecting patients' quality of life and work [9,10,11]. Neurotrophins play an immunoregulatory role [12, 13], and mast cells and eosinophils can produce neurotrophins. Nerve growth factor (NGF) is an immune related protein mainly by enhancing the immune response of TH2 [14]. NGF binds to its high affinity receptor TRKA [15], TRPV-1, activates neuronal ion channels and promotes the production of VIP1, which can enhance TH2 immune response [16].
As a unique external treatment method of Traditional Chinese Medicine, acupoint application method can prevent and treat diseases by applying traditional Chinese medicine into acupoints, such as pills, powder and ointment, and using the dual effects of drug percutaneous absorption and meridian effect [17]. Compared with western medicine, acupoint application therapy (AAT) has less side effects and better curative effect [18]. Nevertheless, the specific mechanism of AAT in inhibiting allergic inflammation is complex, which may be related to inhibition of TH2 immune response [19]. NGF can enhance TH2 immune response [16]. In view of the correlation between the two, AAT may inhibit allergic inflammation by inhibiting the expression of NGF and its downstream proteins, such as IL-4, IL-5 and IL-13. To identify this hypothesis, AR rat models were established to observe the changes of inflammation and the expression of NGF and its downstream proteins. H&E staining and toluidine blue staining were used to observe the pathological structure of nasal mucosa and mast cells in nasal mucosa, and the ultrastructure of nasal mucosa was observed by electron microscopy before and after the treatment in order to evaluate the therapeutic effect of AAT on AR.
All male Sprague-Dawley rats (180~200 g) were bought from Wenzhou Medical University (Wenzhou, China). All rats were housed in a temperature-controlled (20~22 °C) room on a 12 h light/dark cycle at 45 ± 5% humidity and were given standard laboratory diet. Approval for the study was obtained from the Institutional Animal Care and Use Committee of Wenzhou Medical University. All SD rats were randomly divided into four groups: control group, model group, Prescription NO.1 acupoint application group, Prescription NO.2 acupoint application group.
Ovalbumin (OVA) challenge protocol
Except the rats in control group, other SD rats were made into AR model. The rats in experimental groups were sensitized by intraperitoneal injection of 0.9% sodium chloride solution (1 mL) and OVA (0.3 mg) as antigen and aluminium hydroxide 30 mg as adjuvant once every other day for 8 times. Then they were sensitized by nasal drip containing 0.25% OVA and 0.9% sodium chloride solution once a day for 7 days. The control group was intraperitoneally injected with normal saline, nasal drip and atomization using the same method as above.
Drug preparation and location of acupoints
Based on the agreement parties of the rehabilitation center of the Second Affiliated Hospital of Wenzhou Medical University for more than 20 years, the winter disease and summer treatment ointment was prepared. The ingredients of ointment were white mustard seed, asarum, Angelica dahurica, and Corydalis at 1:1:2:2. A total of 100 items of fine powder were studied. The ointment was prepared with ginger juice or honey, and sealed for preservation. The ointment in Prescription NO.1 acupoint application group was mixed with ginger juice, and in Prescription NO.2 acupoint application group, the ointment was mixed with honey. The acupoints applied were Dazhui, Fengmen (Shuang), Feishu (Shuang), Pishu (Shuang). Point Location of Common Laboratory Animals was used as a Reference Basis for Location. Dazhui acupoint is located between the 7th cervical vertebra and the 1st thoracic vertebra in the middle part of the back. The throttle is located between the ribs of the second thoracic vertebra. Feishu is located in the intercostal space under the third thoracic vertebra. Pishu is located in the intercostal space of the 12th thoracic vertebra.
Behavioral tests
To observe the changes of nasal symptoms in SD rats, symptoms were observed and scored after sensitization (before AAT) and after 7, 14 and 28 days of the AAT. The specific method was to administrate 5 uL of 0.25% OVA and 0.9% sodium chloride solution nasal drip into each side. The number of nasal rubbing, sneezing and the degree of runny nose (within 3 min) were observed and the symptoms were scored. Specific scoring criteria are listed in Table 1 (Chinese Medical Association Council of Otolaryngology, Editorial Committee of Chinese Journal of Otorhinolaryngology. Chinese standard of diagnosis and curative effect evaluation criteria of allergic rhinitis [J]. Chin J Otorhinolaryngol, 1998,33 (3): 134–135). The allergic rhinitis model was considered successful when the total score was more than 5 points.
Table 1 Scoring criteria for nasal symptoms
Acupoint application treatment
The application of acupoints was performed as mentioned above. Prescription No.1 was mixed with fresh Ginger Juice uniformly (1HG), and Prescription NO.2 was mixed with Honey uniformly (1HH). Rats in the control group (C group) were fed as usual. Rats in the model group (M group) were administrated 5 μl of OVA solution per nostril once a day. Rats in 1HG and 1HH groups were removed the hair on the back acupoints. In the 1HG group and 1HH group, isoflurane anesthesia was first used in rats, and then the ointment (0.5 cm × 0.5 cm) was applied at the acupoints for 1 h lasting for 28 days.
After removing nasal mucosa tissue, the protein was homogenized and then determined by BCA kit (Thermo Fisher Science, Inc., Waltham, MA, USA). Protein (10 μl) was separated by 12% SDS PAGE and transferred to PDVF membrane. It was sealed at room temperature for 2 h with 5% skimmed milk and incubated with corresponding primary and secondary antibodies. Finally, the film (Thermo Fisher Science, Inc., Waltham, MA, USA) was detected by ECL system and photographed.
Immunofluorescence staining
Nasal mucosa was fixed with 4% paraformaldehyde, and then dehydrated. After that, nasal mucosa was cut into sections (4 μm) following paraffin embedding. Slices were baked and dewaxed to water before incubated at room temperature with 3% hydrogen peroxide for 10 min. Subsequently, the slices were blocked in 10% goat serum and 0.3% Triton X-100 PBS solution for 1 h, followed by incubated overnight with corresponding antibodies (4 °C), and then IL-4 and IFN-gamma were double stained with mast cell markers. The primary antibodies and mast cell markers were rabbit anti-NGF (abcam, 1:100), rat anti-IL-4 (Santa, 1:200) and rabbit anti-Mast Cell Chymase (MCC, affinity, 1:100), rabbit anti-IFN-gamma (affinity, 1:100) and mouse anti-Mast Cell Tryptase (MCT, Santa, 1:200). The secondary antibody corresponds to the primary antibody. The nuclei were stained with DAPI. NGF, IL-4 and IFN-gamma positive cells in nasal mucosa sections were observed by fluorescence microscopy (FluoView FV1000, Olympus). Image Pro Plus 6 software (Media Cybernetics, Inc., Rockville, MD, USA) was used to analyze positive cells.
Quantitative real-time PCR (RT-qPCR)
Total RNA was extracted from nasal mucosa using Trizol (Takara, Tokyo, Japan) reagent. Genes were synthesized according to the instructions of the Bio-Rad kit. Then 1 μl of DNA was taken for polymerase chain reaction (PCR). GADPH was used to normalize based on CT value. All the primers were designed and synthesized by Shanghai Jierui Bioengineering Co., Ltd. The sequences of primers are shown in Table 2.
Table 2 Primers for polymerase chain reaction
Enzyme-linked immunosorbent assay (ELISA)
The levels of NGF, IL-4, IL-5, IL-13, IFN-gamma and IgE in serum of rats were determined by enzyme-linked immunosorbent assay (ELISA). At room temperature, samples and diluents were added to the pore, and biotin antibodies were added to the pore. After washing, HRP and chromogenic solution of biotin were added. Finally, the terminating solution is added. The absorbance (OD) of each pore was measured at the wavelength of 450 nm.
Hemotoxylin and eosin (H&E) staining and toluidine blue (TB) staining
H&E
Nasal mucosa was fixed with 4% paraformaldehyde, followed by dehydration and paraffin-embedding. After cut into sections (4 μm), the slices were baked before permeabilitization by xylene, dehydration by gradient alcohol, and dewaxing to water. Cells were stained by hematoxylin and eosin staining (Sigma Chemical Co.). Eosinophils were observed and counted. Double-blind and randomized analysis was performed.
The pretreatment steps of the slices are as described above. The slices are stained with TB staining solution. Mast cells were observed and counted under a microscope. Double-blind and randomized analysis was performed.
The original data were processed by SPSS 22.0 statistical software. The experimental results were expressed by X (+s) mean (+standard deviation), and all experimental data were analyzed by Graphpadprism 6 statistical software. LSD test was used for the comparison of homogeneous variance and Dunnett'T3 test for the comparison of uneven variance. Statistic with P value < 0.05 was considered as statistically significant.
Effect of AAT on ovalbumin-induced rhinitis symptoms
The number of sneezing, rubbing nose and the degree of runny nose were scored and recorded before and after 7, 14 and 28 days of AAT. The results showed that there were no obvious symptoms of rats in control group, and there was no significant difference in the scores of rats in each group on the 7th day after AAT (P > 0.05). After 14 and 28 days of application, the behavioral scores of both 1HG and 1HH groups were significantly lower than those of M group (P < 0.01). Compared with the 1HG group, the behavioral score of 1HH group was significantly higher (P < 0.05) (Tables 3 and 4) (Fig. 1).
Table 3 The number of nose sneezes that occurred 10 min after OVA intranasal provocation in AR rats before and 7 days, 14 days and 28 days after acupoint application
Table 4 The number of nose rubs that occurred 3 min after OVA intranasal provocation in AR rats before and 7 days, 14 days and 28 days after acupoint application
Effect of AAT on nasal symptoms in AR rats before and 7 days, 14 days and 28 days after acupoint application. Note: a The number of nose sneezes that occurred 10 min after OVA intranasal provocation; b The number of nose rubs that occurred 3 min after OVA intranasal provocation. The values represent the mean ± S.E.M (n = 10/group). Compared with M group, * P < 0.05, **P < 0.01,*** P < 0.001; compared with group 1HG, Significant differences # P < 0.05, ## P < 0.01, ### P < 0.001. AAT, Acupoint Application Therapy; AR, allergic rhinitis; OVA, ovalbumin; 1HH, prescription NO.2 mixed with Honey; 1HG, prescription NO.1 mixed with fresh Ginger Juice; M group, model group; C group, control group
Detection of NGF and its downstream IL-4, IL-5, IL-13 and IFN-gamma in nasal mucosa by western blotting
Compared with the control group, the expressions of NGF, IL-4, IL-5 and IL-13 in nasal mucosa of the model group increased significantly (P < 0.001, P < 0.01), while the expression of IFN-gamma increased slightly and failed to achieve any significant difference (P > 0.05). Compared with the model group, the expression of NGF, IL-4, IL-5 and IL-13 in nasal mucosa of the 1HG and 1HH groups decreased (P < 0.001, P < 0.01, P < 0.05), while the expression of IFN-gamma increased (P < 0.05). Compared with the 1HG group, the expression of NGF, IL-4, IL-5 and IL-13 in nasal mucosa of rats in 1HH group increased significantly (P < 0.05), while the expression of IFN-gamma decreased significantly (P < 0.05) (Fig. 2).
Effect of AAT on the expression of NGF, IL-4, IL-5, IL-13 and IFN-γ protein in nasal mucosa of AR rats. Note: a The protein level of NGF, IL-4, IL-5, IL-13 and IFN-γ was detected by western blot. b The protein level of NGF was detected by Western blot. c The protein level of IL-4 was detected by Western blot. d The protein level of IL-5 was detected by Western blot. e The protein level of IL-13 was detected by Western blot. f The protein level of IFN-γ was detected by Western blot. The values represent the mean ± S.E.M (n = 3/group). Compared with M group, *P < 0.05, **P < 0.01, ***P < 0.001; compared with 1HG group, Significant differences #P < 0.05, ## P < 0.01, ###P < 0.001; 1HH, prescription NO.2 mixed with Honey; 1HG, prescription NO.1 mixed with fresh Ginger Juice; M group, model group; C group, control group; AAT, Acupoint Application Therapy; AR, allergic rhinitis; NGF, nerve growth factor
Expression of cytokines and mast cells were detected by immunofluorescence technique
Compared with the control group, the positive spots of NGF and IL-4 protein in nasal mucosa of rats in model group increased significantly (P < 0.01, P < 0.05), but the positive spots of IFN-gamma protein did not increase significantly (P > 0.05). After 28 days of AAT, immunofluorescence results showed that the positive spots of NGF and IL-4 protein in nasal mucosa of rats in 1HG group and 1HH group significantly decreased compared with model group (P < 0.05). Compared with the 1HG group, the positive spots of NGF and IL-4 protein in nasal mucosa of 1HH group significantly increased (P < 0.05), while the positive spots of IFN-gamma protein significantly decreased (P < 0.05) (Fig. 3).
Effect of AAT on the expression of NGF、IL-4 and IFN-γ protein in nasal mucosa of AR rats. Note: a Effect of AAT on NGF protein expression in nasal mucosa with Olympus microscope. b The effects of Acupoint Application Therapy on mast cells localization of IL-4 with Olympus microscope. c The effects of Acupoint Application Therapy on mast cells localization of IFN-γ with Olympus microscope. The values represent the mean ± S.E.M (n = 3/group). Compared with M group, Significant differences *P < 0.05, **P < 0.01, ***P < 0.001; compared with 1HG group, Significant differences #P < 0.05, ##P < 0.01, ###P < 0.001; AAT, Acupoint Application Therapy; AR, allergic rhinitis; NGF, nerve growth factor; 1HH, prescription NO.2 mixed with Honey; 1HG, prescription NO.1 mixed with fresh Ginger Juice; M group, model group; C group, control group
Detection of cytokines and IgE gene expression in nasal mucosa by real-time fluorescence quantitative PCR
Compared with the control group, the expression of NGF, IL-4, IL-5, IL-13 and IgE mRNA in the model group increased (P < 0.001), while the expression of IFN-gamma mRNA increased slightly (P > 0.05). Compared with the model group, the expression of NGF, IL-4, IL-5, IL-13 and IgE mRNA in the nasal mucosa of rats in 1HG and 1HH groups decreased (P < 0.001, P < 0.01, P < 0.05), while the expression of IFN-gamma mRNA increased (P < 0.01, P < 0.05). Compared with the 1HG group, the expression of NGF, IL-4, IL-5, IL-13 and IgE mRNA in nasal mucosa of rats in 1HH group increased significantly (P < 0.001, P < 0.01), while the expression of IFN-gamma mRNA decreased significantly (P < 0.01) (Fig. 4).
Effect of AAT on the expression of NGF, IL-4, IL-5, IL-13, IgE and IFN-γ mRNA in nasal mucosa of AR rats. Note: a The mRNA level of NGF was detected by real-time qPCR. b The mRNA level of IL-4 was detected by real-time qPCR. c The mRNA level of IL-5 was detected by real-time qPCR. d The mRNA level of IL-13 was detected by real-time qPCR. e The mRNA level of IgE was detected by real-time qPCR. f The mRNA level of IFN-γ was detected by real-time qPCR. The values represent the mean ± S.E.M (n = 3/group). Compared with M group, Significant differences *P < 0.05, **P < 0.01, ***P < 0.001; compared with 1HG group, Significant differences #P < 0.05, ##P < 0.01, ###P < 0.001; AAT, Acupoint Application Therapy; AR, allergic rhinitis; NGF, nerve growth factor; qPCR, quantitative PCR; 1HH, prescription NO.2 mixed with Honey; 1HG, prescription NO.1 mixed with fresh Ginger Juice; M group, model group; C group, control group
The serum levels of cytokines and IgE in AR rats were detected by ELISA
Compared with the control group, the serum levels of NGF, IL-4, IL-5, IL-13 and IgE in the model group increased (P < 0.001), and the expression of IFN-gamma increased slightly (P > 0.05). Compared with the model group, the serum levels of NGF, IL-4, IL-5, IL-13 and IgE in the 1HG group and 1HH group decreased (P < 0.001, P < 0.01, P < 0.05), while the expression of IFN-gamma increased (P < 0.05). Compared with the 1HG group, the serum levels of NGF, IL-4, IL-5, IL-13 and IgE in 1HH group were significantly increased (P < 0.05), while the expression of IFN-gamma was decreased significantly (P < 0.05) (Fig. 5).
Effect of AAT on the expression of NGF, IL-4, IL-5, IL-13, IgE and IFN-γ in serum of AR rats. Note: a The serum level of NGF was detected by enzyme-linked immunosorbent assay (ELISA). b The serum level of IL-4 was detected by ELISA. c The serum level of IL-5 was detected by ELISA. d The serum level of IL-13 was detected by ELISA. e The serum level of IgE was detected by ELISA. f The serum level of IFN-γ was detected by ELISA. The values represent the mean ± S.E.M (n = 3/group). Compared with M group, Significant differences *P < 0.05, **P < 0.01, ***P < 0.001; compared with 1HG group, Significant differences #P < 0.05, ##P < 0.01, ###P < 0.001; AAT, Acupoint Application Therapy; NGF, nerve growth factor; ELISA, enzyme-linked immuno sorbent assay; 1HH, prescription NO.2 mixed with Honey; 1HG, prescription NO.1 mixed with fresh Ginger Juice; M group, model group; C group, control group
Pathological changes of nasal mucosa by H&E staining and the number and morphological changes of mast cells in nasal mucosa by TB staining
H&E staining
No obvious pathological changes were found in nasal mucosa of the control group. In model group, hyperemia, edema, gland hyperplasia, mucus secretion, tissue structure disorder and inflammatory cell infiltration appeared in nasal mucosa. After 28 days of AAT, the pathological degree of 1HG group and 1HH group were significantly reduced, and inflammatory cell infiltration was reduced. The pathological improvement degree in 1HG group was more obvious, and the number of inflammatory cells in nasal mucosa was the less.
TB staining
Mast cells were not found in the nasal mucosa of the control group, but a large number of purple-red mast cells were observed in the model group. After 28 days of treatment, the number of mast cells in both 1HH and 1HG groups decreased, especially in 1HG group (Fig. 6).
Effect of AAT on the proliferation of eosinophils and mast cells in nasal mucosa of AR rats
Note: a Nasal mucosa tissue was stained with H&E for eosinophils. Original magnification 400×, scale bar = 20 μm. b Nasal mucosa tissue was stained with TB for mast cells. Original magnification 400×, scale bar = 20 μm. The values represent the mean ± S.E.M (n = 3/group). Compared with M group, Significant differences *P < 0.05, **P < 0.01, ***P < 0.001; compared with 1HG group, Significant differences #P < 0.05, ##P < 0.01, ###P < 0.001; AAT, Acupoint Application Therapy; H&E,hematoxylin and eosin; TB, toluidine blue; 1HH, prescription NO.2 mixed with Honey; 1HG, prescription NO.1mixed with fresh Ginger Juice; M group, model group; C group, control group
In this paper, we demonstrated that AAT can alleviate allergic inflammation in rats with AR, and inhibit IgE allergic reaction by inhibiting the activation of NGF and reducing the production of inflammatory factors (such as IL-4, IL-5, etc.). These results reveal the mechanism of AAT in the treatment of AR. A previous study reported that the occurrence of AR is closely related to the activation of NGF and neuroimmunity [20].
The common pathogenesis of AR is the imbalance of Th1/Th2 cell immunity. The main manifestation of AR is inflammatory disease with Th2 reaction [21]. Th2 cells mainly secrete cytokines such as IL-4, IL-5 and IL-13, which mainly stimulate humoral immune response. Among those cytokines, IL-4 most closely associated with AR [22, 23]. TH1 cells mainly secrete IFN-gamma and mediate cellular immune response. IFN-gamma closely related to AR [24]. The cytokines secreted by TH2 cells can promote the production of IgE (by B cells). IgE binds to high affinity receptor Fc receptor (Fc epsilon RI) (appeared in mast cells and basophilic granulocyte surface) [25], which promotes the degranulation of mast cells [26], and induces not only the release of histamine, leukotriene and other bioactive mediators, but a variety of pathological reactions (such as increased secretion of smooth muscle contraction and glandular mucus, dilatation of capillaries and small vessels, and increased permeability of blood vessels), leading to the occurrence of AR [27]. From the behavioral point of view, the symptoms of AR rats are consistent with the pathological reaction. After acupoint application, the symptoms of AR rats were alleviated slightly or significantly, indicating that acupoint application is effective for AR treatment.
NGF also participates in this immune response. NGF not only maintains the survival of neurons [28], but also plays an extensive role in immune, reproductive and hematopoietic systems [29,30,31], and directly participates in the immune response [32]. It has been reported that the cells involved in immune response, such as eosinophils, CD4 + T cells, some B cells and mast cells, can also produce and release NGF [33, 34]. There are a large number of sensory nerve fibers in nasal epithelial cells, most of which are markers of nociceptors, including trpv-1 and trpa-1 [35]. TH2 cytokines, such as IL-5, can activate lung noxious neurons and secrete VIP, thus stimulating lymphocyte to produce airway allergic reaction. These lymphocytes can secrete cytokines such as IL-5 and aggregate into effectors. Immune cells enter the disease state and further activate the sensory organs [36]. NGF promotes the proliferation and accumulation of immune cells through the aforementioned activation channels, and induces immune cells to release various bioactive factors (such as IL-4, IL-13, IL-5, IFN-gamma), which leads to the aggravation of allergic inflammation. In addition, immune cells such as eosinophils, mast cells and basophils can synthesize large amounts of NGF and further release [37], thus forming a positive feedback immune response, aggravating the progress of allergic rhinitis.
From the results of Western blot and PCR in this study, AAT can inhibit the mRNA and protein expression levels of NGF, IL-4, IL-5, IL-13, and promote the protein and mRNA expression of IFN-gamma. These results suggested that AAT can inhibit the formation of NGF in nasal mucosa and the positive feedback loop induced by NGF, while reduce the levels of IL-4 and NGF in nasal mucosa through nerve immune pathway of NGF/IL-4, and improve allergic inflammation in AR rats. In addition, our results suggest that IL-4 and IFN-gamma are co-expressed with mast cells. Compared with the control group, the co-expression of IL-4 and mast cell marker (chymase) [38] in nasal mucosa of AR rats increased. The up-regulation of chymase is related to the activation of mast cells. The results showed that mast cells were activated after AR. After acupoint application, the co-expression of IL-4 and chymase in nasal mucosa was lower than that in AR rats, and the co-expression of IFN-gamma and tryptase [39] was significantly higher than that in model group. Therefore, AAT can alleviate allergic inflammation in AR rats by inhibiting the expression of IL-4 in mast cells of nasal mucosa and increasing the expression of IFN-gamma in mast cells.
The powder is composed of four traditional Chinese medicine drugs, white mustard seed, asarum, Angelica dahurica and corydalis. White mustard seed has anti-inflammatory effect [40]. Angelica dahurica has anti-inflammatory effect by inhibiting mast cell degranulation and histamine release [41]. Asarum has anti-immune and anti-allergic effects. Compared with honey group, ginger group had stronger stimulation intensity, less volatilization of local water, and water content in skin increased sharply, which enhanced aseptic inflammation of local skin and made drugs more easily absorbed [42]. Therefore, compared with 1HH group, the symptoms in 1HG group were more obvious, which could inhibit the production of NGF, IL-4, IL-5, IL-13 and promote the production of IFN-gamma.
Acupoint application therapy can improve the allergic inflammation response of AR rats by reducing the expression of NGF, IL-4, IL-13, IL-5 and IgE in nasal mucosa of AR rats and enhancing the expression of IFN-gamma. Moreover, ginger has a stronger therapeutic effect than honey.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Acupoint application
AR:
ELISA:
Enzyme-linked ImmunoSorbent Assay
HE:
Hematoxylin-Eosinstaining
IFN-gama:
Interferon-gama
IgE:
IL-13:
IL-4:
NGF:
Nerve growth factor
OVA:
PBS:
PFA:
Polymerisatum formaldehydum
PVDF:
Polyvinylidenedifluoride
SD:
SDS:
Sodiumdodecyl sulfate
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Yu S, Han B, Liu S, et al. Derp1-modified dendritic cells attenuate allergic inflammation by regulating the development of T helper type1(Th1)/Th2 cells and regulatory T cells in a murine model of allergic rhinitis. Mol Immunol. 2017;90:172–81.
Fouladi S, Masjedi M, Ghasemi R, Hakemi MG, Eskandari N. The in vitro impact of Glycyrrhizic acid on CD4+ T lymphocytes through OX40 receptor in the patients with allergic rhinitis. Inflammation. 2018;41:1690–701.
Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008;454:445–54.
Gelfand EW, Joetham A, Wang M, Takeda K, Schedel M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation. Immunol Rev. 2017;278:63–86.
Kakli HA, Riley TD. Allergic rhinitis. Prim Care. 2016;43:465–75.
Tao Feng ZBaHZ. The relationship between neurotrophic factors and respiratory allergic inflammation. J Southeast Univ (Medical Science Edition). 2007;26:322–5.
Park MJ, Kwak HJ, Lee HC, et al. Nerve growth factor induces endothelial cell invasion and cord formation by promoting matrix metalloproteinase-2 expression through the phosphatidylinositol 3-kinase/Akt signaling pathway and AP-2 transcription factor. J Biol Chem. 2007;282:30485–96.
Shushen BWQ. Immunological effects of nerve growth factor. Int J Immunol. 1995;4:219–20.
Triaca V, Aloe L. Neuronal markers expression of NGF-primed bone marrow cells (BMCs) transplanted in the brain of 6-hydroxydopamine and ibotenic acid lesioned littermate mice. Neurosci Lett. 2005;384:82–6.
Frossard N, Freund V, Advenier C. Nerve growth factor and its receptors in asthma and inflammation. Eur J Pharmacol. 2004;500:453–65.
Kobayashi H, Gleich GJ, Butterfield JH, Kita H. Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli. Blood. 2002;99:2214–20.
Raap U, Goltz C, Deneka N, et al. Brain-derived neurotrophic factor is increased in atopic dermatitis and modulates eosinophil functions compared with that seen in nonatopic subjects. J Allergy Clin Immunol. 2005;115:1268–75.
Trankner D, Hahne N, Sugino K, Hoon MA, Zuker C. Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways. Proc Natl Acad Sci U S A. 2014;111:11515–20.
Talbot S, Abdulnour RE, Burkett PR, et al. Silencing Nociceptor neurons reduces allergic airway inflammation. Neuron. 2015;87:341–54.
Xie Zhihai ZS, Chenglong W, Weihong J. Detection of NGF mRNA expression in nasal mucosa of allergic rhinitis patients. Chin J Otorhinolaryngol-skull Base Surg. 2005;06:374–7.
Le DD, Schmit D, Heck S, et al. Increase of mast cell-nerve association and neuropeptide receptor expression on mast cells in perennial allergic rhinitis. Neuroimmunomodulation. 2016;23:261–70.
Baba S, Kondo K, Suzukawa M, Ohta K, Yamasoba T. Distribution, subtype population, and IgE positivity of mast cells in chronic rhinosinusitis with nasal polyps. Ann Allergy Asthma Immunol. 2017;119:120–8.
Yang R, Zhou Q, Wen C, et al. Mustard seed (Sinapis Alba Linn) attenuates imiquimod-induced psoriasiform inflammation of BALB/c mice. J Dermatol. 2013;40:543–52.
Li D, Wu L. Coumarins from the roots of Angelica dahurica cause anti-allergic inflammation. Exp Ther Med. 2017;14:874–80.
Jinfei Z, Qimiao H, Wenci C, Sisi L, Songhe J. Clinical study of Sanjiu herbal patch on acupoints with different intensity on persistent allergic rhinitis. J Emerg Tradit Chin Med. 2016;25:236–238+247.
This research work was supported by the National Natural Science Foundation of China (No. 81873376), the Appropriate Technology Cultivation Project of Zhejiang Administration of Traditional Chinese Medicine (No.2014ZP005) and Basic Scientific Research Projects of Wenzhou Science and Technology Bureau (No.Y20180207,Y20160215).
the National Natural Science Foundation of China (No. 81873376), the Appropriate Technology Cultivation Project of Zhejiang Administration of Traditional Chinese Medicine (No.2014ZP005) and Basic Scientific Research Projects of Wenzhou Science and Technology Bureau (No.Y20180207,Y20160215).
Wenzhan Tu and Xiaolong Chen contributed equally to this work.
Department of Physical Medicine and Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Wenzhan Tu, Xiaolong Chen, Qiaoyun Wu, Xinwang Ying, Rong He, Guanhu Yang, Kecheng Zhou & Songhe Jiang
Integrative & Optimized Medicine Research Center, China-USA Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, 268 Xue Yuan Xi Road, Wenzhou City, Zhejiang, 325027, People's Republic of China
Wenzhan Tu, Xiaolong Chen, Qiaoyun Wu, Xinwang Ying, Rong He, Xinfa Lou, Guanhu Yang, Kecheng Zhou & Songhe Jiang
Wenzhan Tu
Xiaolong Chen
Qiaoyun Wu
Xinwang Ying
Rong He
Xinfa Lou
Guanhu Yang
Kecheng Zhou
Songhe Jiang
WT, GY, XL, KZ and SJ conceived and designed the analysis. XC, QW, XY and RH collected the data. XC, QW, XY and RH contributed data or analysis tools. XC, QW, XY and RH performed the analysis. XC wrote the paper. All authors read and approved the manuscript.
See information below the heading.
Correspondence to Kecheng Zhou or Songhe Jiang.
All procedures were approved by the Animal Care and Use Committee of The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University.
Tu, W., Chen, X., Wu, Q. et al. Acupoint application inhibits nerve growth factor and attenuates allergic inflammation in allergic rhinitis model rats. J Inflamm 17, 4 (2020). https://doi.org/10.1186/s12950-020-0236-9
Received: 03 September 2019
Accepted: 22 January 2020
Allergic inflammation
Mast cells

redpajama_set_name: RedPajamaCommonCrawl


text:
49"er Faire to help raise funds for…
49"er Faire to help raise funds for Centerville School roof: Butte Creek Canyon volunteers help make the improvements happen
PUBLISHED: June 1, 2006 at 12:00 a.m. | UPDATED: September 14, 2018 at 12:00 a.m.
BUTTE CREEK CANYON — As volunteers get preparations done for the 49"er Day Fair coming up Sunday in Butte Creek Canyon, Sonja Johnson keeps an eye on the Centerville Schoolhouse, where the frayed roof has apparently withstood its last rainy winter.
The annual 49"er Day Fair, set 9 a.m. to 4 p.m. at Centerville"s Colman Museum, is the Centerville Recreation and Historical Association"s main fundraiser. This year, volunteers who serve the historic canyon community know money brought in from the fair will have to go toward a new roof for the schoolhouse built in 1894.
The 38th annual 49"er Day Fair will be put on in conjunction with Honey Run Covered Bridge Association and Butte Creek Watershed Conservancy.
The Covered Bridge Association provides a pancake breakfast served on Honey Run Covered Bridge. The bridge, built in 1886, is the only three-level covered bridge in the United States.
Conservancy volunteers will conduct tours of the PG&E Centerville Power House and discuss the Butte County Resource Conservation District. The powerhouse had its beginnings in the late 1890s and today is the oldest still-running hydro-powerhouse in California.
Johnson has been involved with the Centerville Recreation and Historical Association for more than two decades. She has served as caretaker for the schoolhouse and the adjoining Colman Museum. She is now the museum"s acting curator.
She said it"s been a good year for getting projects done in Centerville, including building upkeep and putting in place displays within the buildings.
Twenty-year Butte Creek Canyon resident Rocky Niles has been spending his evenings painting the schoolhouse with a coat of yellow, white and brown paint. Owner of Corlin Paint, Niles has also donated the paint for the schoolhouse as well as offering paint supplies for Boy Scouts who have completed Eagle projects. Those projects include:
Matt Trueman put in a folding board display rack for posters and maps.
William Carlon installed knotty pine wall siding for the museum"s general store.
Jordan Keables created display areas for the PG&E Centerville Powerhouse.
Spencer Sorenson laid out a concrete walkway and landscaping at the school"s entrance.
Johnson has plans for more scout projects. "This has been a gold mine for us, otherwise we would never have gotten this done," she said Friday.
Johnson has also turned to the energies and talents of Chico State University students. She recruited students in Steve Stewart"s class in the geography and cartography department to help with brochures. Two years ago, students made a museum brochure and map; this year students created brochures that included the covered bridge and the schoolhouse. Also in the works are brochures on the canyon"s gold mining history and the story of the powerhouse.
Students in Steve Dennis" class in the recreation department may be taking on docent roles.
Weed control and other work on the grounds can be credited to the California Conservation Corps that also helps with fire control clearing and volunteering to assist during the fair.
"They make it possible that we can have a fair here," Johnson said. "They do cleanup, you name it."
But it will take more than volunteers to get a new roof on the old school. That will take about $12,000, Johnson said.
"Paradise Recreation District will put $3,000 toward it," said Johnson, but the rest will have to come from canyon fundraisers and donations.
The Centerville Recreation and Historical Association became part of the ridge recreation district when the association was formed in the mid-1970s, Johnson said. The association budgets about $3,500 a year to Centerville, she said.
Johnson said the school has seen three roofs in its lifetime, all still on the building.
Following sales last year of the cookbook "Making It With the Canyon Ladies," there was enough money to purchase laminate wood flooring for the little school. Installation came during a particularly wet winter and spring.
"Days after that was put in, the roof started leaking. All this time, we"ve been on borrowed time. It (the new roof) has to be done this summer," said Johnson.
49"er Faire is Sunday
See a living history lesson Sunday in Butte Creek Canyon as volunteer groups host a pancake breakfast, a free pioneer fair and celebration of the return of spring-run salmon.
Money raised from the 41st annual Honey Run pancake breakfast 7-11 a.m. will go to help maintain the Honey Run Covered Bridge and Park. The Butte County Sheriff"s cook wagon will serve pancakes, sausages, fresh fruit, orange juice and coffee. Cost is $6 per adult and $4 for children under 10.
The Pub Scouts will provide music and Smokey Bear will visit. A raffle will be held and guided nature hikes along Butte Creek are also planned. The bridge is 4.5 miles up Honey Run Road, off the Skyway in east Chico.
Centerville"s 49er Day Faire, 9 a.m. to 4 p.m., will feature fine arts and crafts, music, food, a plant sale, quilt display, displays in the Colman Museum, a country store, silent auction and raffle, and demonstrations on gold panning, blacksmithing and mountain man encampments. The museum is at 13548 Centerville Road.
The bands Coopers Bluff and Churn Creek Waters will perform. Authors Richard Burrell who has penned books on Ishi, and Lyn Bat with her new book on "Settlers and Indians in the Sierra Foothills," will be on hand. An antique toy collection by Caroline Burke will also be featured.
The Butte Creek Watershed Conservancy"s Spring-Run Celebration will be 10 a.m.-noon at the PG&E Centerville Power House. Information will be available on the completed Butte Creek Floodplain Management Plan and the Butte County Flood Mitigation Plan effort.
To get to Honey Run Covered Bridge, take the Skyway south of Chico to Honey Run Road.
To get to Centerville, continue past Honey Run Covered Bridge for five miles. The museum is just past the bridge that crosses Butte Creek. Expanded parking is available this year.
The PG&E Centerville Power House is just up the canyon from Centerville.


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text:
Q: Rubymine :: Git is not working, getting fatal: Could not read from remote repository Rubymine was working fine. I was able to perform all kind of git related operation using rubymine seamlessly. But suddenly its not working. When I want to pull its says:

fatal: Could not read from remote repository.

It also fails for all other read/write > operation.
But git is working fine in my machine. I mean I can push/pull using command line. But now working with rubymine.
I am using Mac.

A: First make sure that you can use git from command line. If you can then,
Go to settings -> Version Control -> Git
Select "SSH executable" -> Native

And then restart Rubymine.

A: Did you init a local git repository, into which this remote is supposed to be added?
Does your local directory have a .git folder?
Try git init...
Step 1 - Attempt adding you public key to Heroku
heroku keys:add ~/.ssh/id_rsa.pub
Step 2 - Generate a new set of SSH keys, then attempt the first step again
https://help.github.com/articles/generating-ssh-keys
Step 3 - Verify and/or modify your config file
vim ~/.ssh/config
Host heroku.com
Hostname heroku.com
Port 22
IdentitiesOnly yes
IdentityFile ~/.ssh/id_rsa    <--- Should be your public SSH key
TCPKeepAlive yes
User jsmith@gmail.com

Step 4 - Remove the heroku remote from git, the recreate the connection
Add the remote via heroku create will only be an option for new repositories. Be sure to delete your old repo that you originally attempted to create
$ git remote rm heroku
$ git heroku create

Step 5: Reinstall Heroku Toolkit
http://hayley.ws/2010/12/04/getting-jekyll-running.html

redpajama_set_name: RedPajamaStackExchange


Our philosophy has always been to look at things differently.We understand the positive effect a student loan can have on your life. It may give you peace of mind and independence, so the credit union always look at your whole story. We only propose student loans with realistic terms, which you can pay back in a way that works best for you.
We don't charge administration fees or transaction charges and you can pay back your student loan early without penalty, if that becomes an option. Remember, in your local credit union, you are not a customer, you are a valued member.
A credit union student loan can help you in many ways. For example whether it's to pay for registration fees, rent, books, course material or just living expenses. At this expensive stage in life, you'll find your local credit union is there to help you. Call in for a chat today and we'll soon have you sorted for the year ahead.
For most people, the transition into third level education is a major change. Whether you're living at home with your folks, in lodgings, an apartment or a house-share, student life means a whole new way of living. You have more choices to make – when to work, when to have fun, how to look after your money.
No matter what your student loan is for – from keeping you going day-to-day or THE "my studies come first" LOAN your credit union will ensure everything is clear, transparent and straightforward.
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We believe in investing in our members futures.


text:
* signup wizard.
* Settings section for the user(employer).
* Wizard for adding a company.
* Wizard for adding employee's.
* Element to calculate hours.
* Employee hour mode (let the employee fill in its own hours and send a accept request to the employer(optional)).
* Settings section for the company.
* Settings section for the employee's.

redpajama_set_name: RedPajamaGithub


Officials at both ends of Pennsylvania Avenue spent Wednesday exploring ways to keep a flood of red ink from engulfing the federal budget. At one end of this city's key thoroughfare, Rudolph G. Penner, director of the Congressional Budget Office (CBO), handed the Senate Budget Committee a report outlining 138 ways to cut the deficit. Included in the 276-page document were 98 spending-cut proposals and 40 tax-boosting methods.
''It is a complicated enough task so that we have to start work on it right away,'' Mr. Penner said. Major tax increases or spending cuts are needed ''just to avoid the possibility of explosive growth in interest'' on the debt, he added.
Meanwhile, negotiators from Capitol Hill and the White House were meeting at Blair House, an official guest residence across Pennsylvania Avenue from the White House. There, congressional and administration representatives began preliminary discussions on the three-year, $100 billion deficit reduction ''down payment'' that President Reagan called for in his State of the Union address.
Events at both ends of Washington show how difficult it will be to achieve meaningful reductions in the deficit in an election year.
When the meeting broke up, the negotiators had agreed that social security benefits would not be cut back this year. ''That is the only thing that has been taken off the table,'' says House majority leader Jim Wright (D) of Texas.
The Democrats proposed that the White House stretch out its military spending plan over an additional year to curb costs.
Senator Laxalt said the Republicans would study the proposal and had suggested almost $100 billion in other deficit-trimming action for the Democrats to consider.
The negotiators said they hoped to met again within two weeks.
But that makes the problem no less important to solve.
Penner says that the deficits must be reduced to keep interest payments on the federal debt from grabbing a growing share of the nation's income - which, according to CBO projections, is happening under current policies.
Such reductions won't be easy. Last year, Congress set a target: By fiscal 1986, it wanted to trim the deficit to 3 percent of the gross national product (GNP), the value of the nation's total output of goods and services. (The CBO's projection for fiscal '84 puts the deficit at 5.3 percent of GNP.) Penner said that if last year's target is extended to fiscal '87, it would require a $110 billion cut in that year's projected deficit. Bringing the deficit to 2 percent of the GNP, typical in the 1970s, would require an '87 deficit $160 billion lower than currently projected.
Lawmakers can attack major programs and still not come close to the 3-percent target. Penner noted that Congress would fall short of its goal even if it froze real growth in defense spending in 1985, skipped the 1985 cost-of-living adjustment in all indexed programs, repealed indexation of income taxes for inflation, and imposed a 1 percent national sales tax in 1987.
Despite the obstacles, however, ''our budgetary predicament requires that we make difficult choices and search for the least damaging package of deficit-reduction options that can command majority support,'' Penner said.
Tax VOX Are low interest rates masking the deficit?


text:
Le Ballon est un tableau attribué à Francisco de Goya (1748–1828), conservé au musée des Beaux-Arts d'Agen, dans le département de Lot-et-Garonne.

Cette huile sur toile, peinte autour de 1812-1816, peut-être par un élève, représente une montgolfière survolant des observateurs dans un paysage montagneux.

Liens externes

 https://www.gazette-drouot.com/article/goya-revu-et-corrige-a-agen/12463

Tableau de Francisco de Goya
Tableau réalisé en 1816
Aéronef dans la peinture
Cheval dans la peinture
Montagne dans la peinture
Culture en Lot-et-Garonne
Agen

redpajama_set_name: RedPajamaWikipedia


text:
Executive Development @ Mason's School of Business
Start your journey as a Chief Marketing Officer
Learn the frameworks, insights, and content you need to effectively orchestrate your organization for impact.
Participants who complete this two-month program will be equipped for a leadership role in marketing. The program curriculum includes CMO role definition with requisite skills, talent, and models, creating a systemic approach to deliver change and growth. New approaches to value creation, OMNI channel, ethics, and intimacy are highlighted in a foundation grounded in marketing fundamentals of strategy, brand, digital, and data analytics. To equip you for effective C-suite participation, topics such as stakeholder management, inclusion and diversity, ESG, and change management are also be incorporated.
The ideal candidate has:
Four to six years of experience in middle to upper management with demonstrated organizational leadership experience.
Working knowledge of business and experience designing and implementing marketing strategies.
Solid communications skills.
An undergraduate degree or equivalent experience.
In-Person Opening October 19-21, 2022
Online Sessions October 27-December 19, 2022
Mid-Program In-Person Session January 9-10, 2023
Online Sessions January 12-March 2, 2023
In-Person Closing March 8-9, 2023
Business and Financial Acumen: 25%
Strategic Mindset for the CMO: 25%
Stakeholder Management: 25%
Data and Metrics-informed Decision Making: 25%
Graduates of this program will be able to:
Develop, in concert with senior leadership, a comprehensive strategic marketing plan with a mission, vision, and measurable goals that are fully aligned with the organization.
Effectively and efficiently execute the strategic marketing plan for organizational growth.
Build the necessary infrastructure to integrate marketing data and metrics into business.
Executive an effective CRM strategy while balancing consumer needs for privacy.
Manage stakeholder aspirations regarding diversity, ethics, and inclusions from the organization.
Engage the organization's leadership team in support of marketing initiatives at the enterprise level.
Lead the marketing function to succeed in the world of Marketing 5.0
Badge of Certification
This program is delivered as a non-degree, School of Business executive certificate. Attendees have the opportunity to add a badge credential from Credly for successful completion of the program to their resume for organizational recognition (internal and external) and to indicate the accomplishment of obtaining a George Mason University credential.
Dates: Coming Soon!
Delivery: Hybrid; online sessions and in-person sessions at Mason Square (formerly the Arlington Campus)
Contact us to schedule an advising session:
Email ❭
(703) 993-8257 ❭
Russell Abratt
Professor, Marketing
Russell Abratt is a professor within the Marketing Area in the School of Business at George Mason University.
Bev Burgess
Founder and Managing Principal, Inflexion Group
Bev Burgess is passionate about the critical role marketing can play in accelerating business growth.
Jim Gerace
Former Marketing Executive, IBM
Jim Gerace has been in Marketing for over 30 years, the last 24 of which were spent at IBM in various Marketing roles.
Emily Goodson
Founder and CEO, CultureSmart
With years of experience building inclusive and supportive workplaces, Emily Goodson's expertise centers on how successful organizations are structured to be more human-focused—highlighting the similarities that unite us through our various forms of diversity and adversity.
Laura Naramore
Executive Director, The MITRE Corporation
Laura Naramore is a positive, pragmatic strategist and program leader with track record of performance gains in B2B activity across a variety of domains, political contexts and market dynamics.
Virginia Sharma
Marketing Head, Google Cloud India
Virginia Sharma is the Marketing Head at Google Cloud India. She is recognized for industry thought leadership and leading highly engaged, high-performance, cross-functional teams.
Katharyn M. White
Vice President, Federal Ecosystem, IBM
A native Arlingtonian, Katharyn Mountain White has lived in five countries and seven states, to return to a house two doors from where she grew up.
Are faculty from George Mason University?
A combination of Mason faculty, adjuncts, and subject matter experts teach in the program.
How was the curriculum created and courses chosen?
An advisory council of professionals at the c-suite level help George Mason University develop the program curricula, which is dynamic and changes based on feedback and emerging practices.
Is this program eligible under the GI Bill?
Not at this time.
Are there any discounts to attend the program?
Preferred pricing for government employees is $7,650. A promotional code will be provided to those accepted into the program. Please call (703) 993-8275 if you are a Mason employee or would like to discuss a group rate.
What does the cost of the program include?
The $8,500 program cost includes all materials, activities, catering, receptions, and a certificate of completion.
How do I register and pay for the program?
You must first submit an online application. Once accepted into the program, you will be provided directions on how to register and pay.
How much time will participants need to devote to the program?
Participants should expect to spend six full days at the George Mason University Arlington Campus as well as participating in 5-6 online topics delivered in two-week increments. For each two-week topic there will be approximately 8-10 hours of learning including readings, videos, video presentations, live sessions, discussion boards, and assignments.
How are the courses conducted?
As a hybrid program, topics are covered during two multi-day in-person sessions and online.
There are six in-person days and approximately four months of online delivery.
Online topics include a combination of asynchronous components such as discussion boards, presentations, videos, and assignments, as well as live synchronous sessions. Expect one to three scheduled live sessions for each online topic. These generally start between 7 and 8 p.m. ET. Live sessions are recorded and posted the next day.
Zoom or Blackboard Collaborate is used for live online sessions. A tutorial is provided to participants in pdf form, and an optional live tutorial session is offered as well. All registered participants are given access to Blackboard approximately two weeks prior to the start of the program.
Do I get university credit for this program? Will I be graded?
This is a non-credit executive development program so you will not earn university credit. However, CEUs (continuing education units) authorized by George Mason University are available upon request. At least two weeks prior to the start of the program, please send your request to execdev@gmu.edu. You will be asked to provide additional personal information in order to have your CEUs properly recorded.
Participants will not be graded, but In order to receive a certificate of completion, participants will need to complete a minimum of 80 percent of the work assigned (including assignments, deliverables, discussion boards, and live sessions). At the end of each topic, faculty are asked to provide a summary of participant's engagement.
How many participants are enrolled?
The maximum number of participants for a single cohort is 20.
What are some common student personas/backgrounds/job titles?
Most participants have at least six years of management experience and are at the Director level or above. Approximately half of the participants have been from the public/non-profit sector and half from the private sector. The average age of participants is 45.
Is there an application deadline?
No. Participants are admitted on a rolling basis up to the start of the program or until the cohort is full.


David: Hello, and welcome to all our new readers, and a fond hello to all our regular readers as well. Today we have a short film called Vesper, sent to us by director Keyvan Sheikhalishahi. The short stars Götz Otto, Agnès Godey, and Keyvan Sheikhalishahi. The film is in French, subtitled in English. We follow a relationship between Marge and Walter, and nephew Christian gets involved in a tangled web of lies and suffering.
Shannon, what was your initial impression of Vesper?
Shannon: My first impression was that I was really confused. I'm not blaming the film here, I'm pretty sure it was my internet connection, but the subtitles were about 2 minutes off from when the people we speaking. So it was hard to tell who was saying what. Even though this was the case, I still pretty much got some of the gist of what was going on. Marge and Walter have a strange relationship and Marge seems terrified of him. But as much as she wants him to go away, he is always there.
David, I'm hoping that you have a better understanding of the movie. Am I way off on this? Also, what do you think they are talking about when the "stars haunt you"? I have an idea, but am curious what you think.
David: Ok, so my subtitles seemed fine, but even I was a little confused. I think there is an element of the paranormal, or at least something Twin Peaks-esque going on here. There is a lot of repeated shots and dialogue that seem to point to a larger story than we are getting. Marge seems to be forgetting something from her past, which is haunting her. The only memory she has of that night is of the stars. Hence "the stars haunt you" line from Walter.
However, this gets more complicated, because what Walter says doesn't seem to have come to fruition, as we learn in the final shot of the film. It's possible that Walter has an additional agenda - is he some kind of demon? A ghost figure? An alien? All of that is left unsaid, possibly because we are to try and figure out a larger story on our own.
Considering that Keyvan is a younger filmmaker, you can see some small mistakes that are attempts to be more artsy. I thought the story itself was fine, if lacking a bit in conclusion. But there are a few camera shots - in particular one on the beach where the camera does a full spin - that leave a lot to be desired. Did anything about the camerawork or the direction stick out for you?
Shannon: I wouldn't say that anything about the camerawork stuck on in my opinion. I do know what you mean about the scene at the beach. Typically, I don't like when the camera spins around like that. For the same reason I don't usually like "found footage" films, but I think it worked well in the scene regardless.
I had the same thoughts about who Walter really was. For most of the film I thought he was a ghost, but then why would her nephew go see him? Perhaps she is schizophrenic?
Speaking of the beach scene, I had a couple thoughts on that. Them walking out towards the ocean was super long. Do they have huge beaches in France? Also, I'm sorry to say, but that crying and screaming was just awful to watch by the nephew. What did you think about the acting, David?
David: Oh I liked the schizophrenic idea - that's something I hadn't really thought of. Maybe Walter is her psychiatrist?
They do have large beaches in France. Think Normandy and D-Day (free history lesson and geography lesson here at DFP!). I thought the acting was a mixed bag. It's obvious that Otto is the most experienced actor, because he brought a menace and a suspicious thrilling air to his lines. I do agree with your sentiment that the wailing could probably have gotten better - I'm also curious as to why he was like that in the light, and why he took so long to put his extra glasses on?
And if he's super sensitive to light… why was he standing outside in the sun at the end??? It kind of reminds me a bit of the movie Kosmos that we watched, where there are a lot of open-ended characters to possibly be developed into a further story.
Can you think of any other comparisons that we have watched?
Shannon: As far as the characters, I don't think so. Nothing comes to mind anyway. But Kosmos is a good comparison for the film altogether. I feel like the whole stars aspect of it really makes that comparison for me, because they are there but you aren't 100% sure why.
I agree with you about Otto, he definitely brought the creepy factor to the screen like he was some sort of stalker to Marge. Is there anything else you'd like to touch on about VESPER?
David: No, I'm pretty happy to tie this one up in a bow. Through I enjoyed pieces of the film, I thought overall it was fairly average and needed a bit of polishing. I'm going to give it a "C-". What is your grade Shannon?
Shannon: I think I'm going to say it's "okay" as far as my rating goes. There wasn't anything terrible about it, other than the fact that I had so many questions throughout and even after it was over, but I too enjoy pieces of the film. Particularly Walter. (2.5/5).
Thank you to the director for reaching out to watch this film!


President Noynoy Aquino frowns on holiday economics. Does this mean that we're saying goodbye to extended weekends?
Former President Gloria Macapagal Arroyo signed this Republic Act 9492 which is known as "An Act Rationalizing the Celebration of National Holidays". That's moving of the celebration of holidays to the nearest Mondays to encourage tourism in the Philippines.
A lot of people rejoiced to this. Especially those who doesn't have to work on holidays (that doesn't include call center agents like me and people who works in the malls :D). Students and teachers and government employees like this RA for sure since they have to spend longer weekends with their family and friends.
They are yet to review the holiday economics. He said that PNoy is just not happy about June 12 (The Philippine Independence Day) being moved on a different day because for him, it's a sacred day.
Call center agents like me are actually looking forward to holidays since we get to enjoy double pays. No holidays for us unless our rest days fall on a holiday. But if we're asked to render overtimes during our rest days, we would more likely to report to work since we will be able to get higher pay for just a day.
But if we talk about nationalism, it's better that we celebrate holidays on the day that it's supposed to be celebrated. That's my stand. Yeah, I'm a bit nationalistic.
Well, I hope they could come up with a good decision for the betterment of our nation.
What about you? Do you like the holiday economics? Or would you rather celebrate holidays on the exact same days?
I'm for the holiday economics.
For someone who had spent ten hours a day working (thank God I now just stay at home and have holidays everyday), a long weekend is such a reprieve - especially if you have your family in the province that you can only see on weekends.
Every worker looks forward to holidays. Kahit ano pa ang dahilan, kahit ano pa ang okasyon. I know, this doesn't sound nationalistic enough but I think it's a fact of life that when you barely have the time to enjoy life because of too much work and stress, sometimes, being nationalistic goes out of the window.


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Los Angeles Capital Management LLC Decreases Stock Holdings in Atlanticus Holdings Co. (NASDAQ:ATLC)
Los Angeles Capital Management LLC trimmed its holdings in Atlanticus Holdings Co. (NASDAQ:ATLC – Get Rating) by 6.5% during the third quarter, according to its most recent 13F filing with the Securities and Exchange Commission (SEC). The institutional investor owned 43,361 shares of the credit services provider's stock after selling 3,019 shares during the quarter. Los Angeles Capital Management LLC owned about 0.30% of Atlanticus worth $1,137,000 as of its most recent SEC filing.
A number of other institutional investors have also bought and sold shares of ATLC. Brandywine Global Investment Management LLC purchased a new position in Atlanticus in the 2nd quarter worth approximately $670,000. Arrowstreet Capital Limited Partnership acquired a new stake in shares of Atlanticus during the 1st quarter worth approximately $715,000. Invesco Ltd. increased its holdings in shares of Atlanticus by 105.0% during the 1st quarter. Invesco Ltd. now owns 18,845 shares of the credit services provider's stock worth $976,000 after buying an additional 9,652 shares during the last quarter. Sawtooth Solutions LLC acquired a new stake in shares of Atlanticus during the 3rd quarter worth approximately $227,000. Finally, Massachusetts Financial Services Co. MA acquired a new stake in shares of Atlanticus during the 2nd quarter worth approximately $281,000.
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A number of analysts have recently issued reports on the stock. JMP Securities cut their price target on shares of Atlanticus from $50.00 to $42.00 and set a "market outperform" rating for the company in a report on Friday, January 13th. StockNews.com assumed coverage on shares of Atlanticus in a report on Wednesday, October 12th. They set a "buy" rating for the company. Finally, B. Riley restated a "buy" rating and set a $50.00 price target on shares of Atlanticus in a report on Friday, October 7th.
Insider Activity at Atlanticus
In other Atlanticus news, Director Deal W. Hudson sold 16,313 shares of the firm's stock in a transaction that occurred on Friday, January 20th. The shares were sold at an average price of $30.65, for a total value of $499,993.45. Following the completion of the transaction, the director now owns 75,452 shares of the company's stock, valued at approximately $2,312,603.80. The sale was disclosed in a filing with the Securities & Exchange Commission, which is accessible through this link. In other Atlanticus news, Chairman David G. Hanna purchased 325,000 shares of the firm's stock in a transaction on Wednesday, December 7th. The stock was bought at an average price of $27.15 per share, with a total value of $8,823,750.00. Following the transaction, the chairman now directly owns 325,000 shares of the company's stock, valued at approximately $8,823,750. The purchase was disclosed in a legal filing with the Securities & Exchange Commission, which can be accessed through this link. Also, Director Deal W. Hudson sold 16,313 shares of the firm's stock in a transaction that occurred on Friday, January 20th. The shares were sold at an average price of $30.65, for a total transaction of $499,993.45. Following the completion of the transaction, the director now directly owns 75,452 shares of the company's stock, valued at approximately $2,312,603.80. The disclosure for this sale can be found here. 53.50% of the stock is owned by insiders.
Atlanticus Stock Down 0.0 %
Atlanticus stock opened at $30.64 on Tuesday. Atlanticus Holdings Co. has a fifty-two week low of $23.15 and a fifty-two week high of $72.38. The company has a debt-to-equity ratio of 0.47, a quick ratio of 1.39 and a current ratio of 1.39. The firm has a 50 day moving average price of $27.42 and a 200 day moving average price of $30.06. The company has a market capitalization of $442.59 million, a PE ratio of 4.40 and a beta of 1.64.
Atlanticus (NASDAQ:ATLC – Get Rating) last posted its earnings results on Tuesday, November 8th. The credit services provider reported $1.41 earnings per share for the quarter, beating the consensus estimate of $1.40 by $0.01. Atlanticus had a net margin of 16.24% and a return on equity of 55.90%. The firm had revenue of $277.87 million during the quarter, compared to the consensus estimate of $292.80 million. Research analysts expect that Atlanticus Holdings Co. will post 6.35 earnings per share for the current year.
Atlanticus Profile
Atlanticus Holdings Corporation provides credit and related financial services and products to customers the United States. It operates in two segments, Credit as a Service, and Auto Finance. The Credit as a Service segment originates a range of consumer loan products, such as private label and general purpose credit cards originated by lenders through various channels, including retail and healthcare, direct mail solicitation, digital marketing, and partnerships with third parties; and offers credit to their customers for the purchase of various goods and services, including consumer electronics, furniture, elective medical procedures, healthcare, educational services, and home-improvements by partnering with retailers and service providers.
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Stephens Inc. AR Has $356,000 Position in Honda Motor Co., Ltd. (NYSE:HMC)
Los Angeles Capital Management LLC Acquires 1,529 Shares of Tractor Supply (NASDAQ:TSCO)
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Godzilla (ゴジラ Gojira) este un film SF Kaijū japonez din 1954 regizat de Ishirō Honda pentru compania Toho. În rolurile principale joacă actorii Akira Takarada, Momoko Kôchi, Takashi Shimura.

Prezentare
Din cauza testelor americane cu bombe nucleare apare o creatură de neoprit, o bestie cu aspect de dinozaur. Aceasta transformă orașul Tokyo în ruine.

Actori
 Akira Takarada este
 Momoko Kōchi este
 Akihiko Hirata este
 Takashi Shimura este
 Fuyuki Murakami este
 Sachio Sakai este  (Journalist)
 Ren Yamamoto este  (fisherman)
 Toyoaki Suzuki este Shinkichi (Masaji's younger brother)
 Tsuruko Umano este Shinkichi's mother
 Tadashi Okabe este Assistant of Dr. Tanabe
 Jiro Mitsuaki este Employee of Nankai Salvage Company
 Ren Imaizumi este Radio Officer Nankai Salvage Company
 Kenji Sahara este Partygoer
 Sokichi Maki este Chief at Maritime Safety Agency
 Haruo Nakajima este Godzilla & un reporter
 Katsumi Tezuka este Godzilla (ca dublura lui Nakajima) & Editor Yamada

Fișa tehnică
 Regia: Ishirō Honda
 Producător: Tomoyuki Tanaka
 Scenariști: Shigeru Kayama, Ishirō Honda, Takeo Murata
 Rolurile principale:
 Akira Takarada
 Momoko Kōchi
 Akihiko Hirata
 Takashi Shimura
 Haruo Nakajima
 Katsumi Tezuka
 Coloana sonoră: Akira Ifukube
 Distribuitor:	Toho
 Premiera 3 noiembrie 1954,  Japonia
 Durata: 98 min.
 Țara:  Japonia
 Limba: japoneză
 Buget: 1.000.000 dolari americani

Note

Legături externe

 Criterion Collection Essay "Godzilla: Poetry After the A-Bomb" by J. Hoberman"
 G,history(Japan)

 G-FAN Magazine
 Monster Zero News

Filme din 1954
Filme japoneze
Filme în limba japoneză
Filme regizate de Ishirō Honda
Filme SF din anii 1950
Filme SF de groază
Filme de groază din anii 1950
Filme cu Godzilla
Filme cu acțiunea în Tokyo
Filme Toho
Filme cu holocaust nuclear


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Precision Pumping Systems Helps Feedlot Feed Millions
Precision Pumping Systems helped Simplot develop a water and wastewater regulation system for one of the largest feedlots in the United States.
InduSoft Web Studio was used to create a water/wastewater regulation system for a 600 acre feedlot.
The application monitors levels, pressures, flows, and pump status. It also allows users to adjust the process set points in the PLCs in all locations.
Simplot reduced power consumption from 30% to 70% depending on the time of day and the current weather conditions. Water requirements of the lot have been reduced by as much as 90%.
Figure 1: The main screen allows operators to view the status of each well individually.
The United States is a major exporter of food, particularly beef. Feedlots, like the Simplot Land and Livestock feedlot in Grandview, Idaho is where much of the livestock within the United States is finished for domestic use and export. At the feedlot, cattle and other livestock are brought up to the proper weight for slaughter. Weight based pricing formulas are generally used to determine the worth of livestock when they are sold from the lot, meaning that ensuring the health of the animals will help a feedlot keep acceptable profit margins.
With so many animals to feed, shelter, and provide water for, it's no surprise that feedlots have some rigorous requirements that must be met, particularly in regulating the water and wastewater of the facility. The Clean Water Act, under the authority of the EPA (Environmental Protection Agency) regulates all animal feeding operations in the United States. Feedlots require large amounts of safe, clean water for the livestock on site. In addition, depending on the season, the number of livestock present on a lot can change dramatically from one month to the next, necessitating careful allocation of resources so that there is less waste of the available water in the times where fewer cattle are being kept.
The Simplot Land and Cattle Feedlot is a 600 acre commercial livestock facility in Grand View, which is located only 60 miles southwest of Boise. Grand View hosts the largest holding capacity for livestock within the United States, with upward capacity of over 150,000 head of cattle. Feed can be distributed to pens holding anywhere from 100 to 1000 head of cattle. The temperature of the area is moderate throughout the year, and the site is protected by natural rimrock, making it an ideal location for this enterprise.
In order to help regulate water use and help automate other things like dust control pumping and cattle cooling, Simplot contacted Precision Pumping Systems in Boise, Idaho. Precision Pumping Systems chose InduSoft Web Studio as the ideal SCADA software solution in monitoring this facility. Thanks to previous experience with InduSoft, PPS( Precision Pumping Systems) was assured a quick and easy development of the application, and a seamless connection with the hardware used for the site.
The feedlot presented some unique challenges for Precision Pumping Systems. Depending on the market environment, the site may house as many as 130,000 head of livestock at one time. During periods of low demand, there may be fewer than 40,000. This huge variation in head of cattle means that water requirements throughout the year may shift in correlation to the current capacity of the lot. With temperatures ranging from zero to 106, the water requirements of the animals also vary by current temperatures. Because of animal waste controls, no water may be discharged from the site, making it critical not to expend more water than necessary during operations.
In addition, Simplot needed a reliable water recycling option to further eliminate waste. The efforts in the water pumping system designed by PPS had to be highly coordinated and automated for maximum efficiency. The system also had to be flexible enough to accommodating the shifting patterns of livestock needs and weather.
Before Simplot contacted PPS, the site was allowed to discharge excess water, and the wells were run at all times using manual coordination. Simplot needed a new system that would eliminate this discharge, save water, labor, and power use. Precision Pumping Systems was able to meet all these requirements using an application developed in InduSoft Web Studio v7.0.
Figure 2: The well screen gives users detailed well information, from well levels to system pressure.
The application developed for the feedlot monitors and controls a wide variety of equipment. PPS also configured the InduSoft Web Studio application with a wireless LAN connection that offers Simplot control and monitoring of everything from the main pond pump system to the remote wells and turbine pumps. The application developed by PPS monitors levels, pressures, flows, and pump status. It also allows users to adjust the process set points in the PLCs in all locations. Fault conditions from the sites are recorded in the log and sent through text message or email to the system operators.
The application was developed using the latest version of InduSoft, and is installed on a PC running Windows XP. This PC is located within the pond pump station panel, for easy access. The application communicates with the pond pump PLC through a serial connection, and uses a wireless Ethernet network using the Modbus TCP protocol to communicate with the remote PLCs in the remote wells and storage tank control panels.
This complex system monitors and controls a large network of equipment. The main pond pump site, where the PC with InduSoft resides, has a three million gallon water storage reservoir. The main pond system includes two 100 horsepower turbine pumps, a 75 horsepower turbine pump, a three inch dump valve, a six inch pressure reducing valve (PRV), a chlorination injector, three flow meters, and two pressure transducers. The remote storage tank is a mile and a half away, and must be monitored for level and flow. The six remote wells all include monitor pressure transducers, well level transducers, flow meters, cabinet temperature sensors, and VFD motor controllers. The remote turbine must be monitored, along with two turbine pumps, a pressure transducer, flow meters, cabinet temperature transducers, and VFD motor controllers.
Without control and oversight of these critical indicators, it would not be possible to regulate water flow, power use, or pump status with the degree of finesse required for such a large operation.
Figure 3: Users can view the status of the pond pump station and adjust the PLC setpoints from the screen.
All the components used for the pumping system developed by PPS, as well as the wireless equipment and application were all shop-tested. When installed onsite, the process worked almost flawlessly, allowing Simplot to quickly take control of their process monitoring. Simplot was very involved in all aspects of the project, from the mechanical architecture, to the design and decision making aspects. As a result, both Simplot and Precision Pumping Systems are proud to showcase this HMI/SCADA solution.
The benefits of this system have been huge. Simplot was able to reduce power consumption by anywhere between 30% and 70% depending on the time of day and the current weather conditions. The water requirements of the lot have been reduced by as much as a staggering 90%, and there is no longer any water discharge.
Precision Pumping Systems has gone on to work with new projects utilizing the InduSoft Web Studio SCADA/HMI software solution, and are currently working on a project with the software now. Simplot continues to grow and expand, thanks to the huge difference the control of their operation has made in terms of energy and water savings.
Figure 4: The user log screen records all changes, and which operator made them.
For more information contact your local distributor or InduSoft directly at
info@indusoft.com or 877-INDUSOFT (877-463-8763) or 512-349-0334.
Precision Pumping Systems Helps Feedlot Feed Millions English
Precision Pumping Systems verhilft zu mehr Effizienz in der Rinderhaltung Deutsch


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A paradise in Greece this quaint island is a delight and an escape from the masses.
Carmen, and her local guide, Unal take us to a few must-see sights in Istanbul.
Carmen shows us some of the famed and traditional local spots.
Athens is huge! Today we take a guided tour with a local to see what not to miss.
When you visit Pompeii the sheer size of the city will surprise you, what's left of it will astound you.
Legendary filmmaker Oliver Stone talks about his latest work and constant passion – emerging filmmakers.