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In the theory system of traditional Chinese medicine (TCM), the condition of the body is a subtle harmony of yin and yang. An imbalance of yin and yang leads to abnormal conditions of the body. To be exact, it is diagnosed as heat-deficiency symptom, when the body is deficiency of yin, leading to an apparent excess of yang, and mild but very specific heat symptoms appear such as constipation and hectic fever; it is diagnosed as cold-deficiency symptom, when the body is deficiency of yang, resulting in an apparent excess of yin, leading to various symptoms such as cold limbs and hypoactivity [1].
Four properties of TCM referred to cold, cool, hot and warm, are often applied to describe the efficacy of TCM. Generally speaking, herbs with the cold or cool property are deemed to clear away heat, eliminate toxic substances, nourish yin, and remedy hot syndromes [2], including Anemarrhenae Rhizoma (Zhi-mu in TCM, cold property, ZM), the rhizome of Anemarrhenae asphodeloides Bge., which are generally used to cure heat-deficiency syndrome [3-4]. In contrast, herbs with the hot or warm property usually dispel cold, warm up the interior, support yang, and thus treat cold syndromes, such as Aconiti Lateralis Radix Praeparaia(Fu-zi in Chinese, hot property, FZ), the root of Aconitum carmichaelii Debx, which could be used in the treatment of cold-deficiency syndrome [5-6].
There also is a special kind of TCM property defined as "flat", of which the cold and heat boundary is not obvious [7], but the understanding of "flat" property remains unclear. Since the increasing use of drugs with "flat" property in the clinic, the study of "flat" property is recently taken more seriously. Poria (Fuling in Chinese, FL) is dry sclerotia of fungus Poria cocos (Schw.) Wolf, whose property is recorded as "flat" in Chinese Pharmacopoeia [8] and has been regarded as "flat and warm" based on textual research of FL[9]. The main efficacy of FL is clearing damp and promoting diuresis, which has been verified in experimental studies [10-11]. Clinically, FL is utilized extensively in prescriptions to cure syndrome of internal stagnation of fluid-dampness [12-13]. However, at present, there is a tendency to desalinate the drug property of FL in clinical practice. Therefore, the present study was carried out to explore the property of FL and provide an experimental basis for the clinical application of FL.
Recent studies have revealed that the property of drug is mainly concerned with the body's energy and substance metabolism by different pathways [14-15]. It has also been confirmed that some hot (or warm) drugs could improve the body's basal metabolic rate or excite endocrine system and central nervous system [16-18], providing a new way to explore the efficacy of TCM. Our study was mainly focused on the relationships between drug property, drug efficacy, energy metabolism, and substance metabolism [19-20] and aimed to evaluate the drug property of FL. Both cold-deficiency model and heat-deficiency model built by classical modeling methods [21-22] were adopted using FZ (hot property) and ZM (cold property) as the reference drugs, respectively.
Several indices correlated with substance metabolism and energy metabolism, endocrine system, nervous system and cyclic nucleotide system, together with appearance score, toe and rectal temperatures, were determined in the rat models of cold-deficiency and heat-deficiency syndromes, respectively, and PCA method was employed to generate an overview for group clustering of all the index data to attribute the drug property. Then the specialty and tendency of the effects were analyzed to explore the drug property of FL. Drug property was considered as trending to "hot or warm" since the drug reversed index changes in cold-deficiency model and had the same trend of effects as FZ, while was regarded as trending to "cold or cool" property if the drug reversed index changes in heat-deficiency model and showed the same trend of effects as ZM.
The present study provided a new way to adopt both cold-deficiency model and heat-deficiency model to explore the property of "flat" drugs, although a comprehensive system and effective ways remain to be established to interpret the scientific connotation of drug properties of TCM in the future.Materials and Methods Instruments, chemicals, and reagents
TDZ4-WS low speed centrifuge was purchased from Xiangyi Centrifuge instrument Co., Ltd. (Changsha, China). Heparin anticoagulative tube (Batch No. 20150116) was purchased from Kehua Inspection of Medical Products Co., Ltd. (Shanghai, China). 5-mL injectors were purchased from Kangli Medical Devices Co., Ltd. (Zhenjiang, China). PCJ-10 Series ultrapure water machine was purchased from Pincheng Science and Technology Ltd. (Chengdu, China). AccuLab analytical balance was purchased from Sartorius group (Goettingen, Germany). UV-2100 spectrophotometer was purchased from Unico Co., Ltd. (Shanghai, China). Normal saline was obtained from Kelun Pharmaceutical Ltd. (Heilongjiang, China). Microplate Reader was purchased from Kate Biological Medical Electronics Technology Co., Ltd. (Shenzhen, China). U570-86 Premium series of ultra-low temperature freezer (-80 ℃) was purchased from NBS companies (Edison, New Jersey, USA).
The glucokinas (GCK) assay kits (Batch No. 20160621), phosphoglycerate kinase (PGK) assay kits (Batch No. 20160621), citrate synthase (CS) assay kits (Batch No. 20160621), cytochrome c reductase (CCR) assay kits (Batch No. 20160621), cytochrome c oxydase (COX) assay kits (Batch No. 20160621), triiodothyronine (T3) assay kits (Batch No. 20160621), thyroxine (T4) assay kits (Batch No. 20160621), 17-hydroxycorticosteroid (17-OHCS) assay kits (Batch No. 20160621), acetyl-coenzyme A (A-CoA) assay kits (Batch No. 20160621), adipose triglyceride lipase (ATGL) assay kits (Batch No. 20160621), cyclic adenosine monophosphate (cAMP) assay kits (Batch No. 20160621), and cyclic guanosine monophosphate (cGMP) assay kits (Batch No. 20160621) were purchased from Beijing Cheng Lin Institute (Beijing, China). The pyruvic acid (PA) assay kits (Batch No. 20160621), acetylcholin esterase (AchE) assay kits (Batch No. 20160505), and Na+-K+-ATPase assay kits (Batch No. 20160505) were purchased from Nanjing Jian Cheng Bioengineering Institute (Nanjing, China).Plant materials
Poria(Batch No. 201211) was purchased from Yunnan Xianghui Biotechnology Co., Ltd. (Yunnan, China), Aconiti Lateralis Radix Praeparaia (Batch No. 130101) was purchased from Henan Renhe herbal pieces Co., Ltd. (Henan, China), Anemarrhenae Rhizoma (Batch No. 130506), Zingiberis Rhizoma(Batch No. 130506), Cinnamomi Cortex(Batch No. 130506), Phellodendri Chinensis Cortex(Batch No. 130506), Gentianae Radix et Rhizoma(Batch No. 130506) and Gypsum Fibrosum (Batch No. 130506) were purchased from Anhui Songshan Hall herbal pieces Co., Ltd. (Anhui, China). All the samples were identified and authenticated by Prof. WANG Bing (Department of Pharmaceutical Botany, College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China), demonstrating that the quality of all samples were in accordance with the requirements of Chinese Pharmacopoeia (The Pharmacopoeia Commission of PRC, 2015).Animals
Male Sprague-Dawley (SD) rats (weighing 170-210 g) were purchased from the Laboratory Animal Center of Changsheng Bio-Technique Co., Ltd. (Benxi, Liaoning, China; qualification number SCXK 2015-0001). The animals were kept in an air-conditioned room (temperature, 22 ℃; relative humidity, 55%) and fed ad libitum with standard feed and water during the entire course of the present study. The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The study protocol was reviewed and approved by the ethics regulations of the Animal Core & Welfare Committee in Liaoning University of TCM (131/2010; NO. 21000092016026, date: 20161010)Sample preparation
The crude herbs of FZ and ZM were separately immersed with 8-fold distilled water for 1 h and then boiled for 1 h. After filtered, 6-fold distilled water was added and boiled again for 1 h. The filtrates were combined and concentrated to the volume at final concentrations of crude drugs (FZ, 0.828 g·mL-1; ZM, 0.553 g·mL-1). The samples were kept at 4 ℃ before use.
The crude herb of FL was immersed with 10-fold distilled water for 1 h and then boiled for 1 h. After filtered, 10-fold distilled water was added and boiled again for 1 h. The filtrates were combined and concentrated at 6 ℃ to the volume at a final concentration of 1.38 g·mL-1. The solution of 0.69 g·mL-1 was obtained by appropriately diluting the solution of 1.38 g·mL-1. The samples were kept at 4 ℃ before use.
In the preliminary work, the chemical constituents in the water decoction of FL were studied and a split-fractions method of the chemical constituents was established. All the chemical components were divided into fractions of polysaccharide (CPF), petroleum ether (PEF), ethyl acetate (EAF), alcohol eluate from macroporous resin (AEF), and water eluate from macroporous resin (WEF). The fingerprints for these constituents were established and each constituent was characterized. Briefly, CPF was mainly composed of polysaccharides, PEF was mainly composed of phthalic acid bis-(2- ethylhexyl) ester, dibutyl phthalate and other Liposoluble compounds; EAF was composed of pachymic acid, dehydropachymic acid and other triterpenoids; AEF was mainly composed amino acid; and WEF was composed of monosaccharides and inorganic salt [23-25].
Decoction of cold-deficiency modeling drug: This experiment adopted the classical modeling method of cold- deficiency syndrome rats [21]. In our study, Gypsum Fibrosum, Gentianae Radix et Rhizoma, Phellodendri Chinensis Cortex and ZMwere weighed by 2 : 1.2 : 1 : 1.5 ratio, soaked in 8-times water for 1 h, quickly heated to boiling, and then kept the state of micro-boiling 20 min, hot filter; 6 times water was added to the remaining drugs, rapidly heated to boiling, and then kept micro-boiling for 15 min, hot filter. All the filtrates were combined and then concentrated at 65 ℃ to the volume at a final concentrate of 4 g·mL-1. The samples were kept at 4 ℃ before use.
Decoction of heat-deficiency modeling drug: This experiment adopted the classical modeling method of heat-deficiency syndrome rats [22]. In our study, FZ, Zingiberis Rhizoma and Cinnamomi Cortex were weighed by 1 : 1 : 1 ratio. First, FZ was soaked in 8-times water for 1 h, quickly heated to boiling, and then kept the state of micro-boiling to taste no hemp, hot filter; 6 times water was added to the remaining dregs, rapidly heated to boiling, and then kept micro-boiling for 20 min, hot filter; the filtrates were combined; 8-times water was added to Zingiberis Rhizoma and Cinnamomi Cortex for 1 h, rapidly heated to boiling, and then kept micro-boiling for 30 min, hot filter; 6-times water was added to remaining dregs, rapidly heated to boiling, and kept micro-boiling for 20 min, hot filter. All the filtrates were combined and then was concentrated at 65 ℃ to the volume at a final concentration of 2 g·mL-1. The samples were kept at 4 ℃ before use.Dose calculation for rats
The doses of different samples were calculated through equivalent dose ratio of human to rat according to body surface area. The one-day maximum dose of FZ for humans is 15 g in accordance with the dose in 2015 Edition of Chinese Pharmacopoeia. Therefore, the equivalent six-fold dose of FZ for rats was calculated as 8.28 g·kg-1. The one-day dose of ZM for humans is 12 g in accordance with the dose in 2015 Edition of Chinese Pharmacopoeia, while the equivalent eight-fold dose of FZ for rats was 8.88 g·kg-1. The one-day dose of FL for human is 15 g in accordance with the dose in 2015 Edition of Chinese Pharmacopoeia, while the equivalent ten-fold dose of FL for rat was 13.8 g·kg-1 and equivalent five-fold dose of FL was 6.9 g·kg-1.Drug administration
Based on cold-deficiency model, 50 healthy male SD rats, SPF grade, were housed for a week in an air-conditioned room (temperature, 22 ℃; relative humidity, 55%) and were randomly divided into 5 groups (n = 10 per group): blank, control, FZ, HWDF (10-fold dose for rat of Poria water decoction), and LWDF (5-fold dose for rat of Poria water decoction) groups.
Based on heat-deficiency model, 40 healthy male SD rats, SPF grade, were housed for a week in an air-conditioned room (temperature, 22 ℃; relative humidity, 55%) and were randomly divided into 4 groups (n = 10 per group): blank, model, ZM, and WDF (water decoction of Poria) groups.
The model drugs (13.8 g·kg-1) were given by oral gavage (i.g.) every morning for 14 days, respectively, while blank group was administered i.g. with the equivalent volume of distilled water. The administration volume was 16 mL·kg-1 of body weight. Since the 15th day, each administration group was administered i.g. with the dose as above every afternoon for 7 consecutive days, while the blank and control groups were given the equivalent volume of distilled water, the administration volume was 10 mL·kg-1 of body weight.Determination of temperature and appearance score
The toe temperature and rectal temperature of rats in cold-deficiency and heat-deficiency groups were measured on Days 0, 14, and 21 (7th day of treatment). Rectal temperature was measured with an electronic rectal thermometer (Acorn Trading Co., Ltd., Shanghai, China). Simultaneously, toe temperature was measured with infrared thermometer (CEM Co., Matthews, North Carolina, USA).
The appearance score of each rat was measured on the Days 7, 14, and 21 (7th day of treatment), according to the Standard of TCM syndrome [26] and National standard for clinical diagnosis and treatment of TCM (State Bureau of Technical Supervision, GB/T 16751.2-1997).Blood and tissue sampling
At 1h after the last drug administration, the rats were intraperitoneally injected with 1% pentobarbital sodium (4 mL·kg-1 body weight). Under anesthesia, the abdominal cavity was exposed, and then blood was collected from the abdominal aortic and then cryogenically centrifuged at 2500 r·min-1 at 4 ℃ for 20 min to prepare the plasma. The liver was removed and approximately 0.1 g of the liver was homogenized in 9 times of saline and then centrifuged at 3, 500 r·min-1 for 15 min. All the dissection parts of the liver were taken from the same spot of the liver of the rats and kept at –80 ℃ before use.Determination of indicators in vivo
All the indices were measured strictly according to manufacturers' instructions.
The contents of T3, T4, cAMP, cGMP, pyruvic acid, and AchE in plasma were evaluated by enzyme linked immunosorbent assay (ELISA). The contents of CCR, COX and Na+-K+-ATPase in liver were assayed to evaluate the effects on energy system. The contents of CS, A-CoA, PGK, GCK, 17-OHCS and ATGL in liver were assayed to evaluate the effects on substance system.Statistical analysis
Measurement data were expressed as means ± SD. Statistical analysis was performed using one-way analysis of variance (ANOVA) with the Least Significant Difference (LSD) test using SPSS version 20.0. The values of P < 0.05 were considered statistically significant.Analysis of drug property attribution by PCA method
The data in vivo were analyzed by principal component analysis (PCA) method to attribute the drug property of FL. Multivariate analysis was performed with EZinfo Software of Masslynx V4.1 version (Waters Corp., Milford, USA). PCA was performed to generate an overview for group clustering of all the index data. Results were visualized in the form of the score plots, where each point represented an individual sample.Results Effects on endocrine system
The main function of thyroid is to synthesize thyroid hormone and regulate the body metabolism. Thyroid secrets biologically active hormones such as T4 and T3, which are the main factors affecting the body's energy metabolism, regulating substance metabolism increasing rate of intracellular oxidation and improving oxygen consumption [27]. 17-OHCS is a metabolite of adrenal glucocorticoids and mineralocorticoids, and the content of 17-OHCS reflects the function of adrenal cortical. As shown in Fig 1 (A, B, and C), the T3, T4, and 17-OHCS levels of the model group were significantly decreased compared with that of the blank control group (P < 0.05 or P < 0.01). The levels of T3, T4 and 17-OHCS in the FZ group were increased compared with that of model group (P < 0.05), and the level of T3 in HWDF group was increased obviously, compared with that of the model group (P < 0.05).
Glycolysis and aerobic oxidation are the major pathways of glucose metabolism. Glycolysis is an effective way to replenish energy in anaerobic condition, while aerobic oxidation is mostly associated with the tricarboxylic acid cycle (TCA). Pyruvic acid (PA) plays an important role for the three major nutrients (sugar, fat, and amino acids) metabolism. GCK, PGK, and CS are key enzymes of glucose metabolism. As shown in Fig. 2 (A, B, C, D), the levels of GCK, PGK, CS, and PA of the model group were significantly decreased compared with that of the blank group (P < 0.01 or P < 0.05). The levels of PGK, CS, and PA of the FZ group were increased compared with that of the model group (P < 0.05 or P < 0.01), and the level of PGK in HWDF group was increased, compared with that of the model group (P < 0.05).
The level of A-CoA of the model group was increased obviously compared with that of the blank group (P < 0.05), and the level of A-CoA of the FZ and LWDF groups were decreased compared with that of the model group (P < 0.01; Fig. 3).
CCR and COX are present in the respiratory chain complex Ⅲ and complex Ⅳ, respectively. They participate in the respiratory chain of electron transport, whose content or activity can reflect the mitochondrial respiratory status and energy release level. CCR catalyzes electron passing from coenzyme Q to cytochrome C. COX is a mitochondrial marker enzyme, whose enzymatic activity plays an important role in maintaining mitochondrial structure and function as well as the production of cellular energy [28]. Na+-K+-ATPase is a kind of transmembrane protein extensively existing at the cell membranes of all most epithelial cells. Na+-K+-ATPase actively extrudes three Na+ out and imports two K+ into the cell for the hydrolysis of every ATP. The results from the present study showed that the levels of COX, CCR, and Na+- K+-ATPase in the model group were significantly decreased, compared with that of the blank group (P < 0.05), the levels of CCR, COX and Na+- K+-ATPase in the FZ group were increased compared with that of the model group (P < 0.05), and the level of CCR in FL group was increased compared with that of the model group (P < 0.05; Figs. 4A, 4B, and 4C).
The intracellular second messengers, cAMP and cGMP, play a critical role in cellular metabolism and physiological effect. The metabolisms of cAMP and cGMP present dynamic equilibrium under normal circumstances and help regulate hormone synthesis and secretion. After long-term research, it has won a widely recognition that cAMP belongs to yang and cGMP belongs to yin [29]. The data from the present study disclosed that cAMP and the cAMP/cGMP ratio of model group were significantly decreased compared with that of the blank group (P < 0.01), and the levels of cAMP and cAMP/cGMP in the FZ group were increased, compared with that of the model group (P < 0.01), while other groups showed no significant difference from the model group (Figs. 5A, 5B, 5C, and 5D).
The results showed that model and blank groups were well separated, and, after treatment, the FZ and model groups were well separated (Figs. 6A and 6B). In addition, both HWDF and LWDF groups could be separated from the blank group, while HWDF and LWDF groups showed obvious overlap with cold-deficiency model group and obvious tendency to FZ group (Figs. 6A and 6B).
The changes in appearance score and indices in vivo suggested the successful establishment of heat-deficiency syndrome model. ZM showed obviously therapeutic effect on heat-deficiency syndrome (appearance score, substance and energy metabolism, and endocrine system), while FL had no significant effect on heat-deficiency syndrome.Discussion
In TCM, drug property is a unique standard to indicate drug's efficacy. The exemplary way to explore the property theory of TCM is to study the characteristics and regularity of drug property based on the pharmacological effects. Recent researches have indicated that the drug properties are primarily associated with the metabolism of substance and energy of organism [14-15]. The present study was mainly focused on the effects of FL on substance and energy metabolism based on the models of cold-deficiency and heat-deficiency syndromes, compared with FZ (hot property) and ZM (cold property), respectively. The index data in vivo were analyzed by PCA to generate an overview for group clustering to attribute the drug property of FL. Drug property was considered as "hot or warm" when the drug reversed index changes in cold-deficiency model and had the same trend of effects as FZ; it was regarded as "cold or cool" property if the drug reversed index changes in heat-deficiency model and showed the same trend of effects as ZM.
The animal models of cold-deficiency syndrome and heat-deficiency syndrome are the basic models of common syndromes in clinical practices of TCM. This experiment adopted the modeling method of cold-deficiency syndrome rats [21], giving continuous lavage with water decoction (Gypsum Fibrosum, Gentianae Radix et Rhizoma, Phellodendri Chinensis Cortex, ZM by 2 : 1.2 : 1 : 1.5 ratio) for 14 days to rats. It was found that the model rats showed the characteristics of cold syndrome, the toe and rectal temperatures were significantly decreased, and the situation of diarrhea and loose stools, chilly curled up, fur filthy, dull, white fur, and so on. After treatment with FZ as a positive drug, the diarrhea state of rats in FZ group was reduced or even disappeared, and the body weight increased, and the toe and rectal temperatures were increased. In FL group, the syndrome of diarrhea was alleviated, body weight, rectal and toe temperatures had been rebounded, suggesting that FL had a certain extent to alleviate the state of cold-deficiency in rats.
This experiment adopted the modeling method of heat- deficiency syndrome rats [22], giving continuous lavage with water decoction (FZ, Zingiberis Rhizoma, Cinnamomi Cortex by 1 : 1 : 1 ratio) for 14 days to rats. It was found that model rats began to show the characteristics of heat-deficiency syndrome, which were slightly manic, irritable, with dry feces, and the increasing secretion around eyes, suggesting that the heat-deficiency model was built successfully. After treatment with ZM for 7 days, the score of sign index was rebounded, suggesting that ZM could alleviate the state of heat-deficiency syndrome. FL did not show obviously effect on heat-deficiency syndrome rats.
Endocrine system plays an important role in regulating physiological function and homeostasis of body. Among them, T3 and T4 can increase the oxygen consumption and heat production of tissues, whose decrease may cause the reduction of heat production, leading to the appearance of "cold" syndrome [30]. It was found that contents of T4 and T3 in cold-deficiency syndrome rats were reduced, indicating the cold-deficiency molding drug inhibited the function of thyroid hormone, thus affecting the substance and energy metabolism of body. After treatment, FZ could increase T3 and T4 significantly in cold-deficiency rats and HWDF could significantly increase the content of T3, indicating that FL could reversed the reduction of T3, thus affecting the endocrine system. In heat-deficiency model, the content of T3 in model rats was increased, showing that heat-deficiency molding drug could promote the secretion of thyroid hormone. After treatment, ZM could alleviate the state of the heat-deficiency syndrome. FL showed no obviously effects on endocrine system of heat-deficiency syndrome model.
Studies have shown that heat drugs can excite the sympathetic adrenal system and promote the production of 17-OHCS, while cold drugs can inhibit the sympathetic adrenal system and decrease the content of 17-OHCS [31]. The level of 17- OHCS in cold-deficiency syndrome group was decreased, showing that the molding drug could inhibite the function of adrenocortical, while FZ showed the opposite action. FL showed no obviously effects on both cold-deficiency and heat-deficiency syndrome models.
Substance metabolism is the basic characteristic of life phenomenon. Through the process of substance metabolism, energy is provided for life activities to maintain organism metabolism [32]. The increase of PA indicated the accelerating of glucose metabolism and the enhancement of energy metabolism of body. The PA level of the cold-deficiency model group was significantly decreased, which was in accordance with the literature reported [33], while the level of PA in FZ group was increased after treatment. The transformation of sugars, fats, and amino acids can be achieved with PA through A-CoA and TCA. A-CoA for citrate synthesis is generated by oxidation of pyruvate, and the generated A-CoA can activate pyruvate dehydrogenase [34]. The present study found that content of A-CoA in cold-deficiency model was increased, but A-CoA of heat-deficiency group was significantly decreased, and ZM could reverse the decreasing tendency of A-CoA activity.
The activity of GCK, PGK, and CS in the aerobic oxidation process of the cold-deficiency was decreased, which suggested that the cold-deficiency modeling medicine slowed the process of aerobic oxidation. The results indicated that heat-deficiency modeling drug improved the substance metabolism, and ZM could reverse the increasing tendency of GCK activity caused by heat-deficiency model drug.
Mitochondria is the center of energy synthesis and supply, and the respiratory chain is the important structure for generating energy in mitochondria. Studies had found that activity of respiratory chain complex in cold-deficiency syndrome people is restrained [35]. It was found that CCR and COX of cold-deficiency syndrome rats were reduced, suggesting that the oxidative respiratory chain complex Ⅲ and Ⅳ were inhibited and the main way to synthesis of ATP was blocked. After treatment, FZ could reverse the decrease of the COX and CCR activity, so that the synthesis of ATP was restored. Meanwhile, FL could regulate energy metabolism of cold- deficiency syndrome though reversing the decrease of CCR activity.
Na+-K+-ATPase can maintain the different gradient concentrations of ions and adjust the transportation of amino acid and glucose [36-37]. Since Na+-K+-ATPase activity was increased, the energy consumption and the heat production would be upwards. Our results manifested that the Na+-K+-ATPase activity of cold-deficiency syndrome was decreased, thus affecting the use and synthesis of ATP, which prompted that CCR, COX and Na+-K+-ATPase were the factors of energy metabolism in rats. FZ could reverse the decrease of Na+-K+-ATPase activity, which was in accordance with the idea that FZ could improve the energy metabolism in rats, by influencing the metabolic process of sugar, lipid and amino acid [38].
In the heat-deficiency model, the heat-deficiency modeling drug promoted energy metabolism and respiration metabolism. After treatment, ZM decreased the contents of CCX, COX, and Na+-K+-ATPase, thus decreasing the level of energy metabolism in heat-deficiency syndrome rats. FL showed no effect on energy metabolism of heat-deficiency syndrome rats.
The theory of TCM considers that the properties of hot and warm belong to yang, while the properties of cold and cool belong to yin [29]. The present study found that the cAMP content of the cold-deficiency rats was decreased, while the cGMP content did not change significantly, so the cAMP/ cGMP ratio was also decreased. This corresponded to the results of Zhang et al. [39], suggesting that the yang deficiency caused by cold-deficiency was achieved and the model was built successfully. After treatment, cAMP and cAMP/cGMP of FZ group were increased, suggesting that FZ could correct the state of yang deficiency in rats and restore the normal physiological effects of cold-deficiency syndrome. Other groups showed no obvious difference.
In the present study, our results showed that there was no obvious relationship between nervous system with either cold-deficiency or heat-deficiency syndrome.
PCA was performed to generate an overview for group clustering of all the index data to attribute the drug property. In the cold-deficiency model, there were significant differences in index data of substance metabolism, energy metabolism, nervous system, and endocrine system between the model group and the normal group. After treatment, FZ group could reverse the tendency of index data in cold-deficiency model to the normal group, which was in accordance with its hot property. The results of PCA showed that FL had a tendency to alleviate the state of the cold-deficiency of rats. In heat-deficiency model, ZM group could reverse the tendency of index data in heat-deficiency model to that of the normal group, which was in accordance with its cold property. There was no obvious tendency of effects seen in FL group.
To sum up, the property of FL was mainly dominated by cold-deficiency model, since the effect of FL on heat-deficiency rats was even less. Comprehensive analysis of the results of appearanceand indices in vivo, FL could alleviate the cold-deficiency syndrome, reverse the appearance score of cold-deficiency and exert certain effects on substance metabolism, energy metabolism, and endocrine system of cold- deficiency rats. FL could not reverse the heat-deficiency syndrome and had no significant effect on indexes of heat-deficiency model. Finally, the property of FL was inferred as trending to "flat and warm", but since the pharmacodynamic material basis and pharmacological action mechanism were very complex, further study should be undertaken to confirm it. The chemical constituents in the water decoction of FL were studied in the preliminary work; considering that the interactions between the components of TCM were complicated, further study should be undertaken to identify the certain components responsible for the effects. The present study provided a new way to explore the efficacy of TCM, but a comprehensive system and effective ways have not been established yet, in order to interpret the scientific connotation of drug property of TCM.Conclusion
Drug property of FL was inferred as trending to "flat and warm" which still need further study. It was advisable to adopt both cold-deficiency model and heat-deficiency model to study the drugs with "flat" property. The present study provided an experimental basis and complement for the guidance to clinical application of FL in the future.
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Zuo W, Lu TL, Mao CQ. Four properties and five tastes of Trad Chin Med[J]. China Pharm, 2010, 21(7): 653-655.
Wang QH, Yang X, Li XL, et al. Based on proteomics to study the property and flavor of Radix Aconiti Lateralis Preparata, Rhizoma Zingiberis, Pricklyash Peel[J]. World Chin Med, 2015, 12(10): 1824-1836.
Chen XY, Zhou YS, Fan YL, et al. An improved rat model of cold syndrome due to Yangqi insufficiency[J]. Acta Lab Anim Sci Sin, 2001, 9(3): 29-33.
Ye YH, Zhang BW, Zheng HM, et al. Establishment and evaluation of rat model with deficient heat syndrome[J]. Chin J Exper Tradit Med Formulae, 2017, 23(14): 134-139.
Lin Z, Xu YB, Ran XK, et al. Splitted fractions and unoverlapping analysis of chemical constituents of Poria cocos[J]. China J Chin Mater Med, 2013, 38(24): 4340-4346.
Wang XF, Hu JL, Lin Z, et al. The research for fraction- splitting of Poria cocos in nature and flavor[J]. Modern Chin Med, 2014, 16(11): 901-907.
Li B, Ding XY, Dou DQ, et al. Diuretic Ingredients of Poria cocos[J]. Int J Pharmacol, 2015, 11(2): 130-136. DOI:10.3923/ijp.2015.130.136
Deng TT. Standard of TCM Syndrome[M]. Guangzhou: Guangdong science and technology press, 1990.
Zhang Y, Yao X, Song YY, et al. Thyroid hormone and metabolic regulation[J]. Chin Bulletin Life Sci, 2013, 25(2): 176-183.
Shi H, Zhang HB, Chen B. Effect of Aslvia miltiorrhiza on the cytochrome C oxidase activity on acuterenal ischemic reperfusion injury[J]. Heilongjiang Med Pharm, 2003, 26(2): 11-12.
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Xue CM, Zhang B, Jin R, et al. Evaluative research of animal model with deficiency cold status[J]. China J Tradit Chin Med and Pharm, 2012, 27(8): 2037-2042.
Yang Y, Liang YH, Wang CZ, et al. Study on the time phase of nerve, endocrine, immune and hemorheology of deficiency- cold and deficiency-heat Model Rats[J]. Basic Med J Chin Med, 2002, 8(2): 29-32.
Jin GQ. Pharmacognostic Chemistry[M]. Shanghai Scientific and Technical Publishers, 2011.
Liu YY, Wang SJ, Han BB, et al. Effects of acetoacetate extract of Radix Aconite on hepatic contents of LA, LDH, PA, Gn, and ATPase activities in deficient cold model rats[J]. Chin J Integr Tradit West Med, 2011, 31(11): 1523-1526.
Wang T, Sun HG, Hua YL, et al. Urine metabonomic study for blood-replenishing mechanism of Angelica sinensis in a blood-deficient mouse model[J]. Chin J Nat Med, 2016, 14(3): 210-219.
Yang LP, Yan PP, Huang R, et al. Research on respiratory chain complex I activity of mitochondrion on deficiency-cold syndrome and deficiency-heat syndrome[J]. China J Trad Chin Med and Pharm, 2014, 29(11): 3440-3442.
Einholm AP Nielsen HN, Holm R, et al. Importance of a potential protein kinase A phosphorylation site of Na+-K+-ATPase and its interaction network for Na+ binding[J]. Amer Soc Biochem Mol Biol, 2016, 3(24): 1-17.
Shi WJ, Zhou H, Rong JF. Effect of Bushen Decoction on Na+-K+-ATPase, Ca2+-Mg2+_ATPase and succinate dehydrogenase in rats with heart failure[J]. Chin J Rehabil Theory Pract, 2012, 18(6): 544-547.
Yu HY, Ji XM, Wu ZC, et al. Effects of aconite root on energy metabolism and expression of related genes in rats[J]. China J Chin Mater Med, 2011, 36(18): 2535-2538.
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I'd already worked for Firestarter Business Solutions for several years when they created their marketing services consultancy in Swindon, Wiltshire. Since then, I've worked regularly with the FMS team to craft a variety of marketing copy for them and their clients.
The work I've done has included case study writing and online articles. The former draws heavily on my interviewing skills, while the latter requires extensive research to create an engaging article of substance.
In particular, case studies are an example of effective copywriting that can be written once and then used several times (online, in email marketing, as hard-copy handouts, for online PR and more). Case studies are just one of my professional copywriting services – something of a speciality as you'll see below or on my case study writing page
Here's a selection of the work that I've done for FMS and clients including Wiltshire-based agricultural engineers, BK Grain and FSB Pensions:
Client case study about FSB Pensions:
That's a taster of the kind of work I produce for a specialist marketing services consultancy like Firestarter. What kind of copywriting do you and your clients need help with? Online articles? Website content? Customer case studies? Brochure copywriting? If it needs to be written but you don't have the time, specialist skills or the inclination to do it yourself, I provide the copywriting help you need.
Whatever your requirement, I write while you get on with other pressing business tasks. With my copywriting services, that vital copywriting gets off your to-do list and starts working for you or your clients.
Do you need to get writing about watches off your to-do list? Click the image below...
Watch Industry Copywriter for the Uchi Horology Series of timepiece art prints and clothing
'Engaging copy...more web enquiries...excellent results...pure genius as always.' – see what my clients say
Take a copywriter for watch companies (me) Then mention 'Baselworld'. Here's what it's all about – from A to Z...
They're a powerful write-once-use-many-times way to get customers to sell the benefits of your products and services in their words – learn more here
Projects for clients facing similar copywriting challenges to you – read more
Experienced copywriter seeks more engineering copywriting opportunities – read more
Experienced copywriter seeks more helicopter-related UK writing opportunities – read more
Lot's of new examples of my work as a case study copywriter – https://t.co/xw5MbeEMk4
Updated page about my work as copywriter for the watch market https://t.co/3BvsUh0UbX
My latest in-depth watch industry mega-article – What Is Water Resistance - Is My Watch Waterproof? via @Watch Gecko
Travel writring about the 24 Hours of Le Mans with The Local Answer – https://t.co/48GgaVzzAm
A-Plan got me the right insurance at the right price. Why not see if they can do the same for you? Click here to ge… https://t.co/VCEYkEfmxM
Paxil (Paroxetine) How Long Does It Stay In Your System? https://t.co/tZKLvUX0Ts via @recoveryvillage
You missed my October 2014 Business Kitchen mini workshop in Cheltenham? Read the handout notes...
Could you use some of the writing that engages Gloucestershire readers of The Local Answer? Click here to get in touch...
Visit Copywriters Gloucestershire: Writing Now

subset: commoncrawl


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"With our hearts filled with love, we count our blessings." ~ David Bennett
This post marks the completion of the seventh year of the outhouse. Seven inconceivable years. I haven't missed a single day in those seven years racking up 2,556 posts as a result. So much for a one-year project, eh? I've gotten much more from this little idea than I ever expected. There have been a few bumps along the way but there's been way more good than bad. 2018 has been a tiring year for a lot of reasons, but that, too, is not a bad thing. It has caused me to reflect in ways that I might not otherwise. For those who've been with me from the start you might recall that after year two, having amassed over 34,000 images during that period, I changed the rules to allow images from the archives to be used in daily posts (prior to this all images had to be created the day of the post). Now, I think it's time to expand the outhouse horizon again. It's time to scale back on the number of posts I make – from the usual daily post to once, twice, maybe three times a week depending on happenings. This will allow me to concentrate on the depth of posts rather than the breadth offered by daily posts. Further, it will allow me to concentrate on a few other artistic outlets I've been entertaining, perhaps finally remodel the house (or part of it anyway), and pay some attention to my aging body. I was still 46 when the outhouse began. I'll be 54 in a week. During this time I've lost and gained more weight than anyone one ought to. I've got more grey hair, more wrinkles, and a lot more age spots. I've been through natural disasters, deaths -some tragic, births – all glorious, surgeries (goodbye gallbladder), a few weddings, a divorce (maybe more), many fun travels, great food, great parties, reconnecting with dear friends, staying connected with others, wonderful family gatherings, and art. Always art. There must always be art; the act of creating something from nothing, or creating something new from something old; reimagining the world and one's place in it; seeing God, the Great Creator, the Universe in all things and channeling that into being. This is central to my existence. I celebrate the work made by others, too. Their visions and their places in this world are important to my own sense of being. In May, I received an unusual curio cabinet. I don't collect curios, but I do collect folk art, usually of the small variety, along with small amulets, not always worn, of great personal significance. I began to assemble all of these into the cabinet and created something more outstanding than I ever imagined. In these few images you see work by Minnie Adkins, Michelle Shute, Sandy Davis, Rebecca Miller-Campbell, Julene Jones, Joe Molinaro, Ron Gevedon, Libby Barnes, Debi Horton, and Chris Terrell among others. You also see the spirits of Lance Hughes, Angie Bliss Fanning, Mindy Gaumer Cardenas, my parents, and my beloved dog Sadie. That's just in these photos. There's a bottom half of the cabinet not shown here. Every single day I look at this cabinet and it glows with love, compassion, integrity, and innovation. Above all I see inspiration and hope. My wish is that you, dear reader, find as much hope and inspiration in your daily lives throughout 2019 as I find in my art life cabinet every day. Here's to us and an improved outhouse in 2019.
I didn't have time (or the best lens) to snap a lot of photos inside Union Terminal, but I got off a few I'd like to share. I know I keep going on about it, but it is truly an architectural wonder and I'm thrilled that Cincinnati understands its historical significance. I look forward to going back one day soon. I'm taking the right lens next time.
The mural spanning the circumference of the lobby is nothing short of amazing. The place is dripping art deco at every turn.
Today I finally got caught up with work produced since November. Yes, I've been that far behind. It has been an extraordinarily busy fall; unexpected, fun, hectic, enlightening, inspiring. It's been a time of uncertainty, confusion, and all the isms that come with real growth. After a fabulous Christmas, working on these last photos from the Silent Night Opera jarred my senses about just how spectacular this year has been. Not in terms of big wows, but in those little things that far outweigh the big things. Things like health and family and friendship; safe travels, warm hugs, sweet smiles, kind words, and bottomless compassion. I have a good job. I have good insurance. I have good health. I have a house with "good bones," as the contractors like to say. I have a dependable car, two cats, one dog, and loads of books. I've even got a band to play with! I've been surrounded by all of this and more. And then there's Terry Keys in a 100% wool WWI uniform singing like a bird and looking like a million bucks. If that doesn't make 2018 epic, nothing can.
I have been sick since last Thursday. I thought it was just an allergy thing making me lose my voice. I had to skip a few things along the way to try to keep from getting worse. It finally caught up with me Christmas Eve. I was in bed by dark only to wake up this morning feeling even worse. Mom and dad went to Aunt Lois' without me for Christmas day dinner. I hated to miss the family (many of whom have this same cold so I wasn't the only one absent today). I slept all day. The folks brought me a plate of deliciousness this evening and I soon started feeling better. My point in all this is that, despite having been sick the entire holiday, it has been one of the best Christmases we've ever had. We were all happy. We were all grateful. We were all present. I'll take a cold every year if it means we're all together and happy.
You've heard me talk about the enormous Abraham Lincoln sculpture in the center of the Special Collections lobby. It's tall. It's heavy, even though it's hollow. It dictates virtually everything that happens in the lobby because, well, it's huge, immobile, and just about as bland as a sculpture can be. Finally, this year, Shell Dunn was given permission to do something creative with 'ol Abe. She made him a fashionable top hat and scarf. Not only is he now seasonal and fun, he matches the latest exhibit of holiday cards in the lobby, too. There are purists who frown upon such things claiming it defaces the artifact. I might agree if 'ol Abe was unique. He is not. This sculpture is one of several throughout the US. What does make him unique is how his approachability engages and entertains researchers and visitors. As far as I can tell, that's a whole lot more useful than a bland bronze head in the middle of the floor. Kudos to management for the spark of fun!
I was granted a rare privilege this evening of photographing dress rehearsal of UK's latest opera production Silent Night. The opera "recounts a miraculous moment of peace…as Christmas Eve falls on a battle field near Belgium, soldiers in French, German, and Scottish trenches begin recalling songs of home, stepping into no-man's-land for a spontaneous truce." My man Terry Keys, above, has a part in the Scottish Army. It's his operatic debut. He has done a lot of musical productions over the years but he hasn't done opera until now. The show opens tomorrow (and runs through Sunday) at the Singletary Center for the Arts but I can't be there. That's basically how I came to shoot the dress rehearsal. Terry reached out to Everett McCorvey on my behalf, who immediately said yes, and I can't thank them enough for letting me practice on them. It was great experience for me and it's a truly beautiful production. I loved it and the audience smart enough to go is going to love it, too. Even if you're not a fan of opera, this production transcends the stereotype. Terry is a gifted performer and Everett is a brilliant producer so you can bet anything with his fingerprint is spectacular. Silent Night is just further proof of that. If you're in the Bluegrass region this weekend I encourage you to go. Maybe Terry will even turn his handsome face toward you, too.
This beautiful sculpture graces an entrance of Northeastern State University in downtown Tahlequah, Oklahoma. Monument to Forgiveness was created by Dutch artist Frances H. Jansen "to honor Tahlequah as the End of the Trail of Tears. 'To inspire, evoke and encourage in all humankind the spirit of reconciliation, transformation and unity through forgiveness.'" The world could use this spirit right now.
Several months ago I bought an incredible piece of art by VL Cox. Lynette (VL) and I have been friends for a couple of decades now (courtesy Angie Bliss Fanning), and her career as an artist has skyrocketed in that time. In fact, right now, she's riding a shooting star, getting noticed in NYC and DC and Lord knows where else. She's doing really great, important work. So when I had a chance to buy a piece, I took it. Today, I drove out to Oklahoma and made a pit stop in Little Rock, Lynette's home base, and picked up the painting entitled "Castile." I met her sweet partner, Sherrie Shepherd herself an accomplished artist (see syndicated cartoon 'Francie'), who helped facilitate the drive by art deal. You know, some people do drug deals. I do art deals. I think it's a habit worth keeping, and if I ever have the means to buy another VL Cox, I'm doing it. A photo does not do this painting justice. It's absolutely stunning. I win Friday.
You might remember Deb and Virgil Alcorn from when they married way back in 2013. It was one of the few weddings I agreed to shoot, and I'm so glad I did. But five years between outhouse appearances is far too long for people I love! Last Saturday, they found me tucked between two booths in the Scarefest exhibit hall trying to be incognito with my long lens (never works, by the way). We talked for a bit, then they went on their way. But I had that long lens so I could follow them without ever leaving the safety of my hidey hole. Deb finally saw me and we had a good laugh. I don't know how I got so lucky to make such fine, fine friends, but I'm sure glad I did.


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Just because your land is sloped doesn't mean building a workshop, storage, agriculture, or another type of shed is impossible. There are a few more steps and considerations, but done properly, it could end up being the best use of that otherwise wasted space. Here's what you need to know. The paving slab and timber sleeper foundation can accommodate a small slope if you cut a little on one side of the slope and build Read More
Sheds can meet a wide variety of needs for homeowners in Western Australia. From storage space to housing machinery, sheds can offer some additional covered space for possessions or hobbies without the more expensive and intricate requirements of other buildings. The process of getting approvals for sheds may also be easier, or completely unnecessary, depending on several factors. Do I Need Shire Approval to Build a Shed? In many situations, you do not need shire Read More
If you're looking at putting up a shed, you're likely considering a number of factors. One detail you may not have thought of is a wind rating. Keep reading to learn what a wind rating is, how it affects the shed you choose, and why it matters. What Is a Wind Rating? The explanation is simple: a wind rating is assigned by your council to certain areas. The rating itself is determined based on a Read More
Barns and farm storage sheds in the Perth area are often used for storing agricultural chemicals and pesticides. Unfortunately, not every barn or shed is up to Australian Standard AS 2507-1998 and not every owner adheres to the Dangerous Goods Act of 1985 or the Dangerous Goods (Storage and Handling) regulations set forth in 2012. At Action Sheds Australia, we are compliance experts with years of experience of providing sheds that are fully compliant Read More
When we do consultations for storage sheds in the Perth area, we often find that little or no thought was put into where to actually put the shed. One of the main advantages of sheds is that they provide the ultimate in flexibility, but a lot of people fail to fully utilise that flexibility. Here are five tips for choosing the perfect place to build a storage shed in your yard, farm or commercial property. Read More
Get Your Shed Summer Ready Now
As all who own sheds know, summers in Perth can be harsh. They produce temperature extremes that can make a shed very uncomfortable to work with. Whether it's a barn, storage shed, garage or industrial shed, the Perth climate can make it dangerous for work and damage its contents if not properly ventilated and insulated. Insulation The choice of materials in a shed can make a huge difference in how well it is insulated. If Read More
Protect Your Crop from the Elements
Farm storage sheds are replacing silos as the preferred choice for storing crops in the Perth area and across WA. As profit margins become slimmer and slimmer for many farmers, it is important to maximise every crop. One of the best ways to do this is to make sure that the storage medium is perfect for your crops. That way, you can ensure less spoilage and higher quality, which can fetch a higher price at Read More
Storage sheds have become common in the Perth area for two main reasons. First of all, space is at a premium in Perth and many suburbs as the average block size has decreased by almost 50% in the last forty years. The other reason is that a well-constructed shed provides the best value for the money you spend on storage. Here are seven things to consider when looking at a storage shed. Price vs Read More


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Nik S Home Run
Nik S Home Run is free HD wallpaper. This wallpaper was upload at January 16, 2019 upload by admin in .You can download it in your computer by clicking resolution image in Download by size:. Don't forget to rate and comment if you interest with this wallpaper.
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We fabricate steel mountain bike frames , we build them for you, ourselves, and the trails
New products are coming soon!
Located in the flats of south east michigan Rad Bicycle Co. strives to put people on bikes handwelded in the USA. All frames are designed and built in house with locally sourced 3/4" chromoly tubing for the rear triangle and Vari-Wall Thermlx double butted 4130 front triangle. Also having any choice color powder coat makes for a much more custom feel. Frame only and complete bikes available.
Earlier in December, I visited three Michigan bicycle companies on a short press junket and this is the first story that I'll write from those travels. My first stop on the trip was to RAD Bicycle Company which is run by Matt Craig and Mark Major in Pinckney Michigan
The small town of Pinckney, Michigan is located roughly halfway between the state's largest city, Detroit; and its capital city, Lansing. Michigan is well known for its industrial and manufacturing lineage, and Matt Craig's personal roots mirror his home state's closely in that regard.
What do you get when you mix a lifetime of automotive manufacturing, years of bicycle racing experience and a newborn child? We get Rad Bicycle Company, the new passion of Michigan's Matt Craig.
We love our customers, so feel free to visit during normal business hours.
call us for appointment
Monday: By appointment
Saturday: By appointment
Sunday: Closed


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The Polar Bear Who Saved Christmas : When Pip the polar bear gets lost and wanders into Santa's workshop, he finds that disaster has struck and the elves are about to cancel Christmas! With time running out to deliver Santa's gifts, Pip embarks upon a magical and unforgettable adventure. NOTE: This is a Scratch and Dent book and may have noticeable dents, scratches and various other cosmetic issues as well as torn or missing dust jacket. These items are only guaranteed to be structurally complete and readable and therefore are sold as is.
|Ficción para Niños
|Action & Adventure
|Ficción para Niños
|Holidays & Festivals - Christmas


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Heat Detector Unit
Long life heat alarm with sealed-in 10 year battery.
- Advanced Thermistor Detectioncontrolled by bespoke software.
- Auto Switch Mounting Plate. Power automatically switched on when the alarm is attached to its mounting plate and off when removed.
- Alarm Silence Button ideal in non-emergency situations (nuisance alarms)
- Silence Low Battery Warning for up to 10 hours. Maintains continuous protection during sleeping hours
- Interlinkable Version – FHH10W available for interlinking to smoke alarms
- Extra large Test Button for ease of use
- Red led flashes once a minute to indicate power and constantly flashes to indicates alarm condition
- Sealed in 10 year Lithium battery power supply


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|Over a month ago in Palo Alto, CA.
OK, now stop humming the song. :-)
My Canon 10D is out of commission, so I am now on film, officially, with no choice. The Epson scanner I ordered should arrive sometime next week. I now have a chance to go back to my archives to look for previously ignored images, which is not a bad thing to do anyway. There are many I haven't looked very closely after I dumped them on my harddrive.
The KRON 4's Bay Area Bloggers Meet-up was very interesting. Over 100 bloggers showed up (I am at the lower right corner in my baseball cap). Of course it's on their evening news.
Some intersting people I met -- Craig from craigslist.org asked me to stop calling him "my hero", which I have to respectfuly disagree; everybody's favorite waitress Valerie told me she is going to present her site and some of her work in SF Apple store this Thuesday; Kevin told me quite a bit about nVidia, the company he is working for; I am sorry Min Jung for the camera flash right in her face (her Flickr stream is here, and the Flickr Group about the event is here); Rich liked the idea I was taking a photo of him taking a photo; Tantek's Technorati business card has his personal blog url, hmm...; I think I may need to consult Rodrick about the font/typography issue for the "Turing Test" php script I am going to write; and so on...


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hong kong
Collected by Nellie DeBruyn
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Tai O, Hong Kong
Tai O is a village on the western side of beautiful Lantau Island. It is just a short ferry ride from Hong Kong, and yet it is a whole other world. The village feels much more traditional Chinese, and the stilt houses hanging over the water are...
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31 Lugard Rd, The Peak, Hong Kong
I'm always looking for a new take on a classic view, and I found this one while marveling at Hong Kong's famous skyline from Victoria Peak. I used a 50mm Lensbaby to compress the distance between buildings, and I played with the plane of focus by...
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best way to make money fast
earn big money
easiest way to earn money online
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fast moneyON 10/17/16 Chuck says: Carol Topp, CPA It's all very congruent and natural. I have a problem I need solved. I buy a product or service to solve that problem, experience the results, hopefully solve my problem and then write about my experiences on my blog. My readers, many of whom are following in my footsteps or at least interested in the same things I am, tend to have the same problems I do, and a select few will purchase on my recommendation. Chris' Graphic design Do you search the Internet? Want to get paid for it? Swagbucks is a site that rewards you for doing various online tasks like taking surveys, watching videos, and using their search engine. When using their search engine, you get reward points after several searches, usually in the amount of 10-15 points. You can start cashing out rewards at the 500 points mark. Invest & Retire Install the ShopTracker app You could pay $10 to get my latest best seller on this strategy OR you could learn everything you need to know about it for FREE. Just download a free chapter from my latest book and a free Special Report here. There are tons of free apps and website available that allow you to earn reward points for cash or discounts. This can be a great way to save on items you frequently purchase — and put some cash back in your pocket! I currently mak money with my cell phone its a affiliate marketing company where you refer friends and family to join solavei.com/isaitellez check out my site guardian labs Fast Money 12/29/17 Dec 29, 2017 Listen SB says Top Travel Spending Cards RadnipUK/TripAdvisor pvik on at Life CreditCards.com Great service from MoneyMe, really helped when desperately needed. Rewards 9Earn money from your credit cards DJs Bios -SAVE MONEY After a major illness or surgery, a person can be inundated with medical claims. If you're familiar with the process (filing and dealing with insurance companies) you can make some serious money straightening out someone's medical claims. Copenhagen 04/10/2017 at 4:54 pm It's a tough one that only after you input the figures through a tax software like H&R Block Online" target="_blank">H&R Block, will it spit out a number. Essentially, tax deductions get phased out over time. https://www.financialsamurai.com/mortgage-interest-deduction-limit-and-income-phaseout/ Experience. Whatever area you want to work in as a consultant, you must be able to show clients that you're qualified to advise them. If there are organizations related to your field, make sure that you're a member of them. Similarly, if you can take a course and become certified or registered in your field, do it and then add that to your credentials. Many people spend thousands of hours online to know how to make money online i think u said every thing in just 5min. Good and i think if any new person who want to make many online if he read this article i am sure he is going to to reach to a big position as he save a lot of time in research 🙂 Nice write up mate. RELX Group The One says Deanna, that's actually wrong. There is ZERO risk when he matter is MINING bitcoin and ethereum or any other cryptocurrency. Mining is 100% safe and guaranteed to make money, so it actually does work as a passive income as long as your electricity bills are low. Craigslist: Craigslist is definitely the scrappiest of the major online resale options. The advantage of Craigslist is its enticing profit potential, thanks to the total lack of listing and selling fees for most items. The disadvantages are many, but include potential safety risks and higher chances of nonpayment. If you do choose Craigslist, keep your wits about you and use the buddy system. P At this point the momentum of the snow ball rolling starts to work in your favor. In that sense, the commission scheme is not solely dependent on sales, so this CPA marketing idea surely has an upside about it. Share this on Facebook Are you a good listener — and a good typist? You can make $15 to $25 an hour as a transcriptionist. 15 vital money lessons you should have been taught in school Find Great Value Stocks Admittedly, starting a pyramid scheme is a lot of work. Much less work just to join an existing one. You need the same skills listed above, good-looking, charismatic, but you don't have to develop a product, just get dummies to sell it for you. Beware of loan sharks or other extortionists. Look for people that can loan you money because they want to help you, not because they want to make a profit. Instead of falling victim to cognitive dissonance, remember this question: 4. Cash out and receive your payment either with PayPal or by mail. Time for Dan to go. 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Overwatch Winter Wonderland Skin LEAKED? NEW Junkrat cosmetic revealed by Blizzard Store?
BLIZZARD may have accidentally leaked a new Overwatch skin by including the design in a shirt that was delisted from its store after going live. Here's what you need to know.
We may have gotten our first look at Winter Wonderland 2018's first skin.
A shirt that was listed (and subsequently taken down) on the Blizzard Gear Store seems to tease a Junkrat design we've never seen before.
The shirt features Zenyatta front and center, decked out in his Nutcracker skin, flanked by Widowmaker in her Odette skin. But then, top right, we see Junkrat in a skin we've never been shown before - some sort of Mouse King, possibly in relation to the festive tale, The Nutcracker (which would suit the other two skins).
It would be very uncharacteristic of Blizzard to reveal a character design like this then not feature it in the game, so we're willing to bet that the company has accidentally made this merch live before it should.
It's worth noting that the shirt has now been taken down from the Blizzard store, but we've got a pic of the item embedded beneath. Sory for the low resolution - you can't zoom on images on the Blizzard store, and the source was pretty lo-res. You can still see what Junkrat will look like, though.
Overwatch is almost as well-known for its seasonal events as it is for its best-in-class, team-based hero shooter gameplay.
As well as seasonal events revolving around Chinese New Year, Halloween and Summer Games events, one of the most popular recurring in-game celebrations revolves around Christmas - perhaps it's because more players get time off in late December to play, perhaps it's because our culture is enamored with the capitalist's dream holiday... either way, Christmas in Overwatch remains one of the game's most popular events
At the time of writing, Blizzard hasn't confirmed that there will be a Christmas event in the game, but as sure as night follows day, we know we're going to get one.
You can read everything we know about the event so far - as well as our best estimations as to when the event is going to start, and what will be involved, at our page dedicated to Overwatch Winter Wonderland 2018.
But when will the event start?
To figure out when we'll see Winter Wonderland come back to Overwatch, we can examine previous years' times and dates;
Winter Wonderland 2016:
The event started on December 13, and ended on January 3.
Winter Wonderland 2017:
The event started on December 12, and ended on January 2.
So by that logic, we can expect Winter Wonderland 2018 to kick off on Thursday, 13 December 2018.
Blizzard events typically kick off on Thursdays and the date above aligns with past events.
We'll update you as soon as we know any official timings.


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Dating women after divorce
Broaden your horizons and see who else is out there for you. Flirting is extremely powerful in the dating world and men will always notice a flirty women. Light flirting is a good way to gain some more confidence and to brush up on your skills. After a divorce, many women are left down and out.
Ensure self-happiness first Before you ever jump back into the dating scene, make sure that your self-happiness and self-confidence are in check. Date around and determine what exactly you want in a man and in a relationship. Instead, take the initiative and be a bit flirtatious.
If you're looking for more than just a fling, here are some tips to help you get started. Here are some things to consider that can help ease the way.
Dating Rules After Divorce - Here are ten handy tips on how to start meeting new men and how to handle yourself during the first date. Instead of boxing yourself in with the thought of only dating your type, try stepping outside of your box and try dating someone new. Take charge of your dating world and control it. Dating Tips - Things to consider as you re-enter the dating scene. In fact, dating after going through a divorce can be pretty tough, confusing, and exciting all at once.
Dating After Divorce - Getting Started
Dating Again After Divorce - Here are seven tips to make sure your post-divorce dating adventures are safe, sane, and successful. How to Overcome Insecurities - Learn how to move past the suspicion and uncertainty as you begin to date after your divorce. But, with the right advice and information in tow, dating after being divorced can be a lot easier and much more pleasurable. Sadly, a divorce can leave you confused as to who the real you really is. Know who you are After a divorce, you may find that you go through a lot of changes, both physically, mentally, and emotionally.
Dating is all about being yourself and showing your true colors to the men you encounter. Going at it alone is never fun. The Divorce and Dating Playbook - Tips for getting back into dating after divorce, especially if it's been a while since you were last single. Finding Love After Divorce - Tips to determine if he is the right man for you.
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Litigation Paralegal job profile
Litigation Paralegal is a professional who supports all phases of the litigation process by providing assistance and coordinating different activities.
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Litigation Paralegal job description
Are you an experienced and ambitious Litigation Paralegal looking for an opportunity to advance your career?
We are looking for a skilled Litigation Paralegal to join our team of highly experienced lawyers who have corporate, litigation, broker-dealer and investment advisory practices.
This position offers an excellent opportunity for long-term professional growth and a competitive compensation package.
Litigation Paralegal duties and responsibilities
- Conduct legal research and initial case assessments
- Draft pleadings, motions and appellate documents and file them with the court
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- Handle trial preparation for the attorney and post-trial procedures
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Litigation Paralegal qualifications and requirements
- Previous working experience as a Litigation Paralegal for (x) year(s)
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RWU Tutoring Jobs
Found 19 listings, displaying 1-19
Post a Tutoring Job
I am currently enlisted in the Army National Guard (E-5), but I want to improve mt score. My current score is keeping me from moving to a different MOS that requires a higher score. I believe a tutor would be perfect for me and hoping it can bring my numbers up to any job I want...more
I am looking for someone to tutor 3 of us in beginning Japanese. We live in Providence RI...more
I'm looking for a tutor who can help me learn to play one song on the piano...more
My son is a sophomore at Johnson & Wales in Providence and is struggling to complete an excel assignment that is due tomorrow night (Saturday 1/12). Looking for someone who is vailable to help him tomorrow, and if it works out, maybe we could set up something 1 - 2 times a week...more
I am hoping to start taking Spanish lessons for business very near term. I work for a medical company and I travel to South America regularly. I have picked up some Spanish passively but I am at a point where I need to step up and do it for real. I travel frequently so I would benefit from our...more
I'm interested in learning how to work and use 3D animation software...more
I'm looking for help with my daughter for SAT prep. She is a junior at High School...more
I'm interested in learning how to illustrate on the computer. I am looking to learn Photoshop...more
I'm looking for help with my daughter for SAT prep. She is a junior at High School...more
I am interested in learning German. I'm mostly interested in becoming conversational...more
My son is a game design major at SNHU and is working on Photoshop. He has some character designs to create silhouettes and iterations...more
I'm a junior in High School. I took honors chemistry last year and am now in AP chem. I am struggling right now and need ongoing tutoring support as my goal is the go to medical school...more
I need help with longitudinal poisson regression in R statistics...more
I am seeking tutoring Monday, Dec 10 at 9 pm. I am trying to learn how to solve problems with deflections of beams and differential equations for the elastic curve. Requested lesson time: Monday, Dec 10 at 6:00 PM PST...more
The Opportunity in Education:The future is here! Join a fast growing community of elite educators who are teaching right from their home. As an independent contractor, you will be matched 1:1 with Chinese students on our secure virtual learning platform to teach English online. All you need is a...more
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Varsity Tutors is looking to contract with tutors to connect with clients across a variety of academic subjects and major test prep through Varsity Tutors' platform. There are many benefits of tutoring through the Varsity Tutors platform. Tutors can: - Receive earnings twice per week - Set...more
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Several other signs and symptoms can mark the onset of diabetes although they are not specific to the disease. In addition to the known ones above, they include blurred vision, headache, fatigue, slow healing of cuts, and itchy skin. Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Long-term vision loss can also be caused by diabetic retinopathy. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.[23]
Complaints about preventative go back to the late 18th century. The spelling reformer James Elphinston wrote in 1787 that preventative could be heard among Londoners in unguarded speech, along with other disapproved pronunciations like umberella and mischievious that sneak in an extra syllable (a process that linguists call "epenthesis"). A 1795 review of the Earl of Lauderdale's "Letters to the Peers of Scotland" criticized the appearance of preventative in the text, declaring that it was "not English." Similarly, Francis Barnett took Andrew Reed's "No Fiction" to task in 1823 for including the word: "In the English language there is no such word as preventative, preventive there is."
For her part, St Clair thought she was inquiring about a technical glitch. Her brother—the brother who along with three other siblings had gifted her the DNA test for her birthday—wasn't showing up right in her family tree. It was not a glitch, the woman on the line had to explain gently, if this news can ever land gently: The man St Clair thought of as her brother only shared enough DNA with her to be a half-sibling. In fact, she didn't match any family members on her father's side. Her biological father must be someone else.
After breaking this down, Brand took questions from the audience. The first was from a person in the third row who said her brother is an addict who keeps coming to her for money. What should she do? Brand moved to the very front of the stage and looked into the back of her eyes and told her she knows what she has to do—which is cut him off, let him hit rock bottom. She said, yes, she knows, and she cried.
According to Jack D. Bragg, DO, associate professor of clinical medicine at the University of Missouri, most diabetes-related GI issues stem from a problem with one thing: motion. The digestive tract is a finely tuned muscular machine. It pulls and pushes, expands and contracts, relaxes and squeezes to carry food from your mouth, down the esophagus, into the stomach, and, finally, through 25 feet of nutrient- and water-extracting intestine that ends in, well, your exit.
Alpha lipoic acid is an antioxidant that helps turn glucose into fuel for the body. It effectively improves insulin sensitivity and reduces symptoms of diabetic neuropathy, such as weakness, pain and numbness that's caused by nerve damage. Although we make alpha lipoic acid and it can be found in some food sources, like broccoli, spinach and tomatoes, taking an ALA supplement will increase the amount that circulates in your body, which can be extremely beneficial when trying to reverse diabetes naturally. (17)
Last year, S-Town blew our minds by taking a novelistic approach to its fascinating characters, plot, and setting. This year, playwrights and journalists came out from behind the page in droves. Podcasts are now regularly adapted for television (Homecoming, 2 Dope Queens, Pod Save America, and Dirty John, to name a few). They became more niche and even self-referential: The Onion's A Very Fatal Murder satirizes true-crime podcasts. There's even a podcast (Before It Had a Theme) about a radio show that is now also a podcast (This American Life). Podcasts, it seems, are the new black hole (a concept that's explained very well on HumaNature), because they feed and feed on whatever is around them.
Some cases of diabetes are caused by the body's tissue receptors not responding to insulin (even when insulin levels are normal, which is what separates it from type 2 diabetes); this form is very uncommon. Genetic mutations (autosomal or mitochondrial) can lead to defects in beta cell function. Abnormal insulin action may also have been genetically determined in some cases. Any disease that causes extensive damage to the pancreas may lead to diabetes (for example, chronic pancreatitis and cystic fibrosis). Diseases associated with excessive secretion of insulin-antagonistic hormones can cause diabetes (which is typically resolved once the hormone excess is removed). Many drugs impair insulin secretion and some toxins damage pancreatic beta cells. The ICD-10 (1992) diagnostic entity, malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code E12), was deprecated by the World Health Organization (WHO) when the current taxonomy was introduced in 1999.[53]
Big pharma are in the early stages of developing their own cell therapy approaches for diabetes. Novo Nordisk, one of the largest providers of diabetes treatments, is bidding for stem cells and an encapsulation device, stating that the first clinical trial could take place in the "next few years." Sanofi, also a big name in diabetes, is working with the German Evotec in a beta cell replacement therapy for diabetics.
Pain has been shown to interfere with self-management activities, sleep, physical functioning, work, family relationships, mood, and quality of life. To make matters worse, pain is often invisible to others, so family members, coworkers, and health-care professionals often have no idea what a person in pain is going through. Many people feel that their physicians don't understand and tell them they "just have to live with it."
The last time I was in Palm Springs was a year ago for the TEDMED conference (relational platform?), and at the time I was mystified. It was a full house at the price of $4,950 a ticket, even though TED Talks are available for free online. The videos can be sped up if the speaker is boring, segments can be skipped, and tabs can be opened to keep the talk running in the background while getting some email done or shopping for shoes. There would seem, then, very little reason to need to go to the actual conference, to sit through marathon sessions where a fair number of speakers mess up or forget their lines (as I did).
Federal health officials said the most likely source of romaine lettuce contamination is from the Central Coastal growing regions in northern and central California. No common grower, supplier, distributor or brand of romaine lettuce has been identified. Several major romaine lettuce producers have agreed to label products with a harvest date by region, and new […]
Some studies show that certain plant foods may help your body fight inflammation and use insulin, a hormone that controls blood sugar. Cinnamon extracts can improve sugar metabolism, triggering insulin release, which also boosts cholesterol metabolism. Clove oil extracts (eugenol) have been found to help insulin work and to lower glucose, total cholesterol, LDL, and triglycerides. An unidentified compound in coffee (not caffeine) may enhance insulin sensitivity and lower the chances of developing type 2 diabetes.
People with diabetes can benefit from education about the disease and treatment, good nutrition to achieve a normal body weight, and exercise, with the goal of keeping both short-term and long-term blood glucose levels within acceptable bounds. In addition, given the associated higher risks of cardiovascular disease, lifestyle modifications are recommended to control blood pressure.[80][81]
Family or personal history. Your risk increases if you have prediabetes — a precursor to type 2 diabetes — or if a close family member, such as a parent or sibling, has type 2 diabetes. You're also at greater risk if you had gestational diabetes during a previous pregnancy, if you delivered a very large baby or if you had an unexplained stillbirth.


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If the casino uses coin-in slot machines, the cage and booth cashier will have the added duty of accepting coin buckets for redemption.
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