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2‐(chalcogen)benzothiazoles are frequently used as core structures for the development of pharmaceutical agents. A strategy for the synthesis of 2‐(chalcogen)benzothiazoles under electrooxidative conditions using isocyanides, thiols or diselenides as substrates was developed. This protocol allows access to structurally diverse 2‐(chalcogen)benzothiazoles in good yields and with good functional group tolerance, which does not require heavy metal catalysts and exogenous oxidants. Furthermore, gram‐scale synthesis was performed to demonstrate the scale‐up applicability of this reaction. [ABSTRACT FROM AUTHOR]

N‐(α‐alkoxyalkyl)benzotriazoles are of great importance for biochemical and antitumor activity. A feasible protocol has been developed for the synthesis of N‐(α‐alkoxyalkyl)benzotriazoles using azoles, aldehydes and alcohols as substrates under electrochemical conditions. The reaction is carried out under acid catalyst‐ and oxidant‐free conditions, so that a variety of synthetically useful nitrogen heterocyclic derivatives can be obtained. More meaningfully, a gram‐scale synthetic approach was employed to demonstrate the scale‐up applicability of this transformation. [ABSTRACT FROM AUTHOR]

Two new isoflavone compounds, Dalhancei A (1) and Dalhancei B (2), along with a known compound epicatechin (3) were isolated from 80% methanol extract of the barks of Dalbergia hancei Benth. The structures of compounds 1–3 were elucidated by comparison with the literature and physical data analysis, including optical rotation, MS, 1D and 2D NMR spectra. Compounds 1 and 2 showed weak inhibitory activity against tyrosinase at 16.22 mmol/L, with inhibition rates of 42.23 ± 0.18% and 45.68 ± 0.17%, respectively; compound 1 exhibited weak inhibitory activity against α-glucosidase with the inhibition rate of 43.72 ± 0.22% at 5.41 mmol/L, compounds 2 and 3 had better α-glucosidase inhibitory activity than compound 1 with IC50 values of 0.90 ± 0.18 and 0.41 ± 0.17 mmol/L, respectively. [ABSTRACT FROM AUTHOR]

One,1-dichloro-2,2 bis(p-chlorophenyl) ethylene ( p, p'-DDE), the major metabolite of 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. It has antiandrogenic effect. However, the mechanism by which p, p'-DDE exposure causes male reproductive toxicity remains unknown. To elucidate the mechanism underpinning the testicular effects of p, p'-DDE, we sought to investigate apoptotic effects and mRNA expression of apoptosis-associated genes in the testis of pubertal rats, including Fas, FasL, calpain-1, cytochrome c, Bax, Bcl-w, Bak, and caspase-3, -8, -9, -12. Animals were administered with different doses of p, p'-DDE (0, 20, 60, 100 mg/kg body weight) every other day by intraperitoneal injection for 10 days. The results indicated that p, p'-DDE exposure at over 20 mg/kg body weight showed the induction of apoptotic cell death. p, p'-DDE could induce decrease in SOD and GSH-Px activity of serum in 60 mg/kg body weight group. Significant elevations in the mRNA levels of Fas, FasL, calpain-1, cytochrome c, Bax, Bak, and caspase-3, -8, -9, -12 were observed in testis of rat treated with p, p'-DDE. Taken together, these results lead us to speculate that in vivo exposure to p, p'-DDE might induce testicular apoptosis in pubertal rats through the involvement of Fas/FasL, mitochondria and endoplasmic reticulum-mediated pathways. © 2011 Wiley Periodicals, Inc. Environ Toxicol 2013. [ABSTRACT FROM AUTHOR]

Abstract: BiYO3 photocatalysts were successfully prepared by a precipitation method and by a solid-state reaction. The products were characterized by X-ray diffraction (XRD), UV–vis diffuse reflectance spectroscopy, high-resolution transmission electron microscopy (HRTEM) and surface area and porosimetry analyzer. UV–vis diffuse reflectance spectra revealed that the crystalline BiYO3 generated via a solid-state reaction had a band gap of 2.64eV, whereas the product generated by precipitation method had a band gap of 2.84eV. Both products exhibited absorption in the visible-light range of 400–700nm. XRD and transmission electron microscopy (TEM) measurements showed that these both samples of BiYO3 were highly crystalline. These results indicated that BiYO3 might perform well as a photocatalyst in the visible-light region. By using photocatalytic degradation of methyl orange as a model system, it was shown that BiYO3 generated by the solid-state reaction showed greater photocatalytic activity than either BiYO3 generated by the precipitation methods or BiVO4 when exposed to visible-light irradiation. [Copyright &y& Elsevier]

Study Design: Retrospective cohort study., Objective: To evaluate the effectiveness of pedicle screw trajectory planning based on artificial intelligence (AI) software in patients with different levels of bone mineral density (BMD)., Summary of Background Data: AI-based pedicle screw trajectory planning has potential to improve pullout force (POF) of screws. However, there is currently no literature investigating the efficacy of AI-based pedicle screw trajectory planning in patients with different levels of BMD., Methods: The patients were divided into 5 groups (group A-E) according to their BMD. The AI software utilizes lumbar spine CT data to perform screw trajectory planning and simulate AO screw trajectories for bilateral L3-5 vertebral bodies. Both screw trajectories were subdivided into unicortical and bicortical modes. The AI software automatically calculating the POF and pullout risk of every screw trajectory. The POF and risk of screw pullout for AI-planned screw trajectories and AO standard trajectories were compared and analyzed., Results: Forty-three patients were included. For the screw sizes, AI-planned screws were greater in diameter and length than those of AO screws (P<0.05). In groups B-E, the AI unicortical trajectories had a POF of over 200N higher than that of AO unicortical trajectories. POF was higher in all groups for the AI bicortical screw trajectories compared with the AO bicortical screw trajectories (P<0.05). AI unicortical trajectories in groups B-E had a lower risk of screw pullout compared with that of AO unicortical trajectories (P<0.05)., Conclusions: AI unicortical screw trajectory planning for lumbar surgery in patients with BMD of 40-120 mg/cm3 can significantly improve screw POF and reduce the risk of screw pullout., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The study was designed to assess the beneficial role of mangiferin (MGN) in lead (Pb)-induced neurological damages in the activation of Nrf2-governed enzymes, genes and proteins., Methods: A total of 96 weaned Wistar rats (48 males and 48 females, 26- to 27-day-old), weighing 50-80 g were used. The experiment was performed in six groups: normal group (control, n  = 16), model group (chronic Pb exposed, n  = 16), Dimercaptosuccinic acid (DMSA)-treated group (positive control, Pb + DMSA, n  = 16), three MGN-treated groups with different doses (Pb + MGN, n  = 48). Normal group freely had access to purified water. DMSA-treated group was given DMSA, which was clinically used as the standard treatment for moderate Pb poisoning, at 50 mg/kg (2 mL suspension with purified water) by intragastric gavage (ig) 4 continual days a week for 4 weeks, MGN-treated groups were given MGN at 50, 100, or 200 mg/kg (2 mL suspension with purified water) by ig daily for 4 weeks. At the end of the treatment, all rats were sacrificed and the brain samples were collected. The haematoxylin and eosin (H&E) staining was used for observation of histopathology. Commercial kit, real-time quantitative polymerase chain reaction (RT-qPCR), Western-blot and immunohistochemistry (IHC) detection were used to detect the mRNA and protein expression., Results: Eight weeks exposure to Pb-containing water resulted in pathological alterations, anti-oxidative system disorder in the brain, all of which were blocked by MGN in a Nrf2-dependent manner. Nrf2 downstream enzymes such as HO-1, NQO1, γ-GCS were activated. Nrf2, GCLC, GCLM, HO-1 mRNA and total Nrf2, Nuclear Nrf2, γ-GCS, HO-1 protein expression were affected too., Conclusion: MGN ameliorated morphological damage in the hippocampus. Its neuroprotective effects were achieved by the activation of the Nrf2 downstream genes. The data from this in vitro study indicates that MGN targeting Nrf2 activation is a feasible approach to reduce adverse health effects associated with Pb exposure. Thus, MGN could be an effective candidate agent for the Pb-induced oxidative stress and neurotoxicity in the human body., Competing Interests: The authors declare no conflict of interests., (© 2020 Tianjin Press of Chinese Herbal Medicines. Published by Elsevier B.V.)

Male infertility is closely associated with spermatogenesis disorders triggered by aberrant gene expression or abnormal signaling pathways in the testis. The mammalian target of rapamycin (mTOR) is a central regulator of cell metabolism, playing an important role in regulating cell proliferation, differentiation, translation, actin polymerization, cycle progression, energy metabolism, autophagy, and other cellular activities. PI3K-Akt and LKB1-AMPK, the two well-defined classic signal transduction pathways, regulate the expressions of mTOR and its downstream p70S6K/4EBP1 through different molecular pathways. Recent studies show that mTOR-p70S6K/4EBP1 signaling participates in the regulation of the proliferation and differentiation of testicular cells and spermatogenesis. This review focuses on the role of PI3K-Akt/LKB1- AMPK-mTOR signaling cascades in testis development and spermatogenesis, providing some new perspectives for the studies of the molecular mechanism underlying male sterility.

One,1-dichloro-2,2 bis(p-chlorophenyl) ethylene (p,p'-DDE), the major metabolite of 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. It has antiandrogenic effect. However, the mechanism by which p,p'-DDE exposure causes male reproductive toxicity remains unknown. To elucidate the mechanism underpinning the testicular effects of p,p'-DDE, we sought to investigate apoptotic effects and mRNA expression of apoptosis-associated genes in the testis of pubertal rats, including Fas, FasL, calpain-1, cytochrome c, Bax, Bcl-w, Bak, and caspase-3, -8, -9, -12. Animals were administered with different doses of p,p'-DDE (0, 20, 60, 100 mg/kg body weight) every other day by intraperitoneal injection for 10 days. The results indicated that p,p'-DDE exposure at over 20 mg/kg body weight showed the induction of apoptotic cell death. p,p'-DDE could induce decrease in SOD and GSH-Px activity of serum in 60 mg/kg body weight group. Significant elevations in the mRNA levels of Fas, FasL, calpain-1, cytochrome c, Bax, Bak, and caspase-3, -8, -9, -12 were observed in testis of rat treated with p,p'-DDE. Taken together, these results lead us to speculate that in vivo exposure to p,p'-DDE might induce testicular apoptosis in pubertal rats through the involvement of Fas/FasL, mitochondria and endoplasmic reticulum-mediated pathways., (Copyright © 2011 Wiley Periodicals, Inc.)

Objective: To explore the effects of p,p'-DDE and beta-BHC on the apoptosis of Sertoli cells in vitro via activation of Caspase., Methods: Sertoli cells were treated in vitro for 24 hours with a serial concentrations of p,p'-DDE (10, 30 and 50 micromol/L), beta-BHC (10, 30 and 50 micromol/L) and p,p'-DDE + beta-BHC (10, 30 and 50 micromol/L). The inhibitory group was first treated with 100 micromol/L Caspase-3 inhibitor Ac-DEVD-CHO treating for 2 hours before 50 micromol/L p, p'-DDE + 50 micromol/L beta-BHC 24 hours-treatment. The vitality of Sertoli cells was determined by MTT and the apoptosis rate was measured by AO/EB double fluorescence staining. The expressions of Caspase-3, Caspase-8 and Caspase-9 were determined by RT-PCR., Results: Average optical density (A) values were 0.498 +/- 0.039, 0.481 +/- 0.065, 0.397 +/- 0.032 and 0.286 +/- 0.049 in p,p'-DDE groups (10, 30, 50 and 70 micromol/L), and 0.518 +/- 0.103, 0.490 +/- 0.060, 0.454 +/- 0.054 and 0.302 +/- 0.030 in beta-BHC groups (10, 30, 50 and 70 micromol/L). In the mixture-treated groups (10, 30 and 50 micromol/L), the average A values were 0.483 +/- 0.048, 0.473 +/- 0.058 and 0.337 +/- 0.052. Compared with the solvent control group (0.527 +/- 0.022) , 50 micromol/L group of p, p'-DDE, beta-BHC or their mixture caused a significant decrease of Sertoli cell viability (t values were 4.599, 2.716, 6.537 respectively, P < 0.05). AO/EB double fluorescence staining analysis showed that apoptosis rates of Sertoli cells were significantly increased with all treated groups. The expressions of Caspase-3, Caspase-8 and Caspase-9 were upregulated as the concentrations of p,p'-DDE, beta-BHC and their mixture were increased., Conclusion: p,p'-DDE, beta-BHC and their mixture could induce the apoptosis of Sertoli cells in vitro which was associated with activation of Caspase-3 mediated by cleavage of Caspase-8 and Caspase-9.

Objective: To study the action mechanism of p,p'-DDE and/or beta-BHC on JNK and MAPK signal transduction pathways in rat Sertoli cells in vitro., Methods: We cultured the Sertoli cells isolated from rat testicular tissues for 2 days in vitro, divided them into a control group incubated with DMSO and 3 case groups exposed to p,p'-DDE and / or beta-BHC at the final concentration of 10, 30, 50 micromol/L for 24 hours, and then detected the expression levels of JNK and c-jun mRNA by two-step RT-PCR., Results: Twenty-four hours after p,p'-DDE treatment, the grayscale values of JNK mRNA were 0.068 +/- 0.001, 0.164 +/- 0.002, 0.207 +/- 0.006 and 0.499 +/- 0.017, and those of c-jun mRNA were 0.122 +/- 0.002, 0.157 +/- 0.006, 0.218 +/- 0.007 and 0.289 +/- 0.004 respectively in the DMSO control and the 10, 30 and 50 micromol/L groups. The expressions of JNK and c-jun mRNA were elevated with increased concentration of p,p'-DDE, with significant differences between the control and the case groups (P < 0.05), and they were also significantly upregulated in the beta-BHC and p,p'-DDE + beta-BHC groups in a dose-dependent manner. The grayscale values of JNK mRNA in the p,p'-DDE, beta-BHC and p,p'-DDE + beta-BHC groups at the concentration of 10 micromol/L were 0.164 +/- 0.002, 0.149 +/- 0.003 and 0.178 +/- 0.004, and those of c-jun mRNA were 0.157 +/- 0.006, 0.131 +/- 0.004 and 0.172 +/- 0.002, respectively, both significantly higher in the combination group than in the former two (P < 0.05). And the same was the case with the 30 and 50 micromol/L concentrations., Conclusion: Both p,p'-DDE and beta-BHC can enhance the expressions of JNK and c-jun in Sertoli cells, and their combination can produce even more obvious effect.

The extraction of active ingredient group, i.e., prim-o-glucosylcimifugin, astragaloside, and 5-o-methylvisammiosode from Yupingfeng powder with one-pot method was studied in this work. A HPLC method was used to determine the content of each active constituent mentioned above in the extract. The influences of extraction temperature, time, volume percent of ethanol in water and its amount added on the content and yield of active ingredient group were investigated by orthogonal test. The experimental results showed that the optimized extraction conditions were as follows: 1g of Yupingfeng powder was one-pot extracted for 4 hours at 80 degrees C with 90% ethanol as solvent, and the yield and content of active ingredient group were 0.16%, 0.53% respectively. The active ingredient group in Yupingfeng powder could be effectively one-pot extracted under the conditions above.

Objective: To investigate the effects of sodium selenite on telomerase activity and expression of hTERT mRNA in cadmium-transformed 16HBE cells., Methods: Telomerase activity and expression of genes were measured after cultured cadmium-transformed 16HBE cells were exposed to sodium selenite at different doses (0.625, 1.25, 2.50, 5.00 micromol/L) for 24 hours., Results: Selenium decreased telomerase activity in cadmium-transformed 16HBE cells. There existed an obvious dose-effect relationship between the selenium concentration and these changes. The expression of hTERT and c-myc mRNA also decreased but the expression of mad1 mRNA increased after exposure to selenium for 24 hours. No difference was found in expression of hTRF1 and hTRF2 mRNA after incubated with sodium selenite for 24 hours, compared with control group., Conclusion: Selenium inhibits telomerase activity by decreasing hTERT and c-myc mRNA expression and increasing mad1 mRNA expression in cadmium-transformed 16HBE cells and selenium concentration is significantly correlated with these changes.

Objective: To study the effects of p, p'-DDE on DNA damage and expression of FasL gene of rat Sertoli cell in vitro., Methods: After separating Sertoli cells from testicular tissue of rats, we cultured these cells for 3 days and then added different doses of p, p'-DDE into the culture medium to study its effect on DNA damage and FasL gene expression with the method of SCGE and RT-PCR., Results: DNA migration and FasL gene expression of Sertoli cell significantly increased with the increase of the dose of p, p'-DDE., Conclusion: p, p'-DDE could induce DNA damage and FasL gene expression of Sertoli cells of rat testis. p, p'-DDE might induce the Sertoli cell damage and destroy the dynamic process of spermatogenesis through the Fas/FasL pathway, which might lead to oligozoospermatism.

Objective: To explore effects of p, p'-DDE and beta-BHC on reproduction and development in mice., Methods: The pregnant Kunming SPF mice of 12 to 14 days were co-administered by oral gavage for 3 days at different concentrations of 0, 1, 5 and 10 mg/kg bw of p, p'-DDE and beta-BHC. The concentrations of estradiol (E2) and progesterone (P) in sera of the dosed mice were determined by the Serozyme kits (Bio-Ekon biotechnology Co., Beijing, China), following the procedures described by the manufacturer. RT-PCR was employed to detect abundant expression of alpha-estrogen receptor (alpha-ER) gonadtropin releasing hormone (GnRH) and beta-endorphin (beta-EP) mRNA in placentae., Results: (1) Reproductive effects: with increase of the administered p,p'-DDE and P-BHC,the organ coefficient of uterus and its intraluminal fluid increased, the unterine nidation quantity decreased, the anogenital distance (AGD) and ratio of female to male raised, the concentration of estradiol and progesterone in sera of the dosed mice went up, and the abundant expression of alpha-ER and GnRH mRNA rised while beta-EP dropped in placentae in a dose-dependant manner. Significant difference of these indexes were found between the treat groups and control (P < 0.05). (2) Developmental effects: with increase of the administered p,p'-DDE and beta-BHC, the gained weights of pregnant mice reduced, organ coefficient of liver increased,the quantity of live foetus decreased, the times of adverse pregnancy outcome went up, and the percent of female foetus increased. They all presented a dose-effect relation and significance of difference (P < 0.05)., Conclusion: p, p'-DDE and beta-BHC disrupt reproductive function, thereby result in dysreproduction and maldevelopment, and unbalance of ratio of female to male.

Objective: To explore effects of p, p'DDE on the expression of androgen binding protein (ABP), transferrin (Tf) and inhibin B (INH B) mRNA in testis Sertoli cells of Sprague Dawley rats., Methods: A method has been set up to obtain a large number of viable Sertoli cells from SD rats of 18-20 days of age. With a series of concentration p,p'-DDE (10, 30, and 50 micromol/L) co-incubating the Sertoli cells in vitro, the expression of ABP, Tf and INH B mRNA were determined by RT-PCR., Results: a) With increase of the incubated p, p'-DDE, the expression of ABP mRNA in Sertoli cells went up while that of Tf and INH B dropped in a dose-dependent manner (P < 0. 05). b) The correlation analysis among ABP, Tf and INH B showed that negative relationships were found between ABP and Tf or INH B, respectively (r = - 0. 391 3, P = 0. 032 5; r = - 0.235 2, P = 0.0158), and that positive correlation was indicated between Tf and INH B (r =0.4516, P =0.0047)., Conclusion: p,p'-DDE is a reproductive toxicant which disrupts the transcription of ABP, Tf and INH B in rat Sertoli cells so as to result in reproductive dysfunction.

Objective: To study the effects of sodium selenite on expression of telomerase reverse transcriptase mRNA, c-Myc and p53 induced by cadmium chloride in rat liver., Methods: Male SD rats were divided randomly into 6 groups, each group had 5 animals. The groups comprised the control group, Se group (5 micromol/kg sodium selenite), 5 micromol/kg cadmium chloride group, 10 micromol/kg cadmium chloride group, Se (5 micromol/kg sodium selenite) + 5 micromol/kg cadmium chloride group, Se (5 micromol/kg sodium selenite) + 10 micromol/kg cadmium chloride group. After 48 hours of the first injection, the expression of TERT mRNA was measured with RT-PCR and c-Myc, and p53 proteins were measured by immunohistochemistry method., Results: Compared with control group, the expression of TERT was increased in 5 micromol/kg Cd group and 10 micromol/kg Cd group, c-Myc protein was increased in 10 micromol/kg Cd group, and the expression of p53 protein was increased in 5 micromol/kg group and 10 micromol/kg Cd group. TERT expression in Se + 10 micromol/kg Cd group was lower than that of 10 micromol/kg Cd group significantly. c-Myc protein was decreased in Se + 10 micromol/kg Cd group compared with 10 micromol/kg Cd group. p53 protein of Se + 5 micromol/kg Cd group and Se + 10 micromol/kg Cd group were decreased significantly compared with 5 micromol/kg Cd group and 10 micromol/kg Cd group respectively., Conclusion: The cadmium at the doses of between 5 and 10 micromol/kg can activate TERT and up-regulate c-Myc and p53 proteins. The selenium at the dose of 5 micromol/kg has the antagonistic effect on expression of TERT, c-Myc and p53 induced by cadmium in rat liver.

Objective: To explore effects of residues of organochlorine pesticides on reproductive endocrine in human., Methods: The accumulative levels of the pesticides in the pregnant women's venous blood were determined and were grouped to understand the associations among the pesticides, hormones, and genes., Results: (1) With the increase of blood burden of organochlorine pesticides, levels of the hormones such as follicle stimulating hormone (FSH), estradiol (E2) and progesterone (P) in the maternal blood and FSH, luteinizing hormone (LH) and E2 in the umbilical cord blood increased in dose-effect manner, respectively. However, the hormones, for example, LH in the women blood and P in the cords blood decreased respectively with the rising pesticides' levels and an obvious dose-effect relationship was found. (2) The expressional abundances of alpha-estrogen receptor (alpha-ER), beta-endorphin (beta-EP) and gonadotropin releasing hormone (GnRH) in the placentae and alpha-ER and beta-EP in the cord tissues went up respectively in dose-effect manner following the rising pesticides' burdens. (3) The times of the previous adverse pregnancy outcomes increased with the increase of the residues' burdens and there were significant differences between the control and various residue groups, but the times in the high-residue was smaller than that in the mid-residue group (P < 0.01). The average weights of the newborn in various residue groups were heavier comparing to the control. There was no significant difference between the high residue group and the control. However, significances existed among the low, intermediate, and control group (P < 0.05). Moreover, the rank from high to low was the low-residue, mid-residue and high residue group., Conclusion: The residues of organochlorine pesticides (DDT and BHC and their metabolites) possess reproductive and developmental toxicities, and present mostly the estrogenic activity under the joint exposure in which the total BHC concentration was higher than that of the total DDT in maternal blood.

Objective: To investigate the effects of fluoride on lipid peroxidation, DNA damage and apoptosis in human embryo hepatocyte L-02 cells., Methods: Lipid peroxide (LPO) level, reduced glutathione (GSH) content, DNA damage, apoptosis, and cell cycle analysis were measured after in vitro cultured L-02 cells were exposed to sodium fluoride at different doses (40 microg/mL, 80 microg/mL, and 160 microg/mL) for 24 hours., Results: Fluoride caused an increase of LPO levels and a decrease of GSH content in L-02 cells. There appeared to be an obvious dose-effect relationship between the fluoride concentration and the observed changes. Fluoride also caused DNA damage and apoptosis and increased the cell number in S phase of cell cycle in the cells tested. There was a statistically significant difference in DNA damage and apoptosis when comparing the high dose of fluoride treated cells with the low dose of fluoride treated cells., Conclusion: Fluoride can cause lipid peroxidation, DNA damage, and apoptosis in the L-02 cell experimental model and there is a significant positive correlation between fluoride concentration and these pathological changes.

Objective: To study the production technology of extraction in combination hydrolysis in situ for isolating diosgenin from Dioscorea nipponica by orthogonal design., Method: The optimum production conditions were investigated with the recovery of diosgenin as an index by extraction in combination hydrolysis in situ, and were compared with the traditional method., Result: Extraction in combination hydrolysis in situ conducted in 1.5 mol x L(-1) sulfuric acid of water containing 75% isopropanol at 100 degrees C for 4.5 h could get higher recovery of diosgenin than traditional methods., Conclusion: This production technology can get higher recovery of diosgenin, and it is simple, time and money saving.