Повышение эффективности контекстной рекламы в Интернете

Рассмотрены пути повышения эффективности рекламной кампании на площадках поисковых систем. Предложен подход к формированию рабочей группы ключевых слов, используемых в рекламных предложениях, разработан механизм изменения состава группы. Выработаны рекомендации по формированию и коррекции цены предложения на рекламном аукционе Google. Выполнена проверка предложенных решений на основе практических данных коммерческой фирмы, занимающейся контекстной рекламой на площадке поисковой системы.Розглянуто шляхи підвищення ефективності рекламної кампанії на площадках пошукових систем. Запропоновано підхід до формування робочої групи ключових слів, використовуваних у рекламних пропозиціях, розроблений механізм зміни складу групи. Вироблено рекомендації з формування й корекції ціни пропозиції на рекламному аукціоні Google. Виконано перевірку запропонованих рішень на основі практичних даних комерційної фірми, що займається контекстною рекламою на площадці пошукової системи.During article were examined new ways of Internet search system advertising efficiency increasing. Have been suggested method of creation optimal keywords workgroup(which are used in advertising sentences) approach. Have been worked out recommendations for bid fixing and correction. on Google advertising auction. Suggested conceptions were tested and implemented on real busyness information of internet-advertising company, which is mostly concentrated on context advertisin

Применение технологии набрызгбетонирования в Новоавстрийском Методе Туннелирования (NATM)

У статті проаналізовані суть і основні принципи Новоавстрійського Методу Тунелювання (NATM), що широко застосовується в зарубіжній практиці будівництва транспортних тунелів. Також розглянуто застосування технології торкретування, яка лежить в основі методу.Essence and basic principles of New Austrian Tunnelling Method (NATM), which widely used in foreign practice building of transport tunnels, is analysed in the article. Application of gunite technology, being the basis of method, is also considered

Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause-effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman's reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause-effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.Peer reviewe

Evaluation of relative effect potencies (REPs) for dioxin-like compounds to derive systemic or human-specific TEFs to improve human risk assessment

Toxic equivalency factors (TEFs) are generally applied for estimating human risk of dioxins and dioxin-like compounds using systemic (e.g., blood) levels, even though these TEFs are established based on intake doses in rodent studies. This review shows that systemic relative effect potencies (REPs) can deviate substantially from intake REPs, but are similar to in vitro-derived REPs. Interestingly, the in vitro REPs for 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) and 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) are up to one order of magnitude higher than their in vivo REPs and WHO-TEFs, based on oral intake. In addition, clear species-differences in in vitro REPs were apparent for some congeners. Especially the human-derived REP for polychlorinated biphenyl 126 is one to two orders of magnitude lower than rodent REPs and its current WHO-TEF. Next, suggested adapted systemic or human-specific TEFs for these congeners were applied to calculate changes in systemic TEQ concentrations in studies from the USA, Germany and Japan and compared with either the JECFA TDI or USEPA RfD of TCDD. Overall, the effect of such TEF changes for these three congeners on total TEQ roughly balances each other out in the general population. However, results may be different for situations in which a specific group of congeners dominates. For those congeners that show a distinct deviation between either intake and systemic REPs or between rodent- and human-based in vitro REPs, we propose that especially REPs derived from human-based in vitro models are weighted more heavily in establishing systemic or human-specific TEF values to improve human health risk assessment

Tissue distribution of dioxin-like compounds: potential impacts on systemic relative potency estimates

Relative effect potencies (REPs) for dioxins and dioxin-like compounds based on tissue concentration or internal dose ( REPs) can be considered of high relevance for human risk assessment. Within the EU-project SYSTEQ, REPs for 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8,-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,3',4,4',5-pentachlorobiphenyl (PCB 118) and 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156) were calculated based on a plasma, adipose tissue or liver concentration in Sprague Dawley rats and C57bl/6 mice three days after a single oral dose. Compound-specific distribution as well as differences in accumulation and elimination can influence the tissue concentration and thereby the relative potency estimate of a congener. Here, we show that distribution patterns are generally similar for the tested congeners between the SYSTEQ dataset and other studies using either a single dose or subchronic dosing. Furthermore, the responding concentration for TCDD in single dose studies is comparable to the responding concentrations reported in subchronic studies. In contrast with data for laboratory rodents, available distribution data for humans in the general population display little or no hepatic sequestration. Because hepatic sequestration due to CYP1A2 protein binding may affect the amount of congener that is bioavailable for the AhR to produce hepatic responses, estimates of relative potencies between congeners with differing degrees of hepatic sequestration based on hepatic responses may be misleading for application to human risk assessment. Therefore, extra-hepatic concentration in blood serum/plasma or adipose tissue together with a biological extra-hepatic response might give a more accurate prediction of the relative potency of a congener for human responses under environmental conditions

Comparison of Intake and Systemic Relative Effect Potencies of Dioxin-like Compounds in Female Mice after a Single Oral Dose

BACKGROUND: Risk assessment for mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) is performed using the toxic equivalency factor (TEF) approach. These TEF values are derived mainly from relative effect potencies (REPs) linking an administered dose to an in vivo toxic or biological effect, resulting in "intake" TEFs. At present, there is insufficient data available to conclude that intake TEFs are also applicable for systemic concentrations (e. g., blood and tissues). OBJECTIVE: We compared intake and systemic REPs of 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3', 4,4', 5-pentachlorobiphenyl (PCB-126), 2,3', 4,4', 5-pentachlorobiphenyl (PCB-118), and 2,3,3', 4,4', 5-hexachlorobiphenyl (PCB-156) in female C57BL/6 mice 3 days after a single oral dose. METHODS: We calculated intake REPs and systemic REPs based on administered dose and liver, adipose, or plasma concentrations relative to TCDD. Hepatic cytochrome P450 1Al-associated ethoxyresorufin-O-deethylase (EROD) activity and gene expression of Cyp1a1, 1a2 and 1b1 in the liver and peripheral blood lymphocytes (PBLs) were used as biological end points. RESULTS: We observed up to one order of magnitude difference between intake REPs and systemic REPs. Two different patterns were discerned. Compared with intake REPs, systemic REPs based on plasma or adipose levels were higher for PeCDD, 4-PeCDF, and PCB-126 but lower for the mono-ortho PCBs 118 and 156. CONCLUSIONS: Based on these mouse data, the comparison between intake REPs and systemic REPs reveals significant congener-specific differences that warrants the development of systemic TEFs to calculate toxic equivalents (TEQs) in blood and body tissues

Comparison of intake and systemic relative effect potencies of dioxin-like compounds in female rats after a single oral dose

Risk assessment for mixtures of dioxin-like compounds uses the toxic equivalency factor (TEF) approach. Although current WHO-TEFs are mostly based on oral administration, they are commonly used to determine toxicity equivalencies (TEQs) in human blood or tissues. However, the use of "intake" TEFs to calculate systemic TEQs in for example human blood, has never been validated. In this study, intake and systemic relative effect potencies (REPs) for 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3′,4,4′,5-pentachlorobiphenyl (PCB-126), 2,3′,4,4′,5-pentachlorobiphenyl (PCB-118) and 2,3,3′,4, 4′,5-hexachlorobiphenyl (PCB-156) were compared in rats. The effect potencies were calculated based on administered dose and liver, adipose or plasma concentrations in female Sprague-Dawley rats 3 days after a single oral dose, relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hepatic ethoxyresorufin-O-deethylase activity and gene expression of Cyp1a1, 1a2, 1b1 and aryl hydrocarbon receptor repressor in liver and peripheral blood lymphocytes were used as endpoints. Results show that plasma-based systemic REPs were generally within a half log range around the intake REPs for all congeners tested, except for 4-PeCDF. Together with our previously reported systemic REPs from a mouse study, these data do not warrant the use of systemic REPs as systemic TEFs for human risk assessment. However, further investigation for plasma-based systemic REPs for 4-PeCDF is desirable

Induction of glutathione synthesis and conjugation by 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dihydroxymethamphetamine (HHMA) in human and rat liver cells, including the protective role of some antioxidants

MDMA (3,4-methylenedioxymethamphetamine) metabolism is a major cause of MDMA-mediated hepatotoxicity. In this study the effects of MDMA and its metabolites on the glutathione system were evaluated. Glutathione (GSH/GSSG) levels and gene expression of glutamate cysteine ligase catalytic subunit (GCLC), glutathione-S-transferase (GST) and pregnane X receptor (PXR) were compared in the immortalized human liver epithelial cell line THLE-Neo lacking phase I metabolism and primary rat hepatocytes expressing both phase I and II metabolism. Furthermore, we evaluated the potential protective effects of two antioxidants, N-acetyl-cysteine (NAC) and sulforaphane (SFN) in these cell systems. In THLE-Neo cells, the MDMA metabolite 3,4-dihydroxymetamphetamine (HHMA) significantly decreased cell viability and depleted GSH levels, resulting in an increased expression of GCLC and GST up to 3.4- and 2.2-fold, respectively. In primary rat hepatocytes, cell viability or GSH levels were not significantly affected upon MDMA exposure. GCLC expression levels where not significantly altered either, although GST expression was increased 2.3-fold. NAC counteracted MDMA-induced cytotoxicity and restored GSH levels. Phase II enzyme expression was also reverted. Conversely, SFN increased MDMA-induced cytotoxicity and GSH depletion, while GCLC and GST expression were significantly induced. In addition, PXR expression decreased after HHMA and MDMA exposure, while co-exposure to SFN induced it up to 3.6- and 3.9-fold compared to vehicle-control in the THLE-Neo cells and rat hepatocytes, respectively. Taken together, these data indicate that HHMA is a major factor in the MDMA-mediated hepatotoxicity through interaction with the glutathione system. The results of our study show that for MDMA intoxication the treatment with an antioxidant such as NAC may counteract the potentially hepatotoxicity. However, SFN supplementation should be considered with care because of the indications of possible drug-drug interactions