Studies on the metabolism and toxicity of hydrazine.

ABSTRACT Hydrazine is extensively utilised in industry and is a m inor metabolite of the clinically used drugs isoniazid and hydralazine. It is toxic, carcinogenic and mutagenic, but the metabolism and biochemical mechanisms of toxicity are not yet fu lly understood. Isolated rat liver microsomes incubated w ith both 2.0 mM and 0.2 m M hydrazine in the presence of NADPH and oxygen at 37°C resulted in the disappearance of hydrazine, which was demonstrated to be due to both enzymatic and chemical oxidation. Boiled microsomes increased the proportion of chemical disappearance whereas incubating the microsomes on ice effectively eliminated it. Further in vitro microsomal studies therefore incorporated samples incubated on ice as controls, allow ing the microsomal enzymatic metabolism of hydrazine to be calculated. Absence of NADPH and oxygen markedly reduced microsomal hydrazine metabolism, as did the presence of each of the cytochrome P450 inhibitors carbon monoxide, piperonyl butoxide and metyrapone, thus indicating that microsomal hydrazine metabolism is catalysed by cytochrome P450. Methimazole, an inhibitor of flavin monooxygenase, also diminished hydrazine metabolism, whereas N ADH in the presence of NADPH, but not alone, increased metabolism. Microsomes prepared from either p-naphthoflavone, acetone or isoniazid pretreated rats did not show significantly increased hydrazine metabolism compared to control microsomes per g protein. However phenobarbitone pretreatment did increase metabolism. Hydrazine metabolism was 20-70% lower in human microsomes prepared from 3 individuals compared to control rats. The dose response for hydrazine hepatotoxicity in vivo, as manifested by triglyceride increase and depletion of ATP and glutathione (GSH), was measured in control rats 6 hr after an i.p. dose. This was then compared to animals which had been pretreated w ith various inhibitors and inducers of cytochrome P450. Pretreatment w ith the inhibitor piperonyl butoxide resulted in an increase in hepatotoxicity, while induction by phenobarbitone (inducer of P450IIB) or p-naphthoflavone (inducer of P450IA) decreased hepatotoxicity. In contrast, acetone or isoniazid (inducers of II PREVIEW x ic /v iixj/ iaiu u ^ u u ii vauovu an 111^1 gaov 111 iic |/a iu iU A iu ijr, i n c 11 i u u u ia u u ii u i hydrazine hepatotoxicity by such pretreatments indicates that different isozymes of cytochrome P450 catalyse the metabolic transformation of hydrazine toxicity by various mechanisms. 6 hr after an acute i.p. hydrazine dose, certain dose related alterations in hepatic microsomal enzyme activity were measured, including a depletion in ethoxyresorufin O-deethylase and p-nitrophenol hydroxylase activity. Repeated adm inistration of 0.78 mM hydrazine in drinking water (2.5 m g.kg^.day'1) had a significant effect on several hepatic biochemical parameters and microsomal enzyme activities after 1,5 and 10 days. This indicated hydrazine to be a probable inducer of cytochrome P450IIE1. Hepatic biochemical parameters and activities of microsomal enzymes were virtually unchanged after repeated administration of 65 pM hydrazine in drinking water (0.25 m g.kg'1.day’1) for 5 or 10 days. In the presence of over 5 pM hydrazine, ATP synthesis in isolated mitochondria was inhibited. Inhibition up to 100 pM hydrazine was found to be dose related and reached a maximum 20-30% inhibition of control. However, above this concentration further inhibition did not occur. Hydrazine was also found to be metabolised by isolated mitochondria, which was not significantly decreased in the presence of either the monoamine oxidase A inhibitor, clorgyline or B inhibitor, pargyline

Enterprise information security risks: a systematic review of the literature

Currently, computer security or cybersecurity is a relevant aspect in the area of networks and communications of a company, therefore, it is important to know the risks and computer security policies that allow a unified management of cyber threats that only seek to affect the reputation or profit from the confidential information of organizations in the business sector. The objective of the research is to conduct a systematic review of the literature through articles published in databases such as Scopus and Dimension. Thus, in order to perform a complete documentary analysis, inclusion and exclusion criteria were applied to evaluate the quality of each article. Then, using a quantitative scale, articles were filtered according to author, period and country of publication, leaving a total of 86 articles from both databases. The methodology used was the one proposed by Kitchenham, and the conclusion reached was that the vast majority of companies do not make a major investment in the purchase of equipment and improvement of information technology (IT) infrastructure, exposing themselves to cyber-attacks that continue to grow every day. This research provides an opportunity for researchers, companies and entrepreneurs to consult so that they can protect their organization's most important assets

Influencia del uso de arena de cuarzo en el desgaste de adoquines que incorporan aluminato de estroncio

La presente investigación se llevó a cabo para diseñar adoquines bicapa fluorescentes con una resistencia a la compresión de 350 kgf/cm2. Estos adoquines incorporaron aluminato de estroncio (SrAl2O4:M), (M=Eu2+, Dy3+) y cuarzo (SiO2) en la mezcla, y se evaluó su influencia en el desgaste de la capa de rodadura. Para ello, se realizaron pruebas para determinar las propiedades físicas y mecánicas de los agregados, los cuales calificaron para ser utilizados en el diseño de la mezcla empleada en la fabricación de los adoquines. Una vez fabricado los adoquines, se llevaron a cabo pruebas de resistencia a la compresión y desgaste (método Böhme). Los resultados de compresión mostraron que, la combinación de aluminato de estroncio y cuarzo, no mejoraron la resistencia a la compresión, sin embargo, a los 14 días de curado la resistencia superaron sin dificultad los 350 kgf/cm2. En cuanto al desgaste, la influencia del SrAl2O4:M y SiO2, contribuyen a la disminución del desgaste en adoquines y el máximo valor que se registró fue de 11 765,13 mm3/5 000 mm2. Por otro lado, dosificar el SrAl2O4:M, respecto al peso del cemento no se obtuvieron resultados visibles de la intensidad de la luminiscencia, por tal motivo se fabricaron especímenes dosificados al peso de la mezcla del recibimiento.The present research was conducted to design fluorescent bilayer pavers with a compression strength of 350 kgf/cm2. These pavers incorporated strontium aluminate (SrAl2O4:M), (M=Eu2+, Dy3+) and quartz (SiO2) in the mix, and their influence on the wear of the wearing layer was evaluated. To achieve this, tests were carried out to determine the physical and mechanical properties of the aggregates, which qualified for use in the mix design employed in the manufacturing of the pavers. Once the pavers were manufactured, tests for compression strength and wear (Böhme method) were conducted. The compression results showed that the combination of strontium aluminate and quartz did not improve the compression strength; however, after 14 days of curing, the strength easily surpassed 350 kgf/cm2. Regarding wear, the influence of SrAl2O4:M and SiO2 contributed to the reduction of wear in the pavers, with the maximum recorded value being 11 765,13 mm3/ 5 000 mm2. On the other hand, dosing SrAl2O4:M, relative to the weight of the cement, did not yield visible results of the luminosity intensity; therefore, specimens were manufactured dosed based on the weight of the mix used

Impact of submarine groundwater discharge on biogeochemistry and microbial communities in pockmarks

The impact of submarine groundwater discharge (SGD) on coastal sea biogeochemistry has been demonstrated in many recent studies. However, only a few studies have integrated biogeochemical and microbiological analyses, especially at sites with pockmarks of different degrees of groundwater influence. This study investigated biogeochemical processes and microbial community structure in sediment cores from three pockmarks in Hanko, Finland, in the northern Baltic Sea. Pockmark data were supplemented by groundwater and seawater measurements. Two active pockmarks showed SGD rates of 0.02 cm d-1 and 0.31 cm d-1, respectively, based on porewater Cl- profiles, while a third pockmark had no SGD influence. Reactive transport modelling (RTM) established that the porewater systems of these active pockmarks are dominated by advection, resulting in the focusing of biogeochemical reactions and the microbial community into a thin zone at the sediment surface. The advection further reduces the accumulation of organic matter in the surface sediments, resulting in the absence of a sulfate-methane transition zone (SMTZ) at these pockmarks. Furthermore, the RTM estimated low rates of consumption of SO42-, and low rates of production of CH4, NH4+, DIC at the active pockmarks. Archaeal communities in the active pockmarks were dominated by ammonia-oxidizing archaea of predominantly groundwater origin. In contrast, at the inactive pockmark, the lack of SGD has permitted rapid deposition of organic-rich mud. The porewater system in the inactive pockmark is dominated by diffusion, leading to orders of magnitude higher metabolite concentrations at depth compared to the active pockmarks. The biogeochemical environment in the inactive pockmark resembles typical organic-rich mud seafloor in the area, with sulphate reduction and methanogenesis dominating organic matter remineralization. Accordingly, methanogens dominate the archaeal community, whereas sulfate reducers dominate the bacterial community. RTM results suggest that sulfate-mediated anaerobic oxidation of methane (S-AOM) also occurs at this site. Although depth-integrated fluxes of SO42-, CH4, NH4, DIC at the inactive pockmark are orders of magnitude higher compared to the active pockmarks, processes at the inactive pockmark represent internal recycling in the coastal sea. Fluxes observed at the active pockmarks, although comparatively small in magnitude, are partly influenced by external inputs to the sea through SGD. Hence, effluxes across the sediment-water interface at these sites partly represent direct external fluxes to the marine environment, in addition to diagenetic recycling at the benthic interface. The study highlights that SGD can result in significant spatial heterogeneity of biogeochemical processes and microbial community structure in the coastal zone, and that the overall effects of SGD and associated solute fluxes at an SGD site are a function of the number of pockmarks, the rate of SGD, and the ratio of active to inactive pockmarks.Peer reviewe

Project BRAHSS: behavioural response of Australian humpback whales to seismic surveys.

BRAHSS is a major project aimed at understanding how humpback whales respond to noise, particularly from seismic air gun arrays. It also aims to infer the longer term biological significance of the responses from the results and knowledge of normal behaviour. The aim is to provide the information that will allow seismic surveys to be conducted efficiently with minimal impact on whales. It also includes a study of the response to ramp-up in sound level. Ramp-up is widely used at the start of operations as a mitigation measure intended to cause whales to move away, but there is little information to show that it is effective. BRAHSS involves four experiments with migrating humpback whales off the east and west coasts of Australia with noise exposures ranging from a single air gun to a full seismic array. Two major experiments have been completed off the east coast, the second involving 70 scientists. Whale movements were tracked using theodolites on two high points ashore and behavioural observations were made from these points and from three small vessels and the source vessel. Vocalising whales were tracked underwater with an array of hydrophones. These and other moored acoustic receivers recorded the sound field at several points throughout the area. Tags (DTAGs) were attached to whales with suction caps for periods of several hours. Observations and measurements during the experiments include the wide range of variables likely to affect whale response and sufficient acoustic measurements to characterise the sound field throughout the area. The remaining two experiments will be conducted further off shore off the west coast in 2013 and 2014

Exhausted CD4+ T Cells during Malaria Exhibit Reduced mTORc1 Activity Correlated with Loss of T-bet Expression

CD4<sup>+</sup> T cell functional inhibition (exhaustion) is a hallmark of malaria and correlates with impaired parasite control and infection chronicity. However, the mechanisms of CD4<sup>+</sup> T cell exhaustion are still poorly understood. In this study, we show that Ag-experienced (<i>Ag-exp</i>) CD4<sup>+</sup> T cell exhaustion during <i>Plasmodium yoelii</i> nonlethal infection occurs alongside the reduction in mammalian target of rapamycin (mTOR) activity and restriction in CD4<sup>+</sup> T cell glycolytic capacity. We demonstrate that the loss of glycolytic metabolism and mTOR activity within the exhausted <i>Ag-exp</i>CD4<sup>+</sup> T cell population during infection coincides with reduction in T-bet expression. T-bet was found to directly bind to and control the transcription of various mTOR and metabolism-related genes within effector CD4<sup>+</sup> T cells. Consistent with this, <i>Ag-exp</i>Th1 cells exhibited significantly higher and sustained mTOR activity than effector T-bet- (non-Th1) <i>Ag-exp</i>T cells throughout the course of malaria. We identified mTOR to be redundant for sustaining T-bet expression in activated Th1 cells, whereas mTOR was necessary but not sufficient for maintaining IFN-γ production by Th1 cells. Immunotherapy targeting PD-1, CTLA-4, and IL-27 blocked CD4<sup>+</sup> T cell exhaustion during malaria infection and was associated with elevated T-bet expression and a concomitant increased CD4<sup>+</sup> T cell glycolytic metabolism. Collectively, our data suggest that mTOR activity is linked to T-bet in <i>Ag-exp</i>CD4<sup>+</sup> T cells but that reduction in mTOR activity may not directly underpin <i>Ag-exp</i>Th1 cell loss and exhaustion during malaria infection. These data have implications for therapeutic reactivation of exhausted CD4<sup>+</sup> T cells during malaria infection and other chronic conditions

EFFECTS OF CIMETIDINE AND RANUTIDINE ON HALOTHANE METABOLISM AND HEPATOTOXICITY IN AN ANIMAL MODEL

ABSTRACT: This study was undertaken to determine the effects of two Hrscsptor antagonists, cimetidine and ranitidine, on halothane metabolism and hepatotoxlclty In the hypoxic FlsMr 344 rat model for halothane he s

RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth

In B cells infected by the cancer-associated Epstein-Barr virus (EBV), RUNX3 and RUNX1 transcription is manipulated to control cell growth. The EBV-encoded EBNA2 transcription factor (TF) activates RUNX3 transcription leading to RUNX3-mediated repression of the RUNX1 promoter and the relief of RUNX1-directed growth repression. We show that EBNA2 activates RUNX3 through a specific element within a −97 kb super-enhancer in a manner dependent on the expression of the Notch DNA-binding partner RBP-J. We also reveal that the EBV TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element. Uncovering a counter-regulatory feed-forward step, we demonstrate EBNA2 activation of a RUNX1 super-enhancer (−139 to −250 kb) that results in low-level RUNX1 expression in cells refractory to RUNX1-mediated growth inhibition. EBNA2 activation of the RUNX1 super-enhancer is also dependent on RBP-J. Consistent with the context-dependent roles of EBNA3B and EBNA3C as activators or repressors, we find that these proteins negatively regulate the RUNX1 super-enhancer, curbing EBNA2 activation. Taken together our results reveal cell-type-specific exploitation of RUNX gene super-enhancers by multiple EBV TFs via the Notch pathway to fine tune RUNX3 and RUNX1 expression and manipulate B-cell growth

Does increasing treatment frequency address sub-optimal responses to ivermectin for the control and elimination of river blindness?

Background Several African countries have adopted a biannual ivermectin distribution strategy in some foci to control and eliminate onchocerciasis. In 2010, the Ghana Health Service started biannual distribution to combat transmission hotspots and sub-optimal responses to treatment. We assessed the epidemiological impact of the first 3 years of this strategy and quantified responses to ivermectin over two consecutive rounds of treatment in 10 sentinel communities. Methods We evaluated Onchocerca volvulus microfilarial intensity and prevalence in those aged +/-20 years before the first, second and fifth (or sixth) biannual treatment rounds using skin snip data from 956 participants. We used longitudinal regression modelling to estimate rates of microfilarial repopulation of the skin in a cohort of 217 participants who were followed-up over the first two rounds of biannual treatment. Results Biannual treatment has had a positive impact, with substantial reductions in infection intensity after 4 or 5 rounds in most communities. We identified three communities—all having been previously recognised as responding sub-optimally to ivermectin—with statistically significantly high microfilarial repopulation rates. We did not find any clear association between microfilarial repopulation rate and the number of years of prior intervention, coverage, or the community level of infection. Conclusions The strategy of biannual ivermectin treatment in Ghana has reduced O. volvulus microfilarial intensity and prevalence, but sub-optimal responses to treatment remain evident in a number of previously and consistently implicated communities. Whether increasing the frequency of treatment will be sufficient to meet the World Health Organization’s 2020 elimination goals remains uncertain