Bisphenol A sulfonation is impaired in metabolic and liver disease

Background: Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. The liver metabolizes and facilitates BPA excretion through glucuronidation and sulfonation. The sulfotransferase enzymes contributing to BPA sulfonation (detected in human and rodents) is poorly understood. Objectives: To determine the impact of metabolic and liver disease on BPA sulfonation in human and mouse livers. Methods: The capacity for BPA sulfonation was determined in human liver samples that were categorized into different stages of metabolic and liver disease (including obesity, diabetes, steatosis, and cirrhosis) and in livers from ob/ob mice. Results: In human liver tissues, BPA sulfonation was substantially lower in livers from subjects with steatosis (23%), diabetes cirrhosis (16%), and cirrhosis (18%), relative to healthy individuals with non-fatty livers (100%). In livers of obese mice (ob/ob), BPA sulfonation was lower (23%) than in livers from lean wild-type controls (100%). In addition to BPA sulfonation activity, Sult1a1 protein expression decreased by 97% in obese mouse livers. Conclusion: Taken together these findings establish a profoundly reduced capacity of BPA elimination via sulfonation in obese or diabetic individuals and in those with fatty or cirrhotic livers versus individuals with healthy livers

Monoamine Neurotransmitters as Substrates for Novel Tick Sulfotransferases, Homology Modeling, Molecular Docking, and Enzyme Kinetics

Blacklegged ticks (Ixodes scapularis) transmit the causative agent of Lyme disease in the Northeastern United States. Current research focuses on elucidating biochemical pathways that may be disrupted to prevent pathogen transmission, thereby preventing disease. Genome screening reported transcripts coding for two putative sulfotransferases in whole tick extracts of the nymphal and larval stages. Sulfotransferases are known to sulfonate phenolic and alcoholic receptor agonists such as 17β-estradiol, thereby inactivating the receptor ligands. We used bioinformatic approaches to predict substrates for Ixosc Sult 1 and Ixosc Sult 2 and tested the predictions with biochemical assays. Homology models of 3D protein structure were prepared, and visualization of the electrostatic surface of the ligand binding cavities showed regions of negative electrostatic charge. Molecular docking identified potential substrates including dopamine, R-octopamine and S-octopamine, which docked into Ixosc Sult 1 with favorable binding affinity and correct conformation for sulfonation. Dopamine, but not R- or S-octopamine, also docked into Ixosc Sult 2 in catalytic binding mode. The predictions were confirmed using cytosolic fractions of whole tick extracts. Dopamine was a good substrate (Km = 0.1−0.4 μM) for the native Ixodes scapularis sulfotransferases from larval and nymphal stages regardless of their fed/unfed status. Octopamine sulfonation was detected only after feeding when gene expression data suggests that Ixosc Sult 1 is present. Because dopamine is known to stimulate salivation in ticks through receptor stimulation, these results imply that the function(s) of Ixosc Sult 1 or 2 may include inactivation of the salivation signal via sulfonation of dopamine and/or octopamine

Učinak resveratrola na razinu ekspresije SIRT2, SIRT3 i oksidacijsko oštećenje DNK kod hepatotoksičnosti izazvane fumonizinom u BALB/c miševa

Oxidative stress, which is characterized by disruption of the oxidant/antioxidant balance, causes pathological processes, including toxicities induced by certain mycotoxins. The present study was designed to investigate the effects of resveratrol on sirtuin deacetylases (SIRT2 and SIRT3), nitric oxide (NO), reduced glutathione (GSH) and malondialdehyde (MDA) in fumonisin B1-induced hepatotoxicity. Regarding the experimental design, forty BALB/c mice were divided into four groups corresponding to the control, resveratrol (10 mg/kg, i.p), fumonisin B1 (2.25 mg/ kg, i.p) and resveratrol + fumonisin B1 (10 mg/kg + 2.25 mg/kg) groups. At the end of the 14 day-treatment, expression levels of SIRT2 and SIRT3 protein in the serum and liver were revealed by western blotting and antioxidant/oxidant activity analysis. SIRT2 and SIRT3 expression levels in the liver were significantly decreased by fumonisin B1 in comparison to the control. However, resveratrol supplementation coupled with fumonisin B1 increased the expression levels of SIRT2 and SIRT3, in relation to the fumonisin B1 treatments alone, but did not exhibit significant differences from those of the control group. As substantial indicators of stress and damage, the 8-OH-2-deoxyguanosine, NO and MDA levels of the liver tissue were assayed, and were higher in the fumonisin B1-treated groups, in relation to the control. As expected, resveratrol treatment significantly reduced the levels of NO and MDA in comparison to the fumonisin B1 treatments alone. Also, resveratrol attenuated the liver 8-OH-2- deoxyguanosine levels in the resveratrol + fumonisin B1 group. In conclusion, the findings revealed that resveratrol might possess protective effects against fumonisin-induced hepatotoxicity through modulation of the expression of sirtuin proteins, and by protecting the cell from oxidative/nitrosative stress.Oksidacijski stres, koji obilježava poremećaj ravnoteže oksidansa i antiksidansa, uzrokuje patološke procese, uključujući toksičnost potaknutu određenim mikotoksinima. U ovom je radu istražen učinak resveratrola na sirtuin-deacetilazu (SIRT2 i SIRT3), dušikov oksid (NO), sniženi glutation (GSH) i malondialdehid (MDA) kod hepatotoksičnosti izazvane fumonizinom B1. Istraživanje je postavljeno tako da je 40 BALB/c miševa podijeljeno u četiri skupine: kontrolnu, skupinu koja je dobivala resveratrol (10 mg/kg, ip.), skupinu koja je dobivala fumonizin B1 (2,25 mg/kg, ip) i skupinu koja je dobivala resveratrol i fumonizin B1 (10 mg/kg+2,25 mg/kg). Nakon 14 dana određena je razina ekspresije proteina SIRT2 i SIRT3 metodom western blotting te analiza aktivnosti antioksidansa i oksidansa u serumu i jetri. Razina ekspresije SIRT2 i SIRT3 u jetri bila znakovito smanjena u skupini s fumonizinom B1 u usporedbi s kontrolnom skupinom. U skupini s dodatkom resveratrola i fumonizina B1, međutim, povećana je razina ekspresije SIRT2 i SIRT3 u usporedbi sa skupinom koja je dobivala fumonizin B1, no bez znakovite razlike između tih skupina i kontrolne skupine. Analizirani su ključni pokazatelji stresa i oštećenja, razine OH-2-deoksigvanozin, NO i MDA u tkivu jetre, koje su bile veće u skupini s fumonizinom B1, u usporedbi s kontrolnom skupinom. Kao što se očekivalo, primjena resveratrola znakovito je smanjila razine NO i MDA u usporedbi sa skupinom kojoj je primijenjen samo fumonizin B1. Također, resveratrol je smanjio razinu 8-OH-2- deoksigvanozina u jetri u skupini kojoj su dani i resveratrol i fumonizin. Rezultati pokazuju da bi resveratrol mogao imati zaštitni učinak u slučaju hepatotoksičnosti uzrokovane fumonizinom putem modulacije ekspresije sirtuin proteina i zaštite stanice od oksidacijskog/nitrosativnog stresa

Molecular characterization of novel sulfotransferases from the tick, Ixodes scapularis

<p>Abstract</p> <p>Background</p> <p><it>Ixodes scapularis</it>, commonly known as the blacklegged or deer tick, is the main vector of Lyme disease in the United States. Recent progress in transcriptome research has uncovered hundreds of different proteins expressed in the salivary glands of hard ticks, the majority of which have no known function, and include many novel protein families. We recently identified transcripts coding for two putative cytosolic sulfotransferases in these ticks which recognized phenolic monoamines as their substrates. In this current study, we characterize the genetic expression of these two cytosolic sulfotransferases throughout the tick life cycle as well as the enzymatic properties of the corresponding recombinant proteins. Interestingly, the resultant recombinant proteins showed sulfotransferase activity against both neurotransmitters dopamine and octopamine.</p> <p>Results</p> <p>The two sulfotransferase genes were coded as <it>Ixosc </it>SULT 1 & 2 and corresponding proteins were referred as <it>Ixosc </it>Sult 1 and 2. Using gene-specific primers, the sulfotransferase transcripts were detected throughout the blacklegged tick life cycle, including eggs, larvae, nymphs, adult salivary glands and adult midgut. Notably, the mRNA and protein levels were altered upon feeding during both the larval and nymphal life stages. Quantitative PCR results confirm that <it>Ixosc </it>SULT1 was statistically increased upon blood feeding while <it>Ixosc </it>SULT 2 was decreased. This altered expression led us to further characterize the function of these proteins in the Ixodid tick. The sulfotransferase genes were cloned and expressed in a bacterial expression system, and purified recombinant proteins <it>Ixosc </it>Sult 1(R) and 2(R) showed sulfotransferase activity against neurotransmitters dopamine and octopamine as well as the common sulfotransferase substrate <it>p-</it>nitrophenol. Thus, dopamine- or octopamine-sulfonation may be involved in altering the biological signal for salivary secretion in <it>I. scapularis.</it></p> <p>Conclusions</p> <p>Collectively, these results suggest that a function of <it>Ixosc </it>Sult 1 and Sult 2 in <it>Ixodid </it>tick salivary glands may include inactivation of the salivation signal via sulfonation of dopamine or octopamine.</p

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

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Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| &lt; 0.03 at 95% confidence level. [Figure not available: see fulltext.

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

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