Effect of farnesyltransferase inhibitor R115777 on mitochondria of plasmodium falciparum

The parasite Plasmodium falciparum causes severe malaria and is the most dangerous to humans. However, it exhibits resistance to their drugs. Farnesyltransferase has been identified in pathogenic protozoa of the genera Plasmodium and the target of farnesyltransferase includes Ras family. Therefore, the inhibition of farnesyltransferase has been suggested as a new strategy for the treatment of malaria. However, the exact functional mechanism of this agent is still unknown. In addition, the effect of farnesyltransferase inhibitor (FTIs) on mitochondrial level of malaria parasites is not fully understood. In this study, therefore, the effect of a FTI R115777 on the function of mitochondria of P. falciparum was investigated experimentally. As a result, FTI R115777 was found to suppress the infection rate of malaria parasites under in vitro condition. It also reduces the copy number of mtDNA-encoded cytochrome c oxidase III. In addition, the mitochondrial membrane potential (Delta psi m) and the green fluorescence intensity of MitoTracker were decreased by FTI R115777. Chloroquine and atovaquone were measured by the mtDNA copy number as mitochondrial non-specific or specific inhibitor, respectively. Chloroquine did not affect the copy number of mtDNA-encoded cytochrome c oxidase III, while atovaquone induced to change the mtDNA copy number. These results suggest that FTI R115777 has strong influence on the mitochondrial function of P. falciparum. It may have therapeutic potential for malaria by targeting the mitochondria of parasites.1133Ysciescopu

Treatment of Linear and Nonlinear Dielectric Property of Molecular Monolayer and Submonolayer with Microscopic Dipole Lattice Model: I. Second Harmonic Generation and Sum-Frequency Generation

In the currently accepted models of the nonlinear optics, the nonlinear radiation was treated as the result of an infinitesimally thin polarization sheet layer, and a three layer model was generally employed. The direct consequence of this approach is that an apriori dielectric constant, which still does not have a clear definition, has to be assigned to this polarization layer. Because the Second Harmonic Generation (SHG) and the Sum-Frequency Generation vibrational Spectroscopy (SFG-VS) have been proven as the sensitive probes for interfaces with the submonolayer coverage, the treatment based on the more realistic discrete induced dipole model needs to be developed. Here we show that following the molecular optics theory approach the SHG, as well as the SFG-VS, radiation from the monolayer or submonolayer at an interface can be rigorously treated as the radiation from an induced dipole lattice at the interface. In this approach, the introduction of the polarization sheet is no longer necessary. Therefore, the ambiguity of the unaccounted dielectric constant of the polarization layer is no longer an issue. Moreover, the anisotropic two dimensional microscopic local field factors can be explicitly expressed with the linear polarizability tensors of the interfacial molecules. Based on the planewise dipole sum rule in the molecular monolayer, crucial experimental tests of this microscopic treatment with SHG and SFG-VS are discussed. Many puzzles in the literature of surface SHG and SFG spectroscopy studies can also be understood or resolved in this framework. This new treatment may provide a solid basis for the quantitative analysis in the surface SHG and SFG studies.Comment: 23 pages, 3 figure

Structural insights into RNA processing by the human RISC-loading complex.

Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2

Relationship between Environmental Phthalate Exposure and the Intelligence of School-Age Children

BACKGROUND: Concern over phthalates has emerged because of their potential toxicity to humans. OBJECTIVE: We investigated the relationship between the urinary concentrations of phthalate metabolites and children`s intellectual functioning. METHODS: This study enrolled 667 children at nine elementary schools in five South Korean cities. A cross-sectional examination of urine phthalate concentrations was performed, and scores on neuro-psychological tests were obtained from both the children and their mothers. RESULTS: We measured mono-2-ethylhexyl phthalate (MEHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), both metabolites of di(2-ethylhexyl)phthalate (DEHP), and mono-n-butyl phthalate (MBP), a metabolite of dibutyl phthalate (DBP), in urine samples. The geometric mean (ln) concentrations of MEHP, MEOHP, and MBP were 21.3 mu g/L [geometric SD (GSD) = 2.2 mu g/L; range, 0.5-445.4], 18.0 mu g/L (GSD = 2.4; range, 0.07-291.1), and 48.9 mu g/L (GSD = 2.2; range, 2.1-1645.5), respectively. After adjusting for demographic and developmental covariates, the Full Scale IQ and Verbal IQ scores were negatively associated with DEHP metabolites but not with DBP metabolites. We also found a significant negative relationship between the urine concentrations of the metabolites of DEHP and DBP and children`s vocabulary subscores. After controlling for maternal IQ, a significant inverse relationship between DEHP metabolites and vocabulary subscale score remained. Among boys, we found a negative association between increasing MEHP phthalate concentrations and the sum of DEHP metabolite concentrations and Wechsler Intelligence Scale for Children vocabulary score; however, among girls, we found no significant association between these variables. CONCLUSION: Controlling for maternal IQ and other covariates, the results show an inverse relationship between phthalate metabolites and IQ scores; however, given the limitations in cross-sectional epidemiology, prospective studies are needed to fully explore these associations.This work was funded by the Eco-Technopia 21 project of Korea Institute of Environmental Science and Technology (091-081-059).Cho SC, 2010, J CHILD PSYCHOL PSYC, V51, P1050, DOI 10.1111/j.1469-7610.2010.02250.xKim BN, 2009, BIOL PSYCHIAT, V66, P958, DOI 10.1016/j.biopsych.2009.07.034Tanida T, 2009, TOXICOL LETT, V189, P40, DOI 10.1016/j.toxlet.2009.04.005Ghisari M, 2009, TOXICOL LETT, V189, P67, DOI 10.1016/j.toxlet.2009.05.004Barnett JH, 2009, AM J PSYCHIAT, V166, P909, DOI 10.1176/appi.ajp.2009.08081251Kim Y, 2009, NEUROTOXICOLOGY, V30, P564, DOI 10.1016/j.neuro.2009.03.012Engel SM, 2009, NEUROTOXICOLOGY, V30, P522, DOI 10.1016/j.neuro.2009.04.001Kamrin MA, 2009, J TOXICOL ENV HEAL B, V12, P157, DOI 10.1080/10937400902729226Brown JS, 2009, SCHIZOPHRENIA BULL, V35, P256, DOI 10.1093/schbul/sbm147Bellinger DC, 2008, NEUROTOXICOLOGY, V29, P828, DOI 10.1016/j.neuro.2008.04.005Wolff MS, 2008, ENVIRON HEALTH PERSP, V116, P1092, DOI 10.1289/ehp.11007van Neerven S, 2008, PROG NEUROBIOL, V85, P433, DOI 10.1016/j.pneurobio.2008.04.006Hatch EE, 2008, ENVIRON HEALTH-GLOB, V7, DOI 10.1186/1476-069X-7-27Zevalkink J, 2008, J GENET PSYCHOL, V169, P72Kolarik B, 2008, ENVIRON HEALTH PERSP, V116, P98, DOI 10.1289/ehp.10498SATHYANARAYANA S, 2008, CURR PROBL PEDIAT AD, V38, P34KHO YL, 2008, J ENV HLTH SCI, V34, P271Huang PC, 2007, HUM REPROD, V22, P2715, DOI 10.1093/humrep/dem205Janjua NR, 2007, ENVIRON SCI TECHNOL, V41, P5564, DOI 10.1021/es0628755Meeker JD, 2007, ENVIRON HEALTH PERSP, V115, P1029, DOI 10.1289/ehp.9852Fromme H, 2007, INT J HYG ENVIR HEAL, V210, P21, DOI 10.1016/j.ijheh.2006.09.005Xu Y, 2007, ARCH TOXICOL, V81, P57, DOI 10.1007/s00204-006-0143-8Pereira C, 2007, ACTA HISTOCHEM, V109, P29, DOI 10.1016/j.acthis.2006.09.008Hauser R, 2006, EPIDEMIOLOGY, V17, P682, DOI 10.1097/01.ede.0000235996.89953.d7Zhu DF, 2006, BRAIN, V129, P2923, DOI 10.1093/brain/awl215Andrade AJM, 2006, TOXICOLOGY, V227, P185, DOI 10.1016/j.tox.2006.07.022Lottrup G, 2006, INT J ANDROL, V29, P172, DOI 10.1111/j.1365-2605.2005.00642.xBreous E, 2005, MOL CELL ENDOCRINOL, V244, P75, DOI 10.1016/j.mce.2005.06.009Wenzel A, 2005, MOL CELL ENDOCRINOL, V244, P63, DOI 10.1016/j.mce.2005.02.008Kato K, 2005, ANAL CHEM, V77, P2985, DOI 10.1021/ac0481248Tanaka T, 2005, FOOD CHEM TOXICOL, V43, P581, DOI 10.1016/j.fct.2005.01.001Duty SM, 2005, HUM REPROD, V20, P604, DOI 10.1093/humrep/deh656Kota BP, 2005, PHARMACOL RES, V51, P85, DOI 10.1016/j.phrs.2004.07.012Hays T, 2005, CARCINOGENESIS, V26, P219, DOI 10.1093/carcin/bgh285Hauser R, 2004, ENVIRON HEALTH PERSP, V112, P1734, DOI 10.1289/ehp.7212Bornehag CG, 2004, ENVIRON HEALTH PERSP, V112, P1393, DOI 10.1289/ehp.7187Ishido M, 2004, J NEUROCHEM, V91, P69, DOI 10.1111/j.1471-4159.2004.02696.xMink PJ, 2004, EPIDEMIOLOGY, V15, P385, DOI 10.1097/01.ede.0000128402.86336.7eBellinger DC, 2004, EPIDEMIOLOGY, V15, P383, DOI 10.1097/01.ede.0000129525.15064.a4Shea KM, 2003, PEDIATRICS, V111, P1467Tanaka T, 2002, FOOD CHEM TOXICOL, V40, P1499, DOI 10.1016/S0278-6915(02)00073-XHoppin JA, 2002, ENVIRON HEALTH PERSP, V110, P515SATTLER JM, 2001, ASSESSMENT CHILDRENRice D, 2000, ENVIRON HEALTH PERSP, V108, P511Bellinger DC, 2000, NEUROTOXICOL TERATOL, V22, P133LIM YR, 2000, KOR J CLIN PSYCHOL, V19, P563Braissant O, 1998, ENDOCRINOLOGY, V139, P2748Peters JM, 1997, CARCINOGENESIS, V18, P2029Baldini IM, 1997, PROG NEURO-PSYCHOPH, V21, P925Roberts RA, 1997, FUND APPL TOXICOL, V38, P107PARK KS, 1996, DEV KEDI WISC INDIVIMONZANI F, 1993, CLIN INVESTIGATOR, V71, P367SILVERSTEIN AB, 1990, J CLIN PSYCHOL, V46, P333HINTON RH, 1986, ENVIRON HEALTH PERSP, V70, P195KIM MK, 1986, SEOUL J PSYCHIAT, V11, P194KAUFMAN AS, 1976, CONTEMP EDUC PSYCHOL, V1, P1801

Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection

Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S. Typhimurium infection. To further understand host-pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S. Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S. Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169+ sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4+CD25+ T cells and an increased number of B220+CD19+ B cells. The reduction in CD4+CD25+ T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome

Optimized two-dimensional thin layer chromatography to monitor the intracellular concentration of acetyl phosphate and other small phosphorylated molecules

Acetyl phosphate (acetyl-P) serves critical roles in coenzyme A recycling and ATP synthesis. It is the intermediate of the Pta-AckA pathway that inter-converts acetyl-coenzyme A and acetate. Acetyl-P also can act as a global signal by donating its phosphoryl group to specific two-component response regulators. This ability derives from its capacity to store energy in the form of a high-energy phosphate bond. This bond, while critical to its function, also destabilizes acetyl-P in cell extracts. This lability has greatly complicated biochemical analysis, leading in part to widely varying acetyl-P measurements. We therefore developed an optimized protocol based on two-dimensional thin layer chromatography that includes metabolic labeling under aerated conditions and careful examination of the integrity of acetyl-P within extracts. This protocol results in greatly improved reproducibility, and thus permits precise measurements of the intracellular concentration of acetyl-P, as well as that of other small phosphorylated molecules

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Role of Palladin Phosphorylation by Extracellular Signal-Regulated Kinase in Cell Migration

Phosphorylation of actin-binding proteins plays a pivotal role in the remodeling of the actin cytoskeleton to regulate cell migration. Palladin is an actin-binding protein that is phosphorylated by growth factor stimulation; however, the identity of the involved protein kinases remains elusive. In this study, we report that palladin is a novel substrate of extracellular signal-regulated kinase (ERK). Suppression of ERK activation by a chemical inhibitor reduced palladin phosphorylation, and expression of active MEK alone was sufficient for phosphorylation. In addition, an in vitro kinase assay demonstrated direct palladin phosphorylation by ERK. We found that Ser77 and Ser197 are essential residues for phosphorylation. Although the phosphorylation of these residues was not required for actin cytoskeletal organization, we found that expression of non-phosphorylated palladin enhanced cell migration. Finally, we show that phosphorylation inhibits the palladin association with Abl tyrosine kinase. Taken together, our results indicate that palladin phosphorylation by ERK has an anti-migratory function, possibly by modulating interactions with molecules that regulate cell migration

Spatiotemporal patterns and environmental drivers of human echinococcoses over a twenty-year period in Ningxia Hui Autonomous Region, China

Background Human cystic (CE) and alveolar (AE) echinococcoses are zoonotic parasitic diseases that can be influenced by environmental variability and change through effects on the parasites, animal intermediate and definitive hosts, and human populations. We aimed to assess and quantify the spatiotemporal patterns of human echinococcoses in Ningxia Hui Autonomous Region (NHAR), China between January 1994 and December 2013, and examine associations between these infections and indicators of environmental variability and change, including large-scale landscape regeneration undertaken by the Chinese authorities. Methods Data on the number of human echinococcosis cases were obtained from a hospital-based retrospective survey conducted in NHAR for the period 1 January 1994 through 31 December 2013. High-resolution imagery from Landsat 4/5-TM and 8-OLI was used to create single date land cover maps. Meteorological data were also collected for the period January 1980 to December 2013 to derive time series of bioclimatic variables. A Bayesian spatio-temporal conditional autoregressive model was used to quantify the relationship between annual cases of CE and AE and environmental variables. Results Annual CE incidence demonstrated a negative temporal trend and was positively associated with winter mean temperature at a 10-year lag. There was also a significant, nonlinear effect of annual mean temperature at 13-year lag. The findings also revealed a negative association between AE incidence with temporal moving averages of bareland/artificial surface coverage and annual mean temperature calculated for the period 11–15 years before diagnosis and winter mean temperature for the period 0–4 years. Unlike CE risk, the selected environmental covariates accounted for some of the spatial variation in the risk of AE. Conclusions The present study contributes towards efforts to understand the role of environmental factors in determining the spatial heterogeneity of human echinococcoses. The identification of areas with high incidence of CE and AE may assist in the development and refinement of interventions for these diseases, and enhanced environmental change risk assessment