Sample records for beta toxicity validated

  1. Compatibility of hydroxypropyl-{beta}-cyclodextrin with algal toxicity bioassays

    Energy Technology Data Exchange (ETDEWEB)

    Fai, Patricia Bi; Grant, Alastair [School of Environmental Sciences, University of East Anglia, Norwich NR4 7TJ (United Kingdom); Reid, Brian J. [School of Environmental Sciences, University of East Anglia, Norwich NR4 7TJ (United Kingdom)], E-mail:


    Numerous reports have indicated that hydrophobic organic compound bioaccessibility in sediment and soil can be determined by extraction using aqueous hydroxypropyl-{beta}-cyclodextrin (HPCD) solutions. This study establishes the compatibility of HPCD with Selenastrum capricornutum and assesses whether its presence influences the toxicity of reference toxicants. Algal growth inhibition (72 h) showed no significant (P > 0.05) difference at HPCD concentrations up to and including 20 mM. HPCD presence did not influence the toxicity of the inorganic reference toxicant (ZnSO{sub 4}), with IC50 values of 0.82 {mu}M and 0.85 {mu}M, in the presence and absence of HPCD (20 mM), respectively. However, HPCD presence (20 mM) reduced the toxicity of 2,4-dichlorophenol and the herbicides diuron and isoproturon. These reductions were attributed to inclusion complex formation between the toxicants and the HPCD cavity. Liberation of complexed toxicants, by sample manipulation prior to toxicity assessment, is proposed to provide a sensitive, high throughput, bioassay that reflects compound bioaccessibility. - Compatibility of the biomimetic HPCD extraction method with algal cell growth inhibition bioassays to assess toxicity of reference toxicants and environmental relevant herbicides.

  2. Exposure-based validation list for developmental toxicity screening assays

    NARCIS (Netherlands)

    Daston, George P.; Beyer, Bruce K.; Carney, Edward W.; Chapin, Robert E.; Friedman, Jan M.; Piersma, Aldert H.; Rogers, John M.; Scialli, Anthony R.


    Validation of alternative assays requires comparison of the responses to toxicants in the alternative assay with in vivo responses. Chemicals have been classified as "positive" or "negative" in vivo, despite the fact that developmental toxicity is conditional on magnitude of exposure. We developed a

  3. Sulfonated dyes attenuate the toxic effects of beta-amyloid in a structure-specific fashion. (United States)

    Pollack, S J; Sadler, I I; Hawtin, S R; Tailor, V J; Shearman, M S


    We recently reported that several sulfate-containing glycosaminoglycans, a class of compounds associated with the beta-amyloid plaques of Alzheimer's disease, attenuate the toxic effects of beta-amyloid fragments beta 25-35 and beta 1-40. The amyloid-binding sulfonated dye Congo Red was shown to have a similar effect. Using two clonal cell lines, we now demonstrate that several sulfonated dyes attenuate beta-amyloid toxicity and that the protective effect appears specific for compounds whose sulfonate groups can interact with the beta-pleated structure of aggregated amyloid. These results suggest that by binding beta-amyloid these compounds may prevent toxic interactions of the peptide with cells.

  4. Identification of distinct physiochemical properties of toxic prefibrillar species formed by A{beta} peptide variants

    Energy Technology Data Exchange (ETDEWEB)

    Goeransson, Anna-Lena, E-mail: [Division of Molecular Biotechnology, Department of Physics, Chemistry and Biology, Linkoeping University (Sweden); Nilsson, K. Peter R., E-mail: [Division of Organic Chemistry, Department of Physics, Chemistry and Biology, Linkoeping University (Sweden); Kagedal, Katarina, E-mail: [Department of Clinical and Experimental Medicine, Linkoeping University (Sweden); Brorsson, Ann-Christin, E-mail: [Division of Molecular Biotechnology, Department of Physics, Chemistry and Biology, Linkoeping University (Sweden)


    Highlights: Black-Right-Pointing-Pointer Identification of toxic prefibrillar A{beta} species. Black-Right-Pointing-Pointer Fluorescence measurements using a combined set of fluorophores. Black-Right-Pointing-Pointer Morphology studies using transmission electron microscopy. -- Abstract: The formation of amyloid-{beta} peptide (A{beta}) aggregates at an early stage during the self-assembly process is an important factor in the development of Alzheimer's disease. The toxic effect is believed to be exerted by prefibrillar species of A{beta}. It is therefore important to identify which prefibrillar species are toxic and characterize their distinct properties. In the present study, we investigated the in vitro aggregation behavior of A{beta}-derived peptides possessing different levels of neurotoxic activity, using fluorescence spectroscopy in combination with transmission electron microscopy. The toxicity of various A{beta} aggregates was assessed by using cultures of human neuroblastoma cells. Through combined use of the fluorescence probe 8-anilino-1-napthalenesulfonate (ANS) and the novel luminescent probe pentamer formyl thiophene acetic acid (p-FTAA), we were able to identify those A{beta} peptide-derived prefibrillar species which exhibited cellular toxicity. In particular, species, which formed early during the aggregation process and showed strong p-FTAA and ANS fluorescence, were the species that possessed toxic activities. Moreover, by manipulating the aggregation conditions, it was possible to change the capacity of the A{beta} peptide to form nontoxic versus toxic species.

  5. Role of human GABA(A) receptor beta3 subunit in insecticide toxicity. (United States)

    Ratra, G S; Kamita, S G; Casida, J E


    The gamma-aminobutyric acid type A (GABA(A)) receptor is the target for the major insecticides alpha-endosulfan, lindane, and fipronil and for many analogs. Their action as chloride channel blockers is directly measured by binding studies with [(3)H]ethynylbicycloorthobenzoate ([(3)H]EBOB). This study tests the hypothesis that GABA(A) receptor subunit composition determines the sensitivity and selectivity of insecticide toxicity. Human receptor subtypes were expressed individually (alpha1, alpha6, beta1, beta3, and gamma2) and in combination in insect Sf9 cells. Binding parameters were similar for [(3)H]EBOB in the beta3 homooligomer, alpha1beta3gamma2 heterooligomer, and native brain membranes, but toxicological profiles were very different. Surprisingly, alpha-endosulfan, lindane, and fipronil were all remarkably potent on the recombinant beta3 homooligomeric receptor (IC50 values of 0.5-2.4 nM), whereas they were similar in potency on the alpha1beta3gamma2 subtype (IC50 values of 16-33 nM) and highly selective on the native receptor (IC50 values of 7.3, 306, and 2470 nM, respectively). The selectivity order for 29 insecticides and convulsants as IC50 ratios for native/beta3 or alpha1beta3gamma2/beta3 was as follows: fipronil > lindane > 19 other insecticides including alpha-endosulfan and picrotoxinin > 4 trioxabicyclooctanes and dithianes (almost nonselective) > tetramethylenedisulfotetramine, 4-chlorophenylsilatrane, or alpha-thujone. Specificity between mammals and insects at the target site (fipronil > lindane > alpha-endosulfan) paralleled that for toxicity. Potency at the native receptor is more predictive for inhibition of GABA-stimulated chloride uptake than that at the beta3 or alpha1beta3gamma2 receptors. Therefore, the beta3 subunit contains the insecticide target and other subunits differentially modulate the binding to confer compound-dependent specificity and selective toxicity.

  6. Toxicity of 17 {beta}-estradiol and dibutyl-n-phthalate to Japanese medaka (Oryzias latipes)

    Energy Technology Data Exchange (ETDEWEB)

    Patvna, P.J.; Cooper, K.R. [Rutgers-The State Univ., Piscataway, NJ (United States)]|[Univ. of Medicine and Dentistry of New Jersey, Piscataway, NJ (United States)


    Phthalate esters are ubiquitous environmental contaminants that are hypothesized to cause developmental toxicity in aquatic organisms via an estrogenic mechanism. Japanese medaka embryos and larvae provide an excellent model for the study of toxicant effects on embryonic development. The following groups were examined (N = 10--20): a non-treatment control, a vehicle control, 17 {beta}-estradiol and Dibutyl-n-phthalate, in individual glass vials. The medaka embryos were treated beginning at the blastula stage, for ten days. At day 10, embryos were changed into fresh rearing solution. The embryos were observed daily, until three days post-hatching, for toxic developmental effects. Exposure to 17 {beta}-estradiol caused urinary bladder lesions at the lowest doses tested. At concentrations {le} 3 {micro}M/0.82 ppm, 17 {beta}-estradiol caused inhibition of swim bladder inflation, pericardial edema, and marked cachexia. Dibutyl-n-phthalate caused pronounced enlargement of the urinary bladder. No other gross lesions were observed. Both 17 {beta}-estradiol and Dibutyl-n-phthalate caused effects on the urinary tract which will be characterized at the light microscopic level. The lesions observed in the embryo medaka following Dibutyl-n-phthalate exposure were at or below water solubility and are in agreement with previously reported toxic levels.

  7. The Protective Role of Carnosic Acid against Beta-Amyloid Toxicity in Rats

    Directory of Open Access Journals (Sweden)

    H. Rasoolijazi


    Full Text Available Oxidative stress is one of the pathological mechanisms responsible for the beta- amyloid cascade associated with Alzheimer’s disease (AD. Previous studies have demonstrated the role of carnosic acid (CA, an effective antioxidant, in combating oxidative stress. A progressive cognitive decline is one of the hallmarks of AD. Thus, we attempted to determine whether the administration of CA protects against memory deficit caused by beta-amyloid toxicity in rats. Beta-amyloid (1–40 was injected by stereotaxic surgery into the Ca1 region of the hippocampus of rats in the Amyloid beta (Aβ groups. CA was delivered intraperitoneally, before and after surgery in animals in the CA groups. Passive avoidance learning and spontaneous alternation behavior were evaluated using the shuttle box and the Y-maze, respectively. The degenerating hippocampal neurons were detected by fluoro-jade b staining. We observed that beta-amyloid (1–40 can induce neurodegeneration in the Ca1 region of the hippocampus by using fluoro-jade b staining. Also, the behavioral tests revealed that CA may recover the passive avoidance learning and spontaneous alternation behavior scores in the Aβ + CA group, in comparison with the Aβ group. We found that CA may ameliorate the spatial and learning memory deficits induced by the toxicity of beta-amyloid in the rat hippocampus.

  8. Formulated Beta-Cyfluthrin Shows Wide Divergence in Toxicity among Bird Species

    Directory of Open Access Journals (Sweden)

    Laura M. Addy-Orduna


    Full Text Available It is generally assumed that the toxicity of pyrethroid insecticides to birds is negligible, though few species have been tested. The oral acute toxicity of formulated beta-cyfluthrin was determined for canaries (Serinus sp., shiny cowbirds (Molothrus bonariensis, and eared doves (Zenaida auriculata. Single doses were administered to adults by gavage. Approximate lethal doses 50 (LD50 and their confidence intervals were determined by approximate D-optimal design. Canaries were found to be substantially more sensitive to formulated beta-cyfluthrin (LD50=(170±41 mg/kg than the other two species tested (LD50=(2234±544 mg/kg and LD50=(2271±433 mg/kg, resp.. The LD50 obtained for canaries was also considerably lower than typical toxicity values available in the literature for pyrethroids. This study emphasizes the need for testing a broader range of species with potentially toxic insecticides, using modern up and down test designs with minimal numbers of birds.

  9. Integral validation of the effective beta parameter for the MOX reactors and incinerators; Validation integrale des estimations du parametre beta effectif pour les reacteurs Mox et incinerateurs

    Energy Technology Data Exchange (ETDEWEB)

    Zammit-Averlant, V


    {beta}{sub eff}, which represents the effective delayed neutron fraction, is an important parameter for the reactor nominal working as well as for studies of its behaviour in accidental situation. In order to improve the safety of nuclear reactors, we propose here to validate its calculation by using the ERANOS code with ERALIB1 library and by taking into account all the fission process physics through the {nu} energy dependence. To validate the quality of this calculation formalism, we calculated uncertainties as precisely as possible. The experimental values of {beta}{sub eff}, as well their uncertainties, have also been re-evaluated for consistency, because these `experimental` values actually contain a calculated component. We therefore obtained an entirely coherent set of calculated and measured {beta}{sub eff}. The comparative study of the calculated and measured values pointed out that the JEF2.2 {nu}{sub d} are already sufficient because the (E-C)/C are inferior to 3 % in average and in their uncertainly bars. The experimental uncertainties, even if lightly superior to those previously edited, remain inferior to the uncertainties of the calculated values. This allowed us to fit {nu}{sub d} with {beta}{sub eff}. This adjustment has brought an additional improvement on the recommendations of the {nu}{sub d} average values, for the classical scheme (thermal energy, fast energy) and for the new scheme which explains the {nu}{sub d} energy dependence. {beta}{sub eff}, for MOX or UOX fuel assemblies in thermal or fast configurations, can therefore be obtained with an uncertainty due to the nuclear data of about 2.0 %. (author) 110 refs.

  10. Rat beta(3)-adrenoceptor protein expression : antibody validation and distribution in rat gastrointestinal and urogenital tissues

    NARCIS (Netherlands)

    Cernecka, Hana; Pradidarcheep, Wisuit; Lamers, Wouter H.; Schmidt, Martina; Michel, Martin C.


    beta(3)-Adrenoceptors play important roles in the regulation of urogenital and probably gastrointestinal function. However, despite recent progress, their detection at the protein level has remained difficult due to a lack of sufficiently validated selective antibodies. Therefore, we have explored t

  11. Carboxymethyl-beta-cyclodextrin mitigates toxicity of cadmium, cobalt, and copper during naphthalene biodegradation. (United States)

    Hoffman, Douglas R; Anderson, Phillip P; Schubert, Carissa M; Gault, Melissa B; Blanford, William J; Sandrin, Todd R


    Hazardous waste sites are commonly contaminated with both organic and metal pollutants. Many metal pollutants have been shown to inhibit organic pollutant biodegradation. We investigated the ability of a modified, polydentate cyclodextrin (carboxymethyl-beta-cyclodextrin, CMCD) to reduce the toxicity of 33.4 microM cadmium, cobalt or copper during naphthalene degradation by a Burkholderia sp. in 120 h aerobic, batch studies. The highest investigated concentration of CMCD, 3340 microM, reduced cadmium, cobalt, and copper toxicity. With each metal, the length of the lag phase was reduced (by as much as 108 h with cobalt or copper), the cell yield was increased (by as much as a factor of 16 with cobalt), and the growth rate was increased (by as much as a factor of 31 with cobalt). The degrader was unable to use CMCD as the sole source of carbon and energy. Our data suggest that the ability of CMCD to complex metals plays an important role in its ability to mitigate metal toxicity and that CMCD has the potential to enhance biodegradation in organic and metal co-contaminated environments.

  12. Mollusc reproductive toxicity tests - Development and validation of test guidelines

    DEFF Research Database (Denmark)

    Ducrot, Virginie; Holbech, Henrik; Kinnberg, Karin Lund

    for P. antipodarum consisted in a comparative 28-day study between four laboratories and with two test substances: cadmium (Cd) and bisphenol A (BPA). For L. stagnalis, pre-validation consisted in a comparative 56-day study between six laboratories and with two test substances: Cd and tributyltin (TBT...

  13. Amyloid Beta: Multiple Mechanisms of Toxicity and Only Some Protective Effects?

    Directory of Open Access Journals (Sweden)

    Paul Carrillo-Mora


    Full Text Available Amyloid beta (Aβ is a peptide of 39–43 amino acids found in large amounts and forming deposits in the brain tissue of patients with Alzheimer’s disease (AD. For this reason, it has been implicated in the pathophysiology of damage observed in this type of dementia. However, the role of Aβ in the pathophysiology of AD is not yet precisely understood. Aβ has been experimentally shown to have a wide range of toxic mechanisms in vivo and in vitro, such as excitotoxicity, mitochondrial alterations, synaptic dysfunction, altered calcium homeostasis, oxidative stress, and so forth. In contrast, Aβ has also shown some interesting neuroprotective and physiological properties under certain experimental conditions, suggesting that both physiological and pathological roles of Aβ may depend on several factors. In this paper, we reviewed both toxic and protective mechanisms of Aβ to further explore what their potential roles could be in the pathophysiology of AD. The complete understanding of such apparently opposed effects will also be an important guide for the therapeutic efforts coming in the future.

  14. Quantitative analysis of toxic and essential elements in human hair. Clinical validity of results. (United States)

    Kosanovic, Melita; Jokanovic, Milan


    Over the last three decades, there has been an increasing awareness of environmental and occupational exposures to toxic or potentially toxic trace elements. The evolution of biological monitoring includes knowledge of kinetics of toxic and/or essential elements and adverse health effects related to their exposure. The debate whether a hair is a valid sample for biomonitoring or not is still attracting the attention of analysts, health care professionals, and environmentalists. Although researchers have found many correlations of essential elements to diseases, metabolic disorders, environmental exposures, and nutritional status, opponents of the concept of hair analysis object that hair samples are unreliable due to the influence of external factors. This review discusses validity of hair as a sample for biomonitoring of essential and toxic elements, with emphasis on pre-analytical, analytical, and post-analytical factors influencing results.

  15. Scientific validation of polyherbal hepatoprotective formulation against paracetamol induced toxicity

    Institute of Scientific and Technical Information of China (English)

    Beerendra Kumar Saroj; Dayanandan Mani; Sunil Kumar Mishra


    Objective: This polyherbal formulation has been traditionally used in the Indian system of medicine as a chief formulation for the treatment of hepatic diseases as hepatoprotective. The aim of the study was to study hepatoprotective activity which will be scientific validation of traditional knowledge claimed about this polyherbal formulation. Methods: Hepatotoxicity was induced by administration of paracetamol (300mg/kg) to the animals. The levels of liver enzymes (SGOT, SGPT, Alkaline phosphatase, Serum Bilirubin), lipid profiles (triglyceride, cholesterol, HDL, LDL), creatinine, urea levels and histopathological parameters were measured in order to evaluate hepatoprotective activity of polyherbal formulation. Results: The polyherbal formulation produced a significant hepatoprotective activity of the decoction of polyherbal formulation. The polyherbal formulation (PHF = 1) shows good hepatoprotective activity by lowering the levels of SGOT, alkaline phosphatase, bilirubin parameters (P<0.05), lipid profiles - cholesterol, triglyceride, LDL and histopathological evaluations shows that PHF = 1 and PHF = 3 formulations have significantly hepatoprotective activity (P<0.05). Conclusions: The study validates that polyherbal formulation has a good hepatoprotective activity. Further standardization processes may be performed in order to make it a beneficial hepatoprotective formulation.

  16. Cholesterol does not affect the toxicity of amyloid beta fragment but mimics its effect on MTT formazan exocytosis in cultured rat hippocampal neurons. (United States)

    Abe, K; Saito, H


    It has recently been reported that methyl-beta-cyclodextrin-solubilized cholesterol protects PC12 cells from amyloid beta protein (Abeta) toxicity. To ask if this is the case in brain neurons, we investigated its effect in primary cultured rat hippocampal neurons. In basal culture conditions with no addition of Abeta, methyl-beta-cyclodextrin-solubilized cholesterol at concentrations of 30-100 microM was toxic to neurons, but at concentrations of 1-10 microM promoted neuronal survival. Methyl-beta-cyclodextrin-solubilized cholesterol at 1-10 microM was also effective in protecting neurons from toxicity of 20 microM Abeta. However, these effects were all mimicked by methyl-beta-cyclodextrin alone, but not by cholesterol solubilized by dimethylsulfoxide or ethanol. The effects of methyl-beta-cyclodextrin-solubilized cholesterol on neuronal survival and Abeta toxicity are probably attributed to the action of methyl-beta-cyclodextrin, but not cholesterol. Alternatively, we found that methyl-beta-cyclodextrin-solubilized cholesterol at lower concentrations ( > 10 nM) inhibited cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT) by promoting the exocytosis of MTT formazan. This effect was shared by dimethylsulfoxide- or ethanol-solubilized cholesterol, but not by methyl-beta-cyclodextrin, supporting that it is attributed to the action of cholesterol. These results suggest that cholesterol does not protect neurons from Abeta toxicity, or rather inhibits cellular MTT reduction in a similar manner to Abeta.

  17. Overexpression of estrogen receptor beta alleviates the toxic effects of beta-amyloid protein on PC12 cells via non-hormonal ligands

    Institute of Scientific and Technical Information of China (English)

    Hui Wang; Lihui Si; Xiaoxi Li; Weiguo Deng; Haimiao Yang; Yuyan Yang; Yan Fu


    After binding to the estrogen receptor, estrogen can alleviate the toxic effects of beta-amyloid protein, and thereby exert a therapeutic effect on Alzheimer's disease patients. Estrogen can increase the incidence of breast carcinoma and endometrial cancer in post-menopausal women, so it is not suitable for clinical treatment of Alzheimer's disease. There is recent evidence that the estrogen receptor can exert its neuroprotective effects without estrogen dependence. Real-time quantitative PCR and flow cytometry results showed that, compared with non-transfected PC12 cells, adenovirus-mediated estrogen receptor β gene-transfected PC12 cells exhibited lower expression of tumor necrosis factor α and interleukin 1β under stimulation with beta-amyloid protein and stronger protection from apoptosis. The Akt-specific inhibitor Abi-2 decreased the anti-inflammatory and anti-apoptotic effects of estrogen receptor β gene-transfection. These findings suggest that overexpression of estrogen receptor β can alleviate the toxic effect of beta-amyloid protein on PC12 cells, without estrogen dependence. The Akt pathway is one of the potential means for the anti-inflammatory and anti-apoptotic effects of the estrogen receptor.

  18. Distribution, Metabolism and Toxic Effects of Beta-Cypermethrin in Lizards (Eremias argus) Following Oral Administration. (United States)

    Chen, Li; Xu, Peng; Diao, Jinling; Di, Shanshan; Li, Ruiting; Zhou, Zhiqiang


    Beta-cypermethrin (BCYP), a synthetic pyrethriod (PYR) pesticide which is a mixture of the alpha- and theta- cypermethrin, have been reported various toxicological profiles to non-target organisms. But little is known about assimilation, accumulation and toxic effects of BCYP in reptiles. The present study firstly elucidated absorption, tissue distribution, excretion of BCYP in Eremias argus . Treated group were administered orally with BCYP 20mg/kg body weight (bw) dissolved in corn oil. Neurotoxicity was observed at 24h after gavage, and the poisoning symptom ameliorated at 72h. The changes of BCYP concentration depended on degradation time and tissues. Lizards had a strong capacity to eliminate BCYP with different tissue distribution. The tissues concentration of BCYP from high to low were intestine, stomach, heart, kidney, blood, lung, liver and brain. Bimodal phenomena were observed in lung, liver and kidney. These results may be due to the activities of enzymes, circadian rhythm, and enterohepatic circulation in lizards. Based on the results of organ coefficient and histopathology analysis in liver, the liver was confirmed as the main target organ.

  19. Preliminary Validation of Tumor Cell Attachment Inhibition Assay for Developmental Toxicants With Mouse S180 Cells

    Institute of Scientific and Technical Information of China (English)



    This study was designed to explore the possibility of using ascitic mouse sarcoma cell line(S180) to validate the mouse tumor cell attachment assay for developmental toxicants, and to test the inhibitory effects of various developmental toxicants. The results showed that 2 of 3 developmental toxicants under consideration, sodium pentobarbital and ethanol, significantly inhibited S180cells attachment to Concanavalin A-coated surfaces. Inhibition was dependent on concentration, and the IC5o(the concentration that reduced attachment by 50% ), of these 2 chemicals was 1.2 ×10-3 mol/L and 1.0 mol/L, respectively. Another developmental toxicant, hydrocortisone, did not show inhibitory activity. Two non-developmental toxicants, sodium chloride and glycine were also testedand these did not decrease attachment rates. The main results reported here were generally similar to those obtained with ascitic mouse ovarian tumor cells as a model. Therefore, this study added further evidence to the conclusion that cell specificity does not limit attachment inhibition to Con A-coated surfaces, so S180 cell may serve as an alternative cell model, especially when other cell lines are unavailable. Furthermore, after optimal validation, it can be suggested that an S180 cell attachment assay may be a candidate for a series of assays to detect developmental toxicants.

  20. First Ex-Vivo Validation of a Radioguided Surgery Technique with beta- Radiation

    CERN Document Server

    Camillocci, E Solfaroli; Bocci, V; Carollo, A; Chiodi, G; Colandrea, M; Collamati, F; Cremonesi, M; Donnarumma, R; Ferrari, M E; Ferroli, P; Ghielmetti, F; Grana, C M; Marafini, M; Morganti, S; Terracciano, C Mancini; Patanè, M; Pedroli, G; Pollo, B; Recchia, L; Russomando, A; Toppi, M; Traini, G; Faccini, R


    Purpose: A radio-guided surgery technique with beta- -emitting radio-tracers was suggested to overcome the effect of the large penetration of gamma radiation. The feasibility studies in the case of brain tumors and abdominal neuro-endocrine tumors were based on simulations starting from PET images with several underlying assumptions. This paper reports, as proof-of-principle of this technique, an ex-vivo test on a meningioma patient. This test allowed to validate the whole chain, from the evaluation of the SUV of the tumor, to the assumptions on the bio-distribution and the signal detection. Methods: A patient affected by meningioma was administered 300 MBq of 90Y-DOTATOC. Several samples extracted from the meningioma and the nearby Dura Mater were analyzed with a beta- probe designed specifically for this radio-guided surgery technique. The observed signals were compared both with the evaluation from the histology and with the Monte Carlo simulation. Results: we obtained a large signal on the bulk tumor (105...

  1. Protective Effects of Some Medicinal Plants from Lamiaceae Family Against Beta-Amyloid Induced Toxicity in PC12 Cell

    Directory of Open Access Journals (Sweden)

    S Saeidnia


    Full Text Available Background: Excessive accumulation of beta-amyliod peptide (Aβ, the major component of senile plaques in Alzheimer's disease (AD, causes neuronal cell death through induction of oxidative stress. Therefore, antioxidants may be of use in the treatment of AD. The medicinal plants from the Lamiaceae family have been widely used in Iranian traditional medicine. These plants contain compounds with antioxidant activity and some species in this family have been reported to have neuroprotective properties. In the present study, methanolic extract of seven plants from salvia and satureja species were evaluated for their protective effects against beta-amyloid induced neurotoxicity.Methods: Aerial parts of the plants were extracted with ethyl acetate and methanol, respectively, by percolation at room temperature and subsequently, methanolic extracts of the plants were prepared. PC12 cells were incubated with different concentrations of the extracts in culture medium 1h prior to incubation with Aβ. Cell toxicity was assessed 24h after addition of Aβ by MTT assay.Results: Satureja bachtiarica, Salvia officinalis and Salvia macrosiphon methanolic extracts exhibited high protective effects against Aβ induced toxicity (P<0.001. Protective effects of Satureja bachtiarica and Salvia officinalis were dose-dependent.Conclusion: The main constituents of these extracts are polyphenolic and flavonoid compounds such as rosmarinic acid, naringenin, apigenin and luteolin which have antioxidant properties and may have a role in neuroprotection. Based on neuroprotective effect of these plants against Aβ induced toxicity, we recommend greater attention to their use in the treatment of Alzheimer disease.

  2. Development and validation of fluorescent receptor assays based on the human recombinant estrogen receptor subtypes alpha and beta

    NARCIS (Netherlands)

    de boer, T; Otjens, D; Muntendam, A; Meulman, E; van Oostijen, M; Ensing, K


    This article describes the development and validation of two fluorescent receptor assays for the hRec-estrogen receptor subtypes alpha and beta. As a labelled ligand an autofluorescent phyto-estrogen (coumestrol) has been used. The estrogen receptor (ER) belongs to the nuclear receptor family, a cla

  3. Development and validation of OECD test guidelines on mollusc reproductive toxicity tests

    DEFF Research Database (Denmark)

    Lagadic, Laurent; Holbech, Henrik; hutchinson, tom

    Validated guidelines in line with the OECD Conceptual Framework for the Testing and Assessment of Endocrine Disrupting Chemicals (EDTA) have been developed for rodents, amphibians, fish, aquatic insects and crustaceans. Only aquatic arthropods have been considered in this test battery although...... the comparison of endpoints relevant for reproduction in invertebrates often shows a much higher sensitivity in molluscs vs. e.g. daphnids. The OECD test guideline programme has thus been extended to cover reproduction effects of chemicals in molluscs. Existing mollusc toxicity test protocols have been reviewed...... reproduction test guideline will be developed describing partial- and full- life-cycle test protocols in these species, so as to propose a balanced suite of apical mollusc toxicity tests applicable for the assessment of any type of chemical, including endocrine disruptors, as level 4 and 5 assays of the EDTA...

  4. Validation of Normal Tissue Complication Probability Predictions in Individual Patient: Late Rectal Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Semenenko, Vladimir A., E-mail: [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Tarima, Sergey S. [Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Devisetty, Kiran [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Pelizzari, Charles A.; Liauw, Stanley L. [Department of Radiation and Cellular Oncology, University of Chicago Pritzker School of Medicine, Chicago, Illinois (United States)


    Purpose: To perform validation of risk predictions for late rectal toxicity (LRT) in prostate cancer obtained using a new approach to synthesize published normal tissue complication data. Methods and Materials: A published study survey was performed to identify the dose-response relationships for LRT derived from nonoverlapping patient populations. To avoid mixing models based on different symptoms, the emphasis was placed on rectal bleeding. The selected models were used to compute the risk estimates of grade 2+ and grade 3+ LRT for an independent validation cohort composed of 269 prostate cancer patients with known toxicity outcomes. Risk estimates from single studies were combined to produce consolidated risk estimates. An agreement between the actuarial toxicity incidence 3 years after radiation therapy completion and single-study or consolidated risk estimates was evaluated using the concordance correlation coefficient. Goodness of fit for the consolidated risk estimates was assessed using the Hosmer-Lemeshow test. Results: A total of 16 studies of grade 2+ and 5 studies of grade 3+ LRT met the inclusion criteria. The consolidated risk estimates of grade 2+ and 3+ LRT were constructed using 3 studies each. For grade 2+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.537 compared with 0.431 for the best-fit single study. For grade 3+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.477 compared with 0.448 for the best-fit single study. No evidence was found for a lack of fit for the consolidated risk estimates using the Hosmer-Lemeshow test (P=.531 and P=.397 for grade 2+ and 3+ LRT, respectively). Conclusions: In a large cohort of prostate cancer patients, selected sets of consolidated risk estimates were found to be more accurate predictors of LRT than risk estimates derived from any single study.

  5. Credible Intervals for Precision and Recall Based on a K-Fold Cross-Validated Beta Distribution. (United States)

    Wang, Yu; Li, Jihong


    In typical machine learning applications such as information retrieval, precision and recall are two commonly used measures for assessing an algorithm's performance. Symmetrical confidence intervals based on K-fold cross-validated t distributions are widely used for the inference of precision and recall measures. As we confirmed through simulated experiments, however, these confidence intervals often exhibit lower degrees of confidence, which may easily lead to liberal inference results. Thus, it is crucial to construct faithful confidence (credible) intervals for precision and recall with a high degree of confidence and a short interval length. In this study, we propose two posterior credible intervals for precision and recall based on K-fold cross-validated beta distributions. The first credible interval for precision (or recall) is constructed based on the beta posterior distribution inferred by all K data sets corresponding to K confusion matrices from a K-fold cross-validation. Second, considering that each data set corresponding to a confusion matrix from a K-fold cross-validation can be used to infer a beta posterior distribution of precision (or recall), the second proposed credible interval for precision (or recall) is constructed based on the average of K beta posterior distributions. Experimental results on simulated and real data sets demonstrate that the first credible interval proposed in this study almost always resulted in degrees of confidence greater than 95%. With an acceptable degree of confidence, both of our two proposed credible intervals have shorter interval lengths than those based on a corrected K-fold cross-validated t distribution. Meanwhile, the average ranks of these two credible intervals are superior to that of the confidence interval based on a K-fold cross-validated t distribution for the degree of confidence and are superior to that of the confidence interval based on a corrected K-fold cross-validated t distribution for the

  6. Protective effects of berberine against amyloid beta-induced toxicity in cultured rat cortical neurons

    Institute of Scientific and Technical Information of China (English)

    Jing Wang; Yanjun Zhang; Shuai Du; Mixia Zhang


    Berberine, a major constituent of Coptidis rhizoma, exhibits neural protective effects. The present study analyzed the potential protective effect of berberine against amyloid G-induced cytotoxicity in rat cerebral cortical neurons. Alzheimer's disease cell models were treated with 0.5 and 2 μmol/Lberberine for 36 hours to inhibit amyloid G-induced toxicity. Methyl thiazolyl tetrazolium assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining results showed that berberine significantly increased cell viability and reduced cell apoptosis in primary cultured rat cortical neurons. In addition, western blot analysis revealed a protective effect of berberine against amyloid β-induced toxicity in cultured cortical neurons, which coincided with significantly decreased abnormal up-regulation of activated caspase-3. These results showed that berberine exhibited a protective effect against amyloid 13-induced cytotoxicity in cultured rat cortical neurons.

  7. Iron promotes the toxicity of amyloid beta peptide by impeding its ordered aggregation. (United States)

    Liu, Beinan; Moloney, Aileen; Meehan, Sarah; Morris, Kyle; Thomas, Sally E; Serpell, Louise C; Hider, Robert; Marciniak, Stefan J; Lomas, David A; Crowther, Damian C


    We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid β (Aβ) peptide in our Drosophila model system. These data point to an important pathogenic role for iron in Alzheimer disease. In this study, we have used an iron-selective chelating compound and RNAi-mediated knockdown of endogenous ferritin to further manipulate iron in the brain. We confirm that chelation of iron protects the fly from the harmful effects of Aβ. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aβ aggregation. We find that iron slows the progression of the Aβ peptide from an unstructured conformation to the ordered cross-β fibrils that are characteristic of amyloid. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aβ toxicity but only if the metal is present throughout the aggregation process. These data support the hypothesis that iron delays the formation of well ordered aggregates of Aβ and so promotes its toxicity in Alzheimer disease.

  8. Expression of the alternative oxidase mitigates beta-amyloid production and toxicity in model systems. (United States)

    El-Khoury, Riyad; Kaulio, Eveliina; Lassila, Katariina A; Crowther, Damian C; Jacobs, Howard T; Rustin, Pierre


    Mitochondrial dysfunction has been widely associated with the pathology of Alzheimer's disease, but there is no consensus on whether it is a cause or consequence of disease, nor on the precise mechanism(s). We addressed these issues by testing the effects of expressing the alternative oxidase AOX from Ciona intestinalis, in different models of AD pathology. AOX can restore respiratory electron flow when the cytochrome segment of the mitochondrial respiratory chain is inhibited, supporting ATP synthesis, maintaining cellular redox homeostasis and mitigating excess superoxide production at respiratory complexes I and III. In human HEK293-derived cells, AOX expression decreased the production of beta-amyloid peptide resulting from antimycin inhibition of respiratory complex III. Because hydrogen peroxide was neither a direct product nor substrate of AOX, the ability of AOX to mimic antioxidants in this assay must be indirect. In addition, AOX expression was able to partially alleviate the short lifespan of Drosophila models neuronally expressing human beta-amyloid peptides, whilst abrogating the induction of markers of oxidative stress. Our findings support the idea of respiratory chain dysfunction and excess ROS production as both an early step and as a pathologically meaningful target in Alzheimer's disease pathogenesis, supporting the concept of a mitochondrial vicious cycle underlying the disease.

  9. Matrix metalloproteinase 2 (MMP-2) degrades soluble vasculotropic amyloid-beta E22Q and L34V mutants, delaying their toxicity for human brain microvascular endothelial cells. (United States)

    Hernandez-Guillamon, Mar; Mawhirt, Stephanie; Fossati, Silvia; Blais, Steven; Pares, Mireia; Penalba, Anna; Boada, Merce; Couraud, Pierre-Olivier; Neubert, Thomas A; Montaner, Joan; Ghiso, Jorge; Rostagno, Agueda


    Patients carrying mutations within the amyloid-beta (Abeta) sequence develop severe early-onset cerebral amyloid angiopathy with some of the related variants manifesting primarily with hemorrhagic phenotypes. Matrix metalloproteases (MMPs) are typically associated with blood brain barrier disruption and hemorrhagic transformations after ischemic stroke. However, their contribution to cerebral amyloid angiopathy-related hemorrhage remains unclear. Human brain endothelial cells challenged with Abeta synthetic homologues containing mutations known to be associated in vivo with hemorrhagic manifestations (AbetaE22Q and AbetaL34V) showed enhanced production and activation of MMP-2, evaluated via Multiplex MMP antibody arrays, gel zymography, and Western blot, which in turn proteolytically cleaved in situ the Abeta peptides. Immunoprecipitation followed by mass spectrometry analysis highlighted the generation of specific C-terminal proteolytic fragments, in particular the accumulation of Abeta-(1-16), a result validated in vitro with recombinant MMP-2 and quantitatively evaluated using deuterium-labeled internal standards. Silencing MMP-2 gene expression resulted in reduced Abeta degradation and enhanced apoptosis. Secretion and activation of MMP-2 as well as susceptibility of the Abeta peptides to MMP-2 degradation were dependent on the peptide conformation, with fibrillar elements of AbetaE22Q exhibiting negligible effects. Our results indicate that MMP-2 release and activation differentially degrades Abeta species, delaying their toxicity for endothelial cells. However, taking into consideration MMP ability to degrade basement membrane components, these protective effects might also undesirably compromise blood brain barrier integrity and precipitate a hemorrhagic phenotype.

  10. Validation of the dynamic direct exposure method for toxicity testing of diesel exhaust in vitro. (United States)

    Joeng, Lucky; Hayes, Amanda; Bakand, Shahnaz


    Diesel exhaust emission is a major health concern because of the complex nature of its gaseous content (e.g., NO2, NO, CO, and CO2) and high concentration of particulate matter (PM) less than 2.5  μ m which allows for deeper penetration into the human pulmonary system upon inhalation. The aim of this research was to elucidate the potential toxic effects of diesel exhaust on a human pulmonary-based cellular system. Validation of a dynamic direct exposure method for both laboratory (230 hp Volvo truck engine) and field (Volkswagen Passat passenger car) diesel engines, at idle mode, was implemented. Human pulmonary type II epithelial cells (A549) grown on porous membranes were exposed to unmodified diesel exhaust at a low flow rate (37.5 mL/min). In parallel, diesel emission sampling was also conducted using real-time air monitoring techniques. Induced cellular effects were assessed using a range of in vitro cytotoxicity assays (MTS, ATP, and NRU). Reduction of cell viability was observed in a time-dependent manner following 30-60 mins of exposure with NRU as the most sensitive assay. The results suggest that the dynamic direct exposure method has the potential to be implemented for both laboratory- and field-based in vitro toxicity studies of diesel exhaust emissions.

  11. Specific in vitro toxicity of crude and refined petroleum products: II. Estrogen (alpha and beta) and androgen receptor-mediated responses in yeast assays.

    NARCIS (Netherlands)

    Vrabie, C.M.; Candido, A.; van Duursen, M.B.M.; Jonker, M.T.O.


    The present study is the second in a series aiming at a systematic inventory of specific toxic effects of oils. By employing a recombinant yeast stably transfected with human estrogen receptor-alpha (ERalpha) or -beta (ERbeta) or androgen receptor (AR) and expressing yeast enhanced green fluorescent

  12. Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoptotic pathways

    DEFF Research Database (Denmark)

    Karlsen, Allan Ertman; Heding, P E; Frobøse, H;


    The proinflammatory cytokine IL-1beta induces apoptosis in pancreatic beta cells via pathways dependent on nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinase, and protein kinase C. We recently showed suppressor of cytokine signalling (SOCS)-3 to be a natural negative feedback...... regulator of IL-1beta- and IFN-gamma-mediated signalling in rat islets and beta cell lines, preventing their deleterious effects. However, the mechanisms underlying SOCS-3 inhibition of IL-1beta signalling and prevention against apoptosis remain unknown....

  13. Effects of zinc toxicity on sugar beet (Beta vulgaris L.) plants grown in hydroponics. (United States)

    Sagardoy, R; Morales, F; López-Millán, A-F; Abadía, A; Abadía, J


    The effects of high Zn concentration were investigated in sugar beet (Beta vulgaris L.) plants grown in a controlled environment in hydroponics. High concentrations of Zn sulphate in the nutrient solution (50, 100 and 300 microm) decreased root and shoot fresh and dry mass, and increased root/shoot ratios, when compared to control conditions (1.2 microm Zn). Plants grown with excess Zn had inward-rolled leaf edges and a damaged and brownish root system, with short lateral roots. High Zn decreased N, Mg, K and Mn concentrations in all plant parts, whereas P and Ca concentrations increased, but only in shoots. Leaves of plants treated with 50 and 100 microm Zn developed symptoms of Fe deficiency, including decreases in Fe, chlorophyll and carotenoid concentrations, increases in carotenoid/chlorophyll and chlorophyll a/b ratios and de-epoxidation of violaxanthin cycle pigments. Plants grown with 300 microm Zn had decreased photosystem II efficiency and further growth decreases but did not have leaf Fe deficiency symptoms. Leaf Zn concentrations of plants grown with excess Zn were high but fairly constant (230-260 microg.g(-1) dry weight), whereas total Zn uptake per plant decreased markedly with high Zn supply. These data indicate that sugar beet could be a good model to investigate Zn homeostasis mechanisms in plants, but is not an efficient species for Zn phytoremediation.

  14. Microbial phenolic metabolites improve glucose-stimulated insulin secretion and protect pancreatic beta cells against tert-butyl hydroperoxide-induced toxicity via ERKs and PKC pathways. (United States)

    Fernández-Millán, Elisa; Ramos, Sonia; Alvarez, Carmen; Bravo, Laura; Goya, Luis; Martín, María Ángeles


    Oxidative stress is accepted as one of the causes of beta cell failure in type 2 diabetes. Therefore, identification of natural antioxidant agents that preserve beta cell mass and function is considered an interesting strategy to prevent or treat diabetes. Recent evidences indicated that colonic metabolites derived from flavonoids could possess beneficial effects on various tissues. The aim of this work was to establish the potential anti-diabetic properties of the microbial-derived flavonoid metabolites 3,4-dihydroxyphenylacetic acid (DHPAA), 2,3-dihydroxybenzoic acid (DHBA) and 3-hydroxyphenylpropionic acid (HPPA). To this end, we tested their ability to influence beta cell function and to protect against tert-butyl hydroperoxide-induced beta cell toxicity. DHPAA and HPPA were able to potentiate glucose-stimulated insulin secretion (GSIS) in a beta cell line INS-1E and in rat pancreatic islets. Moreover, pre-treatment of cells with both compounds protected against beta cell dysfunction and death induced by the pro-oxidant. Finally, experiments with pharmacological inhibitors indicate that these effects were mediated by the activation of protein kinase C and the extracellular regulated kinases pathways. Altogether, these findings strongly suggest that the microbial-derived flavonoid metabolites DHPAA and HPPA may have anti-diabetic potential by promoting survival and function of pancreatic beta cells.

  15. Alzheimer’s Toxic Amyloid Beta Oligomers: Unwelcome Visitors to the Na/K ATPase alpha3 Docking Station (United States)

    DiChiara, Thomas; DiNunno, Nadia; Clark, Jeffrey; Bu, Riana Lo; Cline, Erika N.; Rollins, Madeline G.; Gong, Yuesong; Brody, David L.; Sligar, Stephen G.; Velasco, Pauline T.; Viola, Kirsten L.; Klein, William L.


    Toxic amyloid beta oligomers (AβOs) are known to accumulate in Alzheimer’s disease (AD) and in animal models of AD. Their structure is heterogeneous, and they are found in both intracellular and extracellular milieu. When given to CNS cultures or injected ICV into non-human primates and other non-transgenic animals, AβOs have been found to cause impaired synaptic plasticity, loss of memory function, tau hyperphosphorylation and tangle formation, synapse elimination, oxidative and ER stress, inflammatory microglial activation, and selective nerve cell death. Memory loss and pathology in transgenic models are prevented by AβO antibodies, while Aducanumab, an antibody that targets AβOs as well as fibrillar Aβ, has provided cognitive benefit to humans in early clinical trials. AβOs have now been investigated in more than 3000 studies and are widely thought to be the major toxic form of Aβ. Although much has been learned about the downstream mechanisms of AβO action, a major gap concerns the earliest steps: How do AβOs initially interact with surface membranes to generate neuron-damaging transmembrane events? Findings from Ohnishi et al (PNAS 2005) combined with new results presented here are consistent with the hypothesis that AβOs act as neurotoxins because they attach to particular membrane protein docks containing Na/K ATPase-α3, where they inhibit ATPase activity and pathologically restructure dock composition and topology in a manner leading to excessive Ca++ build-up. Better understanding of the mechanism that makes attachment of AβOs to vulnerable neurons a neurotoxic phenomenon should open the door to therapeutics and diagnostics targeting the first step of a complex pathway that leads to neural damage and dementia. PMID:28356893

  16. [Response to treatment with interferon beta in patients with multiple sclerosis. Validation of the Rio Score]. (United States)

    Rio, J; Rovira, A; Blanco, Y; Sainz, A; Perkal, H; Robles, R; Ramio-Torrenta, Ll; Diaz, R M; Arroyo, R; Urbaneja, P; Fernandez, O; Garcia-Merino, J A; Reyes, M P; Oreja-Guevara, C; Prieto, J M; Izquierdo, G; Olascoaga, J; Alvarez-Cermeno, J C; Simon, E; Pujal, B; Comabella, M; Montalban, X


    Introduccion. Se han propuesto diferentes criterios de respuesta al tratamiento con interferon beta, y el Rio Score es uno de los mas utilizados. El objetivo de este estudio fue validar la utilidad del Rio Score en una cohorte independiente. Pacientes y metodos. Estudio multicentrico, prospectivo y longitudinal de pacientes con esclerosis multiple remitente recurrente tratados con interferon beta. Los pacientes fueron clasificados basandose en la presencia de brotes, lesiones activas (nuevas en T2 o lesiones que captaban gadolinio) en la resonancia magnetica, incremento confirmado de la discapacidad o combinaciones de estas variables (brotes, incremento en la Expanded Disability Status Scale y lesiones activas) tras un año de tratamiento. Se utilizo un analisis de regresion con el fin de identificar las variables de prediccion de respuesta despues de un seguimiento de tres años. Resultados. Se incluyo a 249 pacientes con esclerosis multiple remitente recurrente. El modelo logistico confirmo que la presencia de dos (odds ratio = 6,6; IC 95% = 2,7-16,1; p discapacidad durante el tratamiento con interferon beta.

  17. Mitochondria-targeted antioxidant mitotempo protects mitochondrial function against amyloid beta toxicity in primary cultured mouse neurons. (United States)

    Hu, Hongtao; Li, Mo


    Mitochondrial defects including excess reactive oxygen species (ROS) production and compromised ATP generation are featured pathology in Alzheimer's disease (AD). Amyloid beta (Aβ)-mediated mitochondrial ROS overproduction disrupts intra-neuronal Redox balance, in turn exacerbating mitochondrial dysfunction leading to neuronal injury. Previous studies have found the beneficial effects of mitochondria-targeted antioxidants in preventing mitochondrial dysfunction and neuronal injury in AD animal and cell models, suggesting that mitochondrial ROS scavengers hold promise for the treatment of this neurological disorder. In this study, we have determined that mitotempo, a novel mitochondria-targeted antioxidant protects mitochondrial function from the toxicity of Aβ in primary cultured neurons. Our results showed that Aβ-promoted mitochondrial superoxide production and neuronal lipid oxidation were significantly suppressed by the application of mitotempo. Moreover, mitotempo also demonstrated protective effects on mitochondrial bioenergetics evidenced by preserved mitochondrial membrane potential, cytochrome c oxidase activity as well as ATP production. In addition, the Aβ-induced mitochondrial DNA (mtDNA) depletion and decreased expression levels of mtDNA replication-related DNA polymerase gamma (DNA pol γ) and Twinkle were substantially mitigated by mitotempo. Therefore, our study suggests that elimination of excess mitochondrial ROS rescues mitochondrial function in Aβ-insulted neruons; and mitotempo has the potential to be a promising therapeutic agent to protect mitochondrial and neuronal function in AD.

  18. Coconut oil protects cortical neurons from amyloid beta toxicity by enhancing signaling of cell survival pathways. (United States)

    Nafar, F; Clarke, J P; Mearow, K M


    Alzheimer's disease is a progressive neurodegenerative disease that has links with other conditions that can often be modified by dietary and life-style interventions. In particular, coconut oil has received attention as having potentially having benefits in lessening the cognitive deficits associated with Alzheimer's disease. In a recent report, we showed that neuron survival in cultures co-treated with coconut oil and Aβ was rescued compared to cultures exposed only to Aβ. Here we investigated treatment with Aβ for 1, 6 or 24 h followed by addition of coconut oil for a further 24 h, or treatment with coconut oil for 24 h followed by Aβ exposure for various periods. Neuronal survival and several cellular parameters (cleaved caspase 3, synaptophysin labeling and ROS) were assessed. In addition, the influence of these treatments on relevant signaling pathways was investigated with Western blotting. In terms of the treatment timing, our data indicated that coconut oil rescues cells pre-exposed to Aβ for 1 or 6 h, but is less effective when the pre-exposure has been 24 h. However, pretreatment with coconut oil prior to Aβ exposure showed the best outcomes. Treatment with octanoic or lauric acid also provided protection against Aβ, but was not as effective as the complete oil. The coconut oil treatment reduced the number of cells with cleaved caspase and ROS labeling, as well as rescuing the loss of synaptophysin labeling observed with Aβ treatment. Treatment with coconut oil, as well as octanoic, decanoic and lauric acids, resulted in a modest increase in ketone bodies compared to controls. The biochemical data suggest that Akt and ERK activation may contribute to the survival promoting influence of coconut oil. This was supported by observations that a PI3-Kinase inhibitor blocked the rescue effect of CoOil on Aβ amyloid toxicity. Further studies into the mechanisms of action of coconut oil and its constituent medium chain fatty acids are warranted.

  19. Significant Association of Urinary Toxic Metals and Autism-Related Symptoms—A Nonlinear Statistical Analysis with Cross Validation (United States)

    Adams, James; Kruger, Uwe; Geis, Elizabeth; Gehn, Eva; Fimbres, Valeria; Pollard, Elena; Mitchell, Jessica; Ingram, Julie; Hellmers, Robert; Quig, David; Hahn, Juergen


    Introduction A number of previous studies examined a possible association of toxic metals and autism, and over half of those studies suggest that toxic metal levels are different in individuals with Autism Spectrum Disorders (ASD). Additionally, several studies found that those levels correlate with the severity of ASD. Methods In order to further investigate these points, this paper performs the most detailed statistical analysis to date of a data set in this field. First morning urine samples were collected from 67 children and adults with ASD and 50 neurotypical controls of similar age and gender. The samples were analyzed to determine the levels of 10 urinary toxic metals (UTM). Autism-related symptoms were assessed with eleven behavioral measures. Statistical analysis was used to distinguish participants on the ASD spectrum and neurotypical participants based upon the UTM data alone. The analysis also included examining the association of autism severity with toxic metal excretion data using linear and nonlinear analysis. “Leave-one-out” cross-validation was used to ensure statistical independence of results. Results and Discussion Average excretion levels of several toxic metals (lead, tin, thallium, antimony) were significantly higher in the ASD group. However, ASD classification using univariate statistics proved difficult due to large variability, but nonlinear multivariate statistical analysis significantly improved ASD classification with Type I/II errors of 15% and 18%, respectively. These results clearly indicate that the urinary toxic metal excretion profiles of participants in the ASD group were significantly different from those of the neurotypical participants. Similarly, nonlinear methods determined a significantly stronger association between the behavioral measures and toxic metal excretion. The association was strongest for the Aberrant Behavior Checklist (including subscales on Irritability, Stereotypy, Hyperactivity, and Inappropriate

  20. Field Validation of Toxicity Tests to Evaluate the Potential for Beneficial Use of Produced Water

    Energy Technology Data Exchange (ETDEWEB)

    Joseph Bidwell; Jonathan Fisher; Naomi Cooper


    This study investigated potential biological effects of produced water contamination derived from occasional surface overflow and possible subsurface intrusion at an oil production site along the shore of Skiatook Lake, Oklahoma. We monitored basic chemistry and acute toxicity to a suite of standard aquatic test species (fathead minnow-Pimephales promelas, Daphnia pulex, Daphnia magna, and Ceriodaphnia dubia) in produced water and in samples taken from shallow groundwater wells on the site. Toxicity identification evaluations and ion toxicity modeling were used to identify toxic constituents in the samples. Lake sediment at the oil production site and at a reference site were also analyzed for brine intrusion chemically and by testing sediment toxicity using the benthic invertebrates, Chironomus dilutus, and Hyallela azteca. Sediment quality was also assessed with in situ survival and growth studies with H. azteca and the Asian clam, Corbicula fluminea, and by benthic macroinvertebrate community sampling. The produced water was acutely toxic to the aquatic test organisms at concentrations ranging from 1% to 10% of the whole produced water sample. Toxicity identification evaluation and ion toxicity modeling indicated major ion salts and hydrocarbons were the primary mixture toxicants. The standardized test species used in the laboratory bioassays exhibited differences in sensitivity to these two general classes of contaminants, which underscores the importance of using multiple species when evaluating produced water toxicity. Toxicity of groundwater was greater in samples from wells near a produced water injection well and an evaporation pond. Principle component analyses (PCA) of chemical data derived from the groundwater wells indicated dilution by lake water and possible biogeochemical reactions as factors that ameliorated groundwater toxicity. Elevated concentrations of major ions were found in pore water from lake sediments, but toxicity from these ions was

  1. Geostatistical validation and cross-validation of magnetometric measurements of soil pollution with Potentially Toxic Elements in problematic areas (United States)

    Fabijańczyk, Piotr; Zawadzki, Jarosław


    Field magnetometry is fast method that was previously effectively used to assess the potential soil pollution. One of the most popular devices that are used to measure the soil magnetic susceptibility on the soil surface is a MS2D Bartington. Single reading using MS2D device of soil magnetic susceptibility is low time-consuming but often characterized by considerable errors related to the instrument or environmental and lithogenic factors. In this connection, measured values of soil magnetic susceptibility have to be usually validated using more precise, but also much more expensive, chemical measurements. The goal of this study was to analyze validation methods of magnetometric measurements using chemical analyses of a concentration of elements in soil. Additionally, validation of surface measurements of soil magnetic susceptibility was performed using selected parameters of a distribution of magnetic susceptibility in a soil profile. Validation was performed using selected geostatistical measures of cross-correlation. The geostatistical approach was compared with validation performed using the classic statistics. Measurements were performed at selected areas located in the Upper Silesian Industrial Area in Poland, and in the selected parts of Norway. In these areas soil magnetic susceptibility was measured on the soil surface using a MS2D Bartington device and in the soil profile using MS2C Bartington device. Additionally, soil samples were taken in order to perform chemical measurements. Acknowledgment The research leading to these results has received funding from the Polish-Norwegian Research Programme operated by the National Centre for Research and Development under the Norwegian Financial Mechanism 2009-2014 in the frame of Project IMPACT - Contract No Pol-Nor/199338/45/2013.

  2. Statistically validated QSARs, based on theoretical descriptors, for modeling aquatic toxicity of organic chemicals in Pimephales promelas (fathead minnow). (United States)

    Papa, Ester; Villa, Fulvio; Gramatica, Paola


    The use of Quantitative Structure-Activity Relationships in assessing the potential negative effects of chemicals plays an important role in ecotoxicology. (LC50)(96h) in Pimephales promelas (Duluth database) is widely modeled as an aquatic toxicity end-point. The object of this study was to compare different molecular descriptors in the development of new statistically validated QSAR models to predict the aquatic toxicity of chemicals classified according to their MOA and in a unique general model. The applied multiple linear regression approach (ordinary least squares) is based on theoretical molecular descriptor variety (1D, 2D, and 3D, from DRAGON package, and some calculated logP). The best combination of modeling descriptors was selected by the Genetic Algorithm-Variable Subset Selection procedure. The robustness and the predictive performance of the proposed models was verified using both internal (cross-validation by LOO, bootstrap, Y-scrambling) and external statistical validations (by splitting the original data set into training and validation sets by Kohonen-artificial neural networks (K-ANN)). The model applicability domain (AD) was checked by the leverage approach to verify prediction reliability.

  3. A Review of the External Validity of Clinical Trials with Beta-Blockers in Heart Failure (United States)

    Iyngkaran, Pupalan; Toukhsati, Samia R.; Thomas, Merlin C.; Jelinek, Michael V.; Hare, David L.; Horowitz, John D.


    BACKGROUND Beta-blockers (BBs) are the mainstay prognostic medication for all stages of chronic heart failure (CHF). There are many classes of BBs, each of which has varying levels of evidence to support its efficacy in CHF. However, most CHF patients have one or more comorbid conditions such as diabetes, renal impairment, and/or atrial fibrillation. Patient enrollment to randomized controlled trials (RCTs) often excludes those with certain comorbidities, particularly if the symptoms are severe. Consequently, the extent to which evidence drawn from RCTs is generalizable to CHF patients has not been well described. Clinical guidelines also underrepresent this point by providing generic advice for all patients. The aim of this review is to examine the evidence to support the use of BBs in CHF patients with common comorbid conditions. METHODS We searched MEDLINE, PubMed, and the reference lists of reviews for RCTs, post hoc analyses, systematic reviews, and meta-analyses that report on use of BBs in CHF along with patient demographics and comorbidities. RESULTS In total, 38 studies from 28 RCTs were identified, which provided data on six BBs against placebo or head to head with another BB agent in ischemic and nonischemic cardiomyopathies. Several studies explored BBs in older patients. Female patients and non-Caucasian race were underrepresented in trials. End points were cardiovascular hospitalization and mortality. Comorbid diabetes, renal impairment, or atrial fibrillation was detailed; however, no reference to disease spectrum or management goals as a focus could be seen in any of the studies. In this sense, enrollment may have limited more severe grades of these comorbidities. CONCLUSIONS RCTs provide authoritative information for a spectrum of CHF presentations that support guidelines. RCTs may provide inadequate information for more heterogeneous CHF patient cohorts. Greater Phase IV research may be needed to fill this gap and inform guidelines for a more

  4. A Quantitative Structure Activity Relationship for acute oral toxicity of pesticides on rats: Validation, domain of application and prediction. (United States)

    Hamadache, Mabrouk; Benkortbi, Othmane; Hanini, Salah; Amrane, Abdeltif; Khaouane, Latifa; Si Moussa, Cherif


    Quantitative Structure Activity Relationship (QSAR) models are expected to play an important role in the risk assessment of chemicals on humans and the environment. In this study, we developed a validated QSAR model to predict acute oral toxicity of 329 pesticides to rats because a few QSAR models have been devoted to predict the Lethal Dose 50 (LD50) of pesticides on rats. This QSAR model is based on 17 molecular descriptors, and is robust, externally predictive and characterized by a good applicability domain. The best results were obtained with a 17/9/1 Artificial Neural Network model trained with the Quasi Newton back propagation (BFGS) algorithm. The prediction accuracy for the external validation set was estimated by the Q(2)ext and the root mean square error (RMS) which are equal to 0.948 and 0.201, respectively. 98.6% of external validation set is correctly predicted and the present model proved to be superior to models previously published. Accordingly, the model developed in this study provides excellent predictions and can be used to predict the acute oral toxicity of pesticides, particularly for those that have not been tested as well as new pesticides.

  5. Validation the quantification of beta emitters activity in urine by scintillation spectrometry in the liquid phase; Validacion de la cuantificacion de actividad de emisores beta en orina mediante espectrometria de centelleo en fase liquida

    Energy Technology Data Exchange (ETDEWEB)

    Sierra, I.; Hernandez, C.; Benito, P.; Lopez, C.


    In this paper the methodology used in the validation of the technique for quantifying activity of some beta emitters in urine ({sup 3}H, {sup 1}4C, {sup 3}5S, {sup 3}2P and {sup 9}0Sr) by scintillation spectrometry Liquid Phase (Liquid Scintillation Counting, LSC) is described in bio elimination Laboratory Service CIEMAT Radiation Dosimetry accredited since last year for carrying out assays measure radiation dose based on ISO forth above. (Author)

  6. Daphnia and fish toxicity of (benzo)triazoles: validated QSAR models, and interspecies quantitative activity-activity modelling. (United States)

    Cassani, Stefano; Kovarich, Simona; Papa, Ester; Roy, Partha Pratim; van der Wal, Leon; Gramatica, Paola


    Due to their chemical properties synthetic triazoles and benzo-triazoles ((B)TAZs) are mainly distributed to the water compartments in the environment, and because of their wide use the potential effects on aquatic organisms are cause of concern. Non testing approaches like those based on quantitative structure-activity relationships (QSARs) are valuable tools to maximize the information contained in existing experimental data and predict missing information while minimizing animal testing. In the present study, externally validated QSAR models for the prediction of acute (B)TAZs toxicity in Daphnia magna and Oncorhynchus mykiss have been developed according to the principles for the validation of QSARs and their acceptability for regulatory purposes, proposed by the Organization for Economic Co-operation and Development (OECD). These models are based on theoretical molecular descriptors, and are statistically robust, externally predictive and characterized by a verifiable structural applicability domain. They have been applied to predict acute toxicity for over 300 (B)TAZs without experimental data, many of which are in the pre-registration list of the REACH regulation. Additionally, a model based on quantitative activity-activity relationships (QAAR) has been developed, which allows for interspecies extrapolation from daphnids to fish. The importance of QSAR/QAAR, especially when dealing with specific chemical classes like (B)TAZs, for screening and prioritization of pollutants under REACH, has been highlighted.

  7. Biodegradable beta-Tri-Calciumphosphate/hydroxyethyl methacrylate enhanced three component bone adhesive demonstrates biocompatibility without evidence of systemic toxicity in a rabbit model. (United States)

    Bauer, Natali B; Brinke, Nina; Heiss, Christian; Skorupa, Agnes B; Peters, Fabian; Kraus, Ralf; Schnettler, Reinhard; Moritz, Andreas


    Bone gluing is an attractive surgical technique; however, its use in patients is hampered by a variety of side effects. Therefore, it was the aim of this ethically approved study to evaluate a novel biodegradable beta-Tri-Calciumphosphate (beta-TCP, Cerasorb)-enhanced bone adhesive regarding its toxicity and biocompatibility in a rabbit model. Fifty healthy New Zealand White rabbits were assigned in the study (n = 21) and sham-operated control group (n = 29). In the study group, a cylindrical part (4.6 x 10.0 mm) of the proximal tibia and distal femur was removed, reimplanted, and bone adhesive was applied. Blinded physical examination and sampling for hematology, clinical chemistry, and acute phase proteins (haptoglobin, C-reactive protein (CRP)) was performed before surgery and after 12, 24, 48, 72, 240, and 504 h. Significant findings of the physical examination included a slightly higher grading of warmth (p = 0.0019) and pain (p < 0.0001) of the wound 240 h after surgery in the study group. No significant differences between albumin, haptoglobin, CRP, and urea concentrations in both groups were evident, whereas the study group demonstrated significantly lower leukocyte count, total protein, and globulin concentrations (p < 0.0001). As expected, both groups showed a marked transient increase in muscle enzymes (Creatine Kinase and Aspartate Aminotransferase) following the surgery (p < 0.0001). Twelve to 24 h after surgery, a significant decrease in ionized calcium from 1.38 +/- 0.12 mmol/L to 1.06 +/- 0.13 mmol/L was noted in the study group (p < 0.0001). The results clearly indicated that the novel beta-TCP-enhanced bone adhesive showed good biocompatibility without significant evidence of acute or subacute local or systemic toxicity.

  8. Metabolic changes may precede proteostatic dysfunction in a Drosophila model of amyloid beta peptide toxicity

    DEFF Research Database (Denmark)

    Ott, Stanislav; Vishnivetskaya, Anastasia; Malmendal, Anders;


    Amyloid beta (Aβ) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of Aβ, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of Aβ are not apparent until after day 15. We used shibire(...

  9. Keampferol-3-O-rhamnoside abrogates amyloid beta toxicity by modulating monomers and remodeling oligomers and fibrils to non-toxic aggregates

    Directory of Open Access Journals (Sweden)

    Sharoar Md


    Full Text Available Abstract Background Aggregation of soluble, monomeric β- amyloid (Aβ to oligomeric and then insoluble fibrillar Aβ is a key pathogenic feature in development of Alzheimer’s disease (AD. Increasing evidence suggests that toxicity is linked to diffusible Aβ oligomers, rather than to insoluble fibrils. The use of naturally occurring small molecules for inhibition of Aβ aggregation has recently attracted significant interest for development of effective therapeutic strategies against the disease. A natural polyphenolic flavone, Kaempferol-3-O-rhamnoside (K-3-rh, was utilized to investigate its effects on aggregation and cytotoxic effects of Aβ42 peptide. Several biochemical techniques were used to determine the conformational changes and cytotoxic effect of the peptide in the presence and absence of K-3-rh. Results K-3-rh showed a dose-dependent effect against Aβ42 mediated cytotoxicity. Anti-amyloidogenic properties of K-3-rh were found to be efficient in inhibiting fibrilogenesis and secondary structural transformation of the peptide. The consequence of these inhibitions was the accumulation of oligomeric structural species. The accumulated aggregates were smaller, soluble, non-β-sheet and non-toxic aggregates, compared to preformed toxic Aβ oligomers. K-3-rh was also found to have the remodeling properties of preformed soluble oligomers and fibrils. Both of these conformers were found to remodel into non-toxic aggregates. The results showed that K-3-rh interacts with different Aβ conformers, which affects fibril formation, oligomeric maturation and fibrillar stabilization. Conclusion K-3-rh is an efficient molecule to hinder the self assembly and to abrogate the cytotoxic effects of Aβ42 peptide. Hence, K-3-rh and small molecules with similar structure might be considered for therapeutic development against AD.

  10. Development and validation of cell-based luciferase reporter gene assays for measuring neutralizing anti-drug antibodies against interferon beta

    DEFF Research Database (Denmark)

    Hermanrud, Christina; Ryner, Malin; Luft, Thomas


    Neutralizing anti-drug antibodies (NAbs) against therapeutic interferon beta (IFNβ) in people with multiple sclerosis (MS) are measured with cell-based bioassays. The aim of this study was to redevelop and validate two luciferase reporter-gene bioassays, LUC and iLite, using a cut-point approach...... was validated at Innsbruck Medical University (LUCIMU) and at Rigshospitalet (LUCRH) Copenhagen, and the iLite assay at Karolinska Institutet, Stockholm. For both assays, the optimal serum sample concentration in relation to sensitivity and recovery was 2.5% (v/v) in assay media. A Shapiro-Wilk test indicated...

  11. Amyloidosis in Alzheimer’s Disease: The Toxicity of Amyloid Beta (Aβ, Mechanisms of Its Accumulation and Implications of Medicinal Plants for Therapy

    Directory of Open Access Journals (Sweden)

    Anchalee Prasansuklab


    Full Text Available Alzheimer’s disease (AD is a progressive neurodegenerative disorder that leads to memory deficits and death. While the number of individuals with AD is rising each year due to the longer life expectancy worldwide, current therapy can only somewhat relieve the symptoms of AD. There is no proven medication to cure or prevent the disease, possibly due to a lack of knowledge regarding the molecular mechanisms underlying disease pathogenesis. Most previous studies have accepted the “amyloid hypothesis,” in which the neuropathogenesis of AD is believed to be triggered by the accumulation of the toxic amyloid beta (Aβ protein in the central nervous system (CNS. Lately, knowledge that may be critical to unraveling the hidden pathogenic pathway of AD has been revealed. This review concentrates on the toxicity of Aβ and the mechanism of accumulation of this toxic protein in the brain of individuals with AD and also summarizes recent advances in the study of these accumulation mechanisms together with the role of herbal medicines that could facilitate the development of more effective therapeutic and preventive strategies.

  12. Stabilization of the cyclin-dependent kinase 5 activator, p35, by paclitaxel decreases beta-amyloid toxicity in cortical neurons. (United States)

    Li, Guibin; Faibushevich, Alexander; Turunen, Brandon J; Yoon, Sung Ok; Georg, Gunda; Michaelis, Mary L; Dobrowsky, Rick T


    One hallmark of Alzheimer's disease (AD) is the formation of neurofibrillary tangles, aggregated paired helical filaments composed of hyperphosphorylated tau. Amyloid-beta (Abeta) induces tau hyperphosphorylation, decreases microtubule (MT) stability and induces neuronal death. MT stabilizing agents have been proposed as potential therapeutics that may minimize Abeta toxicity and here we report that paclitaxel (taxol) prevents cell death induced by Abeta peptides, inhibits Abeta-induced activation of cyclin-dependent kinase 5 (cdk5) and decreases tau hyperphosphorylation. Taxol did not inhibit cdk5 directly but significantly blocked Abeta-induced calpain activation and decreased formation of the cdk5 activator, p25, from p35. Taxol specifically inhibited the Abeta-induced activation of the cytosolic cdk5-p25 complex, but not the membrane-associated cdk5-p35 complex. MT-stabilization was necessary for neuroprotection and inhibition of cdk5 but was not sufficient to prevent cell death induced by overexpression of p25. As taxol is not permeable to the blood-brain barrier, we assessed the potential of taxanes to attenuate Abeta toxicity in adult animals using a succinylated taxol analog (TX67) permeable to the blood-brain barrier. TX67, but not taxol, attenuated the magnitude of both basal and Abeta-induced cdk5 activation in acutely dissociated cortical cultures prepared from drug treated adult mice. These results suggest that MT-stabilizing agents may provide a therapeutic approach to decrease Abeta toxicity and neurofibrillary pathology in AD and other tauopathies.

  13. Preliminary toxicity studies on bis-[beta-(N,N-dimorpholino) ethyl] selenide (MOSE). A new radioimaging agent. (United States)

    Kostyniak, P J


    The present study describes the acute toxicity of MOSE, a proposed radioimaging agent for brain scintigraphy . Acute intraperitoneal administration of MOSE in mice revealed an LD50 between 1.35 and 6.25 g/kg, with convulsions preceding death. Intravenous administration of MOSE in rats resulted in an LD50 between 400 and 800 mg/kg, with death also preceded by convulsions. The rabbit was more sensitive to the acute effects of MOSE than the rat. The LD50 for MOSE given i.v. in the rabbit was 80 mg/kg. The predominant toxic sign was convulsions, which immediately preceded death at high doses. At intermediate doses convulsions were elicited, followed by a period of lethargy which gave way to hyperactivity on the following day. Normal appearances were restored within a week. Hematology and blood chemistries were similar to controls, except for increased serum LDH in animals receiving MOSE when sampled two weeks after dosing. Repeated administration of MOSE by the intravenous route in rabbits at a dose rate of 1 mg/kg/da, five days per week for two weeks, resulted in no signs of toxicity. Hematology, clinical chemistry, and histology revealed no changes in animals receiving MOSE when compared to control. It was concluded that barring any unusual susceptibility in man, the proposed diagnostic dose to man is unlikely to precipitate any acute toxic effects.

  14. Efficacy of attractive toxic sugar baits (ATSB) against Aedes albopictus with garlic oil encapsulated in beta-cyclodextrin as the active ingredient. (United States)

    Junnila, Amy; Revay, Edita E; Müller, Gunter C; Kravchenko, Vasiliy; Qualls, Whitney A; Xue, Rui-de; Allen, Sandra A; Beier, John C; Schlein, Yosef


    We tested the efficacy of attractive toxic sugar bait (ATSB) with garlic oil microencapsulated in beta-cyclodextrin as active ingredient against Aedes albopictus in suburban Haifa, Israel. Two three-acre gardens with high numbers of Ae. albopictus were selected for perimeter spray treatment with ATSB and ASB (bait containing no active ingredient). Baits were colored with food dye to verify feeding of the mosquitoes. The mosquito population was monitored by human landing catches and sweep net catches in the surrounding vegetation. Experiments lasted for 44 days. Treatment occurred on day 13. The mosquito population collapsed about 4 days after treatment and continued to drop steadily for 27 days until the end of the study. At the experimental site the average pre-treatment landing rate was 17.2 per 5mins. Two days post-treatment, the landing rate dropped to 11.4, and continued to drop to an average of 2.6 during the following 26 days. During the same period, the control population was stable. Few sugar fed females (8-10%) approached a human bait and anthrone tests showed relatively small amounts of sugar within their crop/gut. Around 60-70 % of males caught near our human bait were sugar positive which may indicate that the males were feeding on sugar for mating related behavior. From the vegetation treated with the toxic bait, we recovered significantly fewer (about 10-14%) males and females stained by ATSB than at the ASB-treated control. This may indicate that the toxic baits alter the resting behavior of the poisoned mosquitoes within the vegetation. Almost no Ae. albopictus females (5.2±1.4) approached human bait after treatment with ATSB. It therefore appears that microencapsulated garlic oil is an effective pesticide against Ae. albopictus when used in an ATSB system.

  15. Development and validation of an OECD reproductive toxicity test guideline with the pond snail Lymnaea stagnalis (Mollusca, Gastropoda). (United States)

    Ducrot, Virginie; Askem, Clare; Azam, Didier; Brettschneider, Denise; Brown, Rebecca; Charles, Sandrine; Coke, Maïra; Collinet, Marc; Delignette-Muller, Marie-Laure; Forfait-Dubuc, Carole; Holbech, Henrik; Hutchinson, Thomas; Jach, Arne; Kinnberg, Karin L; Lacoste, Cédric; Le Page, Gareth; Matthiessen, Peter; Oehlmann, Jörg; Rice, Lynsey; Roberts, Edward; Ruppert, Katharina; Davis, Jessica Elphinstone; Veauvy, Clemence; Weltje, Lennart; Wortham, Ruth; Lagadic, Laurent


    The OECD test guideline development program has been extended in 2011 to establish a partial life-cycle protocol for assessing the reproductive toxicity of chemicals to several mollusk species, including the great pond snail Lymnaea stagnalis. In this paper, we summarize the standard draft protocol for a reproduction test with this species, and present inter-comparison results obtained in a 56-day prevalidation ring-test using this protocol. Seven European laboratories performed semi-static tests with cultured snails of the strain Renilys® exposed to nominal concentrations of cadmium chloride (from 53 to 608μgCdL(-1)). Cd concentrations in test solutions were analytically determined to confirm accuracy in the metal exposure concentrations in all laboratories. Physico-chemical and biological validity criteria (namely dissolved oxygen content >60% ASV, water temperature 20±1°C, control snail survival >80% and control snail fecundity >8 egg-masses per snail over the test period) were met in all laboratories which consistently demonstrated the reproductive toxicity of Cd in snails using the proposed draft protocol. Effect concentrations for fecundity after 56days were reproducible between laboratories (68validation ring-test involving 14 laboratories in Europe, North- and South-America is currently being implemented using four chemicals (Cd, prochloraz, trenbolone

  16. Environmental dose rate heterogeneity of beta radiation and its implications for luminescence dating: Monte Carlo modelling and experimental validation

    DEFF Research Database (Denmark)

    Nathan, R.P.; Thomas, P.J.; Jain, M.;


    simulations. It is concluded that the effect of beta, heterogeneity in complex environments for luminescence dating is two fold: (i) the infinite matrix dose rate is not universally applicable; its accuracy depends on the scale of the heterogeneity, and (ii) the interpretation of D-e distributions is complex...

  17. 1,8-cineole (eucalyptol) mitigates inflammation in amyloid Beta toxicated PC12 cells: relevance to Alzheimer's disease. (United States)

    Khan, Andleeb; Vaibhav, Kumar; Javed, Hayate; Tabassum, Rizwana; Ahmed, Md Ejaz; Khan, Mohd Moshahid; Khan, M Badruzzaman; Shrivastava, Pallavi; Islam, Farah; Siddiqui, M Saeed; Safhi, M M; Islam, Fakhrul


    Inflammatory process has a fundamental role in the pathogenesis of Alzheimer's disease and insoluble amyloid beta deposits and neurofibrillary tangles provide the obvious stimuli for inflammation. The present study demonstrate the effect of pretreatment of 1,8-cineole (Cin) on inflammation induced by Aβ(25-35) in differentiated PC12 cells. The cells were treated with Cin at different doses for 24 h and then replaced by media containing Aβ(25-35) for another 24 h. The cell viability was decreased in Aβ(25-35) treated cells which was significantly restored by Cin pretreatment. Cin successfully reduced the mitochondrial membrane potential, ROS and NO levels in Aβ(25-35) treated cells. Cin also lowered the levels of proinflammatory cytokines TNF-α, IL-1β and IL-6 in Aβ(25-35) treated cells. Moreover, Cin also succeeded in lowering the expression of NOS-2, COX-2 and NF-κB. This study suggests the protective effects of Cin on inflammation and provides additional evidence for its potential beneficial use in therapy as an anti-inflammatory agent in neurodegenerative disease.

  18. Histologic examination of the rat central nervous system after intrathecal administration of human beta-endorphin

    DEFF Research Database (Denmark)

    Hée, P.; Klinken, Leif; Ballegaard, Martin


    Neuropathology, analgesics - intrathecal, central nervous system, histology, human beta-endorphin, toxicity......Neuropathology, analgesics - intrathecal, central nervous system, histology, human beta-endorphin, toxicity...

  19. Binding Studies on Isolated Porcine Small Intestinal Mucosa and in vitro Toxicity Studies Reveal Lack of Effect of C. perfringens Beta-Toxin on the Porcine Intestinal Epithelium

    Directory of Open Access Journals (Sweden)

    Simone Roos


    Full Text Available Beta-toxin (CPB is the essential virulence factor of C. perfringens type C causing necrotizing enteritis (NE in different hosts. Using a pig infection model, we showed that CPB targets small intestinal endothelial cells. Its effect on the porcine intestinal epithelium, however, could not be adequately investigated by this approach. Using porcine neonatal jejunal explants and cryosections, we performed in situ binding studies with CPB. We confirmed binding of CPB to endothelial but could not detect binding to epithelial cells. In contrast, the intact epithelial layer inhibited CPB penetration into deeper intestinal layers. CPB failed to induce cytopathic effects in cultured polarized porcine intestinal epithelial cells (IPEC-J2 and primary jejunal epithelial cells. C. perfringens type C culture supernatants were toxic for cell cultures. This, however, was not inhibited by CPB neutralization. Our results show that, in the porcine small intestine, CPB primarily targets endothelial cells and does not bind to epithelial cells. An intact intestinal epithelial layer prevents CPB diffusion into underlying tissue and CPB alone does not cause direct damage to intestinal epithelial cells. Additional factors might be involved in the early epithelial damage which is needed for CPB diffusion towards its endothelial targets in the small intestine.

  20. Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. (United States)

    Cucchiaroni, Maria Letizia; Viscomi, Maria Teresa; Bernardi, Giorgio; Molinari, Marco; Guatteo, Ezia; Mercuri, Nicola B


    Amyotrophic lateral sclerosis-Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, and Alzheimer's symptoms that is prevalent in the Guam population. beta-N-Methylamino alanine (BMAA) has been proposed as the toxic agent damaging several neuronal types in ALS-PDC, including substantia nigra pars compacta dopaminergic (SNpc DAergic) neurons. BMAA is a mixed glutamate receptor agonist, but the specific pathways activated in DAergic neurons are not yet known. We combined electrophysiology, microfluorometry, and confocal microscopy analysis to monitor membrane potential/current, cytosolic calcium concentration ([Ca(2+)](i)) changes, cytochrome-c (cyt-c) immunoreactivity, and reactive oxygen species (ROS) production induced by BMAA. Rapid toxin applications caused reversible membrane depolarization/inward current and increase of firing rate and [Ca(2+)](i) in DAergic neurons. The inward current (I(BMAA)) was mainly mediated by activation of metabotropic glutamate receptor 1 (mGluR1), coupled to transient receptor potential (TRP) channels, and to a lesser extent, AMPA receptors. Indeed, mGluR1 (CPCCOEt) and TRP channels (SKF 96365; Ruthenium Red) antagonists reduced I(BMAA), and a small component of I(BMAA) was reduced by the AMPA receptor antagonist CNQX. Calcium accumulation was mediated by mGluR1 but not by AMPA receptors. Application of a low concentration of NMDA potentiated the BMAA-mediated calcium increase. Prolonged exposure to BMAA caused significant modifications of membrane properties, calcium overload, cell shrinkage, massive cyt-c release into the cytosol and ROS production. In SNpc GABAergic neurons, BMAA activated only AMPA receptors. Our study identifies the mGluR1-activated mechanism induced by BMAA that may cause the neuronal degeneration and parkinsonian symptoms seen in ALS-PDC. Moreover, environmental exposure to BMAA might possibly also contribute to idiopathic PD.

  1. Development and validation of a HPLC-UV method for the simultaneous determination of the antipsychotics clozapine, olanzapine and quetiapine, several beta-blockers and their metabolites. (United States)

    Gracia, Margarete Silva; Köppl, Alexandra; Unholzer, Sandra; Haen, Ekkehard


    A simple, accurate and selective column-switching high performance liquid chromatography (HPLC) method was developed and validated for simultaneous quantification of six beta-blockers (metoprolol MET, timolol TIM, bisoprolol BIS, propranolol PRO, carvedilol CAR and nebivolol NEB), three of their metabolites (α-hydroxy metoprolol α-HMET, N-desisopropyl propranolol DIPRO and 4'-hydroxy carvedilol 4-HCAR), three antipsychotics (olanzapine OLA, clozapine CLO and quetiapine QUE) and three of their metabolites (N-desmethyl olanzapine DMOLA, N-desmethyl clozapine DMCLO and N-desalkyl quetiapine DAQUE) in human serum. After pretreatment on a Merck LiChrospher RP-4 ADS column (25 μm) drugs were separated on a Phenomenex Gemini Phenyl Hexyl 110 A column (250 mm x 4.6 mm, 5 μm) using a gradient mixture of acetonitrile and potassium dihydrogen phosphate buffer pH 3.1 (containing 10 % methanol) as a mobile phase at a flow rate of 1ml/min. The total analysis time was 40 min. For detection of the analytes, four different UV wavelengths were used: 215 nm, 226 nm, 242 nm and 299 nm. The method was validated according to the guidelines of the Society of Toxicology and Forensic Chemistry (GTFCh) in terms of selectivity, linearity, accuracy, precision and stability and successfully applied for the analysis of the 15 described analytes in human serum.

  2. The alpha7 nicotinic acetylcholine receptor-selective antagonist, methyllycaconitine, partially protects against beta-amyloid1-42 toxicity in primary neuron-enriched cultures. (United States)

    Martin, Shelley E; de Fiebre, Nancy Ellen C; de Fiebre, Christopher M


    Studies have suggested that the neuroprotective actions of alpha7 nicotinic agonists arise from activation of receptors and not from the extensive desensitization which rapidly follows activation. Here, we report that the alpha7-selective nicotinic antagonist, methyllycaconitine (MLA), protects against beta-amyloid-induced neurotoxicity; whereas the alpha4beta2-selective antagonist, dihydro-beta-erythroidine, does not. These findings suggest that neuroprotective actions of alpha7-acting agents arise from receptor inhibition/desensitization and that alpha7 antagonists may be useful neuroprotective agents.

  3. In-house method validation and occurrence of alpha-, beta-endosulfan, endosulfan sulphate, lambda-cyhalothrin, procymidone and trifluralin residues in strawberry

    Directory of Open Access Journals (Sweden)

    Alexandre Augusto Soares


    Full Text Available A method for determination of organohalogen pesticides in strawberry by gas chromatography with electron capture detection was validated and applied in a monitoring program. Linearity, matrix effects, and day effect were evaluated for the analytes alpha-endosulfan, beta-endosulfan, endosulfan sulphate, lambda-cyhalothrin, procymidone, and trifluralin. The linear range varied according to the chromatographic response of the analyte. Significant matrix effects were observed. The mean recoveries ranged from 74.6 to 115.4%, with repeatability standard deviations between 1.6 and 21.0% and intermediate precision between 5.9 and 21.0%. Detection, quantification and decision limit, and detection capacity ranged from 0.003 to 0.007 mg/kg, 0.005 to 0.013 mg/kg; 0.003 to 3.128 mg/kg; and 0.005 to 3.266 mg/kg, respectively. The method was fit for the purpose of monitoring organohalogen residues in strawberries. Residues of these pesticides were detected in 124 of the 186 samples analyzed between 2009 and 2011 in the state of Minas Gerais. Nine of them did not comply with the current legislation requirements; among them, seven (3.8% had residues of unauthorized pesticide for the culture of strawberry, one (0.5% had residues above the maximum residue limit, and another one (0.5% exhibited both non-conformities.

  4. Discovery of potent, novel, non-toxic anti-malarial compounds via quantum modelling, virtual screening and in vitro experimental validation

    Directory of Open Access Journals (Sweden)

    Kaludov Nikola


    Full Text Available Abstract Background Developing resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds. Methods A set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and de novo molecular design. Results Starting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified in silico and tested in vitro; eight of them showed anti-malarial activity (IC50 ≤ 10 μM, with six being very effective (IC50 ≤ 1 μM, and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a

  5. Beta Thalassemia (United States)

    Beta thalassemia is found in people of Mediterranean, Middle Eastern, African, South Asian (Indian, Pakistani, etc.), Southeast Asian and Chinese descent. 1 Beta Thalassemia ßß Normal beta globin genes found on chromosomes ...

  6. How can a beta-sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin-1 in micelles

    DEFF Research Database (Denmark)

    Langham, Allison A; Khandelia, Himanshu; Kaznessis, Yiannis N


    In this work, the naturally occurring beta-hairpin antimicrobial peptide protegrin-1 (PG-1) is studied by molecular dynamics simulation in all-atom sodium dodecylsulfate and dodecylphosphocholine micelles. These simulations provide a high-resolution picture of the interactions between the peptide...

  7. Validation and application of HPLC-ESI-MS/MS method for the quantification of RBBR decolorization, a model for highly toxic molecules, using several fungi strains. (United States)

    Perlatti, Bruno; da Silva, Maria Fátima das Graças Fernandes; Fernandes, João Batista; Forim, Moacir Rossi


    A novel analytical method using HPLC-MS/MS operating in selected reaction monitoring (SRM) for evaluation of fungi efficacy to decolorize Remazol Brilliant Blue R (RBBR) dye solution was developed, validated and applied. The method shows high sensibility allowing the detection of 4.6 pM of RBBR. Four fungal strains were tested in liquid medium, three strains of Aspergillus (Aspergillus aculeatus, Aspergillus flavus and Aspergillus fumigatus) and Phanerochaete chrysosporium. All fungi were able to degrade the dye, with efficiencies ranging from 40% for P. chrysosporium up to 99% for A. flavus during a 30-day incubation period. During the experiment, increased accumulation of degradation products was observed in A. flavus cultures containing RBBR. Through the use of full scan HPLC-MS technique it was possible to propose the biogenesis of the microbial metabolic degradation pathway. Screening using microorganisms and RBBR may be hereafter used to investigate microbial biodegradation of high toxicity molecules such as dioxins.

  8. Validation of a chronic dietary cadmium bioaccumulation and toxicity model for Hyalella azteca exposed to field-contaminated periphyton and lake water. (United States)

    Golding, Lisa A; Borgmann, Uwe; Dixon, D George


    A model previously developed in the laboratory to predict chronic bioaccumulation and toxicity of cadmium to Hyalella azteca from a diet of periphyton was validated by comparing predictions with measurements of Cd in two exposure scenarios: laboratory-cultured H. azteca exposed for 28 d to field-contaminated water and periphyton, and Cd measured in field-collected H. azteca. In both exposure scenarios, model predictions of bioaccumulation were shown to be robust; however, effects on Cd bioaccumulation from complexation with dissolved organic carbon (DOC) and inhibition of Cd bioaccumulation by Ca²⁺ must be incorporated into the model to permit its wider application. The model predicted that 80 to 84% of Cd in H. azteca came from periphyton when H. azteca were chronically exposed to dissolved Cd in lake water at 2.63 to 3.01 nmol/L and periphyton at 1,880 to 2,630 nmol/g ash-free dry mass. Dietary Cd contributed markedly to the model-predicted decrease in 28-d survival to 74% at environmental Cd concentrations in food and water. In reality, survival decreased to 10%. The lower than predicted survival likely was due to the higher nutritional quality of periphyton used to develop the model in the laboratory compared with the field-collected periphyton. Overall, this research demonstrated that Cd in a periphyton diet at environmental concentrations can contribute to chronic toxicity in H. azteca.

  9. Validating a commercially available enzyme immunoassay for the determination of 17beta-estradiol and progestogens in the feces of cheetahs (Acinonyx jubatus): a case report. (United States)

    Borque, C; Perez-Garnelo, S S; Lopez, M; Talavera, C; Delclaux, M; de la Fuente, J


    Fecal 17beta-estradiol and progestogens excretion was monitored in adult, female cheetahs (Acinonyx jubatus; n = 2), ZGG-12301 (born 3 April 1993), gonadotrophin treated and ZGT-3301, (born 19 August 1993), nontreated, for 120 days using commercially available plate enzyme immunoassay kits prepared for human serum or plasma. There were significant differences (P 0.05) between baseline and gestation 17beta-estradiol values; fecal 17beta-estradiol excretion during pregnancy was statistically different (P cheetah (ZGT-3301), basal and increased progestogen concentrations were statistically different (P cheetahs and could be a practical alternative to other enzyme-linked immunosorbent assays which require more complex procedures.

  10. Inter-laboratory validation of organism recovery for use in 42 day sediment toxicity tests with Hyalella azteca. (United States)

    Taylor, Lisa N; Novak, Lesley


    Environment and Climate Change Canada (ECCC) has developed a 42 day sediment toxicity test that includes a reproduction endpoint with the freshwater amphipod Hyalella azteca. The new methodology conducts the entire exposure in sediment; in contrast to existing standardized methods where adults are transferred to a water-only exposure before release of their first brood at Day 28. This mid-test transfer to clean water was due to the results of a juvenile H. azteca recovery trial conducted in the 1990s which concluded that reproductive endpoints could be biased because of low recovery of young amphipods from sediment. Using a new procedure and reduced volume of sediment, an inter-laboratory recovery trial was conducted using 2 to 5 day old H. azteca added to control sediment. A total of 29 technicians from eight laboratories participated in the present study. The average recovery for all laboratories and all technicians was 76% (Coefficient of Variation (CV) = 30%). Based on an initial target recovery of at least 80%, 19 out of 29 (66%) of technicians met this criterion, with an average recovery for this group of 88% (CV = 8.3%). Factors that reduced recovery success included: not using a light table, technicians with minimal sediment testing experience and the use of imported young amphipods with limited acclimation. Excluding those results, the overall average recovery which included 17 participating technicians, increased from 76 to 88% and lowered the CV from 30 to 8.6%. Based on these results, ECCC will recommend ≥85% average recovery of young in control sediment and require ≥80% as a technician performance criterion in its new test design for the reproduction methodology. This article is protected by copyright. All rights reserved.

  11. Interleukin-1beta exacerbates hypoxia-induced neuronal damage, but attenuates toxicity produced by simulated ischaemia and excitotoxicity in rat organotypic hippocampal slice cultures. (United States)

    Pringle, A K; Niyadurupola, N; Johns, P; Anthony, D C; Iannotti, F


    Using organotypic hippocampal slice cultures we have investigated the actions of Interleukin-1 (IL-1) in a number of injury paradigms. Low concentrations of IL-1 potentiated hypoxia-induced neurodegeneration whilst high concentrations had no effect. In contrast, higher concentrations of IL-1 were strongly neuroprotective in models of combined oxygen/glucose deprivation and N-methyl-D-aspartate toxicity, but no potentiation was observed at low IL-1 concentrations. Both protective and toxic effects of IL-1 were fully antagonized by IL-1 receptor antagonist. These data demonstrate that the effects of IL-1 on neuronal injury are complex, and may be directly related to the injury paradigm studied.

  12. Design, synthesis and validation of integrin {alpha}{sub 2}{beta}{sub 1}-targeted probe for microPET imaging of prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chiun-Wei; Li, Zibo; Cai, Hancheng; Chen, Kai; Shahinian, Tony; Conti, Peter S. [University of Southern California, Department of Radiology, Los Angeles, CA (United States)


    The ability of PET to aid in the diagnosis and management of recurrent and/or disseminated metastatic prostate cancer may be enhanced by the development of novel prognostic imaging probes. Accumulating experimental evidence indicates that overexpression of integrin {alpha}{sub 2}{beta}{sub 1} may correlate with progression in human prostate cancer. In this study, {sup 64}Cu-labeled integrin {alpha}{sub 2}{beta}{sub 1}-targeted PET probes were designed and evaluated for the imaging of prostate cancer. DGEA peptides conjugated with a bifunctional chelator (BFC) were developed to image integrin {alpha}{sub 2}{beta}{sub 1} expression with PET in a subcutaneous PC-3 xenograft model. The microPET images were reconstructed by a two-dimensional ordered subsets expectation maximum algorithm. The average radioactivity accumulation within a tumor or an organ was quantified from the multiple region of interest volumes. The PET tracer demonstrated prominent tumor uptake in the PC-3 xenograft (integrin {alpha}{sub 2}{beta}{sub 1}-positive). The receptor specificity was confirmed in a blocking experiment. Moreover, the low tracer uptake in a CWR-22 tumor model (negative control) further confirmed the receptor specificity. The sarcophagine-conjugated DGEA peptide allows noninvasive imaging of tumor-associated {alpha}{sub 2}{beta}{sub 1} expression, which may be a useful PET probe for evaluating the metastatic potential of prostate cancer. (orig.)

  13. Detection and validated quantification of toxic alkaloids in human blood plasma--comparison of LC-APCI-MS with LC-ESI-MS/MS. (United States)

    Beyer, Jochen; Peters, Frank T; Kraemer, Thomas; Maurer, Hans H


    Poisonings with toxic plants may occur after abuse, intentional or accidental ingestion of plants. For diagnosis of such poisonings, multianalyte procedures were developed for detection and validated quantification of the toxic alkaloids aconitine, atropine, colchicine, coniine, cytisine, nicotine and its metabolite cotinine, physostigmine, and scopolamine in plasma using LC-APCI-MS and LC-ESI-MS/MS. After mixed-mode solid-phase extraction of 1 ml of plasma, the analytes were separated using a C8 base select separation column and gradient elution (acetonitrile/ammonium formate, pH 3.5). Calibration curves were used for quantification with cotinine-d(3), benzoylecgonine-d(3), and trimipramine-d(3) as internal standards. The method was validated according to international guidelines. Both assays were selective for the tested compounds. No instability was observed after repeated freezing and thawing or in processed samples. The assays were linear for coniine, cytisine, nicotine and its metabolite cotinine, from 50 to 1000 ng/ml using LC-APCI-MS and 1 to 1000 ng/ml using LC-ESI-MS/MS, respectively, and for aconitine, atropine, colchicine, physostigmine, and scopolamine from 5 to 100 ng/ml for LC-APCI-MS and 0.1 to 100 ng/ml for LC-ESI-MS/MS, respectively. Accuracy ranged from -38.6 to 14.0%, repeatability from 2.5 to 13.5%, and intermediate precision from 4.8 to 13.5% using LC-APCI-MS and from -38.3 to 8.3% for accuracy, from 3.5 to 13.8%, for repeatability, and from 4.3 to 14.7% for intermediate precision using LC-ESI-MS/MS. The lower limit of quantification was fixed at the lowest calibrator in the linearity experiments. With the exception of the greater sensitivity and higher identification power, LC-ESI-MS/MS had no major advantages over LC-APCI-MS. Both presented assays were applicable for sensitive detection of all studied analytes and for accurate and precise quantification, with the exception of the rather volatile nicotine. The applicability of the assays was

  14. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity.

    Directory of Open Access Journals (Sweden)

    Jia Meng

    Full Text Available With the trend of an increasing aged population worldwide, Alzheimer's disease (AD, an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC inhibitor, suberoylanilidehydroxamic acid (SAHA, may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25-35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.

  15. Progress report and technology status development of an EG and G Berthold LB-150 alpha/beta particulate monitor for use on the East Tennessee Technology Park Toxic Substances Control Act Incinerator

    Energy Technology Data Exchange (ETDEWEB)

    Shor, J.T.; Singh, S.P.N. [Oak Ridge National Lab., TN (United States). Chemical Technology Div.; Gibson, L.V. Jr. [East Tennessee Technology Park, Oak Ridge, TN (United States). ASO Customer Services Div.


    The purpose of this project was to modify and evaluate a commercially available EG and G Berthold LB-150 alpha-beta radionuclide particulate monitor for the high-temperature and moisture-saturation conditions of the East Tennessee Technology Park (formerly K-25 Site) Toxic Substances Control Act (TSCA) Incinerator stack. The monitor was originally outfitted for operation at gas temperatures of 150 F on the defunct Los Alamos National Laboratory (LANL) controlled air incinerator, and the objective was to widen its operating envelope. A laboratory apparatus was constructed that simulated the effects of water-saturated air at the TSCA Incinerator stack-gas temperatures, 183 F. An instrumented set of heat exchangers was constructed to then condition the gas so that the radionuclide monitor could be operated without condensation. Data were collected under the conditions of the elevated temperatures and humidities and are reported herein, and design considerations of the apparatus are provided. The heat exchangers and humidification equipment performed as designed, the Mylar film held, and the instrument suffered no ill effects. However, for reasons as yet undetermined, the sensitivity of the radionuclide detection diminishes as the gas temperature is elevated, whether the gas is humidified or not. The manufacturer has had no experience with (a) the operation of the monitor under these conditions and (b) any commercial market that might exist for an instrument that operates under these conditions. The monitor was not installed into the radiologically contaminated environment of the TSCA Incinerator stack pending resolution of this technical issue.

  16. Validation of electro-thermal simulation with experimental data to prepare online operation of a molten salt target at ISOLDE for the Beta Beams

    CERN Document Server

    Cimmino, S; Marzari, S; Stora, T


    The main objective of the Beta Beams is to study oscillation property of pure electrons neutrinos. It produces high energy beams of pure electron neutrinos and anti-neutrinos for oscillation experiments by beta decay of He-6 and Ne-18 radioactive ion beams, stored in a decay ring at gamma = 100. The production of He-6 beam has already been accomplished using a thick beryllium oxide target. However, the production of the needed rate of Ne-18 has proven to be more challenging. In order to achieve the requested yield for Ne-18 a new high power target design based on a circulating molten salt loop has been proposed. To verify some elements of the design, a static molten salt target prototype has been developed at ISOLDE and operated successfully. This paper describes the electro-thermal study of the molten salt target taking into account the heat produced by Joule effect, radiative heat exchange, active water cooling due to forced convection and air passive cooling due to natural convection. The numerical results...

  17. Technical Report Series on Global Modeling and Data Assimilation. Volume 42; Soil Moisture Active Passive (SMAP) Project Calibration and Validation for the L4_C Beta-Release Data Product (United States)

    Koster, Randal D. (Editor); Kimball, John S.; Jones, Lucas A.; Glassy, Joseph; Stavros, E. Natasha; Madani, Nima (Editor); Reichle, Rolf H.; Jackson, Thomas; Colliander, Andreas


    During the post-launch Cal/Val Phase of SMAP there are two objectives for each science product team: 1) calibrate, verify, and improve the performance of the science algorithms, and 2) validate accuracies of the science data products as specified in the L1 science requirements according to the Cal/Val timeline. This report provides analysis and assessment of the SMAP Level 4 Carbon (L4_C) product specifically for the beta release. The beta-release version of the SMAP L4_C algorithms utilizes a terrestrial carbon flux model informed by SMAP soil moisture inputs along with optical remote sensing (e.g. MODIS) vegetation indices and other ancillary biophysical data to estimate global daily NEE and component carbon fluxes, particularly vegetation gross primary production (GPP) and ecosystem respiration (Reco). Other L4_C product elements include surface (<10 cm depth) soil organic carbon (SOC) stocks and associated environmental constraints to these processes, including soil moisture and landscape FT controls on GPP and Reco (Kimball et al. 2012). The L4_C product encapsulates SMAP carbon cycle science objectives by: 1) providing a direct link between terrestrial carbon fluxes and underlying freeze/thaw and soil moisture constraints to these processes, 2) documenting primary connections between terrestrial water, energy and carbon cycles, and 3) improving understanding of terrestrial carbon sink activity in northern ecosystems.

  18. An integrated approach to the toxicity assessment of Irish marine sediments: validation of established marine bioassays for the monitoring of Irish marine sediments. (United States)

    Macken, Ailbhe; Giltrap, Michelle; Foley, Barry; McGovern, Evin; McHugh, Brendan; Davoren, Maria


    This paper describes the ecotoxicological evaluation of marine sediments from three sites around Ireland representative of a range of contaminant burdens. A comprehensive assessment of potential sediment toxicity requires the consideration of multiple exposure phases. In addition to the evaluation of multi-exposure phases the use of a battery of multi-trophic test species has been advocated by a number of researchers as testing of single or few organisms may not detect toxicants with a specific mode of action. The Microtox solid phase test (SPT) and the 10-d acute amphipod test with Corophium volutator were used to assess whole sediment toxicity. Porewater and elutriates were assessed with the Microtox acute test, the marine prasinophyte Tetraselmis suecica, and the marine copepod Tisbe battagliai. Solvent extracts were assayed with the Microtox and T. battagliai acute tests. Alexandra Basin was identified as the most toxic site according to all tests, except the Microtox SPT which identified the Dunmore East site as being more toxic. However, it was not possible to correlate the observed ecotoxicological effects with a specific and/or class of contaminants based on sediment chemistry alone. Therefore porewaters found to elicit significant toxicity (Dunmore East and Alexandra Basin) with the test battery were selected for further TIE assessment with T. battalgiai and the Microtox system. The results of this study have important implications for risk assessment in estuarine and coastal waters in Ireland, where, at present the monitoring of sediment and water quality is predominantly reliant on chemical analysis alone.

  19. Validation of Minim typing for fast and accurate discrimination of extended-spectrum, beta-lactamase-producing Klebsiella pneumoniae isolates in tertiary care hospital. (United States)

    Brhelova, Eva; Kocmanova, Iva; Racil, Zdenek; Hanslianova, Marketa; Antonova, Mariya; Mayer, Jiri; Lengerova, Martina


    Minim typing is derived from the multi-locus sequence typing (MLST). It targets the same genes, but sequencing is replaced by high resolution melt analysis. Typing can be performed by analysing six loci (6MelT), four loci (4MelT) or using data from four loci plus sequencing the tonB gene (HybridMelT). The aim of this study was to evaluate Minim typing to discriminate extended-spectrum beta-lactamase producing Klebsiella pneumoniae (ESBL-KLPN) isolates at our hospital. In total, 380 isolates were analyzed. The obtained alleles were assigned according to both the 6MelT and 4MelT typing scheme. In 97 isolates, the tonB gene was sequenced to enable HybridMelT typing. We found that the presented method is suitable to quickly monitor isolates of ESBL-KLPN; results are obtained in less than 2 hours and at a lower cost than MLST. We identified a local ESBL-KLPN outbreak and a comparison of colonizing and invasive isolates revealed a long term colonization of patients with the same strain.

  20. Toxicity of lead (Pb) to freshwater green algae: Development and validation of a bioavailability model and inter-species sensitivity comparison

    Energy Technology Data Exchange (ETDEWEB)

    De Schamphelaere, K.A.C., E-mail:; Nys, C., E-mail:; Janssen, C.R., E-mail:


    Highlights: • Chronic toxicity of Pb varied 4-fold among three algae species. • The use of an organic P avoided Pb precipitation in the experiments. • pH and Dissolved Organic Carbon strongly affect Pb toxicity, Ca and Mg do not. • A bioavailability model was developed that accurately predicts toxicity. • Algae may become the most sensitive species to Pb above pH 7.4. - Abstract: Scientifically sound risk assessment and derivation of environmental quality standards for lead (Pb) in the freshwater environment are hampered by insufficient data on chronic toxicity and bioavailability to unicellular green algae. Here, we first performed comparative chronic (72-h) toxicity tests with three algal species in medium at pH 6, containing 4 mg fulvic acid (FA)/L and containing organic phosphorous (P), i.e. glycerol-2-phosphate, instead of PO{sub 4}{sup 3−} to prevent lead-phosphate mineral precipitation. Pseudokirchneriella subcapitata was 4-fold more sensitive to Pb than Chlorella kesslerii, with Chlamydomonas reinhardtii in the middle. The influence of medium physico-chemistry was therefore investigated in detail with P. subcapitata. In synthetic test media, higher concentrations of fulvic acid or lower pH protected against toxicity of (filtered) Pb to P. subcapitata, while effects of increased Ca or Mg on Pb toxicity were less clear. When toxicity was expressed on a free Pb{sup 2+} ion activity basis, a log-linear, 260-fold increase of toxicity was observed between pH 6.0 and 7.6. Effects of fulvic acid were calculated to be much more limited (1.9-fold) and were probably even non-existent (depending on the affinity constant for Pb binding to fulvic acid that was used for calculating speciation). A relatively simple bioavailability model, consisting of a log-linear pH effect on Pb{sup 2+} ion toxicity linked to the geochemical speciation model Visual Minteq (with the default NICA-Donnan description of metal and proton binding to fulvic acid), provided relatively

  1. Development and validation of a new spectrofluorimetric method for the determination of some beta-blockers through fluorescence quenching of eosin Y. Application to content uniformity test

    Directory of Open Access Journals (Sweden)

    Derayea Sayed M


    Full Text Available A simple, rapid, sensitive and economic spectrofluorimetric method has been developed and validated for determination of some β-adrenergic blocking agents namely; betaxolol hydrochloride (BTX, carvedilol (CAR, labetalol hydrochloride (LBT, nebivolol hydrochloride (NEB and propranolol hydrochloride (PRO. The method is based on the quenching effect of the cited drugs on the fluorescence intensity of eosin Y at pH 3.4 (acetate buffer. The fluorescence quenching is due to the formation of an ion-pair complex and was measured without extraction at 545 nm (λex. 301.5 nm. The factors affecting the formation of the ion-pair complex were carefully studied and optimized. Under the optimal conditions, the linear ranges for the relationship between the fluorescence quenching value and the concentration of the investigated drugs were 100-2500, 150-2500 and 50-2250 ng mL-1 for (BTX, CAR, (LBT, NEB and (PRO respectively. The method was validated according to ICH guidelines and was applied for determination of the cited drugs in pharmaceutical dosage forms with excellent recoveries. In addition, content uniformity testing of some commercial dosage forms was checked by the proposed method.

  2. $\\beta$-particle energy-summing correction for $\\beta$-delayed proton emission measurements

    CERN Document Server

    Meisel, Z; Crawford, H L; Cyburt, R H; Grinyer, G F; Langer, C; Montes, F; Schatz, H; Smith, K


    A common approach to studying $\\beta$-delayed proton emission is to measure the energy of the emitted proton and corresponding nuclear recoil in a double-sided silicon-strip detector (DSSD) after implanting the $\\beta$-delayed proton emitting ($\\beta$p) nucleus. However, in order to extract the proton-decay energy, the measured energy must be corrected for the additional energy implanted in the DSSD by the $\\beta$-particle emitted from the $\\beta$p nucleus, an effect referred to here as $\\beta$-summing. We present an approach to determine an accurate correction for $\\beta$-summing. Our method relies on the determination of the mean implantation depth of the $\\beta$p nucleus within the DSSD by analyzing the shape of the total (proton + recoil + $\\beta$) decay energy distribution shape. We validate this approach with other mean implantation depth measurement techniques that take advantage of energy deposition within DSSDs upstream and downstream of the implantation DSSD.

  3. Toxicity of lead (Pb) to freshwater green algae: development and validation of a bioavailability model and inter-species sensitivity comparison. (United States)

    De Schamphelaere, K A C; Nys, C; Janssen, C R


    Scientifically sound risk assessment and derivation of environmental quality standards for lead (Pb) in the freshwater environment are hampered by insufficient data on chronic toxicity and bioavailability to unicellular green algae. Here, we first performed comparative chronic (72-h) toxicity tests with three algal species in medium at pH 6, containing 4 mg fulvic acid (FA)/L and containing organic phosphorous (P), i.e. glycerol-2-phosphate, instead of PO4(3-) to prevent lead-phosphate mineral precipitation. Pseudokirchneriella subcapitata was 4-fold more sensitive to Pb than Chlorella kesslerii, with Chlamydomonas reinhardtii in the middle. The influence of medium physico-chemistry was therefore investigated in detail with P. subcapitata. In synthetic test media, higher concentrations of fulvic acid or lower pH protected against toxicity of (filtered) Pb to P. subcapitata, while effects of increased Ca or Mg on Pb toxicity were less clear. When toxicity was expressed on a free Pb(2+) ion activity basis, a log-linear, 260-fold increase of toxicity was observed between pH 6.0 and 7.6. Effects of fulvic acid were calculated to be much more limited (1.9-fold) and were probably even non-existent (depending on the affinity constant for Pb binding to fulvic acid that was used for calculating speciation). A relatively simple bioavailability model, consisting of a log-linear pH effect on Pb(2+) ion toxicity linked to the geochemical speciation model Visual Minteq (with the default NICA-Donnan description of metal and proton binding to fulvic acid), provided relatively accurate toxicity predictions. While toxicity of (filtered) Pb varied 13.7-fold across 14 different test media (including four Pb-spiked natural waters) with widely varying physico-chemistry (72h-EC50s between 26.6 and 364 μg/L), this bioavailability model displayed mean and maximum prediction errors of only 1.4 and 2.2-fold, respectively, thus indicating the potential usefulness of this bioavailability

  4. Validation of the hepatocyte-like HPCT-1E3 cell line as an in vitro model for the prediction of acute in vivo toxicity. (United States)

    Halwachs, Sandra; Lakoma, Cathleen; Honscha, Walther


    In a pilot study, we tested 20 randomly-selected chemicals for their cytotoxicity toward the HPCT-1E3 cell model, in order to prove the ability of this in vitro model to predict human acute in vivo toxicity. The study revealed that, in contrast to most other in vitro models, results from the HPCT-1E3 cell-based system show better correlation with the more-relevant human acute lethal doses, whereas results from most other systems have a high predictivity for human lethal serum concentrations. For the prevalidation of the HPCT-1E3 model as a surrogate for regulatory acute in vivo toxicity tests, we have now expanded the list of tested chemicals to 57 substances, and have compared the results with data from the HepG2 cell assay. Again, a better correlation of HPCT-1E3 IC50 values with human oral lethal doses, as compared to correlation with human lethal serum concentrations, was observed after the pooling of all the tested substances (r(2) = 0.53 [P in vivo toxicity tests.

  5. Induction of rat hepatic cytochromes P450 by toxic ingredients in plants: lack of correlation between toxicity and inductive activity. (United States)

    Yamada, H; Nakamura, T; Oguri, K


    "Animal-Plant Warfare" is one of the hypotheses for the evolution of drug-metabolizing P450s. To address the validity of this hypothesis, we examined the induction of xenobiotic-metabolizing P450s by 12 plant toxins in rats, using hepatic activity for testosterone metabolism as the index. The compounds tested were aconitine, morphine, tubocurarine, physostigmine, pilocarpine, muscarine, cocaine, atropine, amygdalin, digitonin, nicotine and solanine. Drinking water containing a test compound was given to rats for 4 days, and the hepatic activity of testosterone metabolism was determined together with monitoring body weight gain and liver weight as the indices of toxicity. The results showed that while cocaine and nicotine have a minor ability to increase testosterone 16 beta-hydroxylase activity, a marker activity for the CYP2B1 and 2, all other compounds did not have any such effect. No correlation was observed between a change in 16 beta-hydroxylase and toxicity caused by toxins. Therefore, these results did not support the idea that the inducibility of the CYP2B subfamily in animals is acquired through "Animal-Plant Warfare". Several compounds examined here increased or decreased hepatic activities of testosterone 2 alpha-, 6 beta-, 7 alpha- and 16 alpha-hydroxylation and 17-oxidation, indicating a possible effect on the CYP2A, 2C and 3A subfamily. Of these effects, a moderate correlation (r toxicity. It is therefore suggested that inhibition or suppression of the expression of CYP2C11 is one of the mechanisms in the toxicity of plant toxins for rats, although it comes from an examination using limited numbers of compounds.

  6. Rapid and Sensitive Determination of Major Active Ingredients and Toxic Components in GinkgoBiloba Leaves Extract (EGb 761) by a Validated UPLC-MS-MS Method. (United States)

    Wang, Yao; Liu, Yuan; Wu, Qi; Yao, Xin; Cheng, Zongqi


    An accurate, precise and sensitive ultra-performance liquid chromatography tandem mass spectrometric (UPLC-MS-MS) method was developed for the determination of flavonoids, terpene lactones, together with ginkgolic acids in Ginkgo biloba leaves extract (EGb 761). This is the first report of the simultaneous analysis of major active ingredients and toxic components in EGb 761 using UPLC-MS-MS. This analysis afforded good linearity, precision, repeatability and accuracy. In addition, the content of those major bioactive components in EGb 761 prepared by different manufacturers of China was determined to establish the effectiveness of the method. The results indicated that the quantification analysis could be readily utilized as a quality control method for EGb 761 and its other related products using flavonoids, terpene lactones and ginkgolic acids as markers.

  7. Systematic Risk on Istanbul Stock Exchange: Traditional Beta Coefficient Versus Downside Beta Coefficient

    Directory of Open Access Journals (Sweden)

    Gülfen TUNA


    Full Text Available The aim of this study is to test the validity of Downside Capital Asset Pricing Model (D-CAPM on the ISE. At the same time, the explanatory power of CAPM's traditional beta and D-CAPM's downside beta on the changes in the average return values are examined comparatively. In this context, the monthly data for seventy three stocks that are continuously traded on the ISE for the period 1991-2009 is used. Regression analysis is applied in this study. The research results have shown that D-CAPM is valid on the ISE. In addition, it is obtained that the power of downside beta coefficient is higher than traditional beta coefficient on explaining the return changes. Therefore, it can be said that the downside beta is superior to traditional beta in the ISE for chosen period.

  8. Monitoring of beta-receptor sensitivity in cardiac surgery

    DEFF Research Database (Denmark)

    Yndgaard, S; Lippert, F K; Bigler, Dennis Richard


    To determine the repeatability of the hemodynamic response to repeated isoproterenol challenge doses to validate the standardized isoproterenol sensitivity test as an index of cardiovascular beta-receptor function.......To determine the repeatability of the hemodynamic response to repeated isoproterenol challenge doses to validate the standardized isoproterenol sensitivity test as an index of cardiovascular beta-receptor function....

  9. L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice. (United States)

    Luo, Liting; Chen, Jingkao; Su, Dan; Chen, Meihui; Luo, Bingling; Pi, Rongbiao; Wang, Lan; Shen, Wei; Wang, Rikang


    Amounting evidences demonstrated that Rho/Rho-associated kinase (ROCK) might be a novel target for the therapy of Parkinson's disease (PD). Recently, we synthesized L-F001 and revealed it was a potent ROCK inhibitor with multifunctional effects. Here we investigated the effects of L-F001 in PD models. We found that L-F001 potently attenuated 6-OHDA-induced cytotoxicity in PC12 cells and significantly decreased intracellular reactive oxygen species (ROS), prevented the 6-OHDA-induced decline of mitochondrial membrane potential and intracellular GSH levels. In addition, L-F001 increased Akt and GSK-3beta phosphorylation and induced the nuclear Nrf2 and HO-1 expression in a time- and concentration-dependent manner. Moreover, L-F001 restored the levels of p-Akt and p-GSK-3beta (Ser9) as well as HO-1 expression reduced by 6-OHDA. Those effects were blocked by the specific PI3K inhibitor, LY294002, indicating the involvement of Akt/GSK-3beta pathway in the neuroprotective effect of L-F001. In addition, L-F001 significantly attenuated the tyrosinehydroxylase immunoreactive cell loss in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice PD model. Together, our findings suggest that L-F001 prevents 6-OHDA-induced cell death through activating Akt/GSK-3beta and Nrf2/HO-1 signaling pathway and attenuates MPTP-induced dopaminergic neuron toxicity in mice. L-F001 might be a promising drug candidate for PD.

  10. Ellagic acid promotes A{beta}42 fibrillization and inhibits A{beta}42-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Ying [Department of Histology and Embryology, College of Basic Medical Science, China Medical University, Shenyang 110001 (China); Tsinghua University School of Medicine, Haidian District, Beijing 100084 (China); Yang, Shi-gao; Du, Xue-ting; Zhang, Xi; Sun, Xiao-xia; Zhao, Min [Tsinghua University School of Medicine, Haidian District, Beijing 100084 (China); Sun, Gui-yuan, E-mail: [Department of Histology and Embryology, College of Basic Medical Science, China Medical University, Shenyang 110001 (China); Liu, Rui-tian, E-mail: [Tsinghua University School of Medicine, Haidian District, Beijing 100084 (China)


    Smaller, soluble oligomers of {beta}-amyloid (A{beta}) play a critical role in the pathogenesis of Alzheimer's disease (AD). Selective inhibition of A{beta} oligomer formation provides an optimum target for AD therapy. Some polyphenols have potent anti-amyloidogenic activities and protect against A{beta} neurotoxicity. Here, we tested the effects of ellagic acid (EA), a polyphenolic compound, on A{beta}42 aggregation and neurotoxicity in vitro. EA promoted A{beta} fibril formation and significant oligomer loss, contrary to previous results that polyphenols inhibited A{beta} aggregation. The results of transmission electron microscopy (TEM) and Western blot displayed more fibrils in A{beta}42 samples co-incubated with EA in earlier phases of aggregation. Consistent with the hypothesis that plaque formation may represent a protective mechanism in which the body sequesters toxic A{beta} aggregates to render them harmless, our MTT results showed that EA could significantly reduce A{beta}42-induced neurotoxicity toward SH-SY5Y cells. Taken together, our results suggest that EA, an active ingredient in many fruits and nuts, may have therapeutic potential in AD.

  11. Experimental validation of Monte Carlo depth-dose calculations using radiochromic dye film dosimetry for a beta-gamma {sup 153}Sm radionuclide applied to the treatment of rheumatoid arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Villarreal-Barajas, J.E.; Ferro-Flores, G.; Hernandez-Oviedo, O


    In this work we compare the Monte Carlo (MCNP4B) calculated beta-gamma depth-dose profile for a liquid {sup 153}Sm beta-gamma source used in radiation synovectomy with the experimental depth-dose distribution obtained using radiochromic dye film dosimetry. The calculated and experimental depth-dose distribution shows a very good agreement (within 5%) in the region where the dose deposition is dominated by the beta particle component (first 800 {mu}m depth on tissue-equivalent material). The agreement worsens, reaching a maximum deviation of 15%, at depths close to the maximum range of the beta particles. Finally the agreement improves for the region where the gamma component accounts for one-third of the total absorbed dose (depths >1 mm ). The possible contributions to these differences are discussed, as well as their relevance for the application of {sup 153}Sm in the treatment of rheumatoid arthritis. (author)

  12. An experimentally validated panel of subfamily-specific oligonucleotide primers (V alpha 1-w29/V beta 1-w24) for the study of human T cell receptor variable V gene segment usage by polymerase chain reaction. (United States)

    Genevée, C; Diu, A; Nierat, J; Caignard, A; Dietrich, P Y; Ferradini, L; Roman-Roman, S; Triebel, F; Hercend, T


    We report here the characterization of a series of T cell receptor (TcR) V alpha or V beta subfamily-specific oligonucleotide primers. Criteria that have guided the design of each oligonucleotide include appropriate thermodynamic parameters as well as differential base-pairing scores with related and unrelated target sequences. The specificity of the oligonucleotides for each V alpha or V beta subfamily was tested by polymerase chain reaction (PCR) on both a series of TcR encoding plasmid DNA and clonal T cell populations. Unexpected cross-reactivities were observed with plasmid cDNA sequences corresponding to unrelated subfamily gene segments. This led to the synthesis of additional series of oligonucleotides to obtain a relevant panel. A series of V alpha 1-w29/V beta 1-w24 TcR subfamily-specific oligonucleotides was eventually selected which generates little, if any, cross-reactivity. The use of C alpha or C beta primers for the amplification of internal positive control templates (i.e. C beta for the V alpha series and C alpha for the V beta series) has been tested in PCR performed with cDNA derived from peripheral blood lymphocytes; it was shown not to alter the amplification of the V subfamily-specific DNA fragments. This panel of oligonucleotides will be helpful in the study of TcRV gene segment usage and, thus, may lead to a better characterization of T cell responses in physiological and pathological situations.

  13. Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats

    NARCIS (Netherlands)

    Granic, Ivica; Nyakas, Csaba; Luiten, Paul G. M.; Eisel, Ulrich L. M.; Halmy, Laszlo G.; Gross, Gerhard; Schoemaker, Hans; Moeller, Achim; Nimmrich, Volker


    Amyloid-beta (A beta) is toxic to neurons and such toxicity is - at least in part - mediated via the NMDA receptor. Calpain, a calcium dependent cystein protease, is part of the NMDA receptor-induced neurodegeneration pathway, and we previously reported that inhibition of calpain prevents excitotoxi

  14. Toxic Elements

    DEFF Research Database (Denmark)

    Hajeb, Parvaneh; Shakibazadeh, Shahram; Sloth, Jens Jørgen


    Food is considered the main source of toxic element (arsenic, cadmium, lead, and mercury) exposure to humans, and they can cause major public health effects. In this chapter, we discuss the most important sources for toxic element in food and the foodstuffs which are significant contributors to h...

  15. Tungsten toxicity. (United States)

    Witten, Mark L; Sheppard, Paul R; Witten, Brandon L


    There is emerging evidence that tungsten has toxic health effects. We summarize the recent tungsten toxicity research in this short review. Tungsten is widely used in many commercial and military applications because it has the second highest melting temperature of any element. Consequently, it is important to elucidate the potential health effects of tungsten.

  16. Impact of entrainment and impingement on fish populations in the Hudson River estuary. Volume III. An analysis of the validity of the utilities' stock-recruitment curve-fitting exercise and prior estimation of beta technique. Environmental Sciences Division publication No. 1792

    Energy Technology Data Exchange (ETDEWEB)

    Christensen, S. W.; Goodyear, C. P.; Kirk, B. L.


    This report addresses the validity of the utilities' use of the Ricker stock-recruitment model to extrapolate the combined entrainment-impingement losses of young fish to reductions in the equilibrium population size of adult fish. In our testimony, a methodology was developed and applied to address a single fundamental question: if the Ricker model really did apply to the Hudson River striped bass population, could the utilities' estimates, based on curve-fitting, of the parameter alpha (which controls the impact) be considered reliable. In addition, an analysis is included of the efficacy of an alternative means of estimating alpha, termed the technique of prior estimation of beta (used by the utilities in a report prepared for regulatory hearings on the Cornwall Pumped Storage Project). This validation methodology should also be useful in evaluating inferences drawn in the literature from fits of stock-recruitment models to data obtained from other fish stocks.

  17. Beta-carotene (United States)

    ... patches on the tongue and mouth called oral leukoplakia. Taking beta-carotene by mouth for up to 12 months seems to decrease symptoms of oral leukoplakia. Osteoarthritis. Beta-carotene taken by mouth may prevent ...

  18. Human Toxicity

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Fantke, Peter


    . The first section of this chapter outlines the complete cause-effect pathway, from emissions of toxic substances to intake by the population up to damages in terms of human health effects. Section 2 outlines the framework for assessing human toxicity in LCIA. Section 3 discusses the contributing substances......This chapter reviews the human toxicological impacts of chemicals and how to assess these impacts in life cycle impact assessment (LCIA), in order to identify key processes and pollutants. The complete cause-effect pathway – from emissions of toxic substances up to damages on human health...... – demonstrates the importance to account for both outdoor and indoor exposure, including consumer products. Analysing the variations in intake fraction (the fraction of the emitted or applied chemical that is taken in by the consumer and the general population), effect factor and characterisation factor across...

  19. Toxic myopathies. (United States)

    Pasnoor, Mamatha; Barohn, Richard J; Dimachkie, Mazen M


    Muscle tissue is highly sensitive to many substances. Early recognition of toxic myopathies is important, because they potentially are reversible on removal of the offending drug or toxin, with greater likelihood of complete resolution the sooner this is achieved. Clinical features range from mild muscle pain and cramps to severe weakness with rhabdomyolysis, renal failure, and even death. The pathogenic bases can be multifactorial. This article reviews some of the common toxic myopathies and their clinical presentation, histopathologic features, and possible underlying cellular mechanisms.

  20. Forward-Looking Betas

    DEFF Research Database (Denmark)

    Christoffersen, Peter; Jacobs, Kris; Vainberg, Gregory

    Few issues are more important for finance practice than the computation of market betas. Existing approaches compute market betas using historical data. While these approaches differ in terms of statistical sophistication and the modeling of the time-variation in the betas, they are all backward......-looking. This paper introduces a radically different approach to estimating market betas. Using the tools in Bakshi and Madan (2000) and Bakshi, Kapadia and Madan (2003) we employ the information embedded in the prices of individual stock options and index options to compute our forward-looking market beta...

  1. Always around, never the same: Pathways of amyloid beta induced neurodegeneration throughout the pathogenic cascade of Alzheimer's disease

    NARCIS (Netherlands)

    J.J.M. Hoozemans; S.M. Chafekar; F. Baas; P. Eikelenboom; W. Scheper


    There is an increasing amount of evidence showing the importance of intermediate aggregation species of amyloid beta (A beta) in the pathogenic cascade of Alzheimer's disease (AD). Different A beta assembly forms may mediate diverse toxic effects at different stages of the disease. Mouse models for

  2. Diagnosis of allergy against beta-lactams in primary care : prevalence and diagnostic criteria

    NARCIS (Netherlands)

    Salden, Odette A E; Rockmann, Heike; Verheij, Theo J M; Broekhuizen, Berna D L


    BACKGROUND: Secondary care studies showed that a recorded allergy to beta-lactams could not be confirmed by valid allergy testing in >85% of cases. In daily practice, recorded beta-lactam allergies probably cause prescription of secondary choice antibiotics. This overrating of beta-lactam allergy ha

  3. Immune-mediated beta-cell destruction in vitro and in vivo-A pivotal role for galectin-3

    DEFF Research Database (Denmark)

    Karlsen, Allan E; Størling, Zenia M; Sparre, Thomas;


    Pro-apoptotic cytokines are toxic to the pancreatic beta-cells and have been associated with the pathogenesis of Type 1 diabetes (T1D). Proteome analysis of IL-1beta exposed isolated rat islets identified galectin-3 (gal-3) as the most up-regulated protein. Here analysis of human and rat islets...... and insulinoma cells confirmed IL-1beta regulated gal-3 expression of several gal-3 isoforms and a complex in vivo expression profile during diabetes development in rats. Over-expression of gal-3 protected beta-cells against IL-1beta toxicity, with a complete blockage of JNK phosphorylation, essential for IL-1...

  4. Validation of a new yeast-based reporter assay consisting of human estrogen receptors alpha/beta and coactivator SRC-1: application for detection of estrogenic activity in environmental samples. (United States)

    Chu, Wai-Ling; Shiizaki, Kazuhiro; Kawanishi, Masanobu; Kondo, Mami; Yagi, Takashi


    Endocrine disruptors are exogenous substances that act like hormones in the endocrine system and disrupt the physiologic function of endogenous hormones. In the present study, we established reporter yeast strains (Saccharomyces cerevisiae) expressing human estrogen receptors, ERalpha or ERbeta. These strains contain a reporter plasmid carrying an estrogen responsive element (ERE) upstream of the beta-galactosidase gene, and a plasmid expressing a steroid receptor coactivator, SRC-1e. Using these reporter strains, we demonstrated dose-dependent estrogenic activities of different categories of ligands, a natural hormone, 17beta-estradiol (E2); a synthetic drug, diethylstilbestrol (DES); phytoestrogens, genistein, daizein and emodin; and an environmental endocrine disrupter, bisphenol A. EC(50) values of E2 for ERalpha and ERbeta are 5.31 x 10(-10) and 5.85 x 10(-10) M, respectively. We also demonstrated that these yeasts were applicable for measuring estrogenic activities of environmental water samples. Most downstream sites of a river showed similar activity in both ERalpha and ERbeta assays. These yeast strains are useful and convenient for detecting and comparing the estrogenic ligand activities of environmental samples in response to ERalpha and ERbeta.

  5. Betting against Beta

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Heje Pedersen, Lasse


    We present a model with leverage and margin constraints that vary across investors and time. We find evidence consistent with each of the model's five central predictions: (1) Because constrained investors bid up high-beta assets, high beta is associated with low alpha, as we find empirically for......, the return of the BAB factor is low. (4) Increased funding liquidity risk compresses betas toward one. (5) More constrained investors hold riskier assets....... for US equities, 20 international equity markets, Treasury bonds, corporate bonds, and futures. (2) A betting against beta (BAB) factor, which is long leveraged low-beta assets and short high-beta assets, produces significant positive risk-adjusted returns. (3) When funding constraints tighten...

  6. Betting Against Beta

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Heje Pedersen, Lasse

    We present a model with leverage and margin constraints that vary across investors and time. We find evidence consistent with each of the model’s five central predictions: (1) Since constrained investors bid up high-beta assets, high beta is associated with low alpha, as we find empirically for U...... of the BAB factor is low; (4) Increased funding liquidity risk compresses betas toward one; (5) More constrained investors hold riskier assets........S. equities, 20 international equity markets, Treasury bonds, corporate bonds, and futures; (2) A betting-against-beta (BAB) factor, which is long leveraged low beta assets and short high-beta assets, produces significant positive risk-adjusted returns; (3) When funding constraints tighten, the return...

  7. Misfolded amyloid ion channels present mobile beta-sheet subunits in contrast to conventional ion channels. (United States)

    Jang, Hyunbum; Arce, Fernando Teran; Capone, Ricardo; Ramachandran, Srinivasan; Lal, Ratnesh; Nussinov, Ruth


    In Alzheimer's disease, calcium permeability through cellular membranes appears to underlie neuronal cell death. It is increasingly accepted that calcium permeability involves toxic ion channels. We modeled Alzheimer's disease ion channels of different sizes (12-mer to 36-mer) in the lipid bilayer using molecular dynamics simulations. Our Abeta channels consist of the solid-state NMR-based U-shaped beta-strand-turn-beta-strand motif. In the simulations we obtain ion-permeable channels whose subunit morphologies and shapes are consistent with electron microscopy/atomic force microscopy. In agreement with imaged channels, the simulations indicate that beta-sheet channels break into loosely associated mobile beta-sheet subunits. The preferred channel sizes (16- to 24-mer) are compatible with electron microscopy/atomic force microscopy-derived dimensions. Mobile subunits were also observed for beta-sheet channels formed by cytolytic PG-1 beta-hairpins. The emerging picture from our large-scale simulations is that toxic ion channels formed by beta-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic flux. This sharply contrasts intact conventional gated ion channels that consist of tightly interacting alpha-helices that robustly prevent ion leakage, rather than hydrogen-bonded beta-strands. The simulations suggest why conventional gated channels evolved to consist of interacting alpha-helices rather than hydrogen-bonded beta-strands that tend to break in fluidic bilayers. Nature designs folded channels but not misfolded toxic channels.

  8. Imperfect World of $\\beta\\beta$-decay Nuclear Data Sets

    CERN Document Server

    Pritychenko, B


    The precision of double-beta ($\\beta\\beta$) decay experimental half lives and their uncertainties is reanalyzed. The method of Benford's distributions has been applied to nuclear reaction, structure and decay data sets. First-digit distribution trend for $\\beta\\beta$-decay T$_{1/2}^{2\

  9. Bacterial and enzymatic bioassays for toxicity testing in the environment

    Energy Technology Data Exchange (ETDEWEB)

    Bitton, G.; Koopman, B. (Department of Environmental Engineering Sciences, University of Florida, Gainesville (United States))


    Microbioassays using bacteria or enzymes are increasingly applied to measure chemical toxicity in the environment. Attractive features of these assays may include low cost, rapid response to toxicants, high sample throughput, modest laboratory equipment and space requirements, low sample volume, portability, and reproducible responses. Enzymatic tests rely on measurement of either enzyme activity or enzyme biosynthesis. Dehydrogenases are the enzymes most used in toxicity testing. Assay of dehydrogenase activity is conveniently carried out using oxidoreduction dyes such as tetrazolium salts. Other enzyme activity tests utilize ATPases, esterases, phosphatases, urease, luciferase, beta-galactosidase, protease, amylase, or beta-glucosidase. Recently, the inhibition of enzyme (beta-galactosidase, tryptophanase, alpha-glucosidase) biosynthesis has been explored as a basis for toxicity testing. Enzyme biosynthesis was found to be generally more sensitive to organic chemicals than enzyme activity.107 references.

  10. Thermal Stress and Toxicity (United States)

    Elevating ambient temperature above thermoneutrality exacerbates toxicity of most air pollutants, insecticides, and other toxic chemicals. On the other hand, safety and toxicity testing of toxicants and drugs is usually performed in mice and rats maintained at subthermoneutral te...

  11. Universality in Chiral Random Matrix Theory at $\\beta =1$ and $\\beta =4$

    CERN Document Server

    Sener, M K


    In this paper the kernel for spectral correlation functions of the invariant chiral random matrix ensembles with real ($\\beta =1$) and quaternion real ($\\beta = 4$) matrix elements is expressed in terms of the kernel of the corresponding complex Hermitean random matrix ensembles ($\\beta=2$). Such identities are exact in case of a Gaussian probability distribution and, under certain smoothness assumptions, they are shown to be valid asymptotically for an arbitrary finite polynomial potential. They are proved by means of a construction proposed by Brézin and Neuberger. Microscopic universality for all three chiral ensembles then follows from universal behavior for $\\beta =2$ both at the hard edge (shown by Akemann, Damgaard, Magnea and Nishigaki) and at the soft edge of the spectrum (shown by Kanzieper and Freilikher).


    Directory of Open Access Journals (Sweden)

    Ante Perković


    Full Text Available The capital asset pricing model (CAPM is one of the most important models in financial economics and it has a long history of theoretical and empirical investigations. The main underlying concept of the CAPM model is that assets with a high risk (high beta should earn a higher return than assets with a low risk (low beta and vice versa. The implication which can be drawn out of this is that all assets with a beta above zero bear some risk and therefore their expected return is above the return of the risk-free rate. In this research observation on monthly stock prices on Croatian stock market from January 1st 2005 until December 31st 2009 is used to form our sample. CROBEX index is used as proxy of the market portfolio. The results demonstrate that beta can not be trusted in making investment decisions and rejects the validity of the whole CAPM model on Croatian stock market.

  13. Negative Beta Encoder

    CERN Document Server

    Kohda, Tohru; Aihara, Kazuyuki


    A new class of analog-digital (A/D), digital-analog (D/A) converters as an alternative to conventional ones, called $\\beta$-encoder, has been shown to have exponential accuracy in the bit rates while possessing self-correction property for fluctuations of amplifier factor $\\beta$ and quantizer threshold $\

  14. Double beta decay experiments

    CERN Document Server

    Barabash, A S


    The present status of double beta decay experiments is reviewed. The results of the most sensitive experiments are discussed. Proposals for future double beta decay experiments with a sensitivity to the $$ at the level of (0.01--0.1) eV are considered.

  15. beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Park, Catherine C.; Park, Catherine C.; Zhang, Hui J.; Yao, Evelyn S.; Park, Chong J.; Bissell, Mina J.


    {beta}1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of {beta}1 integrin signaling. We showed previously that {beta}1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and {beta}1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo.

  16. Genetics Home Reference: beta thalassemia (United States)

    ... Understand Genetics Home Health Conditions beta thalassemia beta thalassemia Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Beta thalassemia is a blood disorder that reduces the production ...

  17. Rapid synthesis of beta zeolites (United States)

    Fan, Wei; Chang, Chun -Chih; Dornath, Paul; Wang, Zhuopeng


    The invention provides methods for rapidly synthesizing heteroatom containing zeolites including Sn-Beta, Si-Beta, Ti-Beta, Zr-Beta and Fe-Beta. The methods for synthesizing heteroatom zeolites include using well-crystalline zeolite crystals as seeds and using a fluoride-free, caustic medium in a seeded dry-gel conversion method. The Beta zeolite catalysts made by the methods of the invention catalyze both isomerization and dehydration reactions.

  18. Imperfect World of beta beta-decay Nuclear Data Sets

    Energy Technology Data Exchange (ETDEWEB)

    Pritychenko, B. [Brookhaven National Lab. (BNL), Upton, NY (United States). NNDC


    The precision of double-beta ββ-decay experimental half lives and their uncertainties is reanalyzed. The method of Benford's distributions has been applied to nuclear reaction, structure and decay data sets. First-digit distribution trend for ββ-decay T2v1/2 is consistent with large nuclear reaction and structure data sets and provides validation of experimental half-lives. A complementary analysis of the decay uncertainties indicates deficiencies due to small size of statistical samples, and incomplete collection of experimental information. Further experimental and theoretical efforts would lead toward more precise values of-decay half-lives and nuclear matrix elements.

  19. Susceptibility of pancreatic beta cells to fatty acids is regulated by LXR/PPARalpha-dependent stearoyl-coenzyme A desaturase.

    Directory of Open Access Journals (Sweden)

    Karine H Hellemans

    Full Text Available Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARalpha-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRbeta(-/- and LXRalphabeta(-/-, beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARalpha agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARalpha agonists favors their desaturation and subsequent incorporation in neutral lipids.

  20. Beta 2-Microglobulin clearance as measured by radioimmunoassay

    Energy Technology Data Exchange (ETDEWEB)

    Woo, J.; Floyd, M.; Longley, M.A.; Cannon, D.C.


    We describe a radioimmunoassay for beta 2-microglobulin (beta 2 mu) in serum and urine. We incubated aliquots of diluted samples at room temperature for 1 h with /sup 125/I-labeled beta 2 mu and a rabbit antiserum monospecific for human beta 2 mu, and separated the phases by the double-antibody technique. The logit-log transformed dose-response curve was linear in the range 2 to 64 ng, equivalent to 0.5 to 16 mg/L of serum and 0.5 to 320 mg/L of urine. Assay sensitivity was 2.4 ng of beta 2 mu. Validation studies included tests of precision, accuracy, antibody specificity, and parallelism of the dose-response curves for standard and unknown. In a study of 25 normal individuals, serum and urine beta 2 mu ranged from 1.1 to 2.3 mg/L and 40 to 360 micrograms/24 h; the clearance of beta 2 mu was 8 to 130 microL/min. In 21 renal allograft recipients tested one to five weeks after transplantation, serum and urine beta 2 mu ranged from 3.9 to 15.6 mg/L and 7.2 to 611 mg/24 h; beta 2 mu clearance was 0.60 to 33.3 mL/min. Values for both serum and urine correlated well with severity of allograft rejection.

  1. Small-animal PET imaging of amyloid-beta plaques with [11C]PiB and its multi-modal validation in an APP/PS1 mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    André Manook

    Full Text Available In vivo imaging and quantification of amyloid-β plaque (Aβ burden in small-animal models of Alzheimer's disease (AD is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [(11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [(11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months showed the highest uptake followed by old hemizygous (23 months and young homozygous mice (9 months. In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [(11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a

  2. Neutrinoless double beta decay

    Indian Academy of Sciences (India)

    Kai Zuber


    The physics potential of neutrinoless double beta decay is discussed. Furthermore, experimental considerations as well as the current status of experiments are presented. Finally, an outlook towards the future, work on nuclear matrix elements and alternative processes is given.

  3. Alpha and Beta Determinations

    CERN Document Server

    Dunietz, Isard


    Because the Bd -> J/psi Ks asymmetry determines only sin(2 beta), a discrete ambiguity in the true value of beta remains. This note reviews how the ambiguity can be removed. Extractions of the CKM angle alpha are discussed next. Some of the methods require very large data samples and will not be feasible in the near future. In the near future, semi-inclusive CP-violating searches could be undertaken, which are reviewed last.

  4. {beta} - amyloid imaging probes

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Jae Min [Seoul National University College of Medicine, Seoul (Korea, Republic of)


    Imaging distribution of {beta} - amyloid plaques in Alzheimer's disease is very important for early and accurate diagnosis. Early trial of the {beta} -amyloid plaques includes using radiolabeled peptides which can be only applied for peripheral {beta} - amyloid plaques due to limited penetration through the blood brain barrier (BBB). Congo red or Chrysamine G derivatives were labeled with Tc-99m for imaging {beta} - amyloid plaques of Alzheimer patient's brain without success due to problem with BBB penetration. Thioflavin T derivatives gave breakthrough for {beta} - amyloid imaging in vivo, and a benzothiazole derivative [C-11]6-OH-BTA-1 brought a great success. Many other benzothiazole, benzoxazole, benzofuran, imidazopyridine, and styrylbenzene derivatives have been labeled with F-18 and I-123 to improve the imaging quality. However, [C-11]6-OH-BTA-1 still remains as the best. However, short half-life of C-11 is a limitation of wide distribution of this agent. So, it is still required to develop an Tc-99m, F-18 or I-123 labeled agent for {beta} - amyloid imaging agent.

  5. Beta cell dynamics: beta cell replenishment, beta cell compensation and diabetes. (United States)

    Cerf, Marlon E


    Type 2 diabetes, characterized by persistent hyperglycemia, arises mostly from beta cell dysfunction and insulin resistance and remains a highly complex metabolic disease due to various stages in its pathogenesis. Glucose homeostasis is primarily regulated by insulin secretion from the beta cells in response to prevailing glycemia. Beta cell populations are dynamic as they respond to fluctuating insulin demand. Beta cell replenishment and death primarily regulate beta cell populations. Beta cells, pancreatic cells, and extra-pancreatic cells represent the three tiers for replenishing beta cells. In rodents, beta cell self-replenishment appears to be the dominant source for new beta cells supported by pancreatic cells (non-beta islet cells, acinar cells, and duct cells) and extra-pancreatic cells (liver, neural, and stem/progenitor cells). In humans, beta cell neogenesis from non-beta cells appears to be the dominant source of beta cell replenishment as limited beta cell self-replenishment occurs particularly in adulthood. Metabolic states of increased insulin demand trigger increased insulin synthesis and secretion from beta cells. Beta cells, therefore, adapt to support their physiology. Maintaining physiological beta cell populations is a strategy for targeting metabolic states of persistently increased insulin demand as in diabetes.

  6. Determination of urinary 18 beta-glycyrrhetinic acid by gas chromatography and its clinical application in man

    NARCIS (Netherlands)

    Guillaume, CPF; van der Molen, JC; Kerstens, MN; Dullaart, RPF; Wolthers, BG


    A sensitive and quantitative gas chromatographic assay for the determination of 18 beta-glycyrrhetinic acid (18 beta-GA), the main metabolite of glycyrrhizin after oral licorice consumption in human urine, has been developed and validated. For the extraction of 18 beta-GA from urine two Sep-Pak C-18

  7. Design of a superconducting low beta niobium resonator

    Indian Academy of Sciences (India)

    Prakash Potukuchi; Amit Roy


    The proposed high current injector for the superconducting Linac at the InterUniversity Accelerator Centre will have several accelerating structures, including a superconducting module which will contain low beta niobium resonators. A prototype resonator for the low beta module has been designed. The resonator has been carefully modelled to optimize the electromagnetic parameters. In order to validate them, a room-temperature copper model has been built and tested. In this paper we present details of the electromagnetic design of the low beta resonator, briefly discuss the mechanical and engineering design, and present results from the measurements on the room-temperature copper model.

  8. Distributed Structure Searchable Toxicity (United States)

    U.S. Environmental Protection Agency — The Distributed Structure Searchable Toxicity (DSSTox) online resource provides high quality chemical structures and annotations in association with toxicity data....

  9. Bacterial and enzymatic bioassays for toxicity testing in the environment. (United States)

    Bitton, G; Koopman, B


    Microbioassays using bacteria or enzymes are increasingly applied to measure chemical toxicity in the environment. Attractive features of these assays may include low cost, rapid response to toxicants, high sample throughput, modest laboratory equipment and space requirements, low sample volume, portability, and reproducible responses. Enzymatic tests rely on measurement of either enzyme activity or enzyme biosynthesis. Dehydrogenases are the enzymes most used in toxicity testing. Assay of dehydrogenase activity is conveniently carried out using oxidoreduction dyes such as tetrazolium salts. Other enzyme activity tests utilize ATPases, esterases, phosphatases, urease, luciferase, beta-galactosidase, protease, amylase, or beta-glucosidase. Recently, the inhibition of enzyme (beta-galactosidase, tryptophanase, alpha-glucosidase) biosynthesis has been explored as a basis for toxicity testing. Enzyme biosynthesis was found to be generally more sensitive to organic chemicals than enzyme activity. Bacterial toxicity tests are based on bioluminescence, motility, growth, viability, ATP, oxygen uptake, nitrification, or heat production. An important aspect of bacterial tests is the permeability of cells to environmental toxicants, particularly organic chemicals of hydrophobic nature. Physical, chemical, and genetic alterations of the outer membrane of E. coli have been found to affect test sensitivity to organic toxicants. Several microbioassays are now commercially available. The names of the assays and their basis are: Microtox (bioluminescence), Polytox (respiration), ECHA Biocide Monitor (dehydrogenase activity), Toxi-Chromotest (enzyme biosynthesis), and MetPAD (enzyme activity). An important feature common to these tests is the provision of standardized cultures of bacteria in freeze-dried form. Two of the more recent applications of microbioassays are in sediment toxicity testing and toxicity reduction evaluation. Sediment pore water may be assayed directly or

  10. Boosted beta regression.

    Directory of Open Access Journals (Sweden)

    Matthias Schmid

    Full Text Available Regression analysis with a bounded outcome is a common problem in applied statistics. Typical examples include regression models for percentage outcomes and the analysis of ratings that are measured on a bounded scale. In this paper, we consider beta regression, which is a generalization of logit models to situations where the response is continuous on the interval (0,1. Consequently, beta regression is a convenient tool for analyzing percentage responses. The classical approach to fit a beta regression model is to use maximum likelihood estimation with subsequent AIC-based variable selection. As an alternative to this established - yet unstable - approach, we propose a new estimation technique called boosted beta regression. With boosted beta regression estimation and variable selection can be carried out simultaneously in a highly efficient way. Additionally, both the mean and the variance of a percentage response can be modeled using flexible nonlinear covariate effects. As a consequence, the new method accounts for common problems such as overdispersion and non-binomial variance structures.

  11. Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Zumsteg, U; Reimers, J


    In this review we propose that the balance between the action of interleukin 1 (IL-1) and its natural antagonist IL-1ra on the level of the insulin-producing pancreatic beta-cell may play a decisive role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). We argue that IL-1...... by lymphocytic and monocytic cells beta-cells, (3) high molar excesses of IL-1ra over IL-1 needed to prevent IL-1 mediated beta-cell toxicity, (4) increased beta-cell sensitivity to free nitric oxide and oxygen radical formation induced by IL-1 and (5) inadequate oxidative stress response by beta...

  12. Beta and Gamma Gradients

    DEFF Research Database (Denmark)

    Løvborg, Leif; Gaffney, C. F.; Clark, P. A.;


    Experimental and/or theoretical estimates are presented concerning, (i) attenuation within the sample of beta and gamma radiation from the soil, (ii) the gamma dose within the sample due to its own radioactivity, and (iii) the soil gamma dose in the proximity of boundaries between regions...... of differing radioactivity. It is confirmed that removal of the outer 2 mm of sample is adequate to remove influence from soil beta dose and estimates are made of the error introduced by non-removal. Other evaluations include variation of the soil gamma dose near the ground surface and it appears...

  13. Physico-chemical characterization of benzocaine-beta-cyclodextrin inclusion complexes. (United States)

    Pinto, Luciana M A; Fraceto, Leonardo Fernandes; Santana, Maria Helena A; Pertinhez, Thelma A; Junior, Sérgio Oyama; de Paula, Eneida


    Local anesthetics are able to induce pain relief by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of the nervous impulse. Benzocaine (BZC) is a local anesthetic whose low water-solubility limits its application to topical formulations. The present work focuses on the characterization of inclusion complexes of BZC in beta-cyclodextrin (beta-CD). Differential scanning calorimetry and electron microscopy gave evidences of the formation and the morphology of the complex. Fluorescence spectroscopy showed a BZC/beta-CD 1:1 stoichiometry. Phase-solubility diagrams allowed the determination of the association constants between BZC and beta-CD (549 M(-1)) and revealed that a three-fold increase in BZC solubility can be reached upon complexation with beta-CD. The details of BZC/beta-CD molecular interaction were analyzed by 1H 2D NMR allowing the proposition of an inclusion model for BZC into beta-CD where the aromatic ring of the anesthetic is located near the head of the beta-CD cavity. Moreover, in preliminary toxicity studies, the complex seems to be less toxic than BZC alone, since it induced a decrease in the in vitro oxidation of human hemoglobin. These results suggest that the BZC/beta-CD complex represents an effective novel formulation to enhance BZC solubility in water, turning it promising for use outside its traditional application, i.e., in infiltrative anesthesia.

  14. The novel amyloid-beta peptide aptamer inhibits intracellular amyloid-beta peptide toxicity

    Institute of Scientific and Technical Information of China (English)

    Xu Wang; Yi Yang; Mingyue Jia; Chi Ma; Mingyu Wang; Lihe Che; Yu Yang; Jiang Wu


    Amyloid β peptide binding alcohol dehydrogenase (ABAD) decoy peptide (DP) can competitively antagonize binding of amyloid β peptide to ABAD and inhibit the cytotoxic effects of amyloid β peptide. Based on peptide aptamers, the present study inserted ABAD-DP into the disulfide bond of human thioredoxin (TRX) using molecular cloning technique to construct a fusion gene that can express the TRX1-ABAD-DP-TRX2 aptamer. Moreover, adeno-associated virus was used to allow its stable expression. Immunofluorescent staining revealed the co-expression of the transduced fusion gene TRX1-ABAD-DP-TRX2 and amyloid β peptide in NIH-3T3 cells, indicating that the TRX1-ABAD-DP-TRX2 aptamer can bind amyloid β peptide within cells. In addition, cell morphology and MTT results suggested that TRX1-ABAD-DP-TRX2 attenuated amyloid β peptide-induced SH-SY5Y cell injury and improved cell viability. These findings confirmed the possibility of constructing TRX-based peptide aptamer using ABAD-DP. Moreover, TRX1-ABAD-DP-TRX2 inhibited the cytotoxic effect of amyloid β peptide.

  15. Applied Beta Dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Rich, B.L.


    Measurements of beta and/or nonpenetrating exposure results is complicated and past techniques and capabilities have resulted in significant inaccuracies in recorded results. Current developments have resulted in increased capabilities which make the results more accurate and should result in less total exposure to the work force. Continued development of works in progress should provide equivalent future improvements.

  16. Beta Thalassemia (For Parents) (United States)

    ... had their spleens removed. Slower growth rates. The anemia resulting from beta thalassemia can cause children to grow more slowly and also can lead ... boost production of new red blood cells. Some children with moderate anemia may require an occasional blood transfusion , particularly after ...

  17. Trichoderma .beta.-glucosidase (United States)

    Dunn-Coleman, Nigel; Goedegebuur, Frits; Ward, Michael; Yao, Jian


    The present invention provides a novel .beta.-glucosidase nucleic acid sequence, designated bgl3, and the corresponding BGL3 amino acid sequence. The invention also provides expression vectors and host cells comprising a nucleic acid sequence encoding BGL3, recombinant BGL3 proteins and methods for producing the same.

  18. Roughing up Beta

    DEFF Research Database (Denmark)

    Bollerslev, Tim; Li, Sophia Zhengzi; Todorov, Viktor

    Motivated by the implications from a stylized equilibrium pricing framework, we investigate empirically how individual equity prices respond to continuous, or \\smooth," and jumpy, or \\rough," market price moves, and how these different market price risks, or betas, are priced in the cross-section...

  19. Clearance of beta-2-microglobulin and middle molecules in haemodiafiltration. (United States)

    Tattersall, James


    Middle molecules, consisting mostly of peptides and small proteins with molecular weight the range of 500-60,000 Da, accumulate in renal failure and contribute to the uraemic toxic state. Beta2-microglobulin (beta2-MG) with a molecular weight of 11,000 is considered representative of these middle molecules. These solutes are not well cleared by low-flux dialysis. High-flux dialysis will clear middle molecules, partly by internal filtration. This convective component of high-flux dialysis can be enhanced in a predictable way by haemodiafiltration (HDF). The convective and diffusive clearance rates of any middle molecule across any haemodiafilter can be predicted from known or measurable factors such as its sieving coefficient, bound fraction and molecular weight. The removal of middle molecules is also influenced by factors within the patient. Beta2-MG is distributed within the extracellular fluid. During HDF, beta2-MG must transfer into the intravascular compartment across the capillary walls. This transcapillary transfer at a rate of approximately 100 ml/min slows beta2-MG removal from the body. Continuing transfer after the end of a treatment session results in a significant rebound of beta2-MG levels. This intercompartment transfer and its effect on beta2-MG clearance and concentration can be predicted by a 2-compartment model. By extrapolation, the behaviour of other middle molecules can be predicted. The 2-compartment model, which takes non-dialytic beta2-MG clearance at a rate of 3 ml/min and beta2-MG generation at a rate of 0.1 mg/min into account, can predict the effect of any HDF schedule on beta2-MG levels. Low-flux dialysis results in a beta2-MG level of around 40 mg/l. Three times weekly, 4-hour HDF can reduce beta2-MG levels to around 20 mg/l. Long (nocturnal) HDF can reduce beta2-MG levels to around 10 mg/l, compared to physiological levels of less than 5 mg/l.

  20. TGF-beta and osteoarthritis.

    NARCIS (Netherlands)

    Blaney Davidson, E.N.; Kraan, P.M. van der; Berg, W.B. van den


    OBJECTIVE: Cartilage damage is a major problem in osteoarthritis (OA). Growth factors like transforming growth factor-beta (TGF-beta) have great potential in cartilage repair. In this review, we will focus on the potential therapeutic intervention in OA with TGF-beta, application of the growth facto

  1. Encke-Beta Predictor for Orion Bum Targeting and Guidance (United States)

    Robinson, Shane; Scarritt, Sara; Goodman, John L.


    The state vector prediction algorithm selected for Orion on-board targeting and guidance is known as the Encke-Beta method. Encke-Beta uses a universal anomaly (beta) as the independent variable, valid for circular, elliptical, parabolic, and hyperbolic orbits. The variable, related to the change in eccentric anomaly, results in integration steps that cover smaller arcs of the trajectory at or near perigee, when velocity is higher. Some burns in the EM-1 and EM-2 mission plans are much longer than burns executed with the Apollo and Space Shuttle vehicles. Burn length, as well as hyperbolic trajectories, has driven the use of the Encke-Beta numerical predictor by the predictor/corrector guidance algorithm in place of legacy analytic thrust and gravity integrals.

  2. Modeling Amyloid Beta Peptide Insertion into Lipid Bilayers

    CERN Document Server

    Mobley, D L; Singh, R R P; Maddox, M W; Longo, M J; Mobley, David L.; Cox, Daniel L.; Singh, Rajiv R. P.; Maddox, Michael W.; Longo, Marjorie L.


    Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (A-beta), can insert into cell membranes and form harmful ion channels, we model insertion of the peptide into cell membranes using a Monte Carlo code which is specific at the amino acid level. We examine insertion of the regular A-beta peptide as well as mutants causing familial Alzheimer's disease. We present our results and develop the hypothesis that partial insertion into the membrane, leaving the peptide in one leaflet, increases the probability of harmful channel formation. This hypothesis can partly explain why these mutations are neurotoxic simply due to peptide insertion behavior, and also explains why, normally, A-beta 42 is more toxic to some cultured cells than A-beta 40, but the E22Q mutation reverses this effect. We further apply this model to various artificial A-beta mutants which have been examined experimentally, and offer testable experimental predictions contrasting the roles of aggregation and insertion with regard ...

  3. Differential regulation of chemoattractant-stimulated beta 2, beta 3, and beta 7 integrin activity. (United States)

    Sadhu, C; Masinovsky, B; Staunton, D E


    Leukocyte adhesion to endothelium and extravasation are dynamic processes that require activation of integrins. Chemoattractants such as IL-8 and FMLP are potent activators of leukocyte integrins. To compare the chemoattractant-stimulated activation of three integrins, alpha 4 beta 7, alpha L beta 2, and alpha V beta 3, in the same cellular context, we expressed an IL-8 receptor (IL-8RA) and FMLP receptor (FPR) in the lymphoid cell line JY. Chemoattractants induced a rapid increase in alpha L beta 2- and alpha V beta 3-dependent JY adhesion within 5 min, and it was sustained for 30 min. In contrast, stimulation of alpha 4 beta 7-dependent adhesion was transient, returning to basal levels by 30 min. The activation profiles of the integrins were similar regardless of whether IL-8 or FMLP was used for induction. We also demonstrate that alpha 4 beta 7-dependent adhesion was uniquely responsive to the F actin-disrupting agent cytochalasin D and the protein kinase C (PKC) inhibitor chelerythrin. While alpha V beta 3- and alpha L beta 2-mediated cell adhesion was significantly reduced by cytochalasin D, alpha 4 beta 7-mediated adhesion was enhanced. Chelerythrin inhibited both the IL-8 and PMA activation of alpha L beta 2 and alpha V beta 3. In contrast, inducible alpha 4 beta 7 activity was unaffected, and basal activity was increased. These findings demonstrate that the mechanism of alpha 4 beta 7 regulation by chemoattractants is different from that of alpha L beta 2 and alpha V beta 3 and that it appears to involve distinct cytoskeletal and PKC dependencies. In addition, PKC activity may be a positive or negative regulator of integrin-dependent adhesion.

  4. Optimization of a high-throughput whole blood expression profiling methodology and its application to assess the pharmacodynamics of interferon (IFN beta-1a or polyethylene glycol-conjugated IFN beta-1a in healthy clinical trial subjects

    Directory of Open Access Journals (Sweden)

    Allaire Normand E


    Full Text Available Abstract Background Clinical trials offer a unique opportunity to study human disease and response to therapy in a highly controlled setting. The application of high-throughput expression profiling to peripheral blood from clinical trial subjects could facilitate the identification of transcripts that function as prognostic or diagnostic markers of disease or treatment. The paramount issue for these methods is the ability to produce robust, reproducible, and timely mRNA expression profiles from peripheral blood. Single-stranded complementary DNA (sscDNA targets derived from whole blood exhibit improved detection of transcripts and reduced variance as compared to their complementary RNA counterparts and therefore provide a better option for interrogation of peripheral blood on oligonucleotide arrays. High-throughput microarray technologies such as the high-throughput plate array platform offer several advantages compared with slide- or cartridge-based arrays; however, manufacturer’s protocols do not support the use of sscDNA targets. Results We have developed a highly reproducible, high-through put, whole blood expression profiling methodology based on sscDNA and used it to analyze human brain reference RNA and universal human reference RNA samples to identify experimental conditions that most highly correlated with a gold standard quantitative polymerase chain reaction reference dataset. We then utilized the optimized method to analyze whole blood samples from healthy clinical trial subjects treated with different versions of interferon (IFN beta-1a. Analysis of whole blood samples before and after treatment with intramuscular [IM] IFN beta-1a or polyethylene glycol-conjugated IFN (PEG-IFN beta-1a under optimized experimental conditions demonstrated that PEG-IFN beta-1a induced a more sustained and prolonged pharmacodynamic response than unmodified IM IFN beta-1a. These results provide validation of the utility of this new methodology and

  5. 基于不同终点测定土壤中Zn的毒性阈值及其田间验证%Toxicity Thresholds(ECx) of Zn in Soils as Determined by Different Endpoints and Its Validations in Fields

    Institute of Scientific and Technical Information of China (English)

    林蕾; 陈世宝; 程旺大; 张红梅; 王伯仁; 刘继芳; 马义兵


    利用Log-logistic剂量-效应函数模型,在实验室条件下分别利用大麦根伸长、西红柿及小白菜生长毒性及基质诱导硝化毒性测试方法,测定了16种不同性质土壤中Zn的毒性阈值,在此基础上建立了基于土壤性质主控因子的Zn的毒性预测模型,同时选取湖南祁阳酸性土和浙江嘉兴中性土验证了田间条件下土壤中Zn毒性阈值.结果表明:田间条件下,湖南祁阳土壤中Zn对玉米不同生长指标的EC10范围为37~51 mg· kg-1,EC50为127~312 mg·kg-1,不同测试指标的敏感性顺序为苗期叶面积>秸秆生物量>苗期株高>籽粒产量;浙江嘉兴水稻土中Zn的毒性阈值EC10为213~332 mg·kg-1,EC50为682~922 mg·kg-1,不同测定指标间的敏感性顺序为孕穗期叶绿素含量>秸秆生物量>苗期株高>籽粒产量.土壤中Zn的毒性阈值田间验证结果表明,实验室条件下基于不同评价终点测定的土壤中Zn的毒性阈值与田间条件下的吻合性在不同土壤间存在一定差异,相比而言,实验室条件下对偏中性的浙江嘉兴水稻土中Zn的毒性阈值测定结果与田间验证结果更接近;基于实验室条件下不同测试指标所测定的土壤中Zn毒性阈值与土壤主控因子间的预测模型能较好预测浙江嘉兴水稻土中Zn的毒性阈值,田间条件下所测定的ECx(x=10,50)值均在模型预测值的两倍的预测区间内;而对于偏酸性的湖南祁阳土壤,预测模型则低估了土壤中Zn的生态风险.%Sixteen soils were selected to obtain the toxicity thresholds of Zn in soils based on four different bioassay toxicity endpoints(i.e. the barley root elongation, tomato biomass and bok choy growth, potential nitrification rate(PNR)) by using Log-logistic dose-response models, and the predicted models of soil Zn toxicity thresholds were established in laboratory condition. In order to validate the toxicity thresholds of Zn determined in lab condition

  6. Beta-thalassemia

    Directory of Open Access Journals (Sweden)

    Origa Raffaella


    Full Text Available Abstract Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC transfusions. Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands, dilated myocardiopathy, liver fibrosis and cirrhosis. Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Main clinical features in these patients are hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications (osteoporosis, masses of erythropoietic tissue that primarily affect the spleen, liver, lymph nodes, chest and spine, and bone deformities and typical facial changes, gallstones, painful leg ulcers and increased predisposition to thrombosis. Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely

  7. Beta-thalassemia. (United States)

    Galanello, Renzo; Origa, Raffaella


    Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis). Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Main clinical features in these patients are hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications (osteoporosis, masses of erythropoietic tissue that primarily affect the spleen, liver, lymph nodes, chest and spine, and bone deformities and typical facial changes), gallstones, painful leg ulcers and increased predisposition to thrombosis. Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta

  8. Beta and muon decays

    Energy Technology Data Exchange (ETDEWEB)

    Galindo, A.; Pascual, P.


    These notes represent a series of lectures delivered by the authors in the Junta de Energia Nuclear, during the Spring term of 1965. They were devoted to graduate students interested in the Theory of Elementary Particles. Special emphasis was focussed into the computational problems. Chapter I is a review of basic principles (Dirac equation, transition probabilities, final state interactions.) which will be needed later. In Chapter II the four-fermion punctual Interaction is discussed, Chapter III is devoted to the study of beta-decay; the main emphasis is given to the deduction of the formulae corresponding to electron-antineutrino correlation, electron energy spectrum, lifetimes, asymmetry of electrons emitted from polarized nuclei, electron and neutrino polarization and time reversal invariance in beta decay. In Chapter IV we deal with the decay of polarized muons with radiative corrections. Chapter V is devoted to an introduction to C.V.C. theory. (Author)

  9. Realized Beta GARCH

    DEFF Research Database (Denmark)

    Hansen, Peter Reinhard; Lunde, Asger; Voev, Valeri Radkov


    We introduce a multivariate generalized autoregressive conditional heteroskedasticity (GARCH) model that incorporates realized measures of variances and covariances. Realized measures extract information about the current levels of volatilities and correlations from high-frequency data, which...... is particularly useful for modeling financial returns during periods of rapid changes in the underlying covariance structure. When applied to market returns in conjunction with returns on an individual asset, the model yields a dynamic model specification of the conditional regression coefficient that is known...... as the beta. We apply the model to a large set of assets and find the conditional betas to be far more variable than usually found with rolling-window regressions based exclusively on daily returns. In the empirical part of the paper, we examine the cross-sectional as well as the time variation...

  10. Molecular Dynamics Simulation of Amyloid Beta Dimer Formation

    CERN Document Server

    Urbanc, B; Ding, F; Sammond, D; Khare, S; Buldyrev, S V; Stanley, H E; Dokholyan, N V


    Recent experiments with amyloid-beta (Abeta) peptide suggest that formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Abeta oligomers depends on their structure, which is governed by assembly dynamics. Due to limitations of current experimental techniques, a detailed knowledge of oligomer structure at the atomic level is missing. We introduce a molecular dynamics approach to study Abeta dimer formation: (1) we use discrete molecular dynamics simulations of a coarse-grained model to identify a variety of dimer conformations, and (2) we employ all-atom molecular mechanics simulations to estimate the thermodynamic stability of all dimer conformations. Our simulations of a coarse-grained Abeta peptide model predicts ten different planar beta-strand dimer conformations. We then estimate the free energies of all dimer conformations in all-atom molecular mechanics simulations with explicit water. We compare the free energies of Abeta(1-42) and Abeta(1-40...

  11. Coroutine Sequencing in BETA

    DEFF Research Database (Denmark)

    Kristensen, Bent Bruun; Madsen, Ole Lehrmann; Møller-Pedersen, Birger;

    In object-oriented programming, a program execution is viewed as a physical model of some real or imaginary part of the world. A language supporting object-oriented programming must therefore contain comprehensive facilities for modeling phenomena and concepts form the application domain. Many ap...... applications in the real world consist of objects carrying out sequential processes. Coroutines may be used for modeling objects that alternate between a number of sequential processes. The authors describe coroutines in BETA...

  12. Magic Baseline Beta Beam

    CERN Document Server

    Agarwalla, Sanjib Kumar; Raychaudhuri, Amitava


    We study the physics reach of an experiment where neutrinos produced in a beta-beam facility at CERN are observed in a large magnetized iron calorimeter (ICAL) at the India-based Neutrino Observatory (INO). The CERN-INO distance is close to the so-called "magic" baseline which helps evade some of the parameter degeneracies and allows for a better measurement of the neutrino mass hierarchy and $\\theta_{13}$.

  13. Beta cell adaptation in pregnancy

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis


    Pregnancy is associated with a compensatory increase in beta cell mass. It is well established that somatolactogenic hormones contribute to the expansion both indirectly by their insulin antagonistic effects and directly by their mitogenic effects on the beta cells via receptors for prolactin...... and growth hormone expressed in rodent beta cells. However, the beta cell expansion in human pregnancy seems to occur by neogenesis of beta cells from putative progenitor cells rather than by proliferation of existing beta cells. Claes Hellerström has pioneered the research on beta cell growth for decades......, but the mechanisms involved are still not clarified. In this review the information obtained in previous studies is recapitulated together with some of the current attempts to resolve the controversy in the field: identification of the putative progenitor cells, identification of the factors involved...

  14. Regulation of beta cell replication

    DEFF Research Database (Denmark)

    Lee, Ying C; Nielsen, Jens Høiriis


    Beta cell mass, at any given time, is governed by cell differentiation, neogenesis, increased or decreased cell size (cell hypertrophy or atrophy), cell death (apoptosis), and beta cell proliferation. Nutrients, hormones and growth factors coupled with their signalling intermediates have been...... suggested to play a role in beta cell mass regulation. In addition, genetic mouse model studies have indicated that cyclins and cyclin-dependent kinases that determine cell cycle progression are involved in beta cell replication, and more recently, menin in association with cyclin-dependent kinase...... inhibitors has been demonstrated to be important in beta cell growth. In this review, we consider and highlight some aspects of cell cycle regulation in relation to beta cell replication. The role of cell cycle regulation in beta cell replication is mostly from studies in rodent models, but whether...

  15. Toxic Amblyopia (Nutritional Amblyopia) (United States)

    ... Contact Lenses Additional Content Medical News Toxic Amblyopia (Nutritional Amblyopia) By James Garrity, MD, Mayo Clinic NOTE: ... or methyl alcohol), antifreeze, or certain drugs. A nutritional deficiency or toxic substance is often the cause ...

  16. Toxicological validation of a procedure for extracting organic micropollutants form water samples

    NARCIS (Netherlands)

    Vaal MA; Folkerts AJ; Kamp RE van de; Struijs J; ECO


    A procedure, developed to extract micropollutants from water samples into a concentrate that is suitable for the performance of aquatic toxicity tests, was toxicologically validated. Toxicity of known cocktail of toxicants concentrated to a level measurable in short-term toxicity tests was measured

  17. LHCb: $2\\beta_s$ measurement at LHCb

    CERN Multimedia

    Conti, G


    A measurement of $2\\beta_s$, the phase of the $B_s-\\bar{B_s}$ oscillation amplitude with respect to that of the ${\\rm b} \\rightarrow {\\rm c^{+}}{\\rm W^{-}}$ tree decay amplitude, is one of the key goals of the LHCb experiment with first data. In the Standard Model (SM), $2\\beta_s$ is predicted to be $0.0360^{+0.0020}_{-0.0016} \\rm rad$. The current constraints from the Tevatron are: $2\\beta_{s}\\in[0.32 ; 2.82]$ at 68$\\%$CL from the CDF experiment and $2\\beta_{s}=0.57^{+0.24}_{-0.30}$ from the D$\\oslash$ experiment. Although the statistical uncertainties are large, these results hint at the possible contribution of New Physics in the $B_s-\\bar{B_s}$ box diagram. After one year of data taking at LHCb at an average luminosity of $\\mathcal{L}\\sim2\\cdot10^{32}\\rm cm^{-2} \\rm s^{-1}$ (integrated luminosity $\\mathcal{L}_{\\rm int}\\sim 2 \\rm fb^{-1}$), the expected statistical uncertainty on the measurement is $\\sigma(2\\beta_s)\\simeq 0.03$. This uncertainty is similar to the $2\\beta_s$ value predicted by the SM.

  18. Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologycally based kinetic modeling

    NARCIS (Netherlands)

    Louisse, J.; Bosgra, S.; Blaauboer, B.J.; Rietjens, I.; Verwei, M.


    The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity d

  19. Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

    NARCIS (Netherlands)

    Louisse, Jochem; Bosgra, Sieto; Blaauboer, Bas J.; Rietjens, Ivonne M. C. M.; Verwei, Miriam


    The use of laboratory animals for toxicity testing in chemical safety assessment meets increasing ethical, economic and legislative constraints. The development, validation and application of reliable alternatives for in vivo toxicity testing are therefore urgently needed. In order to use toxicity d

  20. R-(-)-{beta}-O-methylsynephrine, a natural product, inhibits VEGF-induced angiogenesis in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Nam Hee [Chemical Genomics Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Pham, Ngoc Bich; Quinn, Ronald J. [Eskitis Institute, Griffith University, Brisbane, QLD 4111 (Australia); Kwon, Ho Jeong, E-mail: [Chemical Genomics Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)


    Research highlights: {yields} R-(-)-{beta}-O-methylsynephrine (OMe-Syn) is a natural compound isolated from a plant of the Rutaceae family. {yields} OMe-Syn possesses lead-like physicochemical properties, conferring good solubility. {yields} OMe-Syn effectively inhibited VEGF-induced angiogenesis in vitro and in vivo. {yields} OMe-Syn could be a novel basis for a small molecule targeting angiogenesis. -- Abstract: R-(-)-{beta}-O-methylsynephrine (OMe-Syn) is an active compound isolated from a plant of the Rutaceae family. We conducted cell proliferation assays on various cell lines and found that OMe-Syn more strongly inhibited the growth of human umbilical vein endothelial cells (HUVECs) than that of other normal and cancer cell lines tested. In angiogenesis assays, it inhibited vascular endothelial growth factor (VEGF)-induced invasion and tube formation of HUVECs with no toxicity. The anti-angiogenic activity of OMe-Syn was also validated in vivo using the chorioallantonic membrane (CAM) assay in growing chick embryos. Expression of the growth factors VEGF, hepatocyte growth factor, and basic fibroblast growth factor was suppressed by OMe-Syn in a dose-dependent manner. Taken together, our results indicate that this compound could be a novel basis for a small molecule targeting angiogenesis.

  1. Alignment validation

    Energy Technology Data Exchange (ETDEWEB)

    ALICE; ATLAS; CMS; LHCb; Golling, Tobias


    The four experiments, ALICE, ATLAS, CMS and LHCb are currently under constructionat CERN. They will study the products of proton-proton collisions at the Large Hadron Collider. All experiments are equipped with sophisticated tracking systems, unprecedented in size and complexity. Full exploitation of both the inner detector andthe muon system requires an accurate alignment of all detector elements. Alignmentinformation is deduced from dedicated hardware alignment systems and the reconstruction of charged particles. However, the system is degenerate which means the data is insufficient to constrain all alignment degrees of freedom, so the techniques are prone to converging on wrong geometries. This deficiency necessitates validation and monitoring of the alignment. An exhaustive discussion of means to validate is subject to this document, including examples and plans from all four LHC experiments, as well as other high energy experiments.

  2. Development and validation of a sensitive gas chromatography-ammonia chemical ionization mass spectrometry method for the determination of tabun enantiomers in hemolysed blood and plasma of different species. (United States)

    Tenberken, Oliver; Worek, Franz; Thiermann, Horst; Reiter, Georg


    The aim of this study was to develop and validate a fast, sensitive and easily applicable GC-MS assay for the chiral quantification of the highly toxic organophosphorus compound tabun (O-ethyl-N,N-dimethylphosphoramidocyanidate, GA) in hemolysed swine blood for further use in toxicokinetic and toxicodynamic studies. These requirements were fulfilled best by a GC-MS assay with positive chemical ionization with ammonia (GC-PCI-MS). Separation was carried out on a beta-cyclodextrin capillary column (Supelco BetaDex 225) after reversed phase (C18) solid-phase extraction. The limit of detection was 1 pg/ml for each enantiomer (approximately 500 fg on column) and the limit of quantification 5 pg/ml. The GC-PCI-MS method was applied for the quantification of tabun enantiomers in spiked swine blood after hemolysis and in spiked plasma of different species including humans.

  3. SANSMIC Validation.

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Paula D.; Rudeen, David Keith; Lord, David L.


    SANSMIC is solution mining software that was developed and utilized by SNL in its role as geotechnical advisor to the US DOE SPR for planning purposes. Three SANSMIC leach modes - withdrawal, direct, and reverse leach - have been revalidated with multiple test cases for each mode. The withdrawal mode was validated using high quality data from recent leach activity while the direct and reverse modes utilized data from historical cavern completion reports. Withdrawal results compared very well with observed data, including the location and size of shelves due to string breaks with relative leached volume differences ranging from 6 - 10% and relative radius differences from 1.5 - 3%. Profile comparisons for the direct mode were very good with relative leached volume differences ranging from 6 - 12% and relative radius differences from 5 - 7%. First, second, and third reverse configurations were simulated in order to validate SANSMIC over a range of relative hanging string and OBI locations. The first-reverse was simulated reasonably well with relative leached volume differences ranging from 1 - 9% and relative radius differences from 5 - 12%. The second-reverse mode showed the largest discrepancies in leach profile. Leached volume differences ranged from 8 - 12% and relative radius differences from 1 - 10%. In the third-reverse, relative leached volume differences ranged from 10 - 13% and relative radius differences were %7E4 %. Comparisons to historical reports were quite good, indicating that SANSMIC is essentially the same as documented and validated in the early 1980's.

  4. Simultaneous beta and gamma spectroscopy (United States)

    Farsoni, Abdollah T.; Hamby, David M.


    A phoswich radiation detector for simultaneous spectroscopy of beta rays and gamma rays includes three scintillators with different decay time characteristics. Two of the three scintillators are used for beta detection and the third scintillator is used for gamma detection. A pulse induced by an interaction of radiation with the detector is digitally analyzed to classify the type of event as beta, gamma, or unknown. A pulse is classified as a beta event if the pulse originated from just the first scintillator alone or from just the first and the second scintillator. A pulse from just the third scintillator is recorded as gamma event. Other pulses are rejected as unknown events.

  5. New Insights in the Amyloid-Beta Interaction with Mitochondria

    Directory of Open Access Journals (Sweden)

    Carlos Spuch


    Full Text Available Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD. Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.

  6. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines

    DEFF Research Database (Denmark)

    Lundh, M; Christensen, D P; Rasmussen, D N;


    Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim...... of the present study was to examine the KDAC gene expression profile of the beta cell and to investigate whether KDAC expression is regulated by cytokines. In addition, the protective effect of the non-selective KDAC inhibitor ITF2357 and interdependent regulation of four selected KDACs were investigated....

  7. Beta section Beta: biogeographical patterns of variation and taxonomy.

    NARCIS (Netherlands)

    Letschert, J.P.W.


    In Chapter 1 an account is given of the historical subdivision of the genus Beta and its sections, and the relations of the sections are discussed. Emphasis is given to the taxonomic treatment of wild section Beta by various authors. The Linnaean names B. vulgaris L. and B. maritima L. are lectotypi

  8. Valores de ferritina sérica em beta talassemia heterozigota Serum ferritin levels in beta thalassemia carrier

    Directory of Open Access Journals (Sweden)

    Isabeth F. Estevão


    Full Text Available A low iron level, the commonest nutritional deficiency in the world, is a public health problem in developing countries. On the other hand, an excessive amount of iron is toxic, causing several organic dysfunctions, such as diabetes, cirrhosis, endocrinopathies and heart disease. Researchers have reported an association of iron overload with beta-thalassemia. The aim of this paper was to compare the serum ferritin levels of women with the beta-thalassemia trait. The results of serologic tests of 137 women of childbearing age were analyzed; 63 had the beta-thalassemia trait and 74 had Hb AA. In the beta-thalassemia carriers, the median ferritin value was 51.90 ng/mL and in the non-carriers 31.60 ng/mL (p = 0.0052. Levels of less than 20 and above 150 ng/mL were observed in 28% and 3% of the non-carriers and in 16% and 11% of the carriers, respectively. With these results it is possible to conclude that women in the reproductive age with the beta-thalassemia trait present higher ferritin levels in the northeastern region of São Paulo State. Further studies are necessary to clarify possible genetic and/or environment factors which interfere in iron absorption.

  9. Cyclic modular beta-sheets. (United States)

    Woods, R Jeremy; Brower, Justin O; Castellanos, Elena; Hashemzadeh, Mehrnoosh; Khakshoor, Omid; Russu, Wade A; Nowick, James S


    The development of peptide beta-hairpins is problematic, because folding depends on the amino acid sequence and changes to the sequence can significantly decrease folding. Robust beta-hairpins that can tolerate such changes are attractive tools for studying interactions involving protein beta-sheets and developing inhibitors of these interactions. This paper introduces a new class of peptide models of protein beta-sheets that addresses the problem of separating folding from the sequence. These model beta-sheets are macrocyclic peptides that fold in water to present a pentapeptide beta-strand along one edge; the other edge contains the tripeptide beta-strand mimic Hao [JACS 2000, 122, 7654] and two additional amino acids. The pentapeptide and Hao-containing peptide strands are connected by two delta-linked ornithine (deltaOrn) turns [JACS 2003, 125, 876]. Each deltaOrn turn contains a free alpha-amino group that permits the linking of individual modules to form divalent beta-sheets. These "cyclic modular beta-sheets" are synthesized by standard solid-phase peptide synthesis of a linear precursor followed by solution-phase cyclization. Eight cyclic modular beta-sheets 1a-1h containing sequences based on beta-amyloid and macrophage inflammatory protein 2 were synthesized and characterized by 1H NMR. Linked cyclic modular beta-sheet 2, which contains two modules of 1b, was also synthesized and characterized. 1H NMR studies show downfield alpha-proton chemical shifts, deltaOrn delta-proton magnetic anisotropy, and NOE cross-peaks that establish all compounds but 1c and 1g to be moderately or well folded into a conformation that resembles a beta-sheet. Pulsed-field gradient NMR diffusion experiments show little or no self-association at low (

  10. Streptococcal toxic shock syndrome


    Gvozdenović Ljiljana; Pasternak Janko; Milovanović Stanislav; Ivanov Dejan; Milić Saša


    Introduction. Streptococcal toxic shock syndrome is now recognized as a toxin-mediated, multisystem illness. It is characterized by an early onset of shock with multiorgan failure and continues to be associated with high morbidity and mortality, caused by group A Streptococcus pyogenes. The symptoms for staphylococcal and streptococcal toxic shock syndrome are similar. Streptococcal toxic shock syndrome was not well described until 1993, when children who had suffered from varicella pre...

  11. Understanding the influence of MgO and SrO binary doping on the mechanical and biological properties of beta-TCP ceramics. (United States)

    Banerjee, Shashwat S; Tarafder, Solaiman; Davies, Neal M; Bandyopadhyay, Amit; Bose, Susmita


    The objective of this study was to evaluate the influence of MgO and SrO doping on the mechanical and biological properties of beta-tricalcium phosphate (beta-TCP). beta-TCP was doped with two different binary compositions, 0.25 and 1.0wt.% SrO along with 1.0wt.% MgO. MgO and SrO doping increased the beta phase stability at a sintering temperature of 1250 degrees C and marginally decreased the compressive strength of beta-TCP. An in vitro cell-material interaction study, using human fetal osteoblast cells (hFOB), indicated that doped beta-TCP was non-toxic, and MgO/SrO dopants improved cell attachment and growth. beta-TCP implants doped with 1.0wt.% MgO and 1.0wt.% SrO showed good in vivo biocompatibility when tested in male Sprague-Dawley rats for 16 weeks. Histomorphology analysis indicated that MgO/SrO-doped beta-TCP promoted more osteogenesis than pure beta-TCP. In vivo osteocalcin and type I collagen assay also revealed faster bone formation in rats with doped beta-TCP implant compared to rats with pure beta-TCP implant. Low Ca(2+) concentration in the urine of rats with doped beta-TCP implant confirmed slower degradation of MgO/SrO-doped beta-TCP than pure beta-TCP.


    Directory of Open Access Journals (Sweden)

    Sermin Cam


    Full Text Available Uranium, occurs naturally in the earth’s crust, is an alpha emitter radioactive element from the actinide group. For this reason, U-235 and U-238, are uranium isotopes with long half lives, have got radiological toxicity. But, for natural-isotopic-composition uranium (NatU, there is greater risk from chemical toxicity than radiological toxicity. When uranium is get into the body with anyway, also its chemical toxicity must be thought. [TAF Prev Med Bull 2007; 6(3.000: 215-220

  13. [Clinical application of beta-glucuronidase (beta-GCD) assay in the diagnosis of malignant tumors--analysis of 743 cases]. (United States)

    Wang, W Z


    Chromatometric assay of beta-GCD in the urine, gastric juice and saliva was conducted in 743 subjects. In the urine of 104 normal persons, 5 (4.8%) were beta-GCD positive. In the urine of 35 urinary bladder cancer patients, 20 (57.1%) were positive. beta-GCD content was very low in the gastric juice and saliva of normal subjects, giving a positivity of 0%. But it was high in the gastric juice of stomach cancer patients, giving a positive rate of 83.3%. The positivities in the saliva of stomach cancer and malignant ovarian tumor patients were both 62.2% which was higher than that of patients suffering from other malignancies or benign tumors. beta-GCD assay is simple, stable and is valid in the diagnosis of stomach cancer and ovarian malignancies. The mechanism of beta-GCD elevation and its relation to metastasis are discussed.

  14. Integration of BETA with Eclipse

    DEFF Research Database (Denmark)

    Andersen, Peter; Madsen, Ole Lehrmann; Enevoldsen, Mads Brøgger


    This paper presents language interoperability issues appearing in order to implement support for the BETA language in the Java-based Eclipse integrated development environment. One of the challenges is to implement plug-ins in BETA and be able to load them in Eclipse. In order to do this, some form...

  15. Measurements of sin 2 $\\beta$

    CERN Document Server

    Tricomi, A


    A review of the most recent measurements of the CP violating parameter sin 2 beta from LEP and CDF is reported. These yield an average value of sin 2 beta =0.91+or-0.35, giving a confidence level that CP violation in the B system has been observed of almost 99%. (10 refs).

  16. Beta decay of Cu-56

    NARCIS (Netherlands)

    Borcea, R; Aysto, J; Caurier, E; Dendooven, P; Doring, J; Gierlik, M; Gorska, M; Grawe, H; Hellstrom, M; Janas, Z; Jokinen, A; Karny, M; Kirchner, R; La Commara, M; Langanke, K; Martinez-Pinedo, G; Mayet, P; Nieminen, A; Nowacki, F; Penttila, H; Plochocki, A; Rejmund, M; Roeckl, E; Schlegel, C; Schmidt, K; Schwengner, R; Sawicka, M


    The proton-rich isotope Cu-56 was produced at the GSI On-Line Mass Separator by means of the Si-28(S-32, p3n) fusion-evaporation reaction. Its beta -decay properties were studied by detecting beta -delayed gamma rays and protons. A half-Life of 93 +/- 3 ms was determined for Cu-56. Compared to the p

  17. Beta Function and Anomalous Dimensions

    DEFF Research Database (Denmark)

    Pica, Claudio; Sannino, Francesco


    We demonstrate that it is possible to determine the coefficients of an all-order beta function linear in the anomalous dimensions using as data the two-loop coefficients together with the first one of the anomalous dimensions which are universal. The beta function allows to determine the anomalou...

  18. RAVEN Beta Release

    Energy Technology Data Exchange (ETDEWEB)

    Rabiti, Cristian [Idaho National Lab. (INL), Idaho Falls, ID (United States); Alfonsi, Andrea [Idaho National Lab. (INL), Idaho Falls, ID (United States); Cogliati, Joshua Joseph [Idaho National Lab. (INL), Idaho Falls, ID (United States); Mandelli, Diego [Idaho National Lab. (INL), Idaho Falls, ID (United States); Kinoshita, Robert Arthur [Idaho National Lab. (INL), Idaho Falls, ID (United States); Wang, Congjian [Idaho National Lab. (INL), Idaho Falls, ID (United States); Maljovec, Daniel Patrick [Idaho National Lab. (INL), Idaho Falls, ID (United States); Talbot, Paul William [Idaho National Lab. (INL), Idaho Falls, ID (United States)


    This documents the release of the Risk Analysis Virtual Environment (RAVEN) code. A description of the RAVEN code is provided, and discussion of the release process for the M2LW-16IN0704045 milestone. The RAVEN code is a generic software framework to perform parametric and probabilistic analysis based on the response of complex system codes. RAVEN is capable of investigating the system response as well as the input space using Monte Carlo, Grid, or Latin Hyper Cube sampling schemes, but its strength is focused toward system feature discovery, such as limit surfaces, separating regions of the input space leading to system failure, using dynamic supervised learning techniques. RAVEN has now increased in maturity enough for the Beta 1.0 release.

  19. [Serum beta 2 microglobulin (beta 2M) following renal transplantation]. (United States)

    Pacheco-Silva, A; Nishida, S K; Silva, M S; Ramos, O L; Azjen, H; Pereira, A B


    Although there was an important improvement in graft and patient survival the last 10 years, graft rejection continues to be a major barrier to the success of renal transplantation. Identification of a laboratory test that could help to diagnose graft rejection would facilitate the management of renal transplanted patients. PURPOSE--To evaluate the utility of monitoring serum beta 2M in recently transplanted patients. METHODS--We daily determined serum beta 2M levels in 20 receptors of renal grafts (10 from living related and 10 from cadaveric donors) and compared them to their clinical and laboratory evolution. RESULTS--Eight patients who presented immediate good renal function following grafting and did not have rejection had a mean serum beta 2M of 3.7 mg/L on the 4th day post transplant. The sensitivity of the test for the diagnosis of acute rejection was 87.5%, but the specificity was only 46%. Patients who presented acute tubular necrosis (ATN) without rejection had a progressive decrease in their serum levels of beta 2M, while their serum creatinine changed as they were dialyzed. In contrast, patients with ATN and concomitance of acute rejection or CSA nephrotoxicity presented elevated beta 2M and creatinine serum levels. CONCLUSION--Daily monitoring of serum beta 2M does not improve the ability to diagnose acute rejection in patients with good renal function. However, serum beta 2M levels seemed to be useful in diagnosing acute rejection or CSA nephrotoxicity in patients with ATN.

  20. SMAP RADAR Calibration and Validation (United States)

    West, R. D.; Jaruwatanadilok, S.; Chaubel, M. J.; Spencer, M.; Chan, S. F.; Chen, C. W.; Fore, A.


    The Soil Moisture Active Passive (SMAP) mission launched on Jan 31, 2015. The mission employs L-band radar and radiometer measurements to estimate soil moisture with 4% volumetric accuracy at a resolution of 10 km, and freeze-thaw state at a resolution of 1-3 km. Immediately following launch, there was a three month instrument checkout period, followed by six months of level 1 (L1) calibration and validation. In this presentation, we will discuss the calibration and validation activities and results for the L1 radar data. Early SMAP radar data were used to check commanded timing parameters, and to work out issues in the low- and high-resolution radar processors. From April 3-13 the radar collected receive only mode data to conduct a survey of RFI sources. Analysis of the RFI environment led to a preferred operating frequency. The RFI survey data were also used to validate noise subtraction and scaling operations in the radar processors. Normal radar operations resumed on April 13. All radar data were examined closely for image quality and calibration issues which led to improvements in the radar data products for the beta release at the end of July. Radar data were used to determine and correct for small biases in the reported spacecraft attitude. Geo-location was validated against coastline positions and the known positions of corner reflectors. Residual errors at the time of the beta release are about 350 m. Intra-swath biases in the high-resolution backscatter images are reduced to less than 0.3 dB for all polarizations. Radiometric cross-calibration with Aquarius was performed using areas of the Amazon rain forest. Cross-calibration was also examined using ocean data from the low-resolution processor and comparing with the Aquarius wind model function. Using all a-priori calibration constants provided good results with co-polarized measurements matching to better than 1 dB, and cross-polarized measurements matching to about 1 dB in the beta release. During the

  1. Pyridostigmine Synergistic Toxicity Study. (United States)


    AND DEET IN THE LABORATORY RAT 1. Executive Sum m ary .............................................................................................. 2 2...TOXICOLOGICAL STUDY 75-48-2665 ACUTE ORAL TOXICITY STUDY OF PYRIDOSTIGMINE BROMIDE. PERMETHRIN. AND DEET IN THE LABORATORY RAT 1. REFERENCES: See Appendix A... LABORATORY RAT 1. PURPOSE: The purpose of this study was to determine potential toxic interactions when pyridostigmine bromide. permethrin. and DEET are given

  2. Toxic proteins in plants. (United States)

    Dang, Liuyi; Van Damme, Els J M


    Plants have evolved to synthesize a variety of noxious compounds to cope with unfavorable circumstances, among which a large group of toxic proteins that play a critical role in plant defense against predators and microbes. Up to now, a wide range of harmful proteins have been discovered in different plants, including lectins, ribosome-inactivating proteins, protease inhibitors, ureases, arcelins, antimicrobial peptides and pore-forming toxins. To fulfill their role in plant defense, these proteins exhibit various degrees of toxicity towards animals, insects, bacteria or fungi. Numerous studies have been carried out to investigate the toxic effects and mode of action of these plant proteins in order to explore their possible applications. Indeed, because of their biological activities, toxic plant proteins are also considered as potentially useful tools in crop protection and in biomedical applications, such as cancer treatment. Genes encoding toxic plant proteins have been introduced into crop genomes using genetic engineering technology in order to increase the plant's resistance against pathogens and diseases. Despite the availability of ample information on toxic plant proteins, very few publications have attempted to summarize the research progress made during the last decades. This review focuses on the diversity of toxic plant proteins in view of their toxicity as well as their mode of action. Furthermore, an outlook towards the biological role(s) of these proteins and their potential applications is discussed.

  3. Engineering Metal Ion Coordination to Regulate Amyloid Fibril Assembly And Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Dong, J.; Canfield, J.M.; Mehta, A.K.; Shokes, J.E.; Tian, B.; Childers, W.S.; Simmons, J.A.; Mao, Z.; Scott, R.A.; Warncke, K.; Lynn, D.G.


    Protein and peptide assembly into amyloid has been implicated in functions that range from beneficial epigenetic controls to pathological etiologies. However, the exact structures of the assemblies that regulate biological activity remain poorly defined. We have previously used Zn{sup 2+} to modulate the assembly kinetics and morphology of congeners of the amyloid {beta} peptide (A{beta}) associated with Alzheimer's disease. We now reveal a correlation among A{beta}-Cu{sup 2+} coordination, peptide self-assembly, and neuronal viability. By using the central segment of A{beta}, HHQKLVFFA or A{beta}(13-21), which contains residues H13 and H14 implicated in A{beta}-metal ion binding, we show that Cu{sup 2+} forms complexes with A{beta}(13-21) and its K16A mutant and that the complexes, which do not self-assemble into fibrils, have structures similar to those found for the human prion protein, PrP. N-terminal acetylation and H14A substitution, Ac-A{beta}(13-21)H14A, alters metal coordination, allowing Cu{sup 2+} to accelerate assembly into neurotoxic fibrils. These results establish that the N-terminal region of A{beta} can access different metal-ion-coordination environments and that different complexes can lead to profound changes in A{beta} self-assembly kinetics, morphology, and toxicity. Related metal-ion coordination may be critical to the etiology of other neurodegenerative diseases.

  4. Mechanisms of Phosphine Toxicity

    Directory of Open Access Journals (Sweden)

    Nisa S. Nath


    Full Text Available Fumigation with phosphine gas is by far the most widely used treatment for the protection of stored grain against insect pests. The development of high-level resistance in insects now threatens its continued use. As there is no suitable chemical to replace phosphine, it is essential to understand the mechanisms of phosphine toxicity to increase the effectiveness of resistance management. Because phosphine is such a simple molecule (PH3, the chemistry of phosphorus is central to its toxicity. The elements above and below phosphorus in the periodic table are nitrogen (N and arsenic (As, which also produce toxic hydrides, namely, NH3 and AsH3. The three hydrides cause related symptoms and similar changes to cellular and organismal physiology, including disruption of the sympathetic nervous system, suppressed energy metabolism and toxic changes to the redox state of the cell. We propose that these three effects are interdependent contributors to phosphine toxicity.

  5. Mechanisms of phosphine toxicity. (United States)

    Nath, Nisa S; Bhattacharya, Ishita; Tuck, Andrew G; Schlipalius, David I; Ebert, Paul R


    Fumigation with phosphine gas is by far the most widely used treatment for the protection of stored grain against insect pests. The development of high-level resistance in insects now threatens its continued use. As there is no suitable chemical to replace phosphine, it is essential to understand the mechanisms of phosphine toxicity to increase the effectiveness of resistance management. Because phosphine is such a simple molecule (PH(3)), the chemistry of phosphorus is central to its toxicity. The elements above and below phosphorus in the periodic table are nitrogen (N) and arsenic (As), which also produce toxic hydrides, namely, NH(3) and AsH(3). The three hydrides cause related symptoms and similar changes to cellular and organismal physiology, including disruption of the sympathetic nervous system, suppressed energy metabolism and toxic changes to the redox state of the cell. We propose that these three effects are interdependent contributors to phosphine toxicity.

  6. Mechanisms of Phosphine Toxicity (United States)

    Nath, Nisa S.; Bhattacharya, Ishita; Tuck, Andrew G.; Schlipalius, David I.; Ebert, Paul R.


    Fumigation with phosphine gas is by far the most widely used treatment for the protection of stored grain against insect pests. The development of high-level resistance in insects now threatens its continued use. As there is no suitable chemical to replace phosphine, it is essential to understand the mechanisms of phosphine toxicity to increase the effectiveness of resistance management. Because phosphine is such a simple molecule (PH3), the chemistry of phosphorus is central to its toxicity. The elements above and below phosphorus in the periodic table are nitrogen (N) and arsenic (As), which also produce toxic hydrides, namely, NH3 and AsH3. The three hydrides cause related symptoms and similar changes to cellular and organismal physiology, including disruption of the sympathetic nervous system, suppressed energy metabolism and toxic changes to the redox state of the cell. We propose that these three effects are interdependent contributors to phosphine toxicity. PMID:21776261

  7. Thermodynamics in $f(R,R_{\\alpha\\beta}R^{\\alpha\\beta},\\phi)$ theory of gravity

    CERN Document Server

    Zubair, M; Bahamonde, Sebastian


    First and second laws of black hole thermodynamics are examined at the apparent horizon of FRW spacetime in $f(R,R_{\\alpha\\beta}R^{\\alpha\\beta} ,\\phi)$ gravity, where $R$, $R_{\\alpha\\beta}$ and $\\phi$ are the Ricci scalar, Ricci invariant and the scalar field respectively. In this modified theory, Friedmann equations are formulated for any spatial curvature. These equations can be presented into the form of first law of thermodynamics $T_{h}d\\hat{S}_{h}+ T_{h}d_{i}\\hat{S}_{h}+W dV=dE$, where $d_{i}\\hat{S}_{h}$ is an extra entropy term because of the non-equilibrium presentation of the equations. The generalized second law of thermodynamics (GSLT) is expressed in an inclusive form where these results can be represented, in GR, $f(R)$ and $f(R, \\phi)$ gravities. Finally to check the validity of GSLT, we take some particular models and produce constraints of the parameters.

  8. Foodborne cereulide causes beta-cell dysfunction and apoptosis.

    Directory of Open Access Journals (Sweden)

    Roman Vangoitsenhoven

    Full Text Available To study the effects of cereulide, a food toxin often found at low concentrations in take-away meals, on beta-cell survival and function.Cell death was quantified by Hoechst/Propidium Iodide in mouse (MIN6 and rat (INS-1E beta-cell lines, whole mouse islets and control cell lines (HepG2 and COS-1. Beta-cell function was studied by glucose-stimulated insulin secretion (GSIS. Mechanisms of toxicity were evaluated in MIN6 cells by mRNA profiling, electron microscopy and mitochondrial function tests.24 h exposure to 5 ng/ml cereulide rendered almost all MIN6, INS-1E and pancreatic islets apoptotic, whereas cell death did not increase in the control cell lines. In MIN6 cells and murine islets, GSIS capacity was lost following 24 h exposure to 0.5 ng/ml cereulide (P<0.05. Cereulide exposure induced markers of mitochondrial stress including Puma (p53 up-regulated modulator of apoptosis, P<0.05 and general pro-apoptotic signals as Chop (CCAAT/-enhancer-binding protein homologous protein. Mitochondria appeared swollen upon transmission electron microscopy, basal respiration rate was reduced by 52% (P<0.05 and reactive oxygen species increased by more than twofold (P<0.05 following 24 h exposure to 0.25 and 0.50 ng/ml cereulide, respectively.Cereulide causes apoptotic beta-cell death at low concentrations and impairs beta-cell function at even lower concentrations, with mitochondrial dysfunction underlying these defects. Thus, exposure to cereulide even at concentrations too low to cause systemic effects appears deleterious to the beta-cell.

  9. Experiments on double beta decay

    Energy Technology Data Exchange (ETDEWEB)

    Busto, J. [Neuchatel Univ. (Switzerland). Inst. de Physique


    The Double Beta Decay, and especially ({beta}{beta}){sub 0{nu}} mode, is an excellent test of Standard Model as well as of neutrino physics. From experimental point of view, a very large number of different techniques are or have been used increasing the sensitivity of this experiments quite a lot (the factor of 10{sup 4} in the last 20 years). In future, in spite of several difficulties, the sensitivity would be increased further, keeping the interest of this very important process. (author) 4 figs., 5 tabs., 21 refs.

  10. Dosimetry of {beta} extensive sources; Dosimetria de fuentes {beta} extensas

    Energy Technology Data Exchange (ETDEWEB)

    Rojas C, E.L.; Lallena R, A.M. [Departamento de Fisica Moderna, Universidad de Granada, E-18071 Granada (Spain)


    In this work, we have been studied, making use of the Penelope Monte Carlo simulation code, the dosimetry of {beta} extensive sources in situations of spherical geometry including interfaces. These configurations are of interest in the treatment of the called cranealfaringyomes of some synovia leisure of knee and other problems of interest in medical physics. Therefore, its application can be extended toward problems of another areas with similar geometric situation and beta sources. (Author)

  11. Developmental toxicity evaluation of three hexabromocyclododecane diastereoisomers on zebrafish embryos

    Energy Technology Data Exchange (ETDEWEB)

    Du Miaomiao [Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); Graduate University of Chinese Academy of Sciences, Beijing 100049 (China); Zhang Dandan; Yan Changzhou [Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China); Zhang Xian, E-mail: [Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021 (China)


    Structural dissimilarities of hexabromocyclododecane diastereoisomers could raise substantial differences in physicochemical, biological and toxicological properties. In order to fully assess the environmental safety and health risk of hexabromocyclododecanes (HBCDs), zebrafish embryos were used to evaluate the developmental toxicity of individual HBCD diastereoisomers ({alpha}-HBCD, {beta}-HBCD and {gamma}-HBCD). Four-hour post-fertilization (hpf) zebrafish embryos were exposed to different concentrations of HBCD diastereoisomers (0, 0.01, 0.1 and 1.0 mg/l) until 120 hpf. The results showed that exposure to HBCDs can affect the development of zebrafish embryos/larvae in a dose-dependent and diastereoselective manner. The diastereoisomers {alpha}-, {beta}- and {gamma}-HBCD at 0.01 mg/l had little effect on the development of zebrafish embryos except that exposure to 0.01 mg/l {gamma}-HBCD significantly delayed hatching (P < 0.05). At 0.1 mg/l, {alpha}-HBCD resulted in depressed heart rate of larvae (96 hpf) and delayed hatching, whereas {beta}- and {gamma}-HBCD both caused significant hatching delay and growth inhibition (P < 0.05). In addition, a remarkable and significant increase in mortality and malformation rate was noted at 0.1 mg/l {gamma}-HBCD exposure groups (P < 0.05). At 1.0 mg/l, {alpha}-, {beta}- and {gamma}-HBCD significantly affected all of the endpoints monitored (P < 0.05). Additionally, HBCD diastereoisomers could induce the generation of reactive oxygen species (ROS) and the activities of caspase-3 and caspase-9 in a dose-dependent manner. The results indicated that HBCD diastereoisomers could cause developmental toxicity to zebrafish embryos through inducing apoptosis by ROS formation. The overall results showed a good agreement confirming that the order of developmental toxicity of HBCD diastereoisomers in zebrafish is {gamma}-HBCD > {beta}-HBCD > {alpha}-HBCD.

  12. Possible Role of DNA Polymerase beta in Protecting Human Bronchial Epithelial Cells Against Cytotoxicity of Hydroquinone

    Institute of Scientific and Technical Information of China (English)



    Objective To explore the toxicological mechanism of hydroquinone in human bronchial epithelial cells and to investigate whether DNA polymerase beta is involved in protecting cells from damage caused by hydroquinone. Methods DNA polymerase beta knock-down cell line was established via RNA interference as an experimental group. Normal human bronchial epithelial cells and cells transfected with the empty vector of pEGFP-Cl were used as controls. Cells were treated with different concentrations of hydroquinone (ranged from 10 μmol/L to 120 μmol/L) for 4 hours. MTT assay and Comet assay [single-cell gel electrophoresis (SCGE)] were performed respectively to detect the toxicity of hydroquinone. Results MTT assay showed that DNA polymerase beta knock-down cells treated with different concentrations of hydroquinone had a lower absorbance value at 490 nm than the control cells in a dose-dependant manner. Comet assay revealed that different concentrations of hydroquinone caused more severe DNA damage in DNA polymerase beta knock-down cell line than in control cells and there was no significant difference in the two control groups. Conclusions Hydroquinone has significant toxicity to human bronchial epithelial cells and causes DNA damage. DNA polymerase beta knock-down cell line appears more sensitive to hydroquinone than the control cells. The results suggest that DNA polymerase beta is involved in protecting cells from damage caused by hydroquinone.

  13. Evolution of outer membrane beta-barrels from an ancestral beta beta hairpin. (United States)

    Remmert, M; Biegert, A; Linke, D; Lupas, A N; Söding, J


    Outer membrane beta-barrels (OMBBs) are the major class of outer membrane proteins from Gram-negative bacteria, mitochondria, and plastids. Their transmembrane domains consist of 8-24 beta-strands forming a closed, barrel-shaped beta-sheet around a central pore. Despite their obvious structural regularity, evidence for an origin by duplication or for a common ancestry has not been found. We use three complementary approaches to show that all OMBBs from Gram-negative bacteria evolved from a single, ancestral beta beta hairpin. First, we link almost all families of known single-chain bacterial OMBBs with each other through transitive profile searches. Second, we identify a clear repeat signature in the sequences of many OMBBs in which the repeating sequence unit coincides with the structural beta beta hairpin repeat. Third, we show that the observed sequence similarity between OMBB hairpins cannot be explained by structural or membrane constraints on their sequences. The third approach addresses a longstanding problem in protein evolution: how to distinguish between a very remotely homologous relationship and the opposing scenario of "sequence convergence." The origin of a diverse group of proteins from a single hairpin module supports the hypothesis that, around the time of transition from the RNA to the protein world, proteins arose by amplification and recombination of short peptide modules that had previously evolved as cofactors of RNAs.

  14. Toxic Shock Syndrome (For Teens) (United States)

    ... Surgery? A Week of Healthy Breakfasts Shyness Toxic Shock Syndrome KidsHealth > For Teens > Toxic Shock Syndrome Print ... it, then take some precautions. What Is Toxic Shock Syndrome? If you're a girl who's had ...

  15. Atomic View of a Toxic Amyloid Small Oligomer

    Energy Technology Data Exchange (ETDEWEB)

    Laganowsky, Arthur; Liu, Cong; Sawaya, Michael R.; Whitelegge, Julian P.; Park, Jiyong; Zhao, Minglei; Pensalfini, Anna; Soriaga, Angela B.; Landau, Meytal; Teng, Poh K.; Cascio, Duilio; Glabe, Charles; Eisenberg, David (UCI); (UCLA)


    Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein {alpha}{beta} crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: {beta}-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the {beta}-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

  16. Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Wallace, Bret D.; Wang, Hongwei; Lane, Kimberly T.; Scott, John E.; Orans, Jillian; Koo, Ja Seol; Venkatesh, Madhukumar; Jobin, Christian; Yeh, Li-An; Mani, Sridhar; Redinbo, Matthew R. (Einstein); (UNC); (North Carolina Central University)


    The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial {beta}-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial {beta}-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial {beta}-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.

  17. Questions Students Ask: Beta Decay. (United States)

    Koss, Jordan; Hartt, Kenneth


    Answers a student's question about the emission of a positron from a nucleus. Discusses the problem from the aspects of the uncertainty principle, beta decay, the Fermi Theory, and modern physics. (YP)

  18. Fluxon Modeling of Low-Beta Plasmas

    CERN Document Server

    DeForest, C E; Forest, Craig E. De; Kankelborg, Charles C.


    We have developed a new, quasi-Lagrangian approach for numerical modeling of magnetohydrodynamics in low to moderate $\\beta$ plasmas such as the solar corona. We introduce the concept of a ``fluxon'', a discretized field line. Fluxon models represent the magnetic field as a skeleton of such discrete field lines, and interpolate field values from the geometry of the skeleton where needed, reversing the usual direction of the field line transform. The fluxon skeleton forms the grid for a collection of 1-D Eulerian models of plasma along individual flux tubes. Fluxon models have no numerical resistivity, because they preserve topology explicitly. Our prototype code, \\emph{FLUX}, is currently able to find 3-D nonlinear force-free field solutions with a specified field topology, and work is ongoing to validate and extend the code to full magnetohydrodynamics. FLUX has significant scaling advantages over conventional models: for ``magnetic carpet'' models, with photospheric line-tied boundary conditions, FLUX simul...

  19. Beta Function and Anomalous Dimensions

    CERN Document Server

    Pica, Claudio


    We demonstrate that it is possible to determine the coefficients of an all-order beta function linear in the anomalous dimensions using as data the two-loop coefficients together with the first one of the anomalous dimensions which are universal. The beta function allows to determine the anomalous dimension of the fermion masses at the infrared fixed point, and the resulting values compare well with the lattice determinations.

  20. Toxics Release Inventory (TRI) (United States)

    U.S. Environmental Protection Agency — The Toxics Release Inventory (TRI) is a dataset compiled by the U.S. Environmental Protection Agency (EPA). It contains information on the release and waste...

  1. Natural toxicants in foods. (United States)

    Coon, J M


    Food constitutes the most complex part of our chemical environment. Naturally occurring substances in food, such as goitrogens and estrogens, are toxicants. However, there is a difference of degree between toxicity and hazard, and the hazard to man in normal good health from naturally occurring toxicants in food is usually slight, because of (a) the small concentrations and (b) antagonistic interactions between toxicants which provide "safety in numbers." Hazard from foods may indeed exist under some circumstances, such as the presence of abnormal contaminants, ingestion of abnormal amounts, or abnormal susceptibility existing in some disease states. However, the major hazards of the dinner table can ordinarily be ascribed to careless food handling, unbalanced or fad diets, or overeating.

  2. Toxicity Reference Database (United States)

    U.S. Environmental Protection Agency — The Toxicity Reference Database (ToxRefDB) contains approximately 30 years and $2 billion worth of animal studies. ToxRefDB allows scientists and the interested...

  3. Aspects of aluminum toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Hewitt, C.D.; Savory, J.; Wills, M.R. (Univ. of Virginia Health Sciences Center, Charlottesville (USA))


    Aluminum is the most abundant metal in the earth's crust. The widespread occurrence of aluminum, both in the environment and in foodstuffs, makes it virtually impossible for man to avoid exposure to this metal ion. Attention was first drawn to the potential role of aluminum as a toxic metal over 50 years ago, but was dismissed as a toxic agent as recently as 15 years ago. The accumulation of aluminum, in some patients with chronic renal failure, is associated with the development of toxic phenomena; dialysis encephalopathy, osteomalacic dialysis osteodystrophy, and an anemia. Aluminum accumulation also occurs in patients who are not on dialysis, predominantly infants and children with immature or impaired renal function. Aluminum has also been implicated as a toxic agent in the etiology of Alzheimer's disease, Guamiam amyotrophic lateral sclerosis, and parkinsonism-dementia. 119 references.

  4. Toxicity of lunar dust

    CERN Document Server

    Linnarsson, Dag; Fubini, Bice; Gerde, Per; Karlsson, Lars L; Loftus, David J; Prisk, G Kim; Staufer, Urs; Tranfield, Erin M; van Westrenen, Wim


    The formation, composition and physical properties of lunar dust are incompletely characterised with regard to human health. While the physical and chemical determinants of dust toxicity for materials such as asbestos, quartz, volcanic ashes and urban particulate matter have been the focus of substantial research efforts, lunar dust properties, and therefore lunar dust toxicity may differ substantially. In this contribution, past and ongoing work on dust toxicity is reviewed, and major knowledge gaps that prevent an accurate assessment of lunar dust toxicity are identified. Finally, a range of studies using ground-based, low-gravity, and in situ measurements is recommended to address the identified knowledge gaps. Because none of the curated lunar samples exist in a pristine state that preserves the surface reactive chemical aspects thought to be present on the lunar surface, studies using this material carry with them considerable uncertainty in terms of fidelity. As a consequence, in situ data on lunar dust...

  5. Polypeptides having beta-glucosidase activity, beta-xylosidase activity, or beta-glucosidase and beta-xylosidase activity and polynucleotides encoding same

    Energy Technology Data Exchange (ETDEWEB)

    Morant, Marc


    The present invention relates to isolated polypeptides having beta-glucosidase activity, beta-xylosidase activity, or beta-glucosidase and beta-xylosidase activity and isolated polynucleotides encoding the polypeptides. The invention also relates to nucleic acid constructs, vectors, and host cells comprising the polynucleotides as well as methods of producing and using the polypeptides.

  6. Mechanisms of Phosphine Toxicity


    Nisa S. Nath; Ishita Bhattacharya; Andrew G. Tuck; Schlipalius, David I.; Paul R. Ebert


    Fumigation with phosphine gas is by far the most widely used treatment for the protection of stored grain against insect pests. The development of high-level resistance in insects now threatens its continued use. As there is no suitable chemical to replace phosphine, it is essential to understand the mechanisms of phosphine toxicity to increase the effectiveness of resistance management. Because phosphine is such a simple molecule (PH3), the chemistry of phosphorus is central to its toxicity...

  7. Rev-erb beta regulates the Srebp-1c promoter and mRNA expression in skeletal muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Ramakrishnan, Sathiya N.; Lau, Patrick; Crowther, Lisa M. [The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Qld 4072 (Australia); Cleasby, Mark E. [Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St. Vincent' s Hospital, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010 (Australia); Millard, Susan; Leong, Gary M. [The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Qld 4072 (Australia); Cooney, Gregory J. [Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St. Vincent' s Hospital, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010 (Australia); Muscat, George E.O., E-mail: [The University of Queensland, Institute for Molecular Bioscience, St. Lucia, Qld 4072 (Australia)


    The nuclear hormone receptor, Rev-erb beta operates as a transcriptional silencer. We previously demonstrated that exogenous expression of Rev-erb{beta}{Delta}E in skeletal muscle cells increased Srebp-1c mRNA expression. We validated these in vitro observations by injection of an expression vector driving Rev-erb{beta}{Delta}E expression into mouse tibialis muscle that resulted in increased Srebp-1c mRNA expression. Paradoxically, Rev-erb{beta} siRNA expression in skeletal muscle cells repressed Srebp-1c expression, and indicated that Rev-erb{beta} expression was necessary for Srebp-1c expression. ChIP analysis demonstrated that Rev-erb{beta} was recruited to the Srebp-1c promoter. Moreover, Rev-erb{beta} trans-activated the Srebp-1c promoter, in contrast, Rev-erb{beta} efficiently repressed the Rev-erb{alpha} promoter, a previously characterized target gene. Finally, treatment with the Rev-erb agonist (hemin) (i) increased the trans-activation of the Srebp-1c promoter by Rev-erb{beta}; and (ii) increased Rev-erb{beta} and Srebp-1c mRNA expression. These data suggest that Rev-erb{beta} has the potential to activate gene expression, and is a positive regulator of Srebp-1c, a regulator of lipogenesis.

  8. Validating SMAP L2/3 Products (United States)

    Jackson, T. J.; Colliander, A.; Bindlish, R.; Chan, S.; Das, N. N.; Entekhabi, D.; Kim, S.; Chen, F.; Crow, W. T.; Burgin, M. S.; Asanuma, J.; Berg, A. A.; Cosh, M. H.; Caldwell, T. G.; Martínez-Fernández, J.; Pacheco, A. M.; Su, Z.; Thibeault, M.; Walker, J. P.; Njoku, E. G.; Yueh, S. H.; O'Neill, P. E.


    The Soil Moisture Active Passive (SMAP) mission entered its one year calibration and validation (cal/val) phase in May, 2015. This began with a focus on instrument measurements, brightness temperature and backscatter, and has now evolved to the geophysical products that include three different spatial resolutions of Level 2/3 surface soil moisture (36, 9, and 3 km) and freeze-thaw state. The goal is to provide validated products by May, 2016. SMAP utilizes five methodologies in soil moisture cal/val: core validation sites, sparse networks of in situ sensors, inter-comparisons with products from other satellite programs, inter-comparisons with model-based products, and field campaigns. Each methodology has a role in the process. Examples of each methodology will be presented including recent field campaigns. The evaluation of the beta version will the explained and plans for the providing the validated products presented.

  9. Streptococcal toxic shock syndrome

    Directory of Open Access Journals (Sweden)

    Gvozdenović Ljiljana


    Full Text Available Introduction. Streptococcal toxic shock syndrome is now recognized as a toxin-mediated, multisystem illness. It is characterized by an early onset of shock with multiorgan failure and continues to be associated with high morbidity and mortality, caused by group A Streptococcus pyogenes. The symptoms for staphylococcal and streptococcal toxic shock syndrome are similar. Streptococcal toxic shock syndrome was not well described until 1993, when children who had suffered from varicella presented roughly 2-4 weeks later with a clinical syndrome highly suggestive of toxic shock syndrome. Characteristics, complications and therapy. It is characterized by a sudden onset of fever, chills, vomiting, diarrhea, muscle aches and rash. It can rapidly progress to severe and intractable hypotension and multisystem dysfunction. Almost every organ system can be involved. Complications of streptococcal toxic shock syndrome may include kidney failure, liver failure and even death. Crystalloids and inotropic agents are used to treat the hypovolemic shock aggressively, with close monitoring of the patient’s mean arterial pressure and central venous pressure. An immediate and aggressive management of hypovolemic shock is essential in streptococcal toxic shock syndrome. Targeted antibiotics are indicated; penicillin or a betalactam antibiotic is used for treating group A streptococci, and clindamycin has emerged as a key portion of the standard treatment.

  10. Combining Physical and Biologic Parameters to Predict Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer Treated With Definitive Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Stenmark, Matthew H. [Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Cai Xuwei [Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Radiation Oncology, Shanghai Cancer Hospital, Fudan University, Shanghai (China); Shedden, Kerby [Department of Biostatistics, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Hayman, James A. [Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Yuan Shuanghu [Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Radiation Oncology, Shangdong Cancer Hospital, Jinan (China); Ritter, Timothy [Veterans Affairs Medical Center, Ann Arbor, Michigan (United States); Ten Haken, Randall K.; Lawrence, Theodore S. [Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Kong Fengming, E-mail: [Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Veterans Affairs Medical Center, Ann Arbor, Michigan (United States)


    Purpose: To investigate the plasma dynamics of 5 proinflammatory/fibrogenic cytokines, including interleukin-1beta (IL-1{beta}), IL-6, IL-8, tumor necrosis factor alpha (TNF-{alpha}), and transforming growth factor beta1 (TGF-{beta}1) to ascertain their value in predicting radiation-induced lung toxicity (RILT), both individually and in combination with physical dosimetric parameters. Methods and Materials: Treatments of patients receiving definitive conventionally fractionated radiation therapy (RT) on clinical trial for inoperable stages I-III lung cancer were prospectively evaluated. Circulating cytokine levels were measured prior to and at weeks 2 and 4 during RT. The primary endpoint was symptomatic RILT, defined as grade 2 and higher radiation pneumonitis or symptomatic pulmonary fibrosis. Minimum follow-up was 18 months. Results: Of 58 eligible patients, 10 (17.2%) patients developed RILT. Lower pretreatment IL-8 levels were significantly correlated with development of RILT, while radiation-induced elevations of TGF-ss1 were weakly correlated with RILT. Significant correlations were not found for any of the remaining 3 cytokines or for any clinical or dosimetric parameters. Using receiver operator characteristic curves for predictive risk assessment modeling, we found both individual cytokines and dosimetric parameters were poor independent predictors of RILT. However, combining IL-8, TGF-ss1, and mean lung dose into a single model yielded an improved predictive ability (P<.001) compared to either variable alone. Conclusions: Combining inflammatory cytokines with physical dosimetric factors may provide a more accurate model for RILT prediction. Future study with a larger number of cases and events is needed to validate such findings.

  11. The GERDA experiment on 0{nu}{beta}{beta} decay

    Energy Technology Data Exchange (ETDEWEB)

    Freund, Kai [Eberhard Karls Universitaet Tuebingen (Germany); Collaboration: GERDA-Collaboration


    The Gerda (Germanium Detector Array) collaboration searches for the neutrinoless double beta decay (0{nu}{beta}{beta}) of {sup 76}Ge. The existence of this decay would give rise to the assumption that the neutrino is a Majorana particle, i.e. its own antiparticle. A measured half-life could be used to determine the effective neutrino mass and hence resolve the neutrino mass hierarchy problem. Germanium diodes, isotopically enriched in {sup 76}Ge, are used as both source and detector. Due to the low rate of this decay (T{sub 1/2}>10{sup 25} y), the experimental background must be reduced to a level of 10{sup -2}counts/(kg y keV) or better in the region around Q{sub {beta}{beta}}. To minimize background from cosmogenically produced secondary particles, a low Z shielding is employed. Thus, the naked diodes are operated in a liquid argon cryostat, which is surrounded by a water tank acting as both passive shield and active muon Cherenkov veto. Gerda started the commissioning runs in 2010 and in November 2011, the first phase of data taking with enriched detectors has begun. In this talk, the first year of the experiment is summarized.

  12. Azetidine-2-carboxylic acid in garden beets (Beta vulgaris). (United States)

    Rubenstein, Edward; Zhou, Haihong; Krasinska, Karolina M; Chien, Allis; Becker, Christopher H


    Azetidine-2-carboxylic acid (L-Aze) is a toxic and teratogenic non-protein amino acid. In many species, including man, L-Aze is misincorporated into protein in place of proline, altering collagen, keratin, hemoglobin, and protein folding. In animal models of teratogenesis, it causes a wide range of malformations. The role of L-Aze in human disease has been unexplored, probably because the compound has not been associated with foods consumed by humans. Herein we report the presence of L-Aze in the garden or table beet (Beta vulgaris).

  13. Assessing health-related quality of life in patients with benign non-toxic goitre

    DEFF Research Database (Denmark)

    Watt, Torquil; Cramon, Per; Frendl, Daniel M


    Health-related quality of life (HRQoL) assessments are increasingly used to evaluate treatment effects and to shape the delivery of value based care. Valid generic and disease specific tools are available for quantifying HRQoL in patients with non-toxic goitre. However, few studies have applied...... these validated instruments to assess HRQoL in patients with benign non-toxic goitre. Limited evidence suggests that patients with non-toxic goitre have HRQoL impairments in multiple HRQoL domains. While the HRQoL-impact of non-toxic goitre may be small relative to other severely disabling medical conditions...

  14. Kidney Toxicity Induced by 13 Weeks Exposure to the Fruiting Body of Paecilomyces sinclairii in Rats


    Jeong, Mihye; Kim, Young-Won; Min, Jeong-Ran; Kwon, Min; Han, Beom-Suk; Kim, Jeong-Gyu; Jeong, Sang-Hee


    Paecilomyces sinclairiis (PS) is known as a functional food or human health supplement. However concerns have been raised about its kidney toxicity. This study was performed to investigate the kidney toxicity of PS by 13 week-oral administration to rats. Blood urea nitrogen (BUN), serum creatinine, and kidney damage biomarkers including beta-2-microglobulin (β2m), glutathione S-transferase alpha (GST-α), kidney injury molecule 1 (KIM-1), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1)...

  15. In-trap decay spectroscopy for {beta}{beta} decays

    Energy Technology Data Exchange (ETDEWEB)

    Brunner, Thomas


    The presented work describes the implementation of a new technique to measure electron-capture (EC) branching ratios (BRs) of intermediate nuclei in {beta}{beta} decays. This technique has been developed at TRIUMF in Vancouver, Canada. It facilitates one of TRIUMF's Ion Traps for Atomic and Nuclear science (TITAN), the Electron Beam Ion Trap (EBIT) that is used as a spectroscopy Penning trap. Radioactive ions, produced at the radioactive isotope facility ISAC, are injected and stored in the spectroscopy Penning trap while their decays are observed. A key feature of this technique is the use of a strong magnetic field, required for trapping. It radially confines electrons from {beta} decays along the trap axis while X-rays, following an EC, are emitted isotropically. This provides spatial separation of X-ray and {beta} detection with almost no {beta}-induced background at the X-ray detector, allowing weak EC branches to be measured. Furthermore, the combination of several traps allows one to isobarically clean the sample prior to the in-trap decay spectroscopy measurement. This technique has been developed to measure ECBRs of transition nuclei in {beta}{beta} decays. Detailed knowledge of these electron capture branches is crucial for a better understanding of the underlying nuclear physics in {beta}{beta} decays. These branches are typically of the order of 10{sup -5} and therefore difficult to measure. Conventional measurements suffer from isobaric contamination and a dominating {beta} background at theX-ray detector. Additionally, X-rays are attenuated by the material where the radioactive sample is implanted. To overcome these limitations, the technique of in-trap decay spectroscopy has been developed. In this work, the EBIT was connected to the TITAN beam line and has been commissioned. Using the developed beam diagnostics, ions were injected into the Penning trap and systematic studies on injection and storage optimization were performed. Furthermore, Ge

  16. Analysis of betaS and betaA genes in a Mexican population with African roots. (United States)

    Magaña, María Teresa; Ongay, Zoyla; Tagle, Juan; Bentura, Gilberto; Cobián, José G; Perea, F Javier; Casas-Castañeda, Maricela; Sánchez-López, Yoaly J; Ibarra, Bertha


    To investigate the origin of the beta(A) and beta(S) genes in a Mexican population with African roots and a high frequency of hemoglobin S, we analyzed 467 individuals (288 unrelated) from different towns in the states of Guerrero and Oaxaca in the Costa Chica region. The frequency of the sickle-cell trait was 12.8%, which may represent a public health problem. The frequencies of the beta-haplotypes were determined from 350 nonrelated chromosomes (313 beta(A) and 37 beta(S)). We observed 15 different beta(A) haplotypes, the most common of which were haplotypes 1 (48.9%), 2 (13.4%), and 3 (13.4%). The calculation of pairwise distributions and Nei's genetic distance analysis using 32 worldwide populations showed that the beta(A) genes are more closely related to those of Mexican Mestizos and North Africans. Bantu and Benin haplotypes and haplotype 9 were related to the beta(S) genes, with frequencies of 78.8, 18.2, and 3.0%, respectively. Comparison of these haplotypes with 17 other populations revealed a high similitude with the population of the Central African Republic. These data suggest distinct origins for the beta(A) and beta(S) genes in Mexican individuals from the Costa Chica region.

  17. Toxic Shock Syndrome (For Parents) (United States)

    ... Feeding Your 1- to 2-Year-Old Toxic Shock Syndrome KidsHealth > For Parents > Toxic Shock Syndrome Print ... en español Síndrome de shock tóxico About Toxic Shock Syndrome Toxic shock syndrome (TSS) is a serious ...

  18. Ideal MHD stability of very high beta tokamaks

    Energy Technology Data Exchange (ETDEWEB)

    Chance, M.S.; Jardin, S.C.; Kessel, C.; Manickam, J.; Monticello, D. (Princeton Univ., NJ (USA). Plasma Physics Lab.); Peng, Y.K.M.; Holmes, J.A.; Strickler, D.J.; Whitson, J.C. (Oak Ridge National Lab., TN (USA)); Glasser, A.H. (Los Alamos National Lab., NM (USA)); Sykes, A. (UKAEA Culham Lab., Abingdon (UK)); Ramos, J.J. (Massachusetts Inst. of Tech., Cambridge, MA (USA). Plasma Fusion Center)


    Achieving very high {beta} and high {beta}{sub p} simultaneously in tokamaks generally implies that the second stability region against ballooning modes must be accessed. We describe several approaches for doing this, which are characterized by the choice of constraints imposed on the equilibrium profiles and the cross-sectional shape of the plasma. The combination of high toroidal beta, restricting the current density to vanish at the edge of the plasma and maintaining a monotonic q profile, proves to be the most stringent. Consideration of equilibria with high {epsilon}{beta}{sub p} but low {beta} facilitates accessibility with peaked pressure profiles and high values of q{sub 0}. Allowing the pressure gradient and, hence, the current density to be finite at the plasma edge allows all surfaces to lie within the second stability regime. For free boundary plasmas with divertors, the divertor stabilized edge region remains in the first stability regime while the plasma core reaches into the second regime. Careful tailoring of the profiles must be used to traverse the unstable barrier commonly seen near the edge of these plasmas. The CAMINO code allows us to compute s-{alpha} curves for general tokamak geometry. These diagrams enable us to construct equilibria whose profiles are only constrained, at worst, to be marginally stable everywhere, but do not necessarily satisfy the constraints on the current or {beta}. There are theoretical indications that under certain conditions the external kinks possess a second region of stability at high q{sub 0} that is analogous to that of the ballooning modes. It is found that extremely accurate numerical means must be developed and applied to confidently establish the validity of these results. 14 refs., 5 figs., 1 tab.

  19. beta (+)-Thalassaemia in the Po river delta region (northern Italy): genotype and beta globin synthesis. (United States)

    Del Senno, L; Pirastu, M; Barbieri, R; Bernardi, F; Buzzoni, D; Marchetti, G; Perrotta, C; Vullo, C; Kan, Y W; Conconi, F


    Six beta(+)-thalassaemic patients from the Po river delta region have been studied. Using synthetic oligonucleotides as specific hybridisation probes, the beta(+) IVS I mutation (G----A at position 108) was demonstrated. This lesion and the enzyme polymorphism pattern in the subjects examined are the same as have been described for other Mediterranean beta(+)-thalassaemias. Antenatal diagnosis through DNA analysis of beta(+)-thalassaemia is therefore possible. The production of beta globin in a beta(+), homozygote and in a beta (+), beta(0) 39 (nonsense mutation at codon 39) double heterozygote is approximately 20% and 10% respectively of total non-alpha globin synthesis. Despite some overlapping of the results, similar beta globin synthesis levels have been obtained in 43 beta(+)-thalassaemia patients. This suggests that in the Po river delta region the most common thalassaemic genes are beta(0) 39 and beta(+) IVS I. Images PMID:2580095

  20. Biotransformation of Benzaldehyde to L-Phenylacetylcarbinol (L-PAC by Free Cells of Torulaspora delbrueckii in presence of Beta-Cyclodextrin

    Directory of Open Access Journals (Sweden)

    Vilas. B. Shukla


    Full Text Available Studies were carried out to explore the possibility of decreasing the toxic and inhibitory effects of the substrate benzaldehyde during its biotransformation to L-PAC by free cells of Torulaspora delbrueckii using beta -cyclodextrin (beta -CD. Use of various levels of benzaldehyde and acetaldehyde in presence of 2% of beta -CD showed that, in presence of beta -CD, the organism could tolerate higher levels of benzaldehyde and acetaldehyde. Semi-continuous feeding of benzaldehyde and acetaldehyde was found to increase the yield of L-PAC in comparison with one time feeding.

  1. Surviving streptococcal toxic shock syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Madhusudhan Thayur R


    Full Text Available Abstract Streptococcal toxic shock syndrome and associated myositis caused by group A beta-hemolytic streptococcus pyogenes generally have a poor outcome despite aggressive operative treatment. Frequently the diagnosis is missed initially as the clinical features are non-specific. The progression to a toxic state is rapid and unless definitive treatment measures are initiated early, the end result can be catastrophic. We report a previously healthy patient who had features of toxic shock syndrome due to alpha haemolytic (viridans streptococcus mitis which was treated successfully with antibiotics, aggressive intensive care support including the use of a 'sepsis care bundle', monitoring and continuous multidisciplinary review. Life and limb threatening emergencies due to streptococcus mitis in an immune-competent person are rare and to our knowledge, have not previously been described in the English scientific literature. Successful outcome is possible provided a high degree of suspicion is maintained and the patient is intensively monitored.

  2. Crystal Structure of Staphylococcal Enterotoxin G (SEG) in Complex with a Mouse T-cell Receptor Beta Chain

    Energy Technology Data Exchange (ETDEWEB)

    Fernandez, M.M.; Robinson, H.; Cho, S.; De Marzi, M. C.; Kerzic, M. C.; Mariuzza, R. A.; Malchiodi, E. L.


    Superantigens (SAgs) are bacterial or viral toxins that bind MHC class II (MHC-II) molecules and T-cell receptor (TCR) in a nonconventional manner, inducing T-cell activation that leads to inflammatory cytokine production, which may result in acute toxic shock. In addition, the emerging threat of purpura fulminans and community-associated meticillin-resistant Staphylococcus aureus emphasizes the importance of a better characterization of SAg binding to their natural ligands that may allow the development of reagents to neutralize their action. The three-dimensional structure of the complex between a mouse TCR {beta} chain (mV{beta}8.2) and staphylococcal enterotoxin G (SEG) at 2.0 {angstrom} resolution revealed a binding site that does not conserve the 'hot spots' present in mV{beta}8.2-SEC2, mV{beta}8.2-SEC3, mV{beta}8.2-SEB, and mV{beta}8.2-SPEA complexes. Analysis of the mV{beta}8.2-SEG interface allowed us to explain the higher affinity of this complex compared with the others, which may account for the early activation of T-cells bearing mV{beta}8.2 by SEG. This mode of interaction between SEG and mV{beta}8.2 could be an adaptive advantage to bestow on the pathogen a faster rate of colonization of the host.

  3. Smart Beta or Smart Alpha

    DEFF Research Database (Denmark)

    Winther, Kenneth Lillelund; Steenstrup, Søren Resen


    Smart beta has become the flavor of the decade in the investment world with its low fees, easy access to rewarded risk premiums, and appearance of providing good investment results relative to both traditional passive benchmarks and actively managed funds. Although we consider it well documented...... that smart beta investing probably will do better than passive market capitalization investing over time, we believe many are coming to a conclusion too quickly regarding active managers. Institutional investors are able to guide managers through benchmarks and risk frameworks toward the same well......-documented smart beta risk premiums and still motivate active managers to avoid value traps, too highly priced small caps, defensives, etc. By constructing the equity portfolios of active managers that resemble the most widely used risk premiums, we show that the returns and risk-adjusted returns measures...

  4. Psychostimulant toxicity in children

    Directory of Open Access Journals (Sweden)

    Ozalp Ekinci


    Full Text Available Methylphenidate is used for the treatment of attention deficit hyperactivity disorder in children above the age of 6 with a high safety and tolerability. When used above the recommended dosage, methylphenidate has been reported to cause toxicity symptoms including neuro-psychiatric and cardiac adverse reactions. In this overview paper, the available literature on psyhcostimulant toxicity in children and the clinical symptoms and follow-up of a 4-year-old child who accidentally used high dose of methylphenidate will be discussed. [Archives Medical Review Journal 2013; 22(2.000: 184-193

  5. Toxic and Metabolic Myelopathies. (United States)

    Ramalho, Joana; Nunes, Renato Hoffmann; da Rocha, Antonio José; Castillo, Mauricio


    Myelopathy describes any neurologic deficit related to the spinal cord. It is most commonly caused by its compression by neoplasms, degenerative disc disease, trauma, or infection. Less common causes of myelopathy include spinal cord tumors, infection, inflammatory, neurodegenerative, vascular, toxic, and metabolic disorders. Conditions affecting the spinal cord must be recognized as early as possible to prevent progression that may lead to permanent disability. Biopsy is rarely performed, thus the diagnosis and management rely on patient׳s history, physical examination, laboratory results, and imaging findings. Here we review the clinical presentations, pathophysiological mechanisms, and magnetic resonance imaging findings of myelopathies related to metabolic or toxic etiologies.

  6. The toxicity of refrigerants

    Energy Technology Data Exchange (ETDEWEB)

    Calm, J.M.


    This paper presents toxicity data and exposure limits for refrigerants. The data address both acute (short-term, single exposure) and chronic (long-term, repeated exposure) effects, with emphasis on the former. The refrigerants covered include those in common use for the last decade, those used as components in alternatives, and selected candidates for future replacements. The paper also reviews the toxicity indicators used in both safety standards and building, mechanical, and fire codes. It then outlines current classification methods for refrigerant safety and relates them to standard and code usage.

  7. The microbial oxidation of (-)-beta-pinene by Botrytis cinerea. (United States)

    Farooq, Afgan; Choudhary, M Iqbal; Tahara, Satoshi; Rahman, Atta-ur; Başer, K Hüsnü Can; Demirci, Fatih


    (-)-beta-pinene, a flavor and fragrance monoterpene is an important constituent of essential oils of many aromatic plants. It was oxidized by a plant-pathogenic fungus, Botrytis cinerea to afford four metabolites characterized as (-)-6a-hydroxy-beta-pinene, (-)-4beta,5beta-dihydroxy-beta-pinene, (-)-2beta,3beta-dihydroxypinane, and (-)-4beta-hydroxy-beta-pinene-6-one by detailed spectroscopic studies along with other known metabolites.

  8. Neutrinoless double beta decay experiments

    CERN Document Server

    Zuber, K


    The study of neutrinoless double beta decay is of outmost importance for neutrino physics. It is considered to be the gold plated channel to probe the fundamental character of neutrinos and to determine the neutrino mass. From the experimental point about nine different isotopes are explored for the search. After a general introduction follows a short discussion on nuclear matrix element calculations and supportive measurements. The current experimental status of double beta searches is presented followed by a short discussion of the ideas and proposals for large scale experiments.

  9. A {beta} - {gamma} coincidence; Metodo de coincidencias {beta} - {gamma}

    Energy Technology Data Exchange (ETDEWEB)

    Agullo, F.


    A {beta} - {gamma} coincidence method for absolute counting is given. The fundamental principles are revised and the experimental part is detailed. The results from {sup 1}98 Au irradiated in the JEN 1 Swimming pool reactor are given. The maximal accuracy is 1 per cent. (Author) 11 refs.

  10. Beta thalassaemia mutations in Turkish Cypriots. (United States)

    Sozuoz, A; Berkalp, A; Figus, A; Loi, A; Pirastu, M; Cao, A


    Using oligonucleotide hybridisation or restriction endonuclease analysis, we have characterised the molecular defect in 94 patients with thalassaemia major and four with thalassaemia intermedia of Turkish Cypriot descent. We found that four mutations, namely beta+ IVS-1 nt 110, beta zero IVS-1 nt, beta+ IVS-1 nt 6, and beta+ IVS-2 nt 745 were prevalent, accounting for 69.9%, 11.7%, 8.7%, and 5.6% respectively of the beta thalassaemia chromosomes. This information may help in the organisation of a large scale prevention programme based on fetal diagnosis of beta thalassaemia by DNA analysis in the Turkish population. PMID:3236356

  11. Experimental oral lead toxicity in young dogs

    Energy Technology Data Exchange (ETDEWEB)

    Stowe, H.D.; Goyer, R.A.; Krigman, M.M.; Wilson, M.; Cates, M.


    Litter-mate male pups were fed a calcium-and-phosphorus-low purified diet with and without 100 ppm of lead as lead acetate from age 6 to 18 weeks. Lead-toxic dogs exhibited cyclic but terminally severe anorexia and cachexia, significant anemia, normoblastocytosis and leukopenia within six weeks, hypoproteinemia, decreased serum albumin, ..cap alpha../sub 1/-globulin, ..beta../sub 2/-globulin, alkaline phosphatase and lactic dehydrogenase 1, elevated serum glutamic oxaloacetic and pyruvic transaminases, delayed closure of the thoracic vertebral epiphyses, lead lines in the distal radii and thoracic spinous processes, enlargement of liver, kidney, and brain, hepatic fatty metamorphosis, focal proximal renal tubular necrosis, hydropic degeneration of spermatognia, and lead inclusion body formation. Approximately 97% of the tissue lead was estimated to be skeletal; the greatest concentration of lead in the brain was found in the occipital gray matter.

  12. Copernicus revisited: amyloid beta in Alzheimer's disease. (United States)

    Joseph, J; Shukitt-Hale, B; Denisova, N A; Martin, A; Perry, G; Smith, M A


    The beta-amyloid hypothesis of Alzheimer's Disease (AD) has dominated the thinking and research in this area for over a decade and a half. While there has been a great deal of effort in attempting to prove its centrality in this devastating disease, and while an enormous amount has been learned about its properties (e.g., putative toxicity, processing and signaling), Abeta has not proven to be both necessary and sufficient for the development, neurotoxicity, and cognitive deficits associated with this disease. Instead, the few treatments that are available have emerged from aging research and are primarily directed toward modification of acetylcholine levels. Clearly, it is time to rethink this position and to propose instead that future approaches should focus upon altering the age-related sensitivity of the neuronal environment to insults involving such factors as inflammation and oxidative stress. In other words "solve the problems of aging and by extension those of AD will also be reduced." This review is being submitted as a rather Lutherian attempt to "nail an alternative thesis" to the gate of the Church of the Holy Amyloid to open its doors to the idea that aging is the most pervasive element in this disease and Abeta is merely one of the planets.

  13. Respiratory Toxicity Biomarkers (United States)

    The advancement in high throughput genomic, proteomic and metabolomic techniques have accelerated pace of lung biomarker discovery. A recent growth in the discovery of new lung toxicity/disease biomarkers have led to significant advances in our understanding of pathological proce...

  14. Nanomaterials and Retinal Toxicity (United States)

    The neuroretina should be considered as a potential site of nanomaterial toxicity. Engineered nanomaterials may reach the retina through three potential routes of exposure including; intra­ vitreal injection of therapeutics; blood-borne delivery in the retinal vasculature an...

  15. Beta Cell Workshop 2013 Kyoto

    DEFF Research Database (Denmark)

    Heller, R Scott; Madsen, Ole D; Nielsen, Jens Høiriis


    The very modern Kyoto International Conference Center provided the site for the 8th workshop on Beta cells on April 23-26, 2013. The preceding workshops were held in Boston, USA (1991); Kyoto, Japan (1994); Helsingør, Denmark (1997); Helsinki, Finland (2003); El Perello, Spain (2006); Peebles...

  16. Estimating $\\beta$-mixing coefficients

    CERN Document Server

    McDonald, Daniel J; Schervish, Mark


    The literature on statistical learning for time series assumes the asymptotic independence or ``mixing' of the data-generating process. These mixing assumptions are never tested, nor are there methods for estimating mixing rates from data. We give an estimator for the $\\beta$-mixing rate based on a single stationary sample path and show it is $L_1$-risk consistent.

  17. Beta-carotene as antioxidant

    NARCIS (Netherlands)

    Bast, A.; Plas, R.M. van der; Berg, H. van den; Haenen, G.R.M.M.


    Objective: Beta-carotene has been shown to exhibit a good radical-trapping antioxidant activity in vitro. We were interested to see if dietary β-carotene in combination with various intake levels for vitamin A would also inhibit lipid peroxidation. Design: Sixty male Wistar rats received vitamin A (

  18. Comparing toxic air pollutant programs

    Energy Technology Data Exchange (ETDEWEB)

    Hawkins, S.C. [ECKENFELDER Inc., Greenville, SC (United States)


    This article compares state and federal toxic air pollutant programs. The Clean Air Act Ammendments created a program for the control of Hazardous Air Pollutants based on the establishment of control technology standards. State toxic programs can be classified into two categories: control technology-based and ambient concentration-based. Many states have opened to implement the MACT standards while enforcing their own state air toxics programs. Specific topics discussed include the following: the Federal air toxics program; existing state regulations; New Jersey Air Toxic Program; New York Toxics program.

  19. Comparison of toxicity neutralization-, ELISA- and PCR tests for typing of Clostridium perfringens and detection of the enterotoxin gene by PCR

    DEFF Research Database (Denmark)

    Møller, Kristian; Ahrens, Peter


    ability to detect the or toxin, the lecithinase test and PCR test (PCR(alpha)) concordantly detected the ct toxin and the alpha toxin gene, respectively. A monoclonal enzyme linked immunosorbent assay (ELISA) and a PCR(beta) test were compared and were in accordance for the detection of the beta toxin......A polymerase chain reaction (PCR) was developed for the specific amplification of a part of each of the five Clostridium perfringens toxin genes: alpha (alpha), beta (beta), epsilon (epsilon), iota (iota), and enterotoxin (CPE). While the toxicity neutralization test (TNT) only showed limited...... (gene) from pure and mixed cultures from piglets suffering from necrotizing enteritis. However, the PCR(beta) test was superior to the ELISA for detection of the beta toxin (gene) in necrotic intestinal mucosa without culturing. An internal standard to be co-amplified with the beta toxin gene...

  20. Neutron Beta Decay Studies with Nab

    CERN Document Server

    Baeßler, S; Alonzi, L P; Balascuta, S; Barrón-Palos, L; Bowman, J D; Bychkov, M A; Byrne, J; Calarco, J R; Chupp, T; Vianciolo, T V; Crawford, C; Frlež, E; Gericke, M T; Glück, F; Greene, G L; Grzywacz, R K; Gudkov, V; Harrison, D; Hersman, F W; Ito, T; Makela, M; Martin, J; McGaughey, P L; McGovern, S; Page, S; Penttilä, S I; Počanić, D; Rykaczewski, K P; Salas-Bacci, A; Tompkins, Z; Wagner, D; Wilburn, W S; Young, A R


    Precision measurements in neutron beta decay serve to determine the coupling constants of beta decay and allow for several stringent tests of the standard model. This paper discusses the design and the expected performance of the Nab spectrometer.

  1. Dynamic Hysteresis Probes High-{\\beta} Nanolaser Emission Regimes

    CERN Document Server

    Pan, Si Hui; Amili, Abdelkrim El; Vallini, Felipe; Fainman, Yeshaiahu


    The quest for an integrated light source that promises high energy efficiency and fast modulation for high-performance photonic circuits has led to the development of room-temperature telecom-wavelength nanoscale laser with high spontaneous emission factors, \\beta. The coherence characterization of this type of lasers is inherently difficult with the conventional measurement of output light intensity versus input pump intensity due to the diminishing kink in the measurement curve. We demonstrate the transition from chaotic to coherent emission of a high-{\\beta} pulse-pump metallo-dielectric nanolaser can be determined by examining the width of a second order intensity correlation peak, which shrinks below and broadens above threshold. Photon fluctuation study, first one ever reported for this type of nanolaser, confirms the validity of this measurement technique. Additionally, we show that the width variation above threshold results from the delayed threshold phenomenon, providing the first indirect observati...

  2. Decoding Beta-Decay Systematics: A Global Statistical Model for Beta^- Halflives

    CERN Document Server

    Costiris, N J; Gernoth, K A; Clark, J W


    Statistical modeling of nuclear data provides a novel approach to nuclear systematics complementary to established theoretical and phenomenological approaches based on quantum theory. Continuing previous studies in which global statistical modeling is pursued within the general framework of machine learning theory, we implement advances in training algorithms designed to improved generalization, in application to the problem of reproducing and predicting the halflives of nuclear ground states that decay 100% by the beta^- mode. More specifically, fully-connected, multilayer feedforward artificial neural network models are developed using the Levenberg-Marquardt optimization algorithm together with Bayesian regularization and cross-validation. The predictive performance of models emerging from extensive computer experiments is compared with that of traditional microscopic and phenomenological models as well as with the performance of other learning systems, including earlier neural network models as well as th...

  3. Key residues for the oligomerization of A{beta}42 protein in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Ngo, Sam [Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA 90095 (United States); Guo, Zhefeng, E-mail: [Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA 90095 (United States)


    Highlights: Black-Right-Pointing-Pointer A{beta} oligomers are neurotoxins and likely the causing agents for Alzheimer's disease. Black-Right-Pointing-Pointer A{beta}42 fusion protein form globular oligomers. Black-Right-Pointing-Pointer A{beta}42 fusion protein oligomers contain SDS-resistant tetramers and hexamers. Black-Right-Pointing-Pointer Cysteine substitutions at residues 31, 32, 34, 39-41 disrupt A{beta}42 oligomerization. -- Abstract: Deposition of amyloid fibrils consisting of amyloid {beta} (A{beta}) protein as senile plaques in the brain is a pathological hallmark of Alzheimer's disease. However, a growing body of evidence shows that soluble A{beta} oligomers correlate better with dementia than fibrils, suggesting that A{beta} oligomers may be the primary toxic species. The structure and oligomerization mechanism of these A{beta} oligomers are crucial for developing effective therapeutics. Here we investigated the oligomerization of A{beta}42 in the context of a fusion protein containing GroES and ubiquitin fused to the N-terminus of A{beta} sequence. The presence of fusion protein partners, in combination with a denaturing buffer containing 8 M urea at pH 10, is unfavorable for A{beta}42 aggregation, thus allowing only the most stable structures to be observed. Transmission electron microscopy showed that A{beta}42 fusion protein formed globular oligomers, which bound weakly to thioflavin T and Congo red. SDS-PAGE shows that A{beta}42 fusion protein formed SDS-resistant hexamers and tetramers. In contrast, A{beta}40 fusion protein remained as monomers on SDS gel, suggesting that the oligomerization of A{beta}42 fusion protein is not due to the fusion protein partners. Cysteine scanning mutagenesis at 22 residue positions further revealed that single cysteine substitutions of the C-terminal hydrophobic residues (I31, I32, L34, V39, V40, and I41) led to disruption of hexamer and tetramer formation, suggesting that hydrophobic interactions

  4. A Simulation Model of Periarterial Clearance of Amyloid-beta from the Brain

    Directory of Open Access Journals (Sweden)

    Alexandra Katharina Diem


    Full Text Available The accumulation of soluble and insoluble amyloid-beta (A-beta in the brain indicates failure of elimination of A-beta from the brain with age and Alzheimer's disease. There is a variety of mechanisms for elimination of A-beta from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of A-beta into the blood and periarterial lymphatic drainage of A-beta. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as A-beta, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of A-beta in the walls of human arteries with age and Alzheimer's disease as cerebral amyloid angiopathy (CAA. Initially, A-beta diffuses through the extracellular spaces of grey matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterised, the exact mechanism whereby perivascular elimination of A-beta occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy.

  5. The beta-decay of Al-22

    NARCIS (Netherlands)

    Achouri, NL; Santos, FDO; Lewitowicz, M; Blank, B; Aysto, J; Canchel, G; Czajkowski, S; Dendooven, P; Emsallem, A; Giovinazzo, J; Guillet, N; Jokinen, A; Larid, AM; Longour, C; Perajarvi, K; Smirnova, N; Stanoiu, M


    In an experiment performed at the LISE3 facility of GANIL, we studied the decay of Al-22 produced by the fragmentation of a Ar-36 primary beam. A beta-decay half-life of T-1/2 = 91.1 +/- 0.5ms was measured. The beta-delayed one- and two-proton emission as well as beta-alpha and beta-delayed gamma-de

  6. Traumatic Brain Injury, Microglia, and Beta Amyloid


    Mannix, Rebekah C.; Whalen, Michael J


    Recently, there has been growing interest in the association between traumatic brain injury (TBI) and Alzheimer's Disease (AD). TBI and AD share many pathologic features including chronic inflammation and the accumulation of beta amyloid (A\\(\\beta\\)). Data from both AD and TBI studies suggest that microglia play a central role in A\\(\\beta\\) accumulation after TBI. This paper focuses on the current research on the role of microglia response to A\\(\\beta\\) after TBI.

  7. Ranking of aquatic toxicity of esters modelled by QSAR. (United States)

    Papa, Ester; Battaini, Francesca; Gramatica, Paola


    Alternative methods like predictions based on Quantitative Structure-Activity Relationships (QSARs) are now accepted to fill data gaps and define priority lists for more expensive and time consuming assessments. A heterogeneous data set of 74 esters was studied for their aquatic toxicity, and available experimental toxicity data on algae, Daphnia and fish were used to develop statistically validated QSAR models, obtained using multiple linear regression (MLR) by the OLS (Ordinary Least Squares) method and GA-VSS (Variable Subset Selection by Genetic Algorithms) to predict missing values. An ESter Aquatic Toxicity INdex (ESATIN) was then obtained by combining, by PCA, experimental and predicted toxicity data, from which model outliers and esters highly influential due to their structure had been eliminated. Finally this integrated aquatic toxicity index, defined by the PC1 score, was modelled using only a few theoretical molecular descriptors. This last QSAR model, statistically validated for its predictive power, could be proposed as a preliminary evaluative method for screening/prioritising esters according to their integrated aquatic toxicity, just starting from their molecular structure.


    NARCIS (Netherlands)



    We have identified a new protein fold-the alpha/beta-hydrolase fold-that is common to several hydrolytic enzymes of widely differing phylogenetic origin and catalytic function. The core of each enzyme is similar: an alpha/beta-sheet, not barrel, of eight beta-sheets connected by alpha-helices. These

  9. Beta-lactamases in Enterobacteriaceae in broilers

    NARCIS (Netherlands)

    Dierikx, C.M.


    Resistance to cephalosprins due to the production of extended spectrum beta-lactamases (ESBLs) or plasmid mediated AmpC beta-lactamases is increasingly found in infections in humans outside the hospital. The genes encoding for these beta-lactamases are located on mobile DNA (plasmids), which can be

  10. Higher-Order Beta Matching with Solutions in Long Beta-Eta Normal Form

    DEFF Research Database (Denmark)

    Støvring, Kristian


    up to beta-eta equivalence is a long-standing open problem.We show that higher-order matching up to beta-eta equivalence is decidable if and only if a restricted form of higher-order matching up to beta equivalence is decidable: the restriction is that solutions must be in long beta-eta normal form....

  11. Predictive Modeling of Developmental Toxicity (United States)

    The use of alternative methods in conjunction with traditional in vivo developmental toxicity testing has the potential to (1) reduce cost and increase throughput of testing the chemical universe, (2) prioritize chemicals for further targeted toxicity testing and risk assessment,...

  12. Early and continuing effects of combined alpha and beta irradiation of the lung:

    Energy Technology Data Exchange (ETDEWEB)

    Scott, B.R.; Hahn, F.F.; Snipes, M.B.; Newton, G.J.; Eidson, A.F.; Mauderly, J.L.; Boecker, B.B.


    This report summarizes an inhalation exposure experiment that concerns early and continuing effects of combined alpha and beta irradiation of the lung of rats. Both morbidity at 18 months and mortality within 18 months after exposure were examined for rats exposed to the beta-emitter /sup 147/Pm, the alpha-emitter /sup 238/Pu, or both combined. The results were used to validate hazard-function models that were developed (1)for pulmonary functional morbidity at 18 months and (2) for lethality from radiation pneumonitis and pulmonary fibrosis within 18 months. Both models were found to adequately predict the experimental observations after combined chronic alpha and beta irradiation of the lung. A relative biological effectiveness of approximately 7 was obtained for /sup 238/Pu alpha radiation compared to /sup 147/Pm beta radiation for both pulmonary functional morbidity and lethality from radiation pneumonitis and pulmonary fibrosis. 12 refs., 16 figs., 11 tabs.

  13. Selective extinction drives taxonomic and functional alpha and beta diversities in island bird assemblages. (United States)

    Si, Xingfeng; Baselga, Andrés; Leprieur, Fabien; Song, Xiao; Ding, Ping


    observed values of correlations were significantly different from null expectations of random extinction. Our assessment of island bird assemblages validated the predictions of no distance effects and low beta diversity due to pervasive dispersal events among islands and also suggested that selective extinction drives taxonomic and functional alpha and beta diversities. The contrasting turnover and nestedness-resultant components of taxonomic and functional beta diversities demonstrate the importance of considering the multifaceted nature of biodiversity when examining community assembly.

  14. Damage Theory Validation

    DEFF Research Database (Denmark)

    Simonsen, Bo Cerup


    This report contains a series of validation examples for the theoretical model implemented in the computer program DAMAGE. note that the validation examples are for assembled structures.......This report contains a series of validation examples for the theoretical model implemented in the computer program DAMAGE. note that the validation examples are for assembled structures....

  15. Olfactory toxicity in fishes. (United States)

    Tierney, Keith B; Baldwin, David H; Hara, Toshiaki J; Ross, Peter S; Scholz, Nathaniel L; Kennedy, Christopher J


    Olfaction conveys critical environmental information to fishes, enabling activities such as mating, locating food, discriminating kin, avoiding predators and homing. All of these behaviors can be impaired or lost as a result of exposure to toxic contaminants in surface waters. Historically, teleost olfaction studies have focused on behavioral responses to anthropogenic contaminants (e.g., avoidance). More recently, there has been a shift towards understanding the underlying mechanisms and functional significance of contaminant-mediated changes in fish olfaction. This includes a consideration of how contaminants affect the olfactory nervous system and, by extension, the downstream physiological and behavioral processes that together comprise a normal response to naturally occurring stimuli (e.g., reproductive priming or releasing pheromones). Numerous studies spanning several species have shown that ecologically relevant exposures to common pollutants such as metals and pesticides can interfere with fish olfaction and disrupt life history processes that determine individual survival and reproductive success. This represents one of the pathways by which toxic chemicals in aquatic habitats may increasingly contribute to the decline and at-risk status of many commercially and ecologically important fish stocks. Despite our emerging understanding of the threats that pollution poses for chemical communication in aquatic communities, many research challenges remain. These include: (1) the determination of specific mechanisms of toxicity in the fish olfactory sensory epithelium; (2) an understanding of the impacts of complex chemical mixtures; (3) the capacity to assess olfactory toxicity in fish in situ; (4) the impacts of toxins on olfactory-mediated behaviors that are still poorly understood for many fish species; and (5) the connections between sublethal effects on individual fish and the long-term viability of wild populations. This review summarizes and integrates

  16. Toxic Substances Control Act

    Energy Technology Data Exchange (ETDEWEB)


    This Reference Book contains a current copy of the Toxic Substances Control Act and those regulations that implement the statute and appear to be most relevant to DOE activities. The document is provided to DOE and contractor staff for informational purposes only and should not be interpreted as legal guidance. Questions concerning this Reference Book may be directed to Mark Petts, EH-231 (202/586-2609).

  17. Dopamine transporter binding in rat striatum: a comparison of [O-methyl-{sup 11}C]{beta}-CFT and [N-methyl-{sup 11}C]{beta}-CFT

    Energy Technology Data Exchange (ETDEWEB)

    Yoder, Karmen K.; Hutchins, Gary D.; Mock, Bruce H.; Fei, Xiangshu; Winkle, Wendy L. [Department of Radiology, Indiana University School of Medicine, L3-208, Indianapolis, IN 46202 (United States); Gitter, Bruce D.; Territo, Paul R. [Lilly Center for Anatomical and Molecular Imaging, Integrative Biology Division, Lilly Research Laboratories, Greenfield, IN 46140 (United States); Zheng Qihuang [Department of Radiology, Indiana University School of Medicine, L3-208, Indianapolis, IN 46202 (United States)], E-mail:


    Introduction: Positron emission tomography scanning with radiolabeled phenyltropane cocaine analogs is important for quantifying the in vivo density of monoamine transporters, including the dopamine transporter (DAT). [{sup 11}C]{beta}-CFT is useful for studying DAT as a marker of dopaminergic innervation in animal models of psychiatric and neurological disorders. [{sup 11}C]{beta}-CFT is commonly labeled at the N-methyl position. However, labeling of [{sup 11}C]{beta}-CFT at the O-methyl position is a simpler procedure and results in a shorter synthesis time [desirable in small-animal studies, where specific activity (SA) is crucial]. In this study, we sought to validate that the O-methylated form of [{sup 11}C]{beta}-CFT provides equivalent quantitative results to that of the more commonly reported N-methyl form. Methods: Four female Sprague-Dawley rats were scanned twice on the IndyPET II small-animal scanner, once with [N-methyl-{sup 11}C]{beta}-CFT and once with [O-methyl-{sup 11}C]{beta}-CFT. DAT binding potentials (BP{identical_to}B'{sub avail}/K{sub d}) were estimated for right and left striata with a nonlinear least-squares algorithm, using a reference region (cerebellum) as the input function. Results: [N-Methyl-{sup 11}C]{beta}-CFT and [O-methyl-{sup 11}C]{beta}-CFT were synthesized with 40-50% radiochemical yields (HPLC purification). Radiochemical purity was >99%. SA at end of bombardment was 258{+-}30 GBq/{mu}mol. Average BP values for right and left striata with [N-methyl-{sup 11}C]{beta}-CFT were 1.16{+-}0.08 and 1.23{+-}0.14, respectively. BP values for [O-methyl-{sup 11}C]{beta}-CFT were 1.18{+-}0.08 (right) and 1.22{+-}0.16 (left). Paired t tests demonstrated that labeling position did not affect striatal DAT BP. Conclusions: These results suggest that [O-methyl-{sup 11}C]{beta}-CFT is quantitatively equivalent to [N-methyl-{sup 11}C]{beta}-CFT in the rat striatum.

  18. Invasieve infecties door beta-haemolytische Streptokokken Lancefield Groep A (Streptococcus pyogenes, GAS) in Nederland, 1992-1993

    NARCIS (Netherlands)

    Schellekens JFP; Schouls LM; van Silfhout A; Elzenaar CP; Brunings HA; Blokpoel MCJ; Top J; van Leeuwen WJ; LBA; MMB


    In recent years an increase of severe invasive infections and toxic shock syndrome (TSS) with beta-haemolytic Group A streptococci (Streptococcus pyogenes, GAS) has been reported from North-America and North-Western Europe. In the spring of 1992 several reports of cases suggested that this epidemic

  19. Separations chemistry of toxic metals

    Energy Technology Data Exchange (ETDEWEB)

    Smith, P.; Barr, M.; Barrans, R. [and others


    Sequestering and removing toxic metal ions from their surroundings is an increasingly active area of research and is gaining importance in light of current environmental contamination problems both within the DOE complex and externally. One method of separating metal ions is to complex them to a molecule (a ligand or chelator) which exhibits specific binding affinity for a toxic metal, even in the presence of other more benign metals. This approach makes use of the sometimes subtle differences between toxic and non-toxic metals resulting from variations in size, charge and shape. For example, toxic metals such as chromium, arsenic, and technetium exist in the environment as oxyanions, negatively charged species with a characteristic tetrahedral shape. Other toxic metals such as actinides and heavy metals are positively charged spheres with specific affinities for particular donor atoms such as oxygen (for actinides) and nitrogen (for heavy metals). In most cases the toxic metals are found in the presence of much larger quantities of less toxic metals such as sodium, calcium and iron. The selectivity of the chelators is critical to the goal of removing the toxic metals from their less toxic counterparts. The approach was to build a ligand framework that complements the unique characteristics of the toxic metal (size, charge and shape) while minimizing interactions with non-toxic metals. The authors have designed ligands exhibiting specificity for the target metals; they have synthesized, characterized and tested these ligands; and they have shown that they exhibit the proposed selectivity and cooperative binding effects.

  20. Lung inflammation caused by inhaled toxicants: a review

    Directory of Open Access Journals (Sweden)

    Wong J


    Full Text Available John Wong, Bruce E Magun, Lisa J Wood School of Nursing, MGH Institute of Health Professions, Boston, MA, USA Abstract: Exposure of the lungs to airborne toxicants from different sources in the environment may lead to acute and chronic pulmonary or even systemic inflammation. Cigarette smoke is the leading cause of chronic obstructive pulmonary disease, although wood smoke in urban areas of underdeveloped countries is now recognized as a leading cause of respiratory disease. Mycotoxins from fungal spores pose an occupational risk for respiratory illness and also present a health hazard to those living in damp buildings. Microscopic airborne particulates of asbestos and silica (from building materials and those of heavy metals (from paint are additional sources of indoor air pollution that contributes to respiratory illness and is known to cause respiratory illness in experimental animals. Ricin in aerosolized form is a potential bioweapon that is extremely toxic yet relatively easy to produce. Although the aforementioned agents belong to different classes of toxic chemicals, their pathogenicity is similar. They induce the recruitment and activation of macrophages, activation of mitogen-activated protein kinases, inhibition of protein synthesis, and production of interleukin-1 beta. Targeting either macrophages (using nanoparticles or the production of interleukin-1 beta (using inhibitors against protein kinases, NOD-like receptor protein-3, or P2X7 may potentially be employed to treat these types of lung inflammation without affecting the natural immune response to bacterial infections. Keywords: cigarette, mycotoxin, trichothecene, ricin, inflammasome, macrophage, inhibitors

  1. beta (+)-Thalassaemia in the Po river delta region (northern Italy): genotype and beta globin synthesis.


    del Senno, L; Pirastu, M; Barbieri, R.; De Bernardi, F.; Buzzoni, D; Marchetti, G.; Perrotta, C; Vullo, C; Kan, Y W; Conconi, F


    Six beta(+)-thalassaemic patients from the Po river delta region have been studied. Using synthetic oligonucleotides as specific hybridisation probes, the beta(+) IVS I mutation (G----A at position 108) was demonstrated. This lesion and the enzyme polymorphism pattern in the subjects examined are the same as have been described for other Mediterranean beta(+)-thalassaemias. Antenatal diagnosis through DNA analysis of beta(+)-thalassaemia is therefore possible. The production of beta globin in...

  2. Comment on "Closing the neutrinoless double beta decay window into VEP and/or VLI"

    CERN Document Server

    Klapdor-Kleingrothaus, H V; Sarkar, U


    The constraints from the non-observation of neutrinoless double beta decay onthe violations of Lorentz invariance (VLI) or violations of the equivalenceprinciple (VEP) have recently been re-examined and it was claimed that theconstraints are not valid. In this reply we point out that this statement isnot correct and prove that the arguments given are wrong.

  3. Nanoparticle toxicity and cancer (United States)

    Prevenslik, T.


    Nanoparticles (NPs) have provided significant advancements in cancer treatment. But as in any technology, there is a darkside. Experiments have shown NPs in body fluids pose a health risk by causing DNA damage that in of itself may lead to cancer. To avoid the dilemma that NPs are toxic to both cancer cells and DNA alike, the mechanism of NP toxicity must be understood so that the safe use of NPs may go forward. Reactive oxidative species (ROS) of peroxide and hydroxyl radicals damage the DNA by chemical reaction, but require NPs provide energies of about 5 eV not possible by surface effects. Only electromagnetic (EM) radiations beyond ultraviolet (UV) levels may explain the toxicity of NPs. Indeed, experiments show DNA damage from radiation, Hence, it is reasonable to hypothesize that NPs produce their own source of UV radiation, albeit at low intensity. Ionizing radiation from NPs at UV levels is consistent with the theory of QED induced EM radiation. QED stands for quantum electrodynamics. By this theory, fine radiation need not be limited to natural or man-made NPs. Extensions suggest UV radiation is produced from biological NPs within the body, e.g., enzyme induced fragmentation of epithelial tissue, exocytosis of small proteins, and ironically, the same molecular markers used to detect cancer itself.

  4. The toxicity of methanol

    Energy Technology Data Exchange (ETDEWEB)

    Tephly, T.R. (Univ. of Iowa, Iowa City (USA))


    Methanol toxicity in humans and monkeys is characterized by a latent period of many hours followed by a metabolic acidosis and ocular toxicity. This is not observed in most lower animals. The metabolic acidosis and blindness is apparently due to formic acid accumulation in humans and monkeys, a feature not seen in lower animals. The accumulation of formate is due to a deficiency in formate metabolism which is, in turn, related, in part, to low hepatic tetrahydrofolate (H{sub 4}folate). An excellent correlation between hepatic H{sub 4} folate and formate oxidation rates has been shown within and across species. Thus, humans and monkeys possess low hepatic H{sub 4}folate levels, low rates of formate oxidation and accumulation of formate after methanol. Formate, itself, produces blindness in monkeys in the absence of metabolic acidosis. In addition to low hepatic H{sub 4}folate concentrations, monkeys and humans also have low hepatic 10-formyl H{sub 4}folate dehydrogenase levels, the enzyme which is the ultimate catalyst for conversion of formate to carbon dioxide. This review presents the basis for the role of folic acid-dependent reactions in the regulation of methanol toxicity.

  5. Comparative metal oxide nanoparticle toxicity using embryonic zebrafish

    Directory of Open Access Journals (Sweden)

    Leah C. Wehmas


    Full Text Available Engineered metal oxide nanoparticles (MO NPs are finding increasing utility in the medical field as anticancer agents. Before validation of in vivo anticancer efficacy can occur, a better understanding of whole-animal toxicity is required. We compared the toxicity of seven widely used semiconductor MO NPs made from zinc oxide (ZnO, titanium dioxide, cerium dioxide and tin dioxide prepared in pure water and in synthetic seawater using a five-day embryonic zebrafish assay. We hypothesized that the toxicity of these engineered MO NPs would depend on physicochemical properties. Significant agglomeration of MO NPs in aqueous solutions is common making it challenging to associate NP characteristics such as size and charge with toxicity. However, data from our agglomerated MO NPs suggests that the elemental composition and dissolution potential are major drivers of toxicity. Only ZnO caused significant adverse effects of all MO particles tested, and only when prepared in pure water (point estimate median lethal concentration = 3.5–9.1 mg/L. This toxicity was life stage dependent. The 24 h toxicity increased greatly (∼22.7 fold when zebrafish exposures started at the larval life stage compared to the 24 h toxicity following embryonic exposure. Investigation into whether dissolution could account for ZnO toxicity revealed high levels of zinc ion (40–89% of total sample were generated. Exposure to zinc ion equivalents revealed dissolved Zn2+ may be a major contributor to ZnO toxicity.

  6. First secondary metabolites from Herissantia crispa L (Brizicky) and the toxicity activity against Artemia salina Leach

    Energy Technology Data Exchange (ETDEWEB)

    Costa, Danielly Albuquerque da; Matias, Wemerson Neves; Lima, Igara Oliveira; Xavier, Aline Lira; Costa, Vivian Bruna Machado; Diniz, Margareth de Fatima Formiga Melo; Agra, Maria de Fatima; Batista, Leonia Maria; Souza, Maria de Fatima Vanderlei de [Universidade Federal da Paraiba (UFPB), Joao Pessoa, PB (Brazil). Lab. de Tecnologia Farmaceutica Prof. Delby Fernandes de Medeiros; Silva, Davi Antas e [Universidade Federal Rural de Pernambuco, Serra Talhada, PE (Brazil). Dept. de Quimica


    The phytochemical investigation of Herissantia crispa led to the isolation of seven compounds, identified as: sitosterol 3-O-{beta}-D-glucopyranoside, stigmasterol 3-O-{beta}-D-glucopyranoside, 3,5,7,4'-tetrahydroxyflavone (kaempferol), 3,5,7,3',4'-pentahydroxyflavone (quercetin), unpublished in the genus Herissantia, besides {beta}-sitosterol, kaempferol 3-O-{beta}-D-(6''-E-p-coumaroil) (tiliroside) glucopyranoside and kaempferol 3,7-di-O-{alpha}-L-ramnopyranoside (lespedin), described for the first time in the species. The structural determination of the compounds was made by means of spectroscopy methods such as Infrared Spectroscopy, {sup 1}H and {sup 13}C Nuclear Magnetic Resonance, with the aid of two dimensional techniques, and by comparison with literature data. The toxicity activity of the MeOH extract and lespedin on Artemia salina Leach. was also carried out. (author)

  7. Specific Triazine Herbicides Induce Amyloid-beta(42) Production

    NARCIS (Netherlands)

    Portelius, Erik; Durieu, Emilie; Bodin, Marion; Cam, Morgane; Pannee, Josef; Leuxe, Charlotte; Mabondzo, Aloise; Oumata, Nassima; Galons, Herve; Lee, Jung Yeol; Chang, Young-Tae; Stuber, Kathrin; Koch, Philipp; Fontaine, Gaelle; Potier, Marie-Claude; Manousopoulou, Antigoni; Garbis, Spiros D.; Covaci, Adrian; Van Dam, Debby; De Deyn, Peter; Karg, Frank; Flajolet, Marc; Omori, Chiori; Hata, Saori; Suzuki, Toshiharu; Blennow, Kaj; Zetterberg, Henrik; Meijer, Laurent


    Proteolytic cleavage of the amyloid-beta protein precursor (A beta PP) ecretases leads to extracellular release of amyloid-beta (A beta) peptides. Increased production of A beta(42) over A beta(40) and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark. Identifyin

  8. Modern toxic antipersonnel projectiles. (United States)

    Gaillard, Yvan; Regenstreif, Philippe; Fanton, Laurent


    In the spring of 1944, Kurt von Gottberg, the SS police chief in Minsk, was shot and injured by 2 Soviet agents. Although he was only slightly injured, he died 6 hours later. The bullets were hollow and contained a crystalline white powder. They were 4-g bullets, semi-jacketed in cupronickel, containing 28 mg of aconitine. They were later known as akonitinnitratgeschosse. The Sipo (the Nazi security police) then ordered a trial with a 9-mm Parabellum cartridge containing Ditran, an anticholinergic drug with hallucinogenic properties causing intense mental confusion. In later years, QNB was used and given the NATO code BZ (3-quinuclidinyl-benzylate). It was proven that Saddam Hussein had this weapon (agent 15) manufactured and used it against the Kurds. Serbian forces used the same type of weapon in the Bosnian conflict, particularly in Srebrenica.The authors go on to list the Cold War toxic weapons developed by the KGB and the Warsaw pact countries for the discreet elimination of dissidents and proindependence leaders who had taken refuge in the West. These weapons include PSZh-13 launchers, the Troika electronic sequential pistol, and the ingenious 4-S110T captive piston system designed by the engineer Stechkin. Disguised as a cigarette case, it could fire a silent charge of potassium cyanide. This rogues gallery also includes the umbrella rigged to inject a pellet of ricin (or another phytalbumin of similar toxicity, such as abrin or crotin) that was used to assassinate the Bulgarian writer and journalist Georgi Markov on September 7, 1978, in London.During the autopsy, the discovery of a bullet burst into 4 or 5 parts has to make at once suspecting the use of a toxic substance. Toxicological analysis has to look for first and foremost aconitine, cyanide, suxamethonium, Ditran, BZ, or one of the toxic phytalbumins. The use of such complex weapons has to make suspect a powerful organization: army, secret service, terrorism. The existence of the Russian UDAR spray

  9. Future double beta decay experiments

    Energy Technology Data Exchange (ETDEWEB)

    Piquemal, F. [Laboratoire Souterrain de Modane, Modane (France); Centre d' Etudes Nucleaire, Bordeaux-Gradignan (France)


    The search of neutrinoless double beta decay is very challenging because of the expected half-life of the process and the backgrounds from the natural radioactivity. Many projects exist to try to reach a sensitivity of ∼50 meV on the effective neutrino mass corresponding to a mass of isotopes of ∼100 kg. In this article some of the futur projects are presented.

  10. Stochastic and coherent dynamics of single and coupled beta cells

    DEFF Research Database (Denmark)

    phenomenon, modeled by a slow-fast nonlinear system of ordinary differential equations (ODEs). The single cell oscillations are complex as the dynamical behavior is a result of traversing a series of saddle node and homoclinic bifurcations, controlled by the slow variable. We shall present results...... is the simplest reaction-diffusion partial differential equation....... on the burst period as function of an external applied stochastic term and use a technique for reducing the stochastic differential equations to ODEs for the average and higher order moments. The later method is approximate and we shall discuss the limits of validity. The individual beta cells are coupled...

  11. Review of Quantitative Structure - Activity Relationships for Acute Mammalian Toxicity

    Directory of Open Access Journals (Sweden)

    Iglika Lessigiarska


    Full Text Available This paper reviews Quantitative Structure-Activity Relationship (QSAR models for acute mammalian toxicity published in the last decade. A number of QSAR models based on cytotoxicity data from mammalian cell lines are also included because of their possible use as a surrogate system for predicting acute toxicity to mammals. On the basis of the review, the following conclusions can be made: i a relatively small number of models for in vivo toxicity are published in the literature. This is due to the nature of the endpoint - acute systemic toxicity is usually related to whole body phenomena and therefore is very complex. The complexity of the mechanisms involved leads to difficulties in the QSAR modelling; ii most QSAR models identify hydrophobicity as a parameter of high importance for the modelled toxicity. In addition, many models indicate the role of the electronic and steric effects; iii most of the literature-based models are restricted to single chemical classes. Models based on more heterogeneous data sets are those incorporated in expert systems. In general, the QSAR models for mammalian toxicity identified in this review are considered useful for investigating the mechanisms of toxicity of defined chemical classes. However, for predictive purposes in the regulatory assessment of chemicals most of the models require additional information to satisfy internationally agreed validation principles. In addition, the development of new models covering larger chemical domains would be useful for the regulatory assessment of chemicals.

  12. Myokardinfarkt und Beta-Blocker

    Directory of Open Access Journals (Sweden)

    Stühlinger H-G


    Full Text Available Im Rahmen eines akuten koronaren Syndroms (akuter Herzinfarkt, Angina pectoris kommt es, aufgrund eines Ungleichgewichtes zwischen Angebot und Bedarf, zu einem akuten Mangel an Sauerstoff im Herzmuskel. Ursache ist eine reduzierte Sauerstoffzufuhr durch verengte bzw. verschlossene Gefäße. Bis zur Behebung der Ursache vergehen oft mehrere Stunden. In dieser Phase muß - durch Verminderung des Sauerstoffbedarfs im Herzmuskel - eine Verlangsamung der Nekroseentwicklung erreicht werden. Das Ausmaß der Nekrose wird reduziert, somit die für die Langzeitprognose wichtige Linksventrikelfunktion verbessert. Eine Verminderung des Sauerstoffbedarfs erreicht man durch kontrollierte Frequenzsenkung mittels intravenöser Beta-Blockade. In optimaler Weise wird diese Methode durch die Anwendung eines kardioselektiven Beta-Blockers mit kurzer Halbwertszeit durchgeführt. Beta-Blocker haben nicht nur auf die Nekroseentwicklung, sondern auch auf die Inzidenz von Rhythmusstörungen - besonders in der Akutphase - Auswirkungen. Vor allem die mit dieser therapeutischen Maßnahme verbundene Reduktion von Kammerflimmern ist von großer Bedeutung.

  13. Size-dependent neurotoxicity of beta-amyloid oligomers. (United States)

    Cizas, Paulius; Budvytyte, Rima; Morkuniene, Ramune; Moldovan, Radu; Broccio, Matteo; Lösche, Mathias; Niaura, Gediminas; Valincius, Gintaras; Borutaite, Vilmante


    The link between the size of soluble amyloid beta (Abeta) oligomers and their toxicity to rat cerebellar granule cells (CGC) was investigated. Variation in conditions during in vitro oligomerization of Abeta(1-42) resulted in peptide assemblies with different particle size as measured by atomic force microscopy and confirmed by dynamic light scattering and fluorescence correlation spectroscopy. Small oligomers of Abeta(1-42) with a mean particle z-height of 1-2 nm exhibited propensity to bind to phospholipid vesicles and they were the most toxic species that induced rapid neuronal necrosis at submicromolar concentrations whereas the bigger aggregates (z-height above 4-5 nm) did not bind vesicles and did not cause detectable neuronal death. A similar neurotoxic pattern was also observed in primary cultures of cortex neurons whereas Abeta(1-42) oligomers, monomers and fibrils were non-toxic to glial cells in CGC cultures or macrophage J774 cells. However, both oligomeric forms of Abeta(1-42) induced reduction of neuronal cell densities in the CGC cultures.

  14. Beta-Amyloid Deposition and Alzheimer's Type Changes Induced by Borrelia Spirochetes

    Energy Technology Data Exchange (ETDEWEB)

    Miklossy,J.; Kis, A.; Radenovic, A.; Miller, L.; Forro, L.; Martins, R.; Reiss, K.; Darbinian, N.; Darekar, P.; et al.


    The pathological hallmarks of Alzheimer's disease (AD) consist of {beta}-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of {beta}-amyloid presursor protein (A{beta}PP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.

  15. [Toxicity of puffer fish fins]. (United States)

    Honda, Shunichi; Ichimaru, Shunichi; Arakawa, Osamu; Takatani, Tomohiro; Noguchi, Tamao; Ishizaki, Shoichiro; Nagashima, Yuji


    Puffer fish is prized as a Japanese traditional food and its fin is also used in the cuisine. However, whether the fin is edible or not is determined for convenience from the toxicity of skin, since little information is available about the toxicity of puffer fish fins. In the present study, we examined the toxicity of fins and skin of three toxic species, Takifugu vermicularis, T. snyderi, and T. porphyreus. The toxicity of T. vermicularis fins (< 5-52.4 MU/g) was significantly lower than that of skin (<5-1200 MU/g). HPLC analysis showed that tetrodotoxin was a major toxic principle irrespective of the toxicity value in each tissue of T. vermicularis. In the case of T. snyderi and T. porphyreus, the toxicity of fins was at almost the same level as that of the skin. The toxicity (< 10-12 MU/g) of caudal fins of T. porphyreus was apparently increased to 16.5-22.0 MU/g by drying. However, the toxin amounts in the dried fins were slightly decreased as compared with those of the non-dried fins. These results demonstrate that puffer fish with toxic skin also have toxic fins.

  16. NMDA receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss


    Tackenberg, C; Grinschgl, S; Trutzel, A; Santuccione, A C; Frey, M C; Konietzko, U; Grimm, J.; Brandt, R.; Nitsch, R M


    Aggregates of amyloid-beta (Aβ) and tau are hallmarks of Alzheimer's disease (AD) leading to neurodegeneration and synaptic loss. While increasing evidence suggests that inhibition of N-methyl--aspartate receptors (NMDARs) may mitigate certain aspects of AD neuropathology, the precise role of different NMDAR subtypes for Aβ- and tau-mediated toxicity remains to be elucidated. Using mouse organotypic hippocampal slice cultures from arcAβ transgenic mice combined with Sindbis virus-mediated ex...

  17. Uncommon toxicity of low-dose methotrexate: case report

    Directory of Open Access Journals (Sweden)

    Zohreh Yousefi


    Full Text Available Background: Standard treatment of Gestational Trophoblastic Disease (GTD is chemotherapy. Single-agent chemotherapy regime including Methotrexate (MTX or Actinomycin. Single-agent is widely used in treatment of persistent trophoblastic disease. We reported an uncommon toxicity of low-dose single-agent methotrexate in a patient. Case Presentation: A 20-year-old woman, primary gravid after two months missed period and spotting with diagnosis of incomplete abortion with uterine size equivalent of ten weeks pregnancy (8-10 cm underwent evacuation curettage. In serial follow-up, based on rise of beta-hCG titer and absence of metastatic disease, it was categorized as low-risk persistent trophoblastic disease. She was referred to gynecology oncology center of Ghaem Hospital, Mashhad University of Medical Sciences in May 2014. Because of rise of beta-hCG titer, after complete metastatic work-up and lack of disease in other sites, persistent disease was diagnosed and candidate for chemotherapy (single agent low-dose. The patient received first course of therapy with MTX (50 mg/m², intra muscular. Unfortunately, after two days of treatment she developed uncommon severe toxicity, fever, severe nausea and vomiting, tachycardia, and generalized weakness. Also, we found hematologic abnormality (WBC: -14000-15000 µI, platelet- 540 µI and sever neutropenia, and abnormal rising in liver function test (SGOT, SGPT (three to four times and renal function test (BUN and Creatinine (two times. In addition, she had disseminated erosive lesion in all of body especially in face. Due to the fatal side effects of chemotherapy, she was admitted to intensive care unit (ICU. Fortunately, after two to three weeks, she was improved by conservative management. After few weeks beta-hCG titer was in normal limit. However she had normal serial beta-hCG in one year of follow-up. Conclusion: It is important to emphasis unpredictable side effects of chemotherapy with low

  18. [Toxic shock syndrome]. (United States)

    Tyll, T; Bílková, M; Revinová, A; Müller, M; Čurdová, M; Zlámal, M; Holub, M


    The authors present an up-to-date review of toxic shock syndrome (TSS) - a life-threatening condition where toxins of the Gram-positive bacteria Staphyloccocus aureus and Streptococcus pyogenes play a key role in the pathogenesis. The authors provide insight into the epidemiology and pathogenesis of the disease and point out the relevant patient history data and clinical signs and symptoms that may indicate progression of TSS. Last but not least, the state of the art diagnostic and therapeutic approaches to early and full blown TSS are summarized. Case reports are presented to illustrate two different etiological forms of this relatively rare nosological entity.

  19. Neurological oxygen toxicity. (United States)

    Farmery, Scott; Sykes, Oliver


    SCUBA diving has several risks associated with it from breathing air under pressure--nitrogen narcosis, barotrauma and decompression sickness (the bends). Trimix SCUBA diving involves regulating mixtures of nitrogen, oxygen and helium in an attempt to overcome the risks of narcosis and decompression sickness during deep dives, but introduces other potential hazards such as hypoxia and oxygen toxicity convulsions. This study reports on a seizure during the ascent phase, its potential causes and management and discusses the hazards posed to the diver and his rescuer by an emergency ascent to the surface.

  20. Copper enhances amyloid-beta peptide neurotoxicity and non beta-aggregation: a series of experiments conducted upon copper-bound and copper-free amyloid-beta peptide. (United States)

    Dai, Xueling; Sun, Yaxuan; Gao, Zhaolan; Jiang, Zhaofeng


    Alzheimer's disease is characterized by the abnormal aggregation of amyloid-beta peptide (Abeta) in extracellular deposits known as senile plaques. However, the nature of the toxic Abeta species and its precise mechanism of action remain unclear. Previous reports suggest that the histidine residues are involved in copper-Abeta interaction, by which resulting in the neurotoxicity of Abeta and free radical damage. Here, we employed a mutant Abeta (Abeta H13R) in which a histidine residue was replaced by arginine. Copper facilitated the precipitation of both wild-type and mutant Abeta in the spectrophotometric absorbance assay but suppressed beta-structure aggregates according to Thioflavine-T assay. Wild-type Abeta alone is more cytotoxic but produced less amount of H(2)O(2) than AbetaH13R-copper complexes, suggesting that Abeta-membrane interaction may also implicated in the pathologic progress. Abeta toxicity is in positive correlation to its competence to aggregate despite the aggregation is mainly composed of non-beta fibril substances. In short, these findings may provide further evidence on the role of copper in the pathogenesis of Alzheimer's disease.

  1. Cephalosporin Induced Toxic Epidermal Necrolysis and Subsequent Penicillin Drug Exanthem


    Amanda Lam; Inderpal Randhawa; William Klaustermeyer


    Background: Drug hypersensitivity is classically divided into IgE mediated and non-IgE mediated disease. We report a rare case of consequent IgE mediated and non-IgE mediated reactions within the beta lactam class of antibiotics. Case Summary: An 84-year-old man developed toxic epidermal necrolysis (TEN) due to ceftriaxone, a third generation cephalosporin, involving 72% of the body surface area. The patient recovered but within weeks subsequently developed an acute IgE mediated allergic r...

  2. Avisalmvac: evaluation studies of stability and toxicity

    Directory of Open Access Journals (Sweden)

    Daniela Botus,


    Full Text Available In Pasteur Institute laboratories there was developed AVISALMVAC, a vaccine against avian Salmonella, a biological product that contains S. enteritidis and S. typhimurium bacterin, with oil adjuvant. This paper presents the results of the studies regarding the stability and toxicity evaluation of this vaccine stored under conditions recommended by the manufacturer (2-80C at the end of the period of validity. The vaccine stability was assessed by serological and histopathological analysis of samples from SPF chickens vaccinated with the product at the end of the period of validity. The study of Avisalmvac toxicity was carried out by inoculation of the product or its components on Vero cell monolayer, and the effects were microscopically recorded or by MTT test, applied at 6 days post-inoculation. Antibody titers recorded at 2 and 3 weeks post vaccination demonstrated the vaccine ability (used after an year since manufacture to induce synthesis of specific antibodies and therefore, the product stability was proven. Histopathological examinations carried out on samples taken at 18 days post vaccinationfrom the vaccination site (skeletal muscle and skin and spleen, did not show any lesions associated to vaccination with Avisalmvac. The cytotoxicity analysis made by inoculating the vaccine or its components on Vero cell monolayer and the microscopic examination did not record visible cytopathic effects for any vaccine dilutions or vaccine components. The cell metabolism evaluation by MTT assay made at 6 days after vaccine/vaccine components inoculation on Vero monolayer, shown the ability of the vaccine and oil adjuvant to stimulate cell metabolism, and a certain degree of toxicity / inhibition of dehydrogenase metabolism associated to one of emulsifier but at dilutions higher than those used in the vaccine formula.

  3. BETA (Bitter Electromagnet Testing Apparatus) Design and Testing (United States)

    Bates, Evan; Birmingham, William; Rivera, William; Romero-Talamas, Carlos


    BETA is a 1T water cooled Bitter-type magnetic system that has been designed and constructed at the Dusty Plasma Laboratory of the University of Maryland, Baltimore County to serve as a prototype of a scaled 10T version. Currently the system is undergoing magnetic, thermal and mechanical testing to ensure safe operating conditions and to prove analytical design optimizations. These magnets will function as experimental tools for future dusty plasma based and collaborative experiments. An overview of design methods used for building a custom made Bitter magnet with user defined experimental constraints is reviewed. The three main design methods consist of minimizing the following: ohmic power, peak conductor temperatures, and stresses induced by Lorentz forces. We will also discuss the design of BETA which includes: the magnet core, pressure vessel, cooling system, power storage bank, high powered switching system, diagnostics with safety cutoff feedback, and data acquisition (DAQ)/magnet control Matlab code. Furthermore, we present experimental data from diagnostics for validation of our analytical preliminary design methodologies and finite element analysis calculations. BETA will contribute to the knowledge necessary to finalize the 10 T magnet design.

  4. [Toxicity of monkshood. Review.]. (United States)

    Ingolfsdottir, K; Olafsson, K


    Monkshood, Aconitum napellus L. (Ranunculaceae), is considered one of the most poisonous plants growing in Europe. Monkshood and other Aconitum species are still used in Oriental and homeopathic medicine as analgesics, febrifuges and hypotensives. The neurotoxin aconitine is the principal alkaloid in most subspecies of monkshood. A review is presented, which includes historical aspects of monkshood as a poisonous and medicinal plant, the mode of action of aconitine, symptoms of toxicity, treatment and reports of recent poisoning incidents. In addition, results of quantitative HPLC examination of hypogeous and epigeous organs from a population of A. napellus ssp. vulgare cultivated in Iceland are discussed. The fact that children in Iceland have commonly been known to eat the sweet tasting nectaries in monkshood prompted an investigation of the alkaloidal content of these organs specifically. The low aconitine content found in the nectaries as well as in whole flowers accords with the absence of reported toxicity arising from the handling of flowers and consumption of nectaries from A. napellus in this country.

  5. Biochemical toxicity of benzene. (United States)

    Rana, S V S; Verma, Yeshvandra


    Human exposure to benzene in work environment is a global occupational health problem. After inhalation or absorption, benzene targets organs viz. liver, kidney, lung, heart and brain etc. It is metabolized mainly in the liver by cytochrome P450 multifunctional oxygenase system. Benzene causes haematotoxicity through its phenolic metabolites that act in concert to produce DNA strand breaks, chromosomal damage, sister chromatid exchange, inhibition of topoisomerase II and damage to mitotic spindle. The carcinogenic and myelotoxic effects of benzene are associated with free radical formation either as benzene metabolites or lipid peroxidation products. Benzene oxide and phenol have been considered as proheptons. Liver microsomes play an important role in biotransformation of benzene whereas in kidney, it produces degenerative intracellular changes. Cohort studies made in different countries suggest that benzene induces multiple myeloma in petrochemical workers. Though extensive studies have been performed on its toxicity, endocrinal disruption caused by benzene remains poorly known. Transgenic cytochrome P450 IIE1 mice may help in understanding further toxic manifestations of benzene.

  6. Toxic compounds in honey. (United States)

    Islam, Md Nazmul; Khalil, Md Ibrahim; Islam, Md Asiful; Gan, Siew Hua


    There is a wealth of information about the nutritional and medicinal properties of honey. However, honey may contain compounds that may lead to toxicity. A compound not naturally present in honey, named 5-hydroxymethylfurfural (HMF), may be formed during the heating or preservation processes of honey. HMF has gained much interest, as it is commonly detected in honey samples, especially samples that have been stored for a long time. HMF is a compound that may be mutagenic, carcinogenic and cytotoxic. It has also been reported that honey can be contaminated with heavy metals such as lead, arsenic, mercury and cadmium. Honey produced from the nectar of Rhododendron ponticum contains alkaloids that can be poisonous to humans, while honey collected from Andromeda flowers contains grayanotoxins, which can cause paralysis of limbs in humans and eventually leads to death. In addition, Melicope ternata and Coriaria arborea from New Zealand produce toxic honey that can be fatal. There are reports that honey is not safe to be consumed when it is collected from Datura plants (from Mexico and Hungary), belladonna flowers and Hyoscamus niger plants (from Hungary), Serjania lethalis (from Brazil), Gelsemium sempervirens (from the American Southwest), Kalmia latifolia, Tripetalia paniculata and Ledum palustre. Although the symptoms of poisoning due to honey consumption may differ depending on the source of toxins, most common symptoms generally include dizziness, nausea, vomiting, convulsions, headache, palpitations or even death. It has been suggested that honey should not be considered a completely safe food.

  7. Molecular toxicity of nanomaterials. (United States)

    Chang, Xue-Ling; Yang, Sheng-Tao; Xing, Gengmei


    With the rapid developments in the fields of nanoscience and nanotechnlogy, more and more nanomaterials and their based consumer products have been used into our daily life. The safety concerns of nanomaterials have been well recognized by the scientific community and the public. Molecular mechanism of interactions between nanomaterials and biosystems is the most essential topic and final core of the biosafety. In the last two decades, nanotoxicology developed very fast and toxicity phenomena of nanomaterials have been reported. To achieve better understanding and detoxication of nanomaterials, thorough studies of nanotoxicity at molecular level are important. The interactions between nanomaterials and biomolecules have been widely investigated as the first step toward the molecular nanotoxicology. The consequences of such interactions have been discussed in the literature. Besides this, the chemical mechanism of nanotoxicology is gaining more attention, which would lead to a better design of nontoxic nanomaterials. In this review, we focus on the molecular nanotoxicology and explore the toxicity of nanomaterials at molecular level. The molecular level studies of nanotoxicology are summarized and the published nanotoxicological data are revisited.

  8. Systematic Review of Radiation Therapy Toxicity Reporting in Randomized Controlled Trials of Rectal Cancer: A Comparison of Patient-Reported Outcomes and Clinician Toxicity Reporting

    Energy Technology Data Exchange (ETDEWEB)

    Gilbert, Alexandra, E-mail: [Leeds Institute of Cancer & Pathology, University of Leeds, Leeds (United Kingdom); Ziegler, Lucy; Martland, Maisie [Leeds Institute of Cancer & Pathology, University of Leeds, Leeds (United Kingdom); Davidson, Susan [The Christie Hospital, Manchester (United Kingdom); Efficace, Fabio [Italian Group for Adult Hematologic Diseases, Rome (Italy); Sebag-Montefiore, David; Velikova, Galina [Leeds Institute of Cancer & Pathology, University of Leeds, Leeds (United Kingdom)


    The use of multimodal treatments for rectal cancer has improved cancer-related outcomes but makes monitoring toxicity challenging. Optimizing future radiation therapy regimens requires collection and publication of detailed toxicity data. This review evaluated the quality of toxicity information provided in randomized controlled trials (RCTs) of radiation therapy in rectal cancer and focused on the difference between clinician-reported and patient-reported toxicity. Medline, EMBASE, and the Cochrane Library were searched (January 1995-July 2013) for RCTs reporting late toxicity in patients treated with regimens including preoperative (chemo)radiation therapy. Data on toxicity measures and information on toxicity reported were extracted using Quantitative Analyses of Normal Tissue Effects in the Clinic recommendations. International Society for Quality of Life Research standards on patient-reported outcomes (PROs) were used to evaluate the quality of patient-reported toxicity. Twenty-one RCT publications met inclusion criteria out of 4144 articles screened. All PRO studies reported higher rates of toxicity symptoms than clinician-reported studies and reported on a wider range and milder symptoms. No clinician-reported study published data on sexual dysfunction. Of the clinician-reported studies, 55% grouped toxicity data related to an organ system together (eg “Bowel”), and 45% presented data only on more-severe (grade ≥3) toxicity. In comparison, all toxicity grades were reported in 79% of PRO publications, and all studies (100%) presented individual symptom toxicity data (eg bowel urgency). However, PRO reporting quality was variable. Only 43% of PRO studies presented baseline data, 28% did not use any psychometrically validated instruments, and only 29% of studies described statistical methods for managing missing data. Analysis of these trials highlights the lack of reporting standards for adverse events and reveals the differences between clinician and

  9. Psychological Test Validity

    Directory of Open Access Journals (Sweden)

    Gessmann H.-W.


    Full Text Available This paper presents a theoretical overview of current aspects about the validity problems of psychological tests. The article demonstrates the importance of the development of psychological tests and the scientific studies of their validity, describes the different types of validity and the possible ways of measurement and determination of the validity coefficients. The paper is recommended for researchers, whose work is dedicated to the development, modification or adaptation of the psychological test.

  10. 药品不良反应信号的验证和统计分析研究方法的探索——基于克林霉素注射剂致肾毒性的不良反应监测数据%Exploration on Adverse Drug Reaction Signal Detection, Validation and Statistics Analysis Methods: Based on the Clindamycin Injection's Renal Toxicity Adverse Reaction Monitoring Data.

    Institute of Scientific and Technical Information of China (English)

    路长飞; 田春华; 田月洁; 刘翠丽; 谢彦军


    目的 探索自愿报告药品不良反应信号的提取、验证及分析研究方法和模式.方法 利用比例失衡法和单因素分析方法,对国家药品不良反应数据库中有关克林霉素注射剂肾毒性的不良反应数据,进行信号的提取、验证和分析.结果 克林霉素注射剂致肾损害的ROR值为65.0,盐酸盐和磷酸酯致肾损害的ROR值分别为114.0、14.7;调整年龄、单次给药剂量后,盐酸克林霉素注射剂致肾损害的风险分别是克林霉素磷酸酯注射剂的6.6倍和5.5倍(P <0.001);药品不良反应评价流程包括药品不良反应信号的提取、药品不良反应信号的验证、药品不良反应信号的分析研究3个流程.结论 克林霉素注射剂与肾毒性不良反应存在关联性,盐酸克林霉素注射剂致肾损害风险高于克林霉素磷酸酯注射剂,但其机制仍需要进一步研究分析;综合运用数据挖掘和统计方法,可在药品不良反应信号提取、验证和分析研究中提供更有利的证据.%Objective To establish the model of adverse drug reaction signal detection, validation and statistics analysis methods. Methods Using the measures of disproportionality and stratified analysis to establish the model of adverse drug reaction signal detection, validation and analysis research by the clindamycin injection's renal toxicity adverse reaction monitoring data. Rssults The ROR of clindamycin injection, clindamycin hydrochloride injection and clindamycin phosphate injection were 65.0, 114.0 and 14.7, respectively. The risks of renal damage of clindamycin hydrochloride injection were 6.6 times and 5.5 times than clindamycin phosphate injection after adjusting the age and single drug dose(P <0.001). It has been successfully established the model of adverse drug reaction signal detection, validation and analysis research. Conclusion There is strong relevance between clindamycin and renal toxicity adverse reaction, and the risk of renal

  11. Resistance training & beta-hydroxy-beta-methylbutyrate supplementation on hormones

    Directory of Open Access Journals (Sweden)

    Hamid Arazi


    Full Text Available RESUMOIntroduction:In recent years, there was an increased interest on the effects of beta-hydroxy-beta-methylbutyrate (HMB supplementation on skeletal muscle due to its anti-catabolic effects.Objectives:To investigate the effect of HMB supplementation on body composition, muscular strength and anabolic-catabolic hormones after resistance training.Methods:Twenty amateur male athletes were randomly assigned to supplement and control groups in a double-blind crossover design and participated in four weeks resistance training. Before and after the test period fasting blood samples were obtained to determine anabolic (the growth hormone and testosterone and catabolic (cortisol hormones, and fat mass, lean body mass (LBM and muscular strength were measured. Dependent and independent t-tests were used to analyze data.Results:After the training period, there were no significant differen-ces between the groups with respect to fat mass, LBM and anabolic-catabolic hormones. HMB supplementation resulted in a significantly greater strength gain (p≤0.05.Conclusion:Greater increase in strength for HMB group was not accompanied by body composition and basal circulating anabolic-catabolic hormonal changes. It seems that HMB supplementation may have beneficial effects on neurological adaptations of strength gain.

  12. Principles of Proper Validation

    DEFF Research Database (Denmark)

    Esbensen, Kim; Geladi, Paul


    Validation in chemometrics is presented using the exemplar context of multivariate calibration/prediction. A phenomenological analysis of common validation practices in data analysis and chemometrics leads to formulation of a set of generic Principles of Proper Validation (PPV), which is based...

  13. Mercury-induced hepatotoxicity in zebrafish: in vivo mechanistic insights from transcriptome analysis, phenotype anchoring and targeted gene expression validation

    Directory of Open Access Journals (Sweden)

    Mathavan Sinnakaruppan


    Full Text Available Abstract Background Mercury is a prominent environmental contaminant that causes detrimental effects to human health. Although the liver has been known to be a main target organ, there is limited information on in vivo molecular mechanism of mercury-induced toxicity in the liver. By using transcriptome analysis, phenotypic anchoring and validation of targeted gene expression in zebrafish, mercury-induced hepatotoxicity was investigated and a number of perturbed cellular processes were identified and compared with those captured in the in vitro human cell line studies. Results Hepato-transcriptome analysis of mercury-exposed zebrafish revealed that the earliest deregulated genes were associated with electron transport chain, mitochondrial fatty acid beta-oxidation, nuclear receptor signaling and apoptotic pathway, followed by complement system and proteasome pathway, and thereafter DNA damage, hypoxia, Wnt signaling, fatty acid synthesis, gluconeogenesis, cell cycle and motility. Comparative meta-analysis of microarray data between zebrafish liver and human HepG2 cells exposed to mercury identified some common toxicological effects of mercury-induced hepatotoxicity in both models. Histological analyses of liver from mercury-exposed fish revealed morphological changes of liver parenchyma, decreased nucleated cell count, increased lipid vesicles, glycogen and apoptotic bodies, thus providing phenotypic evidence for anchoring of the transcriptome analysis. Validation of targeted gene expression confirmed deregulated gene-pathways from enrichment analysis. Some of these genes responding to low concentrations of mercury may serve as toxicogenomic-based markers for detection and health risk assessment of environmental mercury contaminations. Conclusion Mercury-induced hepatotoxicity was triggered by oxidative stresses, intrinsic apoptotic pathway, deregulation of nuclear receptor and kinase activities including Gsk3 that deregulates Wnt signaling

  14. Abstraction Mechanisms in the BETA Programming Language

    DEFF Research Database (Denmark)

    Kristensen, Bent Bruun; Madsen, Ole Lehrmann; Møller-Pedersen, Birger


    ]) --- covering both data, procedural and control abstractions, substituting constructs like class, procedure, function and type. Correspondingly objects, procedure activation records and variables are all regarded as special cases of the basic building block of program executions: the entity. A pattern thus......The BETA programming language is developed as part of the BETA project. The purpose of this project is to develop concepts, constructs and tools in the field of programming and programming languages. BETA has been developed from 1975 on and the various stages of the language are documented in [BETA...... a]. The application area of BETA is programming of embedded as well as distributed computing systems. For this reason a major goal has been to develop constructs that may be efficiently implemented. Furthermore the BETA language is intended to have a few number of basic but general constructs...

  15. Comparative toxicities of oxygen, ozone, chlorine dioxide, and chlorine bleaching filtrates - microtox toxicities of raw and processed filtrates

    Energy Technology Data Exchange (ETDEWEB)

    Ard, T.A.; McDonough, T.J.


    It has claimed that effluents from the bleaching of kraft pulp with chlorine and its compounds have deleterious effects on the aquatic environment. It has been further suggested that bleaching without the use of chlorine or its compounds will produce innocuous effluents. To obtain information on the validity of these claims, we have conducted a laboratory study of the toxicity of filtrates from chlorine-based and nonchlorine bleaching processes. We have also examined two related issues. The first is whether any toxicants generated during bleaching are rendered harmless (by neutralization, storage, and biological treatment) before being discharged to the environment. The second related issue is whether any toxicity observed in mill effluents actually originates in the bleaching process, as opposed to being due to raw material components or compounds formed during the pulping step that precedes bleaching. Several conclusions were drawn from this study. (1) There is a background level of toxicity which originates in the oxygen stage, process steps prior to bleaching, or in the wood raw material. It is decreased by neutralization and storage, but residual toxicity may still be detected after two weeks. (2) If the sum of the first and second stage toxicities is taken as an indicator of overall toxicity, the untreated filtrates may be ranked as follows: Control (Background) > D(EO) > Z(EO) > C(EO). However, these toxicities are of no importance in regard to environmental effects because of their ephemeral nature and the likelihood of their being reduced or eliminated prior to effluent discharge. Evidence for this statement is the ease with which all except the C(EO) were detoxified by neutralization and storage. (3) After neutralization and storage for two weeks at room temperature the ranking of toxicities becomes: C(EO) > D(EO) > Z(EO) > Background. The last three are similar in magnitude.

  16. The plain beta-angle measured on radiographs in the assessment of femoroacetabular impingement. (United States)

    Brunner, A; Hamers, A T; Fitze, M; Herzog, R F


    The beta-angle is a radiological tool for measuring the distance between the pathological head-neck junction and the acetabular rim with the hip in 90 degrees of flexion in patients with femoroacetabular impingement. Initially it was measured using an open-chamber MRI. We have developed a technique to measure this angle on plain radiographs. Correlation analysis was undertaken to determine the relationship between the range of movement and the beta-angle in 50 patients with femoroacetabular impingement and 50 asymptomatic control subjects. Inter- and intra-observer reliability of the beta-angle was also evaluated. Patients with femoroacetabular impingement had a significantly smaller (p angle (15.6 degrees, 95% confidence interval (CI) 13.3 to 17.7) compared with the asymptomatic group (38.7 degrees, 95% CI 36.5 to 41.0). Correlation between internal rotation and the beta-angle was high in the impingement group and moderate in the asymptomatic group. The beta-angle had excellent inter- and intra-observer reliability in both groups. Our findings suggest that the measurement of the beta-angle on plain radiography may represent a valid, reproducible and cost-effective alternative to open MRI in the assessment of the pathological bony anatomy in patients with cam, pincer and mixed femoroacetabular impingement.

  17. Milk Intolerance, Beta-Casein and Lactose. (United States)

    Pal, Sebely; Woodford, Keith; Kukuljan, Sonja; Ho, Suleen


    True lactose intolerance (symptoms stemming from lactose malabsorption) is less common than is widely perceived, and should be viewed as just one potential cause of cows' milk intolerance. There is increasing evidence that A1 beta-casein, a protein produced by a major proportion of European-origin cattle but not purebred Asian or African cattle, is also associated with cows' milk intolerance. In humans, digestion of bovine A1 beta-casein, but not the alternative A2 beta-casein, releases beta-casomorphin-7, which activates μ-opioid receptors expressed throughout the gastrointestinal tract and body. Studies in rodents show that milk containing A1 beta-casein significantly increases gastrointestinal transit time, production of dipeptidyl peptidase-4 and the inflammatory marker myeloperoxidase compared with milk containing A2 beta-casein. Co-administration of the opioid receptor antagonist naloxone blocks the myeloperoxidase and gastrointestinal motility effects, indicating opioid signaling pathway involvement. In humans, a double-blind, randomized cross-over study showed that participants consuming A1 beta-casein type cows' milk experienced statistically significantly higher Bristol stool values compared with those receiving A2 beta-casein milk. Additionally, a statistically significant positive association between abdominal pain and stool consistency was observed when participants consumed the A1 but not the A2 diet. Further studies of the role of A1 beta-casein in milk intolerance are needed.

  18. Sawtooth crashes at high beta on JET

    Energy Technology Data Exchange (ETDEWEB)

    Alper, B.; Huysmans, G.T.A.; Sips, A.C.C. [Commission of the European Communities, Abingdon (United Kingdom). JET Joint Undertaking; Nave, M.F.F. [Universidade Tecnica, Lisbon (Portugal). Inst. Superior Tecnico


    The sawtooth crashes on JET display features which depend on beta. The main observation is a transient bulging of flux surfaces (duration inferior to 30 microsec.), which is predominantly on the low field side and extends to larger radii as beta increases. This phenomenon reaches the plasma boundary when beta{sub N} exceeds 0.5 and in these cases is followed by an ELM within 50 microsec. These sawtooth/ELM events limit plasma performance. Modelling of mode coupling shows qualitative agreement between observations of the structure of the sawtooth precursor and the calculated internal kink mode at high beta. (authors). 6 refs., 5 figs.

  19. Milk Intolerance, Beta-Casein and Lactose

    Directory of Open Access Journals (Sweden)

    Sebely Pal


    Full Text Available True lactose intolerance (symptoms stemming from lactose malabsorption is less common than is widely perceived, and should be viewed as just one potential cause of cows’ milk intolerance. There is increasing evidence that A1 beta-casein, a protein produced by a major proportion of European-origin cattle but not purebred Asian or African cattle, is also associated with cows’ milk intolerance. In humans, digestion of bovine A1 beta-casein, but not the alternative A2 beta-casein, releases beta-casomorphin-7, which activates μ-opioid receptors expressed throughout the gastrointestinal tract and body. Studies in rodents show that milk containing A1 beta-casein significantly increases gastrointestinal transit time, production of dipeptidyl peptidase-4 and the inflammatory marker myeloperoxidase compared with milk containing A2 beta-casein. Co-administration of the opioid receptor antagonist naloxone blocks the myeloperoxidase and gastrointestinal motility effects, indicating opioid signaling pathway involvement. In humans, a double-blind, randomized cross-over study showed that participants consuming A1 beta-casein type cows’ milk experienced statistically significantly higher Bristol stool values compared with those receiving A2 beta-casein milk. Additionally, a statistically significant positive association between abdominal pain and stool consistency was observed when participants consumed the A1 but not the A2 diet. Further studies of the role of A1 beta-casein in milk intolerance are needed.

  20. Immunological aspects of nonimmediate reactions to beta-lactam antibiotics. (United States)

    Rodilla, Esther Morena; González, Ignacio Dávila; Yges, Elena Laffond; Bellido, Francisco Javier Múñoz; Bara, María Teresa Gracia; Toledano, Félix Lorente


    beta-lactam antibiotics are the agents most frequently implied in immune drug adverse reactions. These can be classified as immediate or nonimmediate according to the time interval between the last drug administration and their onset. Mechanisms of immediate IgE-mediated reactions are widely studied and are therefore better understood. Nonimmediate reactions include a broad number of clinical entities like mild maculopapular exanthemas, the most common, and other less frequent but more severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute exanthematic pustulosis or cytopenias. These nonimmediate reactions are mainly mediated by T cells but the precise underlying mechanisms are not well elucidated. This fact complicates the allergological evaluation of patients with this type of reaction and available tests have demonstrated poor sensitivity and specificity.

  1. Anticorrosion Nanocrystalline Beta Zeolite Thin Film for Advanced Applications

    Directory of Open Access Journals (Sweden)

    Maha Saud M. Al-subaie


    Full Text Available Steel alloys corrosion is ubiquitous and is conventionally protected by anticorrosion chromate coatings. However, the process suffers from the release of carcinogenic hexavalent chromium ions that needs to be replaced by an ecofriendly alternative. In this context, the need for the development of satisfactory ecofriendly chromium-free coating with superior corrosion performance is highly desirable. In the present study, we synthesized fully dispersible nanocrystalline Beta zeolite seeds and coated on steel alloys followed by steaming. The samples were characterized by XRD, FE-SEM, and DLS analyses. The anticorrosion behavior of the synthesized nanoparticle coatings on steel alloys was investigated by electrochemical measurements (DC polarization and electrochemical impedance spectroscopy (EIS in NaCl and acid and alkaline media under identical experimental conditions. The present study demonstrated that the nanozeolite coating can be a potential alternative for toxic and carcinogenic chromate coating.

  2. Rapid determination of gross alpha/beta activity in milk using liquid scintilation counter technique

    Directory of Open Access Journals (Sweden)

    Sas Daniel


    Full Text Available Rapid determination of gross alpha and beta emitters in milk by liquid scintillation counter is discussed. This method is based on direct addition of different types of milk into scintillation cocktail and therefore it is very promising for fast determination of alpha/beta activity due to direct alpha and beta separation, measurement in close 4p geometry and without sample treatment. The selected group of radionuclides was chosen with the respect to military significance, radio-toxicity, and possibility of potential misuse. As model radionuclides 241Am, 239Pu, and 90Sr were selected. The Liquid Scintilation Counter Hidex 300 SL equipped with triple-double-coincidence-ratio technique was used for sample measurement. The aim of the work was focused on comparison of different cocktails produced by Hidex and Perkin Elmer, choosing the best cocktail based on our measurement results and adjustment of its appropriate volume. Furthermore, the optimization of ratio between the volume of scintillation cocktail and the volume of urine was investigated with the respect to the model radionuclides. According to the obtained results, the efficiency for alpha emitters was greater than 85% and for beta, greater than 95%. The obtained results allowed this method to be used for rapid determination of gross alpha/beta activity in cases where time is an essence, such as first responders or mass-scale samples, where ordinary means suffer from lack of capacity or simply collapse under the onslaught.

  3. alpha7 Nicotinic acetylcholine receptor knockout selectively enhances ethanol-, but not beta-amyloid-induced neurotoxicity. (United States)

    de Fiebre, Nancyellen C; de Fiebre, Christopher M


    The alpha7 subtype of nicotinic acetylcholine receptor (nAChR) has been implicated as a potential site of action for two neurotoxins, ethanol and the Alzheimer's disease related peptide, beta-amyloid. Here, we utilized primary neuronal cultures of cerebral cortex from alpha7 nAChR null mutant mice to examine the role of this receptor in modulating the neurotoxic properties of subchronic, "binge" ethanol and beta-amyloid. Knockout of the alpha7 nAChR gene selectively enhanced ethanol-induced neurotoxicity in a gene dosage-related fashion. Susceptibility of cultures to beta-amyloid induced toxicity, however, was unaffected by alpha7 nAChR gene null mutation. Further, beta-amyloid did not inhibit the binding of the highly alpha7-selective radioligand, [(125)I]alpha-bungarotoxin. On the other hand, in studies in Xenopus oocytes ethanol efficaciously inhibited alpha7 nAChR function. These data suggest that alpha7 nAChRs modulate the neurotoxic effects of binge ethanol, but not the neurotoxicity produced by beta-amyloid. It is hypothesized that inhibition of alpha7 nAChRs by ethanol provides partial protection against the neurotoxic properties of subchronic ethanol.

  4. The MAJORANA experiment: an ultra-low background search for neutrinoless double-beta decay

    Energy Technology Data Exchange (ETDEWEB)

    Phillips, D.; Aguayo Navarrete, Estanislao; Avignone, Frank T.; Back, Henning O.; Barabash, Alexander S.; Bergevin, M.; Bertrand, F.; Boswell, M.; Brudanin, V.; Busch, Matthew; Chan, Yuen-Dat; Christofferson, Cabot-Ann; Collar, J. I.; Combs, Dustin C.; Cooper, R. J.; Detwiler, Jason A.; Doe, Peter J.; Efremenko, Yuri; Egorov, Viatcheslav; Ejiri, H.; Elliott, Steven R.; Esterline, James H.; Fast, James E.; Fields, N.; Finnerty, P.; Fraenkle, Florian; Gehman, Victor; Giovanetti, G. K.; Green, Matthew P.; Guiseppe, Vincente; Gusey, K.; Hallin, A. L.; Hazama, R.; Henning, Reyco; Hime, Andrew; Hoppe, Eric W.; Horton, Mark; Howard, Stanley; Howe, M. A.; Johnson, R. A.; Keeter, K.; Keller, C.; Kidd, Mary; Knecht, A.; Kochetov, Oleg; Konovalov, S.; Kouzes, Richard T.; LaFerriere, Brian D.; LaRoque, B. H.; Leon, Jonathan D.; Leviner, L.; Loach, J. C.; MacMullin, S.; Marino, Michael G.; Martin, R. D.; Mei, Dong-Ming; Merriman, Jason H.; Miller, M. L.; Mizouni, Leila; Nomachi, Masaharu; Orrell, John L.; Overman, Nicole R.; Poon, Alan; Perumpilly, Gopakumar; Prior, Gersende; Radford, D. C.; Rielage, Keith; Robertson, R. G. H.; Ronquest, M. C.; Schubert, Alexis G.; Shima, T.; Shirchenko, M.; Snavely, Kyle J.; Steele, David; Strain, J.; Thomas, K.; Timkin, V.; Tornow, W.; Vanyushin, I.; Varner, R. L.; Vetter, Kai; Vorren, Kris R.; Wilkerson, J. F.; Wolfe, B. A.; Yakushev, E.; Young, A.; Yu, Chang-Hong; Yumatov, Vladimir; Zhang, C.


    The observation of neutrinoless double-beta decay would resolve the Majorana nature of the neutrino and could provide information on the absolute scale of the neutrino mass. The initial phase of the Majorana Experiment, known as the Demonstrator, will house 40 kg of Ge in an ultra-low background shielded environment at the 4850' level of the Sanford Underground Laboratory in Lead, SD. The objective of the Demonstrator is to validate whether a future 1-tonne experiment can achieve a background goal of one count per tonne-year in a narrow region of interest around the 76Ge neutrinoless double-beta decay peak.

  5. A new 4π(LS)-γ coincidence counter at NCBJ RC POLATOM with TDCR detector in the beta channel. (United States)

    Ziemek, T; Jęczmieniowski, A; Cacko, D; Broda, R; Lech, E


    A new 4π(LS)-γ coincidence system (TDCRG) was built at the NCBJ RC POLATOM. The counter consists of a TDCR detector in the beta channel and scintillation detector with NaI(Tl) crystal in the gamma channel. The system is equipped with a digital board with FPGA, which records and analyses coincidences in the TDCR detector and coincidences between the beta and gamma channels. The characteristics of the system and a scheme of the FPGA implementation with behavioral simulation are given. The TDCRG counter was validated by activity measurements on (14)C and (60)Co solutions standardized in RC POLATOM using previously validated methods.

  6. Challenges in Double Beta Decay

    Directory of Open Access Journals (Sweden)

    Oliviero Cremonesi


    Full Text Available In the past ten years, neutrino oscillation experiments have provided the incontrovertible evidence that neutrinos mix and have finite masses. These results represent the strongest demonstration that the electroweak Standard Model is incomplete and that new Physics beyond it must exist. In this scenario, a unique role is played by the Neutrinoless Double Beta Decay searches which can probe lepton number conservation and investigate the Dirac/Majorana nature of the neutrinos and their absolute mass scale (hierarchy problem with unprecedented sensitivity. Today Neutrinoless Double Beta Decay faces a new era where large-scale experiments with a sensitivity approaching the so-called degenerate-hierarchy region are nearly ready to start and where the challenge for the next future is the construction of detectors characterized by a tonne-scale size and an incredibly low background. A number of new proposed projects took up this challenge. These are based either on large expansions of the present experiments or on new ideas to improve the technical performance and/or reduce the background contributions. In this paper, a review of the most relevant ongoing experiments is given. The most relevant parameters contributing to the experimental sensitivity are discussed and a critical comparison of the future projects is proposed.

  7. Inflammatory and toxic myopathies. (United States)

    Dalakas, M C


    The major advances in the immunopathogenesis and treatment of inflammatory myopathies, and the main criteria that distinguish polymyositis (PM) from dermatomyositis (DM) or inclusion-body myositis (IBM) are presented. The origin and implications of the amyloid and ubiquitin deposits found within the vacuolated fibers of patients with IBM are considered. The pathogenesis of human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus (HTLV)-I-associated PM is presented, and the role of retroviruses in triggering PM, even in the absence of detectable viral genome within the muscle fibers, is discussed. In addition, three toxic myopathies with distinct morphologic, biochemical, or molecular characteristics, caused by zidovudine [azidothymidine (AZT) myopathy], the cholesterol-lowering-agent myopathy (CLAM), and the combination of blocking agents with corticosteroids are presented.

  8. Lead toxicity: Current concerns

    Energy Technology Data Exchange (ETDEWEB)

    Goyer, R.A. (Univ. of Western Ontario, London (Canada))


    Over the 20-year period since the first issue of Environmental Health Perspectives was published, there has been considerable progress in the understanding of the potential toxicity of exposure to lead. Many of these advances have been reviewed in published symposia, conferences, and review papers in EHP. This brief review identifies major advances as well as a number of current concerns that present opportunities for prevention and intervention strategies. The major scientific advance has been the demonstration that blood lead (PbB) levels of 10-15 micrograms/dL in newborn and very young infants result in cognitive and behavioral deficits. Further support for this observation is being obtained by prospective or longitudinal studies presently in progress. The mechanism(s) for the central nervous system effects of lead is unclear but involve lead interactions within calcium-mediated intracellular messenger systems and neurotransmission. Effects of low-level lead exposure on blood pressure, particularly in adult men, may be related to the effect of lead on calcium-mediated control of vascular smooth muscle contraction and on the renin-angiotensin system. Reproductive effects of lead have long been suspected, but low-level effects have not been well studied. Whether lead is a carcinogen or its association with renal adenocarcinoma is a consequence of cystic nephropathy is uncertain. Major risk factors for lead toxicity in children in the United States include nutrition, particularly deficiencies of essential metals, calcium, iron, and zinc, and housing and socioeconomic status. A goal for the year 2000 is to reduce prevalence of blood lead levels exceeding 15 micrograms/dL. 97 refs.

  9. p35/Cyclin-dependent kinase 5 is required for protection against beta-amyloid-induced cell death but not tau phosphorylation by ceramide. (United States)

    Seyb, Kathleen I; Ansar, Sabah; Li, Guibin; Bean, Jennifer; Michaelis, Mary L; Dobrowsky, Rick T


    Ceramide is a bioactive sphingolipid that can prevent calpain activation and beta-amyloid (A beta) neurotoxicity in cortical neurons. Recent evidence supports A beta induction of a calpain-dependent cleavage of the cyclin-dependent kinase 5 (cdk5) regulatory protein p35 that contributes to tau hyperphosphorylation and neuronal death. Using cortical neurons isolated from wild-type and p35 knockout mice, we investigated whether ceramide required p35/cdk5 to protect against A beta-induced cell death and tau phosphorylation. Ceramide inhibited A beta-induced calpain activation and cdk5 activity in wild-type neurons and protected against neuronal death and tau hyperphosphorylation. Interestingly, A beta also increased cdk5 activity in p35-/- neurons, suggesting that the alternate cdk5 regulatory protein, p39, might mediate this effect. In p35 null neurons, ceramide blocked A beta-induced calpain activation but did not inhibit cdk5 activity or cell death. However, ceramide blocked tau hyperphosphorylation potentially via inhibition of glycogen synthase kinase-3beta. These data suggest that ceramide can regulate A beta cell toxicity in a p35/cdk5-dependent manner.

  10. Diabetes and beta cell function: from mechanisms to evaluation and clinical implications. (United States)

    Cernea, Simona; Dobreanu, Minodora


    Diabetes is a complex, heterogeneous condition that has beta cell dysfunction at its core. Many factors (e.g. hyperglycemia/glucotoxicity, lipotoxicity, autoimmunity, inflammation, adipokines, islet amyloid, incretins and insulin resistance) influence the function of pancreatic beta cells. Chronic hyperglycaemia may result in detrimental effects on insulin synthesis/secretion, cell survival and insulin sensitivity through multiple mechanisms: gradual loss of insulin gene expression and other beta-cell specific genes; chronic endoplasmic reticulum stress and oxidative stress; changes in mitochondrial number, morphology and function; disruption in calcium homeostasis. In the presence of hyperglycaemia, prolonged exposure to increased free fatty acids result in accumulation of toxic metabolites in the cells ("lipotoxicity"), finally causing decreased insulin gene expression and impairment of insulin secretion. The rest of the factors/mechanisms which impact on the course of the disease are also discusses in detail. The correct assessment of beta cell function requires a concomitant quantification of insulin secretion and insulin sensitivity, because the two variables are closely interrelated. In order to better understand the fundamental pathogenetic mechanisms that contribute to disease development in a certain individual with diabetes, additional markers could be used, apart from those that evaluate beta cell function. The aim of the paper was to overview the relevant mechanisms/factors that influence beta cell function and to discuss the available methods of its assessment. In addition, clinical considerations are made regarding the therapeutical options that have potential protective effects on beta cell function/mass by targeting various underlying factors and mechanisms with a role in disease progression.

  11. Nanoparticle-chelator conjugates as inhibitors of amyloid-beta aggregation and neurotoxicity: a novel therapeutic approach for Alzheimer disease. (United States)

    Liu, Gang; Men, Ping; Kudo, Wataru; Perry, George; Smith, Mark A


    Oxidative stress and amyloid-beta are considered major etiological and pathological factors in the initiation and promotion of neurodegeneration in Alzheimer disease (AD). Insomuch as causes of such oxidative stress, transition metals, such as iron and copper, which are found in high concentrations in the brains of AD patients and accumulate specifically in the pathological lesions, are viewed as key contributors to the altered redox state. Likewise, the aggregation and toxicity of amyloid-beta is dependent upon transition metals. As such, chelating agents that selectively bind to and remove and/or "redox silence" transition metals have long been considered as attractive therapies for AD. However, the blood-brain barrier and neurotoxicity of many traditional metal chelators has limited their utility in AD or other neurodegenerative disorders. To circumvent this, we previously suggested that nanoparticles conjugated to iron chelators may have the potential to deliver chelators into the brain and overcome such issues as chelator bioavailability and toxic side-effects. In this study, we synthesized a prototype nanoparticle-chelator conjugate (Nano-N2PY) and demonstrated its ability to protect human cortical neurons from amyloid-beta-associated oxidative toxicity. Furthermore, Nano-N2PY nanoparticle-chelator conjugates effectively inhibited amyloid-beta aggregate formation. Overall, this study indicates that Nano-N2PY, or other nanoparticles conjugated to metal chelators, may provide a novel therapeutic strategy for AD and other neurodegenerative diseases associated with excess transition metals.

  12. The pharmacokinetics of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin in the rat

    NARCIS (Netherlands)

    Frijlink, H W; Visser, J; Hefting, N R; Oosting, R; Meijer, D K; Lerk, C F


    Hydroxypropyl-beta-cyclodextrin was analyzed by HPLC using postcolumn complexation with phenolphthalein and negative colorimetric detection, with a detection limit of 20 micrograms/ml. The pharmacokinetics of beta-cyclodextrin and of hydroxypropyl-beta-cyclodextrin were studied after intravenous adm

  13. The impact of beta-elemene on beta-tubulin of human hepatoma hepg2 cells

    Institute of Scientific and Technical Information of China (English)

    Yuqiu Mao; Liying Ban; Jielin Zhang; Li Hou; Xiaonan Cui


    Objective:The aim of this study was to investigate the impact of beta-elemene injection on the growth and beta-tubulin of human hepatocarcinoma HepG2 cells. Methods:cellproliferation was assessed by MTT assay. cellcycle distribution was detected by flow cytometry (FCM). The mRNA expression of beta-tubulin was measured by RT-PCR. West-ern blot analysis was used to determine protein expression of beta-tubulin and the polymerization of beta-tubulin. Results:Beta-elemene injection inhibited HepG2 cells proliferation in a dose-and time-dependent manner;FCM analysis indicated beta-elemene injection induced cellcycle arrested at S phase. RT-PCR and western-blot analysis showed that beta-elemene injection down-regulated beta-tubulin expression at both mRNA and protein levels, presenting a dose-dependent manner. Moreover, beta-elemene injection reduced the polymerization of microtubules in a dose-dependent manner. Conclusion:Beta-elemene injection can inhibit the proliferation of hepatoma HepG2 cells, the mechanism might be partly related to the down-regulation of beta-tubulin and inhibition of microtubular polymerization.

  14. Expressions of GSK-3beta, Beta-Catenin and PPAR-Gamma in Medulloblastoma

    Institute of Scientific and Technical Information of China (English)

    Xiong Zhang; Lu Si; Yu Li; Can Mi


    Objective: To investigate the expressions of GSK-3beta, Beta-catenin and PPAR-gamma, and their relationship in medulloblastoma, and to explore their value in clinic application.Methods: Immunohistochemical staining with SP method was conducted to determine the expressions of GSK-3beta, Beta-catenin and PPAR-gamma in 48 cases of medulloblastoma and 10 normal cerebellar tissues.Results: The rate of abnormal expressions of beta-catenin and PPAR-gamma in MB was higher than that in normal. Conversely, GSK-3beta in MB was lower than that in the normal (P<0.05). Furthermore, in medulloblastoma, beta-catenin and GSK-3beta showed a negative correlation, PPAR-gamma and beta-catenin had a positive correlation.Conclusion: Abnormal expression of beta-catenin plays a crucial role in the development of medulloblastoma. Meanwhile, PPAR-gamma and GSK-3beta which are tightly related with beta-catenin are both involved in the genesis and development of medulloblastoma.

  15. Radiation-induced polymerization of {beta}(+)-pinene and synthesis of optically active {beta}(+)/{beta}(-)pinene polymers and copolymers

    Energy Technology Data Exchange (ETDEWEB)

    Cataldo, Franco, E-mail: franco.cataldo@fastwebnet.i [Lupi Chemical Research, Via Casilina 1626/A, 00133 Rome (Italy); Lilla, Edo; Ursini, Ornella [Institute of Chemical Methodologies, CNR, Via Salaria Km. 29300, Monterotondo Stazione 00016, Rome (Italy)


    Poly-{beta}(+)-pinene (pB(+)p) was synthesized with {gamma} irradiation of the monomer {beta}(+)-pinene in bulk under vacuum at 1181 kGy. Also scalemic mixtures of {beta}(+)-pinene and {beta}(-)-pinene were irradiated at 1181 kGy to obtain synthetic copolymers of pB(+)/B(-)p. For comparison also {beta}(-)-pinene was converted into poly-{beta}(-)-pinene (pB(-)p) under the identical conditions adopted for its enantiomer. Furthermore pB(+)p and pB(-)p were also synthesized by thermal processing under the action of a chemical free radical initiator. The optical rotatory dispersion (ORD) of all pBp resins synthesized were accurately studied in the spectral range comprised between 375 and 625 nm and a curious asymmetry in the ORD of pB(+)p versus the ORD of pB(-)p is reported. Furthermore, it is shown that (+)-p-menth-1-ene and (-)-p-menth-1-ene are useful as a model compounds for the pBp resins and for the explanation of the amplification of the optical activity of the {beta}(+)-pinene and {beta}(-)-pinene after their ring-opening polymerization to pB(+)p and pB(-)p. The pBp resins were studied also by FT-IR spectroscopy and by thermal analysis (TGA and DTG).

  16. Beta-glucosidase I variants with improved properties

    Energy Technology Data Exchange (ETDEWEB)

    Bott, Richard R.; Kaper, Thijs; Kelemen, Bradley; Goedegebuur, Frits; Hommes, Ronaldus Wilhelmus; Kralj, Slavko; Kruithof, Paulien; Nikolaev, Igor; Van Der Kley, Wilhelmus Antonious Hendricus; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander


    The present disclosure is generally directed to enzymes and in particular beta-glucosidase variants. Also described are nucleic acids encoding beta-glucosidase variants, compositions comprising beta-glucosidase variants, methods of using beta-glucosidase variants, and methods of identifying additional useful beta-glucosidase variants.

  17. Dosimetry of low-energy beta radiation

    Energy Technology Data Exchange (ETDEWEB)

    Borg, J.


    Useful techniques and procedures for determination of absorbed doses from exposure in a low-energy {beta} radiation field were studied and evaluated in this project. The four different techniques included were {beta} spectrometry, extrapolation chamber dosimetry, Monte Carlo (MC) calculations, and exoelectron dosimetry. As a typical low-energy {beta} radiation field a moderated spectrum from a {sup 14}C source (E{sub {beta}},{sub max} =156 keV) was chosen for the study. The measured response of a Si(Li) detector to photons (bremsstrahlung) showed fine agreement with the MC calculated photon response, whereas the difference between measured and MC calculated responses to electrons indicates an additional dead layer thickness of about 12 {mu}m in the Si(Li) detector. The depth-dose profiles measured with extrapolation chambers at two laboratories agreed very well, and it was confirmed that the fitting procedure previously reported for {sup 147}Pm depth-dose profiles is also suitable for {beta} radiation from {sup 14}C. An increasing difference between measured and MC calculated dose rates for increasing absorber thickness was found, which is explained by limitations of the EGS4 code for transport of very low-energy electrons (below 10-20 keV). Finally a study of the thermally stimulated exoelectron emission (TSEE) response of BeO thin film dosemeters to {beta} radiation for radiation fields with maximum {beta} energies ranging from 67 keV to 2.27 MeV is reported. For maximum {beta} energies below approximately 500 keV, a decrease in the response amounting to about 20% was observed. It is thus concluded that a {beta} dose higher than about 10 {mu}Gy can be measured with these dosemeters to within 0 to -20% independently of the {beta}energy for E{sub {beta}},{sub max} values down to 67 keV. (au) 12 tabs., 38 ills., 71 refs.

  18. A structure-toxicity study of Aß42 reveals a new anti-parallel aggregation pathway.

    Directory of Open Access Journals (Sweden)

    Hélène Vignaud

    Full Text Available Amyloid beta (Aβ peptides produced by APP cleavage are central to the pathology of Alzheimer's disease. Despite widespread interest in this issue, the relationship between the auto-assembly and toxicity of these peptides remains controversial. One intriguing feature stems from their capacity to form anti-parallel ß-sheet oligomeric intermediates that can be converted into a parallel topology to allow the formation of protofibrillar and fibrillar Aβ. Here, we present a novel approach to determining the molecular aspects of Aß assembly that is responsible for its in vivo toxicity. We selected Aß mutants with varying intracellular toxicities. In vitro, only toxic Aß (including wild-type Aß42 formed urea-resistant oligomers. These oligomers were able to assemble into fibrils that are rich in anti-parallel ß-sheet structures. Our results support the existence of a new pathway that depends on the folding capacity of Aß .

  19. Quantitative structure-toxicity relationship (QSTR) studies on the organophosphate insecticides. (United States)

    Can, Alper


    Organophosphate insecticides are the most commonly used pesticides in the world. In this study, quantitative structure-toxicity relationship (QSTR) models were derived for estimating the acute oral toxicity of organophosphate insecticides to male rats. The 20 chemicals of the training set and the seven compounds of the external testing set were described by means of using descriptors. Descriptors for lipophilicity, polarity and molecular geometry, as well as quantum chemical descriptors for energy were calculated. Model development to predict toxicity of organophosphate insecticides in different matrices was carried out using multiple linear regression. The model was validated internally and externally. In the present study, QSTR model was used for the first time to understand the inherent relationships between the organophosphate insecticide molecules and their toxicity behavior. Such studies provide mechanistic insight about structure-toxicity relationship and help in the design of less toxic insecticides.

  20. Toxic encephalopathy induced by capecitabine. (United States)

    Niemann, B; Rochlitz, C; Herrmann, R; Pless, M


    Toxic encephalopathy is a rarely described side effect of 5-fluorouracil which usually presents with cerebellar, neuropsychiatric, and focal neurological symptoms. Magnetic resonance imaging findings are described as patchy white matter alterations. We report the 1st case of capecitabine-induced toxic encephalopathy with epilepsy-like symptoms and diffuse white matter alterations on magnetic resonance imaging.

  1. [Toxic effects of essential oil of Cannabis sativa L. and main constituents on planarian (Dugesia tigrina) (author's transl)]. (United States)

    Fournier, G; Lenicque, P M; Paris, M R


    Regenerating pieces of planarian worms are able to absorbe insoluble substances deposited on the base of the vessels in which they are cultivated. This biological test was used to study the toxic effects of the essential oil of Cannabis sativa L. The hydrocarbons such as pinene (alpha and beta), caryophyllene and so on were not toxic. On the contrary caryophyllene oxide was highly toxic. It was not possible to detect any protection by 5-hydroxytryptamine as it was the case against delta 1-tétrahydro-cannabinol and cannabidiol.


    Energy Technology Data Exchange (ETDEWEB)

    Simmons, F


    Reproductive toxicants are a very important class of compounds. They present unique hazards to those of child bearing ages, perform their 'dirty work' using a wide variety of mechanisms on a number of different organs, and are regulatorily important. Because of all of this, properly identifying reproductive toxicants is important, but fraught with difficulty. In this paper we will describe types or reproductive toxicants, their importance, and both mistakes and good practices that people who are not experts in reproductive toxicology may use in their attempts to identify them. Additionally, this paper will focus on chemical reproductive toxicants and will not address biological agents that could affect reproductive toxicity although many principles outlined here could be applied to that endeavor.

  3. Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4

    DEFF Research Database (Denmark)

    Richter, Wito; Day, Peter; Agrawal, Rani


    Beta1- and beta2-adrenergic receptors (betaARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta1AR but not beta2AR signaling, and chronic stimulation of the two receptors has opposing...

  4. Localization of thymosin beta-4 in tumors

    DEFF Research Database (Denmark)

    Larsson, L. -I.; Holck, Susanne


    Overexpression of thymosin beta-4 has been linked to malignant progression but the localization of this polypeptide within tumors is incompletely known. We therefore examined breast cancers for thymosin beta-4 using immunofluorescence. Reactive cells were identified with monoclonal cell marker...... in the tumor microenvironment may modulate tumor behavior....

  5. Nebivolol : third-generation beta-blockade

    NARCIS (Netherlands)

    de Boer, Rudolf A.; Voors, Adriaan A.; van Veldhuisen, Dirk J.


    Nebivolol is a third generation beta-blocker. It is highly selective for the beta 1-adrenoceptor, and has additional nitric oxide-mediated vasodilating and antioxidant properties, along with a favourable metabolic profile. Nebivolol is well tolerated by patients with hypertension and heart failure.

  6. The beta subunit of casein kinase II

    DEFF Research Database (Denmark)

    Boldyreff, B; Piontek, K; Schmidt-Spaniol, I;


    cDNAs encoding the beta subunit of pig and mouse CKII were isolated. The porcine cDNA was expressed as a fusion protein in Escherichia coli and used for the production of anti-CKII-beta subunit specific antibodies....

  7. Venus: Geology of Beta Regio rift system (United States)

    Nikishin, A. M.; Borozdin, V. K.; Bobina, N. N.


    Beta Regio is characterized by the existence of rift structures. We compiled new geologic maps of Beta Regio according to Magellan data. There are many large uplifted tesserae on beta upland. These tesserae are partly buried by younger volcanic cover. We can conclude, using these observations, that Beta upland formed mainly due to lithospheric tectonic uplifting and was only partly constructed by volcanism. Theia Mons is the center of the Beta rift system. Many rift belts are distributed radially to Theia Mons. Typical widths of rifts are 40-160 km. Rift valleys are structurally represented by crustal grabens or half-grabens. There are symmetrical and asymmetrical rifts. Many rifts have shoulder uplifts up to 0.5-1 km high and 40-60 km wide. Preliminary analysis for rift valley structural cross sections lead to the conclusion that rifts originated due to 5-10 percent crustal extension. Many rifts traverse Beta upland and spread to the surrounding lowlands. We can assume because of these data that Beta rift system has an active-passive origin. It formed due to regional tectonic lithospheric extension. Rifting was accelerated by upper-mantle hot spot origination under the center of passive extension (under the Beta Regio).

  8. Beta-agonists and animal welfare (United States)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  9. Shielding for beta-gamma radiation. (United States)

    Fletcher, J J


    The build-up factor, B, for lead was expressed as a polynominal cubic function of the relaxation length, mu x, and incorporated in a "general beta-gamma shielding equation." A computer program was written to determine shielding thickness for polyenergetic beta-gamma sources without resorting to the conventional "add-one-HVL" method.

  10. Prediction of Halocarbon Toxicity from Structure: A Hierarchical QSAR Approach

    Energy Technology Data Exchange (ETDEWEB)

    Gute, B D; Balasubramanian, K; Geiss, K; Basak, S C


    Mathematical structural invariants and quantum theoretical descriptors have been used extensively in quantitative structure-activity relationships (QSARs) for the estimation of pharmaceutical activities, biological properties, physicochemical properties, and the toxicities of chemicals. Recently our research team has explored the relative importance of various levels of chemodescriptors, i.e., topostructural, topochemical, geometrical, and quantum theoretical descriptors, in property estimation. This study examines the contribution of chemodescriptors ranging from topostructural to quantum theoretic calculations up to the Gaussian STO-3G level in the prediction of the toxicity of a set of twenty halocarbons. We also report the results of experimental cell-level toxicity studies on these twenty halocarbons to validate our models.

  11. Combinatorial QSAR modeling of chemical toxicants tested against Tetrahymena pyriformis. (United States)

    Zhu, Hao; Tropsha, Alexander; Fourches, Denis; Varnek, Alexandre; Papa, Ester; Gramatica, Paola; Oberg, Tomas; Dao, Phuong; Cherkasov, Artem; Tetko, Igor V


    Selecting most rigorous quantitative structure-activity relationship (QSAR) approaches is of great importance in the development of robust and predictive models of chemical toxicity. To address this issue in a systematic way, we have formed an international virtual collaboratory consisting of six independent groups with shared interests in computational chemical toxicology. We have compiled an aqueous toxicity data set containing 983 unique compounds tested in the same laboratory over a decade against Tetrahymena pyriformis. A modeling set including 644 compounds was selected randomly from the original set and distributed to all groups that used their own QSAR tools for model development. The remaining 339 compounds in the original set (external set I) as well as 110 additional compounds (external set II) published recently by the same laboratory (after this computational study was already in progress) were used as two independent validation sets to assess the external predictive power of individual models. In total, our virtual collaboratory has developed 15 different types of QSAR models of aquatic toxicity for the training set. The internal prediction accuracy for the modeling set ranged from 0.76 to 0.93 as measured by the leave-one-out cross-validation correlation coefficient ( Q abs2). The prediction accuracy for the external validation sets I and II ranged from 0.71 to 0.85 (linear regression coefficient R absI2) and from 0.38 to 0.83 (linear regression coefficient R absII2), respectively. The use of an applicability domain threshold implemented in most models generally improved the external prediction accuracy but at the same time led to a decrease in chemical space coverage. Finally, several consensus models were developed by averaging the predicted aquatic toxicity for every compound using all 15 models, with or without taking into account their respective applicability domains. We find that consensus models afford higher prediction accuracy for the

  12. Multisensor system for toxic gases detection generated on indoor environments (United States)

    Durán, C. M.; Monsalve, P. A. G.; Mosquera, C. J.


    This work describes a wireless multisensory system for different toxic gases detection generated on indoor environments (i.e., Underground coal mines, etc.). The artificial multisensory system proposed in this study was developed through a set of six chemical gas sensors (MQ) of low cost with overlapping sensitivities to detect hazardous gases in the air. A statistical parameter was implemented to the data set and two pattern recognition methods such as Principal Component Analysis (PCA) and Discriminant Function Analysis (DFA) were used for feature selection. The toxic gases categories were classified with a Probabilistic Neural Network (PNN) in order to validate the results previously obtained. The tests were carried out to verify feasibility of the application through a wireless communication model which allowed to monitor and store the information of the sensor signals for the appropriate analysis. The success rate in the measures discrimination was 100%, using an artificial neural network where leave-one-out was used as cross validation method.

  13. Computational selection of inhibitors of Abeta aggregation and neuronal toxicity. (United States)

    Chen, Deliang; Martin, Zane S; Soto, Claudio; Schein, Catherine H


    Alzheimer's disease (AD) is characterized by the cerebral accumulation of misfolded and aggregated amyloid-beta protein (Abeta). Disease symptoms can be alleviated, in vitro and in vivo, by 'beta-sheet breaker' pentapeptides that reduce plaque load. However the peptide nature of these compounds, made them biologically unstable and unable to penetrate membranes with high efficiency. The main goal of this study was to use computational methods to identify small molecule mimetics with better drug-like properties. For this purpose, the docked conformations of the active peptides were used to identify compounds with similar activities. A series of related beta-sheet breaker peptides were docked to solid state NMR structures of a fibrillar form of Abeta. The lowest energy conformations of the active peptides were used to design three dimensional (3D)-pharmacophores, suitable for screening the NCI database with Unity. Small molecular weight compounds with physicochemical features and a conformation similar to the active peptides were selected, ranked by docking and biochemical parameters. Of 16 diverse compounds selected for experimental screening, 2 prevented and reversed Abeta aggregation at 2-3microM concentration, as measured by Thioflavin T (ThT) fluorescence and ELISA assays. They also prevented the toxic effects of aggregated Abeta on neuroblastoma cells. Their low molecular weight and aqueous solubility makes them promising lead compounds for treating AD.

  14. Validation Measures in CMMI


    Khraiwesh, Mahmoud


    Validation is one of the software engineering disciplines that help build quality into software. The major objective of software validation process is to determine that the software performs its intended functions correctly and provide information about its quality and reliability. This paper identifies general measures for the specific goals and its specific practices of Validation Process Area (PA) in Capability Maturity Model Integration (CMMI). CMMI is developed by Software Engineering In...

  15. Beta-glucuronidase in physiology and disease. (United States)

    Basińska, Agnieszka; Floriańczyk, Bolesław


    beta-glucoronidase (EC is a lysosomal enzyme catylysing the decomposition of beta-D-glucoronides--compounds arising as a result of the combination of beta-D-glucoronic acid and a number of compounds both exo- and endogenous, containing hydroxylic, carboxylic, amine, imine or thiol groups. The most common test evaluating the activity of the enzyme is that using phenolphtalein glucoronide as a biosynthetic substrate. The freed aglycons are colorimetrically assayed. The activity of beta-glucoronidase increases in many pathological conditions: liver infammations, cirrhosis of the liver, inflammations of other organs, cholestatic jaundice, tuberculosis, sarcoidosis and also in neoplasms. Many authors point to beta-glucoronidase as a sensitive indicator signalling cell damage.

  16. Precision measurements in 20F beta decay (United States)

    Hughes, Maximilian; Naviliat-Cuncic, Oscar; Voytas, Paul; George, Elizabeth; Paulauskas, Stan; Huyan, Xueying


    Precision measurements of the shape of the beta particle energy spectrum provide a sensitive window to search for new interactions beyond the standard model. The decay of 20F offers an attractive system due to the simple decay scheme for a coincidence measurement. A beam of 20F ions, produced at the National Superconducting Cyclotron Laboratory, was implanted into a beta-detector. A gamma-ray detection system surrounded the beta detector to detect the beta-delayed gammas in coincidence to reduce the background. Preliminary analysis of these data focus on the half-life of 20F due to the statistical inconsistency of previous work. Monte Carlo simulations are ongoing to analyze the shape of the beta energy spectrum. Results of the analysis of the half-life will be presented. Supported by National Science Foundation Grant PHY-1102511.

  17. Ranking Beta Sheet Topologies of Proteins

    DEFF Research Database (Denmark)

    Fonseca, Rasmus; Helles, Glennie; Winter, Pawel


    One of the challenges of protein structure prediction is to identify long-range interactions between amino acids.  To reliably predict such interactions, we enumerate, score and rank all beta-topologies (partitions of beta-strands into sheets, orderings of strands within sheets and orientations...... of paired strands) of a given protein.  We show that the beta-topology corresponding to the native structure is, with high probability, among the top-ranked. Since full enumeration is very time-consuming, we also suggest a method to deal with proteins with many beta-strands. The results reported...... in this paper are highly relevant for ab initio protein structure prediction methods based on decoy generation. The top-ranked beta-topologies can be used to find initial conformations from which conformational searches can be started. They can also be used to filter decoys by removing those with poorly...

  18. The search for neutrinoless double beta decay

    CERN Document Server

    Gomez-Cadenas, J J; Mezzetto, M; Monrabal, F; Sorel, M


    In the last few years the search for neutrinoless double beta decay has evolved from being almost a marginal activity in neutrino physics to one of the highest priorities for understanding neutrinos and the origin of mass. There are two main reasons for this paradigm shift: the discovery of neutrino oscillations, which clearly established the existence of massive neutrinos; and the existence of an unconfirmed, but not refuted, claim of evidence for neutrinoless double decay in 76Ge. As a consequence, a new generation of experiments, employing different detection techniques and {\\beta}{\\beta} isotopes, is being actively promoted by experimental groups across the world. In addition, nuclear theorists are making remarkable progress in the calculation of the neutrinoless double beta decay nuclear matrix elements, thus eliminating a substantial part of the theoretical uncertainties affecting the particle physics interpretation of this process. In this report, we review the main aspects of the double beta decay pro...

  19. Experimental beta-alaninuria induced by (aminooxyacetate.

    Directory of Open Access Journals (Sweden)

    Kurozumi Y


    Full Text Available Experimental beta-alaninuria was induced in rats by injection of (aminooxyacetate (AOA, a potent inhibitor of aminotransferases, in order to elucidate the pathogenesis of hyper-beta-alaninemia. A 27-fold increase of beta-alanine (BALA excretion was induced by subcutaneous injection of 1 5 mg of AOA per kg of body weight. A 13-fold and a 9-fold increase of beta-aminoisobutyric acid (BAIBA and gamma-aminobutyric acid (GABA, respectively, were also induced simultaneously by the AOA injection. Identification of BALA and BAIBA isolated from the rat urine was performed by chromatographic and mass spectrometric analyses. The effects of AOA injection on the tissue levels of these amino acids were also studied. Contents of BALA in the liver and kidney and GABA in the brain increased significantly in response to AOA injection. The present study indicates that BALA transaminase is involved in hyper-beta-alaninemia.

  20. Validation of simulation models

    DEFF Research Database (Denmark)

    Rehman, Muniza; Pedersen, Stig Andur


    of models with regards to their purpose, character, field of application and time dimension inherently calls for a similar diversity in validation approaches. A classification of models in terms of the mentioned elements is presented and used to shed light on possible types of validation leading...... of models has been somewhat narrow-minded reducing the notion of validation to establishment of truth. This article puts forward the diversity in applications of simulation models that demands a corresponding diversity in the notion of validation....

  1. Complement activation by the amyloid proteins A beta peptide and beta 2-microglobulin

    DEFF Research Database (Denmark)

    Nybo, Mads; Nielsen, E H; Svehag, S E


    Complement activation (CA) has been reported to play a role in the pathogenesis of Alzheimer's disease (AD). To investigate whether CA may contribute to amyloidogenesis in general, the CA potential of different amyloid fibril proteins was tested. CA induced by A beta preparations containing soluble...... protein, protofilaments and some fibrils or only fibrils in a solid phase system (ELISA) was modest with a slow kinetics compared to the positive delta IgG control. Soluble A beta induced no detectable CA in a liquid phase system (complement consumption assay) while fibrillar A beta caused CA at 200 mg....../ml and higher concentrations. Soluble beta 2-microglobulin (beta 2M) purified from peritoneal dialysates was found to be as potent a complement activator as A beta in both solid and liquid phase systems while beta 2M purified from urine exhibited lower activity, a difference which may be explained...

  2. Clusters of conserved beta cell marker genes for assessment of beta cell phenotype

    DEFF Research Database (Denmark)

    Martens, Geert A; Jiang, Lei; Hellemans, Karine H;


    The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those...... of a large panel of other tissue and cell types, and transcripts with beta cell-abundant and -selective expression were identified. Iteration of this analysis in mouse, rat and human tissues generated a panel of conserved beta cell biomarkers. This panel was then used to compare isolated versus laser capture...... microdissected beta cells, monitor adaptations of the beta cell phenotype to fasting, and retrieve possible conserved transcriptional regulators....

  3. Painlev\\'e representation of Tracy-Widom$_\\beta$ distribution for $\\beta = 6$

    CERN Document Server

    Rumanov, Igor


    In \\cite{betaFP1}, we found explicit Lax pairs for the soft edge of beta ensembles with even integer values of $\\beta$. Using this general result, the case $\\beta=6$ is further considered here. This is the smallest even $\\beta$, when the corresponding Lax pair and its relation to Painlev\\'e II (PII) have not been known before, unlike cases $\\beta=2$ and $4$. It turns out that again everything can be expressed in terms of the Hastings-McLeod solution of PII. In particular, a second order nonlinear ODE for the logarithmic derivative of Tracy-Widom distribution for $\\beta=6$ involving the PII function in the coefficients, is found, which allows one to compute asymptotics for the distribution function. The ODE is a consequence of a linear system of three ODEs for which the local Painlev\\'e analysis yields series solutions with exponents in the set $4/3$, $1/3$ and $-2/3$.

  4. [Toxicity of sulpiride]. (United States)

    Ciszowski, Krzysztof; Szpak, Dorota; Wilimowska, Jolanta


    Sulpiride is a benzamide neuroleptic used in the treatment of some psychiatric and gastroenterological disorders. Its antipsychotic, antiautistic, activizing and antidepressive properties result from antagonistic action to dopaminergic D2, D3 and D4 receptors in the central nervous system (CNS). The oral bioavailability of sulpiride is poor and it does not appear to have an extensive first-pass metabolism, nor is it extensively protein-bound. Elimination of sulpiride appears to depend primarily on the kidneys. The acute sulpiride poisoning includes mainly neuropsychiatric (i.e., agitation, hallucinations, and CNS depression) as well as cardiac effects (i.e., hypotension, dysrhythmias, and sinus tachycardia). The life-threatening conditions with sometimes fatal outcome after sulpiride poisoning are prolongation of QTc interval with consequent torsade de pointes (TdP) and neuroleptic malignant syndrome (NMS). The quantitative methods for the measurement of sulpiride blood concentration are not routinely available and the toxic blood concentration is probably higher than 2 mg/L. Treatment of acute sulpiride poisoning includes standard protocols of gastrointestinal decontamination and further symptomatic and supportive measures, among them TdP (magnesium sulphate, isoproterenol, electrotherapy) and NMS treatment (benzodiazepines, bromocriptine, dantrolene, physical cooling).

  5. Toxic epidermal necrolysis. (United States)

    Castelain, Florence; Humbert, Philippe


    Toxic epidermal necrolysis (TEN) is a severe mucocutaneous drug-induced syndrome that causes massive keratinocyte apoptosis and therefore hydro-electrolytic disorders and systemic infection. TEN approximately affects one to two cases per million per year. Mortality rate may reach thirty percent of cases. Thus, TEN constitutes a therapeutic emergency at diagnosis. Typically, clinical examination shows a mucocutaneous detachment involving more than thirty percent of body area. Definitive diagnosis is made on cutaneous biopsy with histological exam that shows the blister of necrotic keratinocytes. Main differential diagnosis are acute staphylococcus epidermis, acute generalized exanthematous pustulosis, linear IgA bullous dermatosis, paraneoplastic pemphigus, bullous fixed pigmented erythema, acute lupus erythematosus. In the early days, SCORTEN gives a good estimation and is now widely used as prognostic score. Drugs are generally considered as the main etiology of TEN but in some cases bacterial or viral infections could be involved. Physiopathology remains unclear even if recent advances have reported the possible implication of immune pathways based on activation of T and NK cells. Treatment of TEN requires to be instituted as soon as the diagnosis is made and the patient is preferentially referred to a specialized unit. Supportive care consist of covering areas of cutaneous detachment. No other therapy has demonstrated its efficiency, but high-dose intravenous immunoglobulin might improve the prognosis.

  6. A Global Model of $\\beta^-$-Decay Half-Lives Using Neural Networks

    CERN Document Server

    Costiris, N; Gernoth, K A; Mavrommatis, E


    Statistical modeling of nuclear data using artificial neural networks (ANNs) and, more recently, support vector machines (SVMs), is providing novel approaches to systematics that are complementary to phenomenological and semi-microscopic theories. We present a global model of $\\beta^-$-decay halflives of the class of nuclei that decay 100% by $\\beta^-$ mode in their ground states. A fully-connected multilayered feed forward network has been trained using the Levenberg-Marquardt algorithm, Bayesian regularization, and cross-validation. The halflife estimates generated by the model are discussed and compared with the available experimental data, with previous results obtained with neural networks, and with estimates coming from traditional global nuclear models. Predictions of the new neural-network model are given for nuclei far from stability, with particular attention to those involved in r-process nucleosynthesis. This study demonstrates that in the framework of the $\\beta^-$-decay problem considered here, ...

  7. New regulators of Wnt/beta-catenin signaling revealed by integrative molecular screening. (United States)

    Major, Michael B; Roberts, Brian S; Berndt, Jason D; Marine, Shane; Anastas, Jamie; Chung, Namjin; Ferrer, Marc; Yi, XianHua; Stoick-Cooper, Cristi L; von Haller, Priska D; Kategaya, Lorna; Chien, Andy; Angers, Stephane; MacCoss, Michael; Cleary, Michele A; Arthur, William T; Moon, Randall T


    The identification and characterization of previously unidentified signal transduction molecules has expanded our understanding of biological systems and facilitated the development of mechanism-based therapeutics. We present a highly validated small interfering RNA (siRNA) screen that functionally annotates the human genome for modulation of the Wnt/beta-catenin signal transduction pathway. Merging these functional data with an extensive Wnt/beta-catenin protein interaction network produces an integrated physical and functional map of the pathway. The power of this approach is illustrated by the positioning of siRNA screen hits into discrete physical complexes of proteins. Similarly, this approach allows one to filter discoveries made through protein-protein interaction screens for functional contribution to the phenotype of interest. Using this methodology, we characterized AGGF1 as a nuclear chromatin-associated protein that participates in beta-catenin-mediated transcription in human colon cancer cells.

  8. Interaction of ochratoxin A with quaternary ammonium beta-cyclodextrin. (United States)

    Poór, Miklós; Kunsági-Máté, Sándor; Szente, Lajos; Matisz, Gergely; Secenji, Györgyi; Czibulya, Zsuzsanna; Kőszegi, Tamás


    Ochratoxin A (OTA) is a widely spread nephrotoxic food contaminant mycotoxin. Unfortunately, attenuation or prevention of the toxic effects of OTA is still an unresolved problem. Molecular inclusion of OTA by cyclodextrins (CDs) results in complexes with low stability. In the human organism, OTA exists mostly in the dianionic state (OTA(2-)). Therefore, our major goal was to develop a chemically modified cyclodextrin which gives a more stable complex with OTA than the previously published derivatives and which shows stronger preference towards OTA(2-). In our fluorescence spectroscopic study we demonstrate that quaternary ammonium beta-cyclodextrin (QABCD) fulfils both of these requirements. The calculated stability constant of the QABCD-OTA(2-) complex was 28,840 M(-1) (about 200-fold higher than that of the β-CD-OTA(2-) complex). We hypothesize, that QABCD may be a suitable tool for the decontamination of different OTA-contaminated drinks; furthermore, for alleviation of the toxic effects of OTA, such complex formation may reduce its absorption from the intestine.

  9. Expression of TGF-beta1, TGF-beta2, TGF-beta3 and the receptors TGF-betaRI and TGF-betaRII in placentomes of artificially inseminated and nuclear transfer derived bovine pregnancies. (United States)

    Ravelich, S R; Shelling, A N; Wells, D N; Peterson, A J; Lee, R S F; Ramachandran, A; Keelan, J A


    Bovine nuclear transfer pregnancies are characterized by a high incidence of placental abnormalities, notably, increased placentome size and deficiencies in trophoblast cell function and establishment of placental vasculature. Alterations in gene expression during placental growth and development may contribute to the appearance of large placentomes in pregnancies derived from nuclear transfer. The placenta synthesizes a number of cytokines and growth factors, including the transforming growth factor-betas (TGF-betas) that are involved in the establishment, maintenance and/or regulation of pregnancy. All forms of TGF-beta and their receptors are present at the fetal-maternal interface of the bovine placentome, where they are thought to play an important role in regulating growth, differentiation, and function of the placenta. Using real-time RT-PCR, we have examined the expression of TGF-beta1, TGF-beta2, TGF-beta3 and the receptors TGF-betaRI and TGF-betaRII in placentomes of artificially inseminated (AI) and nuclear transfer (NT)-derived bovine pregnancies at days 50, 100 and 150 of gestation. TGF-beta1, TGF-beta2 and TGF-beta3 mRNA expression increased by 2.0-2.8-fold, while TGF-betaRI and TGF-betaRII mRNA expression decreased by 1.7-2.0-fold in NT placentomes compared to AI controls at all gestational ages examined. These findings indicate that NT placentomes may be resistant to the growth suppressive effects of TGF-betas and could contribute to the placental proliferative abnormalities observed in NT-derived placentas. Alternatively, deficiencies in placentation may provide a mechanism whereby TGF-betas are dysregulated in NT pregnancies.

  10. A test strategy for the assessment of additive attributed toxicity of tobacco products. (United States)

    Kienhuis, Anne S; Staal, Yvonne C M; Soeteman-Hernández, Lya G; van de Nobelen, Suzanne; Talhout, Reinskje


    The new EU Tobacco Product Directive (TPD) prohibits tobacco products containing additives that are toxic in unburnt form or that increase overall toxicity of the product. This paper proposes a strategy to assess additive attributed toxicity in the context of the TPD. Literature was searched on toxicity testing strategies for regulatory purposes from tobacco industry and governmental institutes. Although mainly traditional in vivo testing strategies have been applied to assess toxicity of unburnt additives and increases in overall toxicity of tobacco products due to additives, in vitro tests combined with toxicogenomics and validated using biomarkers of exposure and disease are most promising in this respect. As such, tests are needed that are sensitive enough to assess additive attributed toxicity above the overall toxicity of tobacco products, which can associate assay outcomes to human risk and exposure. In conclusion, new, sensitive in vitro assays are needed to conclude whether comparable testing allows for assessment of small changes in overall toxicity attributed to additives. A more pragmatic approach for implementation on a short-term is mandated lowering of toxic emission components. Combined with risk assessment, this approach allows assessment of effectiveness of harm reduction strategies, including banning or reducing of additives.

  11. Naphthalene toxicity and antioxidant nutrients. (United States)

    Stohs, Sidney J; Ohia, Sunny; Bagchi, Debasis


    Naphthalene is a bicyclic aromatic compound that has wide industrial and commercial applications. It is used as the starting material for the synthesis of other compounds, as a moth repellent, soil fumigant and lavatory deodorant. Most exposure occurs through low dose chronic inhalation, dermal contact or ingestion through the food chain. The lungs and eyes appear to be most susceptible to toxicity, although biochemical markers of toxicity can be demonstrated in other tissues, such as the kidney, brain and liver. In addition to lens opacification (cataracts) and histological changes associated with pneumotoxicity, other biomarkers of toxic effects include glutathione depletion, lipid peroxidation, DNA fragmentation and the production of the active oxygen species as superoxide anion and hydroxyl radical. In addition, the urinary excretion of lipid metabolites occurs. A role for the tumor suppressor gene p53 has been demonstrated. Toxic manifestations of naphthalene are associated with its oxidative metabolism to various products including quinones. The ability to protect against the toxic effects of naphthalene by using various antioxidants and free radical scavengers has been demonstrated. Studies have been conducted with vitamin E, vitamin E succinate, melatonin, curcumin, various L-cysteine prodrugs, several aldose reductase inhibitors and spin-trapping agents. The ability to prevent the toxic manifestations of naphthalene is dependent on the pharmacokinetic properties of the agents, which have been studied. The appropriate selection of chemoprotectants can be useful in preventing naphthalene toxicity.

  12. Tadpole toxicity prediction using chromatographic systems. (United States)

    Fernández-Pumarega, Alejandro; Amézqueta, Susana; Fuguet, Elisabet; Rosés, Martí


    Toxicity has been emulated in tadpole species through chromatographic systems. The parameter studied to evaluate the non-specific toxicity of a compound is the narcosis concentration (Cnar), which is defined as the concentration needed for the immobilization of the organism. Because experimental investigation with animals is lengthy, costly, technically difficult, and ethically questionable, there is a great interest in developing surrogate physicochemical systems able to emulate biological systems to obtain the same information in a faster, more economic, and easier manner. In order to see which chromatographic systems would be able to emulate tadpole narcosis, both, tadpole narcosis data and data in several chromatographic and electrophoretic systems, were fitted to a linear solvation energy relationship (LSER) model. Thus, by comparison of the models it was possible to see which of the chromatographic systems were more similar to the biological one. The physicochemical systems that best emulate tadpole narcosis were an HPLC system based on an immobilized artificial membrane (IAM) column, and two micellar electrokinetic chromatography (MEKC) systems based on sodium taurocholate (STC) and a mixture of sodium dodecylsulphate (SDS) and Brij 35 as surfactants. A system based on a RP18 HPLC column also was selected for comparison because it is a common column in most analytical laboratories. To establish the models, a set of compounds with known Cnar values were analyzed in the chromatographic, and electrophoretic selected systems and, then, the retention factor (k) was correlated to the concentration of narcosis. Statistics showed that the system based on STC micelles was the best to emulate toxicity in tadpoles. The robustness and predictive ability of the developed models were validated.

  13. Molecular toxicity mechanism of nanosilver

    Directory of Open Access Journals (Sweden)

    Danielle McShan


    Full Text Available Silver is an ancient antibiotic that has found many new uses due to its unique properties on the nanoscale. Due to its presence in many consumer products, the toxicity of nanosilver has become a hot topic. This review summarizes recent advances, particularly the molecular mechanism of nanosilver toxicity. The surface of nanosilver can easily be oxidized by O2 and other molecules in the environmental and biological systems leading to the release of Ag+, a known toxic ion. Therefore, nanosilver toxicity is closely related to the release of Ag+. In fact, it is difficult to determine what portion of the toxicity is from the nano-form and what is from the ionic form. The surface oxidation rate is closely related to the nanosilver surface coating, coexisting molecules, especially thiol-containing compounds, lighting conditions, and the interaction of nanosilver with nucleic acids, lipid molecules, and proteins in a biological system. Nanosilver has been shown to penetrate the cell and become internalized. Thus, nanosilver often acts as a source of Ag+ inside the cell. One of the main mechanisms of toxicity is that it causes oxidative stress through the generation of reactive oxygen species and causes damage to cellular components including DNA damage, activation of antioxidant enzymes, depletion of antioxidant molecules (e.g., glutathione, binding and disabling of proteins, and damage to the cell membrane. Several major questions remain to be answered: (1 the toxic contribution from the ionic form versus the nano-form; (2 key enzymes and signaling pathways responsible for the toxicity; and (3 effect of coexisting molecules on the toxicity and its relationship to surface coating.

  14. An SAT® Validity Primer (United States)

    Shaw, Emily J.


    This primer should provide the reader with a deeper understanding of the concept of test validity and will present the recent available validity evidence on the relationship between SAT® scores and important college outcomes. In addition, the content examined on the SAT will be discussed as well as the fundamental attention paid to the fairness of…

  15. National Air Toxic Assessments (NATA) Results (United States)

    U.S. Environmental Protection Agency — The National Air Toxics Assessment was conducted by EPA in 2002 to assess air toxics emissions in order to identify and prioritize air toxics, emission source types...

  16. Toxic Picoplanktonic Cyanobacteria—Review

    Directory of Open Access Journals (Sweden)

    Natalia Jakubowska


    Full Text Available Cyanobacteria of a picoplanktonic cell size (0.2 to 2.0 µm are common organisms of both freshwater and marine ecosystems. However, due to their small size and relatively short study history, picoplanktonic cyanobacteria, in contrast to the microplanktonic cyanobacteria, still remains a poorly studied fraction of plankton. So far, only little information on picocyanobacteria toxicity has been reported, while the number of reports concerning their presence in ecosystems is increasing. Thus, the issue of picocyanobacteria toxicity needs more researchers’ attention and interest. In this report, we present information on the current knowledge concerning the picocyanobacteria toxicity, as well as their harmfulness and problems they can cause.

  17. Toxic picoplanktonic cyanobacteria--review. (United States)

    Jakubowska, Natalia; Szeląg-Wasielewska, Elżbieta


    Cyanobacteria of a picoplanktonic cell size (0.2 to 2.0 µm) are common organisms of both freshwater and marine ecosystems. However, due to their small size and relatively short study history, picoplanktonic cyanobacteria, in contrast to the microplanktonic cyanobacteria, still remains a poorly studied fraction of plankton. So far, only little information on picocyanobacteria toxicity has been reported, while the number of reports concerning their presence in ecosystems is increasing. Thus, the issue of picocyanobacteria toxicity needs more researchers' attention and interest. In this report, we present information on the current knowledge concerning the picocyanobacteria toxicity, as well as their harmfulness and problems they can cause.

  18. Methylmercury toxicity and functional programming

    DEFF Research Database (Denmark)

    Grandjean, Philippe


    PURPOSE: Adverse health effects of developmental toxicants may induce abnormal functional programming that leads to lasting functional deficits. This notion is considered from epidemiological evidence using developmental methylmercury neurotoxicity as an example. MOST IMPORTANT FINDINGS...... of certain brain functions, thereby causing confounding bias. The functional deficits caused by prenatal methylmercury exposure appear to be permanent, and their extent may depend on the joint effect of toxicants and nutrients. PRINCIPAL CONCLUSIONS: The lasting functional changes caused...... by neurodevelopmental methylmercury toxicity fit into the pattern of functional programming, with effects opposite to those linked to beneficial stimuli....

  19. Toxicity of Uranium Adsorbent Materials using the Microtox Toxicity Test

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jiyeon [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Jeters, Robert T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Gill, Gary A. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Kuo, Li-Jung [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Bonheyo, George T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)


    The Marine Sciences Laboratory at the Pacific Northwest National Laboratory evaluated the toxicity of a diverse range of natural and synthetic materials used to extract uranium from seawater. The uranium adsorbent materials are being developed as part of the U. S. Department of Energy, Office of Nuclear Energy, Fuel Resources Program. The goal of this effort was to identify whether deployment of a farm of these materials into the marine environment would have any toxic effects on marine organisms.

  20. Toxicity of staphylococcal toxic shock syndrome toxin 1 in rabbits.


    de Azavedo, J C; Arbuthnott, J P


    Strains of Staphylococcus aureus associated with toxic shock syndrome produce toxic shock syndrome toxin 1 (TSST 1), which is lethal to conventional rabbits and acts synergistically with gram-negative lipopolysaccharide. The lethal effect of TSST 1 was examined in specific-pathogen-free rabbits on the basis that these rabbits, being less colonized by gram-negative bacteria, would be less susceptible than conventional animals. Although there was no significant difference in mortality between s...

  1. Multidrug toxicity involving sumatriptan. (United States)

    Knittel, Jessica L; Vorce, Shawn P; Levine, Barry; Hughes, Rhome L; Bosy, Thomas Z


    A multidrug fatality involving sumatriptan is reported. Sumatriptan is a tryptamine derivative that acts at 5-HT(1B/1D) receptors and is used for the treatment of migraines. The decedent was a 21-year-old white female found dead in bed by her spouse. No signs of physical trauma were observed and a large number of prescription medications were discovered at the scene. Toxicological analysis of the central blood revealed sumatriptan at a concentration of 1.03 mg/L. Following therapeutic dosing guidelines, sumatriptan concentrations do not exceed 0.095 mg/L. Sumatriptan was isolated by solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode. A tissue distribution study was completed with the following concentrations measured: 0.61 mg/L in femoral blood, 0.56 mg/L in iliac blood, 5.01 mg/L in urine, 0.51 mg/kg in liver, 3.66 mg/kg in kidney, 0.09 mg/kg in heart, 0.32 mg/kg in spleen, 0.01 mg/kg in brain, 15.99 mg/kg in lung and 78.54 mg/45 mL in the stomach contents. Carisoprodol, meprobamate, fluoxetine, doxylamine, orphenadrine, dextromethorphan and hydroxyzine were also present in the blood at the following concentrations: 3.35, 2.36, 0.63, 0.19, 0.06, 0.55 and 0.16 mg/L. The medical examiner ruled the cause of death as acute mixed drug toxicity and the manner of death as accident.

  2. Checklists for external validity

    DEFF Research Database (Denmark)

    Dyrvig, Anne-Kirstine; Kidholm, Kristian; Gerke, Oke;


    RATIONALE, AIMS AND OBJECTIVES: The quality of the current literature on external validity varies considerably. An improved checklist with validated items on external validity would aid decision-makers in judging similarities among circumstances when transferring evidence from a study setting...... to an implementation setting. In this paper, currently available checklists on external validity are identified, assessed and used as a basis for proposing a new improved instrument. METHOD: A systematic literature review was carried out in Pubmed, Embase and Cinahl on English-language papers without time restrictions....... The retrieved checklist items were assessed for (i) the methodology used in primary literature, justifying inclusion of each item; and (ii) the number of times each item appeared in checklists. RESULTS: Fifteen papers were identified, presenting a total of 21 checklists for external validity, yielding a total...

  3. Bibliometrics for Social Validation. (United States)

    Hicks, Daniel J


    This paper introduces a bibliometric, citation network-based method for assessing the social validation of novel research, and applies this method to the development of high-throughput toxicology research at the US Environmental Protection Agency. Social validation refers to the acceptance of novel research methods by a relevant scientific community; it is formally independent of the technical validation of methods, and is frequently studied in history, philosophy, and social studies of science using qualitative methods. The quantitative methods introduced here find that high-throughput toxicology methods are spread throughout a large and well-connected research community, which suggests high social validation. Further assessment of social validation involving mixed qualitative and quantitative methods are discussed in the conclusion.

  4. Bibliometrics for Social Validation (United States)


    This paper introduces a bibliometric, citation network-based method for assessing the social validation of novel research, and applies this method to the development of high-throughput toxicology research at the US Environmental Protection Agency. Social validation refers to the acceptance of novel research methods by a relevant scientific community; it is formally independent of the technical validation of methods, and is frequently studied in history, philosophy, and social studies of science using qualitative methods. The quantitative methods introduced here find that high-throughput toxicology methods are spread throughout a large and well-connected research community, which suggests high social validation. Further assessment of social validation involving mixed qualitative and quantitative methods are discussed in the conclusion. PMID:28005974

  5. Clusters of conserved beta cell marker genes for assessment of beta cell phenotype

    DEFF Research Database (Denmark)

    Martens, Geert A; Jiang, Lei; Hellemans, Karine H;


    The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those...... microdissected beta cells, monitor adaptations of the beta cell phenotype to fasting, and retrieve possible conserved transcriptional regulators.......The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those...... of a large panel of other tissue and cell types, and transcripts with beta cell-abundant and -selective expression were identified. Iteration of this analysis in mouse, rat and human tissues generated a panel of conserved beta cell biomarkers. This panel was then used to compare isolated versus laser capture...

  6. Evidence for Novel [beta]-Sheet Structures in Iowa Mutant [beta]-Amyloid Fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Tycko, Robert; Sciarretta, Kimberly L.; Orgel, Joseph P.R.O.; Meredith, Stephen C.; (IIT); (NIH); (UC)


    Asp23-to-Asn mutation within the coding sequence of {beta}-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-A{beta}40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-A{beta}40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10{sup -3} min{sup -1} and 1.07 x 10{sup -4} min{sup -1} for D23N-A{beta}40 and the wild-type peptide WT-A{beta}40, respectively) and without a lag phase. Electron microscopy shows that D23N-A{beta}40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-{beta} pattern, with a sharp reflection at 4.7 {angstrom} and a broad reflection at 9.4 {angstrom}, which is notably smaller than the value for WT-A{beta}40 fibrils (10.4 {angstrom}). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-A{beta}40 fibrils containing the in-register, parallel {beta}-sheet structure commonly found in WT-A{beta}40 fibrils and most other amyloid fibrils. Antiparallel {beta}-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through 13C-13C and 15N-13C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-A{beta}40 fibrils and the unusual vasculotropic clinical picture in these patients.

  7. In vivo toxicity of nitroaromatics: A comprehensive quantitative structure-activity relationship study. (United States)

    Gooch, Aminah; Sizochenko, Natalia; Rasulev, Bakhtiyor; Gorb, Leonid; Leszczynski, Jerzy


    The toxicity data of 90 nitroaromatic compounds related to their 50% lethal dose concentration for rats (LD50) were analyzed to develop quantitative structure-activity relationship (QSAR) models. Quantum-chemically calculated descriptors together with molecular descriptors generated by DRAGON, PaDEL, and HiT-QSAR software were utilized to build QSAR models. Quality and validity of the models were determined by internal and external validation techniques. The results show that the toxicity of nitroaromatic compounds depends on various factors, such as the number of nitro-groups, the topological state, and the presence of certain structural fragments. The developed models based on the largest (to date) dataset of nitroaromatics in vivo toxicity showed a good predictive ability. The results provide important input that could be applied in a preliminary assessment of nitroaromatic compounds' toxicity to mammals. Environ Toxicol Chem 2017;9999:1-7. © 2017 SETAC.

  8. Non-Toxic HAN Monopropellant Propulsion Project (United States)

    National Aeronautics and Space Administration — Non-toxic monopropellants have been developed that provide better performance than toxic hydrazine. Formulations based on hydroxylammonium nitrate (HAN) have...

  9. Two-generation reproduction toxicity study in rats with methoxychlor. (United States)

    Aoyama, Hiroaki; Hojo, Hitoshi; Takahashi, Ken L; Shimizu-Endo, Naoko; Araki, Masayuki; Takeuchi-Kashimoto, Yukiko; Saka, Machiko; Teramoto, Shoji


    A two-generation reproduction toxicity study was conducted in rats with a reference estrogenic pesticide, methoxychlor, to validate the sensitivity and competency of current guidelines recommended by the United States Environmental Protection Agency; Japanese Ministry of Agriculture, Forestry and Fisheries; and Organisation for Economic Co-operation and Development for predicting reproductive toxicity of the test compound based on estrogenic endocrine disrupting effects. Both sexes of SD rats were exposed to methoxychlor in the diet at concentrations of 0, 10, 500 and 1500 ppm for two successive generations. The present study has successfully detected estrogenic activities and reproductive toxicities of methoxychlor, as well as its systemic toxicity. Body weights, body weight gains and food consumption of both sexes of animals were suppressed significantly in the 500 and 1500 ppm groups. Typical reproductive toxicities observed in females of these groups included, but were not limited to, prolonged estrous cycle, reduced fertility, decreased numbers of implantation sites and newborns, decreased ovary weights and/or increased incidences of cystic ovary. Uterine weights of weanlings increased significantly in these groups, suggesting that the sensitivity of this parameter for predicting estrogenic ability of the test compound is comparable to that of the uterotrophic assay. Reproductive toxicities of methoxychlor seemed less potent in males than in females. Methoxychlor delayed preputial separation and significantly reduced sperm counts and reproductive organ weights of males of the 500 and/or 1500 ppm groups; however, most males that failed to impregnate females in the same group showed normal fertility when they were re-mated with untreated females. Neither systemic nor reproductive toxicities appeared in the 10 ppm group.

  10. Dosimetry of Low-Energy Beta Radiation

    DEFF Research Database (Denmark)

    Borg, Jette

    Useful techniques and procedures for derermination of absorbed doses from exposure in a low-energy beta radiation were studied and evaluated. The four techniques included were beta spectrometry, extrapolation chamber dosimetry, Monte Carlo (MC) calculations, and exoelectron dosimetry. As a typical...... low-energy beta radiation field a moderated spectrum from a carbon-14 source was used. The measured responce of a Si(Li) detector to photons (bremsstrahlung) showed fine agreemant with the MC calculated photon response, whereas the difference between measured and MC calculated response to electrons...

  11. Scintillating bolometers for Double Beta Decay search

    CERN Document Server

    Gironi, Luca


    In the field of Double Beta Decay (DBD) searches, the use of high resolution detectors in which background can be actively discriminated is very appealing. Scintillating bolometers containing a Double Beta Decay emitter can largely fulfill this very interesting possibility. In this paper we present the latest results obtained with CdWO4 and CaMoO4 crystals. Moreover we report, for the first time, a very interesting feature of CaMoO4 bolometers: the possibility to discriminate beta-gamma events from those induced by alpha particles thanks to different thermal pulse shape.

  12. Beta-2-mikroglobulin ved medicinske sygdomme

    DEFF Research Database (Denmark)

    Hansen, P B; Olsen, Niels Vidiendal


    -interstitial nephropathy, increased quantities of beta 2M are excreted in the urine. If the rate of glomerular filtration is reduced, serum-beta 2M is increased and this is also the case in persons with increased cell division despite normal renal function. Serum-beta 2M is, therefore, raised in numerous malignant...... must be presumed to be of value not only in the diagnosis of cerebral AIDS and other (latent) CNS infections but also to demonstrate complicating cerebral malignant lymphomata at an early stage....

  13. Silent ischemia and beta-blockade

    DEFF Research Database (Denmark)

    Egstrup, K


    and should also be directed at the other coronary artery risk factors of the patients. The effects of beta-blockers, which reduce the duration and frequency of silent ischemic episodes, is well described. The effect is most pronounced in the morning, when the frequency of ischemia is highest......, and the mechanism of action seems mainly mediated through a reduction in myocardial oxygen demand. beta-Blockers have shown effectiveness in both effort-induced angina and mixed angina, and increased anti-ischemic potency may be achieved by combination therapy with a calcium antagonist. Abrupt withdrawal of beta-blockers...

  14. Construction of a {gamma}-{gamma} and {beta}-{gamma} coincidence measurement system for precise determination of nuclear data

    Energy Technology Data Exchange (ETDEWEB)

    Furutaka, Kazuyoshi; Nakamura, Shoji; Harada, Hideo; Katoh, Toshio [Japan Nuclear Cycle Development Institute, Tokai Works, Tokai, Ibaraki (Japan)


    A {gamma}-{gamma} and {beta}-{gamma} coincidence measurement system was constructed for the precise determination of nuclear data, such as thermal neutron capture cross sections and {gamma}-ray emission probabilities. The validity of the system was tested by a {gamma}-{gamma} coincidence measurement with a {sup 60}Co standard source. (author)

  15. 2011 NATA - Air Toxics Monitors (United States)

    U.S. Environmental Protection Agency — This dataset includes annual (2005 - 2013) statistics of measured ambient air toxics concentrations (in micrograms per cubic meter) and associated risk estimates for...

  16. Low-Toxicity PMR Polyimide (United States)

    Pater, Ruth H.; Ely, Robert M.; Stanfield, Clarence E.; Dickerson, George E.; Snoha, John J.; Srinivasan, Krishna; Hou, Tan


    New low-toxicity PMR system developed and designated LaRC-RP46. Exhibits better processability, toughness, and thermo-oxidative stability than does PMR-15. Polyimide inexpensive and readily processed into high-quality graphite-fiber-reinforced composite. Used as high-performance, high-temperature-resistant adhesive, molding, composite, film, and coating material where low toxicity desired characteristic. Significantly extends applications of PMR-type polyimides.

  17. Dopamine beta-hydroxylase deficiency

    Directory of Open Access Journals (Sweden)

    Senard Jean-Michel


    Full Text Available Abstract Dopamine beta-hydroxylase (DβH deficiency is a very rare form of primary autonomic failure characterized by a complete absence of noradrenaline and adrenaline in plasma together with increased dopamine plasma levels. The prevalence of DβH deficiency is unknown. Only a limited number of cases with this disease have been reported. DβH deficiency is mainly characterized by cardiovascular disorders and severe orthostatic hypotension. First symptoms often start during a complicated perinatal period with hypotension, muscle hypotonia, hypothermia and hypoglycemia. Children with DβH deficiency exhibit reduced ability to exercise because of blood pressure inadaptation with exertion and syncope. Symptoms usually worsen progressively during late adolescence and early adulthood with severe orthostatic hypotension, eyelid ptosis, nasal stuffiness and sexual disorders. Limitation in standing tolerance, limited ability to exercise and traumatic morbidity related to falls and syncope may represent later evolution. The syndrome is caused by heterogeneous molecular alterations of the DBH gene and is inherited in an autosomal recessive manner. Restoration of plasma noradrenaline to the normal range can be achieved by therapy with the synthetic precursor of noradrenaline, L-threo-dihydroxyphenylserine (DOPS. Oral administration of 100 to 500 mg DOPS, twice or three times daily, increases blood pressure and reverses the orthostatic intolerance.

  18. Identification of a novel group of putative Arabidopsis thaliana beta-(1,3)-galactosyltransferases

    DEFF Research Database (Denmark)

    Qu, Yongmei; Egelund, Jack; Gilson, Paul R;


    ,3)-GalT activity. This bioinformatic/molecular study of CAZy GT-family-31 was validated by the recent report of Strasser et al. (Plant Cell 19:2278-2292, 2007) that another member of this family (At1g26810; GALT1) encodes a beta-(1,3)-GalT involved in the biosynthesis of the Lewis a epitope of N...

  19. Energetic, Structural, and Antimicrobial Analyses of [beta]-Lactam Side Chain Recognition by [beta]-Lactamases

    Energy Technology Data Exchange (ETDEWEB)

    Caselli, E.; Powers, R.A.; Blaszczak, L.C.; Wu, C.Y.E.; Prati, F.; Shoichet, B.K. (NWU)


    Penicillins and cephalosporins are among the most widely used and successful antibiotics. The emergence of resistance to these {beta}-lactams, most often through bacterial expression of {beta}-lactamases, threatens public health. To understand how {beta}-lactamases recognize their substrates, it would be helpful to know their binding energies. Unfortunately, these have been difficult to measure because {beta}-lactams form covalent adducts with {beta}-lactamases. This has complicated functional analyses and inhibitor design. To investigate the contribution to interaction energy of the key amide (R1) side chain of {beta}-lactam antibiotics, eight acylglycineboronic acids that bear the side chains of characteristic penicillins and cephalosporins, as well as four other analogs, were synthesized. These transition-state analogs form reversible adducts with serine {beta}-lactamases. Therefore, binding energies can be calculated directly from K{sub i} values. The K{sub i} values measured span four orders of magnitude against the Group I {beta}-lactamase AmpC and three orders of magnitude against the Group II {beta}-lactamase TEM-1. The acylglycineboronic acids have K{sub i} values as low as 20 nM against AmpC and as low as 390 nM against TEM-1. The inhibitors showed little activity against serine proteases, such as chymotrypsin. R1 side chains characteristic of {beta}-lactam inhibitors did not have better affinity for AmpC than did side chains characteristic of {beta}-lactam substrates. Two of the inhibitors reversed the resistance of pathogenic bacteria to {beta}-lactams in cell culture. Structures of two inhibitors in their complexes with AmpC were determined by X-ray crystallography to 1.90 {angstrom} and 1.75 {angstrom} resolution; these structures suggest interactions that are important to the affinity of the inhibitors. Acylglycineboronic acids allow us to begin to dissect interaction energies between {beta}-lactam side chains and {beta}-lactamases. Surprisingly

  20. Data on acute toxicity of the progestin STS 557. (United States)

    Hillesheim, H G; Hoffmann, H


    In mice and rabbits of both sexes the acute toxicity of STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one) was determined after its oral or parenteral (i.p., s.c.) administration. In rabbits increasing lethality was observed following STS 557 suspended in tylose solution at the dose range of 1.0 to 3.0 g/kg p.o. or i.p. The approximate LD50-values were 1.0 to 1.5 g/kg for the i.p. route and 1.0 to 2.0 g/kg for the oral route. Levonorgestrel injected i.p. did not cause any lethality up to the dose of 3.0 g/kg. After oral or s.c. administration to mice, doses of 4.0 g/kg STS 557 were well tolerated. A dose-related toxicity occurred only after i.p. doses between 0.5 and 1.0 g/kg (STS 557), and between 2.0 and 4.0 g/kg (levonorgestrel), respectively. Using an oily vehicle for the oral route in mice, the lethal threshold dose for STS 557 was lowered to about 2.0 g/kg. In conclusion, a low oral acute toxicity was determined for STS 557 corresponding to that of other progestagens like levonorgestrel or norethisterone.

  1. Ocular toxicity of targeted therapies. (United States)

    Renouf, Daniel J; Velazquez-Martin, Juan P; Simpson, Rand; Siu, Lillian L; Bedard, Philippe L


    Molecularly targeted agents are commonly used in oncology practice, and many new targeted agents are currently being tested in clinical trials. Although these agents are thought to be more specific and less toxic then traditional cytotoxic chemotherapy, they are associated with a variety of toxicities, including ocular toxicity. Many of the molecules targeted by anticancer agents are also expressed in ocular tissues. We reviewed the literature for described ocular toxicities associated with both approved and investigational molecularly targeted agents. Ocular toxicity has been described with numerous approved targeted agents and also seems to be associated with several classes of agents currently being tested in early-phase clinical trials. We discuss the proposed pathogenesis, monitoring guidelines, and management recommendations. It is important for oncologists to be aware of the potential for ocular toxicity, with prompt recognition of symptoms that require referral to an ophthalmologist. Ongoing collaboration between oncologists and ocular disease specialists is critical as the use of molecularly targeted agents continues to expand and novel targeted drug combinations are developed.

  2. Determination of Toxic Metals in Different Brand of Chocolates and Candies, Marketed in Pakistan


    Nusrat Jalbani; Tasneem Gul Kazi; Hassan I. Afridi; Mohammad Bilal Arain


    In present study three toxic metals, cadmium (Cd), nickel (Ni) and lead (Pb) were determined in chocolates and candy samples available in local markets of Hyderabad, Pakistan. Concentrations of understudy toxic metals (TMs) were determined by electrothermal atomic absorption spectrometry (ETAAS) prior to microwave assisted acid digestion. Validation of the methodology was performed by standard addition method and conventional acid digestion on electric hot plate to obtained TMs concentration,...

  3. alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells

    NARCIS (Netherlands)

    Kazmierczak, Anna; Strosznajder, Joanna B.; Adamczyk, Agata


    alpha-Synuclein is the fundamental component of Lewy bodies which occur in the brain of 60% of sporadic and familial Alzheimer's disease patients. Moreover, a proteolytic fragment of alpha-synuclein, the so-called non-amyloid component of Alzheimer's disease amyloid, was found to be an integral part

  4. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

    DEFF Research Database (Denmark)

    Larsen, L; Tonnesen, M; Ronn, S G;


    by immunoblotting and by immunoblotting combined with electrophoretic mobility shift assay, respectively. Viability was analysed by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and histone...

  5. [In vitro inhibition of granulopoiesis by beta-lactam antibiotics. Comparison of piperacillin, mezlocillin, ceftriaxone and ceftazidime]. (United States)

    Marie, J P; Thevenin, D; Zittoun, R


    The mechanism of neutropenia induced by beta-lactam antibiotics was explored by studying the action of these drugs on granulopoiesis in vitro. Normal bone marrows were cultivated in the presence of increasing concentrations of piperacillin (10 marrows), mezlocillin, ceftriaxone and ceftazidime (5 marrows each) in order to find out whether these antibiotics exhibited toxicity to granulocyte-monocyte precursors. A dose-dependent inhibition of granulopoiesis was found in all cases. When the doses used were equivalent to maximum plasma concentrations in vivo, inhibition was minimal with piperacillin and mezlocillin and much more pronounced with the cephalosporins. This dose-dependent inhibition suggests that toxicity is involved in the mechanism of neutropenia induced by beta-lactam antibiotics.

  6. Model Validation Status Review

    Energy Technology Data Exchange (ETDEWEB)

    E.L. Hardin


    The primary objective for the Model Validation Status Review was to perform a one-time evaluation of model validation associated with the analysis/model reports (AMRs) containing model input to total-system performance assessment (TSPA) for the Yucca Mountain site recommendation (SR). This review was performed in response to Corrective Action Request BSC-01-C-01 (Clark 2001, Krisha 2001) pursuant to Quality Assurance review findings of an adverse trend in model validation deficiency. The review findings in this report provide the following information which defines the extent of model validation deficiency and the corrective action needed: (1) AMRs that contain or support models are identified, and conversely, for each model the supporting documentation is identified. (2) The use for each model is determined based on whether the output is used directly for TSPA-SR, or for screening (exclusion) of features, events, and processes (FEPs), and the nature of the model output. (3) Two approaches are used to evaluate the extent to which the validation for each model is compliant with AP-3.10Q (Analyses and Models). The approaches differ in regard to whether model validation is achieved within individual AMRs as originally intended, or whether model validation could be readily achieved by incorporating information from other sources. (4) Recommendations are presented for changes to the AMRs, and additional model development activities or data collection, that will remedy model validation review findings, in support of licensing activities. The Model Validation Status Review emphasized those AMRs that support TSPA-SR (CRWMS M&O 2000bl and 2000bm). A series of workshops and teleconferences was held to discuss and integrate the review findings. The review encompassed 125 AMRs (Table 1) plus certain other supporting documents and data needed to assess model validity. The AMRs were grouped in 21 model areas representing the modeling of processes affecting the natural and

  7. Synthesis of mesoporous Beta and Sn-Beta zeolites and their catalytic performances. (United States)

    Jin, Junjiang; Ye, Xinxin; Li, Yongsheng; Wang, Yanqin; Li, Liang; Gu, Jinlou; Zhao, Wenru; Shi, Jianlin


    Mesoporous Beta zeolite has been successfully prepared through hydrothermal synthesis in the presence of cationic ammonium-modified chitosan as the meso-template. Through a subsequent solid-gas reaction between highly dealuminated mesoporous Beta zeolite and SnCl4 steam at an elevated temperature, mesoporous Sn-Beta has been facilely obtained. It was revealed that the addition of cationic chitosan induced the nanocrystal aggregation to particle sizes of ∼300 nm, giving rise to the intercrystalline/interparticle mesoporosity. In the Sn-implanting procedure, Sn species were demonstrated to be doped into the framework of the resulting mesoporous Beta zeolite in a tetrahedral environment without structural collapse. Due to the micro/mesoporous structures, both mesoporous Beta and Sn-Beta exhibited superior performances in α-pinene isomerization, Baeyer-Villiger oxidation of 2-adamantanone by hydrogen peroxide and the isomerization of glucose in water, respectively.

  8. Degradation of starch-poly(beta-hydroxybutyrate-co-beta-hydroxyvalerate) bioplastic in tropical coastal waters. (United States)

    Imam, S H; Gordon, S H; Shogren, R L; Tosteson, T R; Govind, N S; Greene, R V


    Extruded bioplastic was prepared from cornstarch or poly(beta-hydroxybutyrate-co-beta-hydroxyvalerate) (PHBV) or blends of cornstarch and PHBV. The blended formulations contained 30 or 50% starch in the presence or absence of polyethylene oxide (PEO), which enhances adherence of starch granules to PHBV. Degradation of these formulations was monitored for 1 year at four stations in coastal water southwest of Puerto Rico. Two stations were within a mangrove stand. The other two were offshore; one of these stations was on a shallow shoulder of a reef, and the other was at a location in deeper water. Microbial enumeration at the four stations revealed considerable flux in the populations over the course of the year. However, in general, the overall population densities were 1 order of magnitude less at the deeper-water station than at the other stations. Starch degraders were 10- to 50-fold more prevalent than PHBV degraders at all of the stations. Accordingly, degradation of the bioplastic, as determined by weight loss and deterioration of tensile properties, correlated with the amount of starch present (100% starch >50% starch > 30% starch > 100% PHBV). Incorporation of PEO into blends slightly retarded the rate of degradation. The rate of loss of starch from the 100% starch samples was about 2%/day, while the rate of loss of PHBV from the 100% PHBV samples was about 0.1%/day. Biphasic weight loss was observed for the starch-PHBV blends at all of the stations. A predictive mathematical model for loss of individual polymers from a 30% starch-70% PHBV formulation was developed and experimentally validated. The model showed that PHBV degradation was delayed 50 days until more than 80% of the starch was consumed and predicted that starch and PHBV in the blend had half-lives of 19 and 158 days, respectively. Consistent with the relatively low microbial populations, bioplastic degradation at the deeper-water station exhibited an initial lag period, after which degradation

  9. Expression of transforming growth factor beta (TGF beta) receptors and expression of TGF beta 1, TGF beta 2 and TGF beta 3 in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Damstrup, L; Rygaard, K; Spang-Thomsen, M;


    A panel of 21 small cell lung cancer cell (SCLC) lines were examined for the presence of Transforming growth factor beta receptors (TGF beta-r) and the expression of TGF beta mRNAs. By the radioreceptor assay we found high affinity receptors to be expressed in six cell lines. scatchard analysis...... of the binding data demonstrated that the cells bound between 4.5 and 27.5 fmol mg-1 protein with a KD ranging from 16 to 40 pM. TGF beta 1 binding to the receptors was confirmed by cross-linking TGF beta 1 to the TGF beta-r. Three classes of TGF beta-r were demonstrated, type I and type II receptors with M......(r) = 65,000 and 90,000 and the betaglycan (type III) with M(r) = 280,000. Northern blotting showed expression of TGF beta 1 mRNA in ten, TGF beta 2 mRNA in two and TGF beta 3 mRNA in seven cell lines. Our results provide, for the first time, evidence that a large proportion of a broad panel of SCLC cell...

  10. Design optimization of beta- and photovoltaic conversion devices

    Energy Technology Data Exchange (ETDEWEB)

    Wichner, R.; Blum, A.; Fischer-Colbrie, E.; Chau, H.


    This report presents the theoretical and experimental results of an LLL Electronics Engineering research program aimed at optimizing the design and electronic-material parameters of beta- and photovoltaic p-n junction conversion devices. To meet this objective, a comprehensive computer code has been developed that can handle a broad range of practical conditions. The physical model upon which the code is based is described first. Then, an example is given of a set of optimization calculations along with the resulting optimized efficiencies for silicon (Si) and gallium-arsenide (GaAs) devices. The model we have developed, however, is not limited to these materials. It can handle any appropriate material--single or polycrystalline-- provided energy absorption and electron-transport data are available. To check code validity, the performance of experimental silicon p-n junction devices (produced in-house) were measured under various light intensities and spectra as well as under tritium beta irradiation. The results of these tests were then compared with predicted results based on the known or best estimated device parameters. The comparison showed very good agreement between the calculated and the measured results.

  11. Guidelines for Use of the Approximate Beta-Poisson Dose-Response Model. (United States)

    Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie


    For dose-response analysis in quantitative microbial risk assessment (QMRA), the exact beta-Poisson model is a two-parameter mechanistic dose-response model with parameters α>0 and β>0, which involves the Kummer confluent hypergeometric function. Evaluation of a hypergeometric function is a computational challenge. Denoting PI(d) as the probability of infection at a given mean dose d, the widely used dose-response model PI(d)=1-(1+dβ)-α is an approximate formula for the exact beta-Poisson model. Notwithstanding the required conditions α1, issues related to the validity and approximation accuracy of this approximate formula have remained largely ignored in practice, partly because these conditions are too general to provide clear guidance. Consequently, this study proposes a probability measure Pr(0 (22α̂)0.50 for 0.020.99) . This validity measure and rule of thumb were validated by application to all the completed beta-Poisson models (related to 85 data sets) from the QMRA community portal (QMRA Wiki). The results showed that the higher the probability Pr(0 dose-response curve.

  12. Beta-2 Microglobulin Kidney Disease Test (United States)

    ... Beta 2 Microglobulin, Serum or Urine Related tests: Albumin , Creatinine , BUN , Heavy Metals Were you looking for ... monitor persons with end-stage renal disease (ESRD) Excess B2M can accumulate in joint spaces ( synovitis ) in ...

  13. Probing neutrinoless double beta decay with SNO+

    CERN Document Server

    Arushanova, Evelina


    Probing neutrinoless double beta decay is one of the primary goals for SNO+, SNOLAB's multi-purpose neutrino detector. In order to achieve this goal the SNO detector has been adapted so that it can be filled with Te-loaded liquid scintillator. During the initial double beta phase the target loading is 0.3% natural Te, which equates to $\\sim790$ kg of double beta isotope. Estimating the sensitivity to neutrinoless double beta decay requires a well understood background model. For SNO+ this is provided by a comprehensive study considering all possible background contributions, whether they originate from within the liquid scintillator cocktail, the surrounding parts of the detector or other irreducible backgrounds. Given these considerations, for five years running in the initial phase, the expected sensitivity is $T_{1/2}^{0\

  14. Neutrino potential for neutrinoless double beta decay

    CERN Document Server

    Iwata, Yoritaka


    Neutrino potential for neutrinoless double beta decay is studied with focusing on its statistical property. The statistics provide a gross view of understanding amplitude of constitutional components of the nuclear matrix element.

  15. Beta cell proliferation and growth factors

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis; Svensson, C; Møldrup, Annette


    Formation of new beta cells can take place by two pathways: replication of already differentiated beta cells or neogenesis from putative islet stem cells. Under physiological conditions both processes are most pronounced during the fetal and neonatal development of the pancreas. In adulthood little...... increase in the beta cell number seems to occur. In pregnancy, however, a marked hyperplasia of the beta cells is observed both in rodents and man. Increased mitotic activity has been seen both in vivo and in vitro in islets exposed to placental lactogen (PL), prolactin (PRL) and growth hormone (GH......). Receptors for both GH and PRL are expressed in islet cells and are upregulated during pregnancy. By mutational analysis we have identified different functional domains of the cytoplasmic part of the GH receptor. Thus the mitotic signaling only requires the membrane proximal part of the receptor...

  16. Phenomenology of neutrinoless double beta decay

    CERN Document Server

    Gómez-Cadenas, J J


    This paper reviews the current status and future outlook of neutrinoless double beta decay searches, which try to provide an answer to the fundamental question of whether neutrinos are Dirac or Majorana particles.

  17. Literature in Focus Beta Beams: Neutrino Beams

    CERN Multimedia


    By Mats Lindroos (CERN) and Mauro Mezzetto (INFN Padova, Italy) Imperial Press, 2009 The beta-beam concept for the generation of electron neutrino beams was first proposed by Piero Zucchelli in 2002. The idea created quite a stir, challenging the idea that intense neutrino beams only could be produced from the decay of pions or muons in classical neutrino beams facilities or in future neutrino factories. The concept initially struggled to make an impact but the hard work by many machine physicists, phenomenologists and theoreticians over the last five years has won the beta-beam a well-earned position as one of the frontrunners for a possible future world laboratory for high intensity neutrino oscillation physics. This is the first complete monograph on the beta-beam concept. The book describes both technical aspects and experimental aspects of the beta-beam, providing students and scientists with an insight into the possibilities o...

  18. [Beta 3 adrenergic receptor polymorphism and obesity]. (United States)

    Yoshida, T; Umekawa, T


    The beta 3-adrenoceptor plays a significant role in the control of lipolysis and thermogenesis in the brown adipose tissue of rodents and humans. In human beta 3-adrenoceptor, a Trp to Arg replacement has recently been discovered. This change which occurs at position 64, in the first coding exon, has been correlated with increased weight gain, difficulty in losing weight, insulin resistance syndrome, and worsened diabetic situation. Higher percentages of this mutation are observed in Pima Indians (over 30%) and Japanese (20%). The possible functional mechanism of Trp54Arg is reported using human HEK293 cell line stably expressing the wild type and the [Arg64] beta 3-adrenoceptor type. Beta 3-adrenoceptor agonists available for humans are been also developing. In this paper we describe these points up-to-date.

  19. [Allergy to beta-lactam antibiotics]. (United States)

    Comte, D; Petitpierre, S; Spertini, F; Bart, P-A


    Beta-lactam antibiotics allergies are common. Up to 10% of the population describe a former allergy to penicillins. However only 10 to 15% of these individuals are actually allergic. In most cases, beta-lactam antibiotics will be avoided and replaced by other antibiotics such as quinolones. This fear of a serious allergic reaction has an economic impact and may lead to the emergence of antibiotic resistance. A thorough allergic work-up can accurately determine true allergic patients. Most of the patients with a proven allergy will be able to tolerate other antibiotics belonging to the beta-lactam family. This article focuses on the management of beta-lactam allergic patients.

  20. Metabolic response to various beta-adrenoceptor agonists in beta3-adrenoceptor knockout mice: evidence for a new beta-adrenergic receptor in brown adipose tissue. (United States)

    Preitner, F; Muzzin, P; Revelli, J P; Seydoux, J; Galitzky, J; Berlan, M; Lafontan, M; Giacobino, J P


    The beta3-adrenoceptor plays an important role in the adrenergic response of brown and white adipose tissues (BAT and WAT). In this study, in vitro metabolic responses to beta-adrenoceptor stimulation were compared in adipose tissues of beta3-adrenoceptor knockout and wild type mice. The measured parameters were BAT fragment oxygen uptake (MO2) and isolated white adipocyte lipolysis. In BAT of wild type mice (-)-norepinephrine maximally stimulated MO2 4.1+/-0.8 fold. Similar maximal stimulations were obtained with beta1-, beta2- or beta3-adrenoceptor selective agonists (dobutamine 5.1+/-0.3, terbutaline 5.3+/-0.3 and CL 316,243 4.8+/-0.9 fold, respectively); in BAT of beta3-adrenoceptor knockout mice, the beta1- and beta2-responses were fully conserved. In BAT of wild type mice, the beta1/beta2-antagonist and beta3-partial agonist CGP 12177 elicited a maximal MO2 response (4.7+/-0.4 fold). In beta3-adrenoceptor knockout BAT, this response was fully conserved despite an absence of response to CL 316,243. This unexpected result suggests that an atypical beta-adrenoceptor, distinct from the beta1-, beta2- and beta3-subtypes and referred to as a putative beta4-adrenoceptor is present in BAT and that it can mediate in vitro a maximal MO2 stimulation. In isolated white adipocytes of wild type mice, (-)-epinephrine maximally stimulated lipolysis 12.1+/-2.6 fold. Similar maximal stimulations were obtained with beta1-, beta2- or beta3-adrenoceptor selective agonists (TO509 12+/-2, procaterol 11+/-3, CL 316,243 11+/-3 fold, respectively) or with CGP 12177 (7.1+/-1.5 fold). In isolated white adipocytes of beta3-adrenoceptor knockout mice, the lipolytic responses to (-)epinephrine, to the beta1-, beta2-, beta3-adrenoceptor selective agonists and to CGP 12177 were almost or totally depressed, whereas those to ACTH, forskolin and dibutyryl cyclic AMP were conserved.

  1. Prediction of organ toxicity endpoints by QSAR modeling based on precise chemical-histopathology annotations. (United States)

    Myshkin, Eugene; Brennan, Richard; Khasanova, Tatiana; Sitnik, Tatiana; Serebriyskaya, Tatiana; Litvinova, Elena; Guryanov, Alexey; Nikolsky, Yuri; Nikolskaya, Tatiana; Bureeva, Svetlana


    The ability to accurately predict the toxicity of drug candidates from their chemical structure is critical for guiding experimental drug discovery toward safer medicines. Under the guidance of the MetaTox consortium (Thomson Reuters, CA, USA), which comprised toxicologists from the pharmaceutical industry and government agencies, we created a comprehensive ontology of toxic pathologies for 19 organs, classifying pathology terms by pathology type and functional organ substructure. By manual annotation of full-text research articles, the ontology was populated with chemical compounds causing specific histopathologies. Annotated compound-toxicity associations defined histologically from rat and mouse experiments were used to build quantitative structure-activity relationship models predicting subcategories of liver and kidney toxicity: liver necrosis, liver relative weight gain, liver lipid accumulation, nephron injury, kidney relative weight gain, and kidney necrosis. All models were validated using two independent test sets and demonstrated overall good performance: initial validation showed 0.80-0.96 sensitivity (correctly predicted toxic compounds) and 0.85-1.00 specificity (correctly predicted non-toxic compounds). Later validation against a test set of compounds newly added to the database in the 2 years following initial model generation showed 75-87% sensitivity and 60-78% specificity. General hepatotoxicity and nephrotoxicity models were less accurate, as expected for more complex endpoints.

  2. Validity in Qualitative Evaluation

    Directory of Open Access Journals (Sweden)

    Vasco Lub


    Full Text Available This article provides a discussion on the question of validity in qualitative evaluation. Although validity in qualitative inquiry has been widely reflected upon in the methodological literature (and is still often subject of debate, the link with evaluation research is underexplored. Elaborating on epistemological and theoretical conceptualizations by Guba and Lincoln and Creswell and Miller, the article explores aspects of validity of qualitative research with the explicit objective of connecting them with aspects of evaluation in social policy. It argues that different purposes of qualitative evaluations can be linked with different scientific paradigms and perspectives, thus transcending unproductive paradigmatic divisions as well as providing a flexible yet rigorous validity framework for researchers and reviewers of qualitative evaluations.

  3. Validation Measures in CMMI

    CERN Document Server

    Khraiwesh, Mahmoud


    Validation is one of the software engineering disciplines that help build quality into software. The major objective of software validation process is to determine that the software performs its intended functions correctly and provide information about its quality and reliability. This paper identifies general measures for the specific goals and its specific practices of Validation Process Area (PA) in Capability Maturity Model Integration (CMMI). CMMI is developed by Software Engineering Institute (SEI). CMMI is a framework for improvement and assessment of a software development process. CMMI needs a measurement program that is practical. The method we used to define the measures is to apply the Goal Question Metrics (GQM) paradigm to the specific goals and its specific practices of Validation Process Area in CMMI.

  4. On Validating Boolean Optimizers

    CERN Document Server

    Morgado, Antonio


    Boolean optimization finds a wide range of application domains, that motivated a number of different organizations of Boolean optimizers since the mid 90s. Some of the most successful approaches are based on iterative calls to an NP oracle, using either linear search, binary search or the identification of unsatisfiable sub-formulas. The increasing use of Boolean optimizers in practical settings raises the question of confidence in computed results. For example, the issue of confidence is paramount in safety critical settings. One way of increasing the confidence of the results computed by Boolean optimizers is to develop techniques for validating the results. Recent work studied the validation of Boolean optimizers based on branch-and-bound search. This paper complements existing work, and develops methods for validating Boolean optimizers that are based on iterative calls to an NP oracle. This entails implementing solutions for validating both satisfiable and unsatisfiable answers from the NP oracle. The wo...

  5. Isotope Effects in the Bonds of beta-CrOOH and beta-CrOOD

    DEFF Research Database (Denmark)

    Nørlund Christensen, A.; Hansen, P.; Lehmann, M. S.


    Samples of orthorhombic chromium oxide hydroxide, beta -CrOOH, and the deuterated compound, beta -CrOOD, were prepared hydrothermally. The crystal structures were determined by powder profile refinement technique using neutron diffraction data. Unit cells are: beta -CrOOH: a equals 4. 862(2) A, b...... equals 4. 298(a) A, c equals 2. 995(1) A; beta -CrOOD: a equals 4. 873(5) A, b equals 4. 332(7) A, c equals 2. 963(2) A, with Z equals 2. The space group is P2//1nm or Pnnm....

  6. AE activity during transient beta drops in high poloidal beta discharges (United States)

    Huang, J.; Gong, X. Z.; Ren, Q. L.; Ding, S. Y.; Qian, J. P.; Pan, C. K.; Li, G. Q.; Heidbrink, W. W.; Garofalo, A. M.; McClenaghan, J.


    Enhanced AE activity has been observed during transient beta drops in high poloidal beta DIII-D discharges with internal transport barriers (ITBs). These drops in beta are believed to be caused by n=1 external kink modes. In some discharges, beta recovers within 200 ms but, in others, beta stays suppressed. A typical discharge has βP 3, qmin 3, and q95 12. The drop in beta affects both fast ions and thermal particles, and a drop is also observed in the density and rotation. The enhanced AE activity follows the instability that causes the beta drop, is largest at the lowest beta, and subsides as beta recovers. MHD stability analysis is planned. A database study of the plasma conditions associated with the collapse will be also presented. Supported in part by the US Department of Energy under DE-FC02-04ER54698, DE-AC05-06OR23100, and by the National Natural Science Foundation of China 11575249, and the National Magnetic Confinement Fusion Program of China No. 2015GB110005.

  7. Verification and validation benchmarks.

    Energy Technology Data Exchange (ETDEWEB)

    Oberkampf, William Louis; Trucano, Timothy Guy


    Verification and validation (V&V) are the primary means to assess the accuracy and reliability of computational simulations. V&V methods and procedures have fundamentally improved the credibility of simulations in several high-consequence fields, such as nuclear reactor safety, underground nuclear waste storage, and nuclear weapon safety. Although the terminology is not uniform across engineering disciplines, code verification deals with assessing the reliability of the software coding, and solution verification deals with assessing the numerical accuracy of the solution to a computational model. Validation addresses the physics modeling accuracy of a computational simulation by comparing the computational results with experimental data. Code verification benchmarks and validation benchmarks have been constructed for a number of years in every field of computational simulation. However, no comprehensive guidelines have been proposed for the construction and use of V&V benchmarks. For example, the field of nuclear reactor safety has not focused on code verification benchmarks, but it has placed great emphasis on developing validation benchmarks. Many of these validation benchmarks are closely related to the operations of actual reactors at near-safety-critical conditions, as opposed to being more fundamental-physics benchmarks. This paper presents recommendations for the effective design and use of code verification benchmarks based on manufactured solutions, classical analytical solutions, and highly accurate numerical solutions. In addition, this paper presents recommendations for the design and use of validation benchmarks, highlighting the careful design of building-block experiments, the estimation of experimental measurement uncertainty for both inputs and outputs to the code, validation metrics, and the role of model calibration in validation. It is argued that the understanding of predictive capability of a computational model is built on the level of

  8. Introduction to Validity

    Institute of Scientific and Technical Information of China (English)



    The designing of a test paper strictly follows the specification of the relevant Testing Syllabus, which covers various skills and abilities needed for real communicative situation. A test with high content validity is likely to have a positive impact upon the teaching. Therefore, a test with a high content validity will undoubtedly promote the college English education and it will certainly facilitate the implementation of the Syllabus.

  9. Beta adrenergic receptors in human cavernous tissue

    Energy Technology Data Exchange (ETDEWEB)

    Dhabuwala, C.B.; Ramakrishna, C.V.; Anderson, G.F.


    Beta adrenergic receptor binding was performed with /sup 125/I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1 fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of /sup 125/iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non- linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype.

  10. Development of marine sediment toxicity identification evaluation methods using Strongylocentrotus purpuratus, Mytilus edulis, and Eohaustorius estuarius

    Energy Technology Data Exchange (ETDEWEB)

    Wortham, G.; Cotsifas, J.S.; Taberski, K.; Hansen, S.R. [S.R. Hansen and Associates, Concord, CA (United States)


    Widespread sediment toxicity, including ``clean`` reference sites, dictates that the causes of toxicity in sediments be determined. Toxicity Identification Evaluations (TIE) are useful tools in characterizing compounds responsible for toxicity, but were unavailable for sediment samples. TIE methods were developed for sediment porewater and included the following components: determination of an appropriate porewater extraction process; control TIE tests using marine water and porewater evaluating species sensitivities to the fractionation procedures; validation experiments investigating the removal efficiencies of organics using C18 solid phase extraction, and metals chelation using EDTA and STS; spiking experiments to determine the effectiveness of the TIE procedure in identifying multiple toxicants. The authors determined that fractionation procedures could be applied to both marine water and porewater using S. purpuratus, M. edulis and E. estuarius as biological detectors.

  11. Estimating Security Betas Using Prior Information Based on Firm Fundamentals

    NARCIS (Netherlands)

    Cosemans, Mathijs; Frehen, Rik; Schotman, Peter; Bauer, Rob


    We propose a hybrid approach for estimating beta that shrinks rolling window estimates toward firm-specific priors motivated by economic theory. Our method yields superior forecasts of beta that have important practical implications. First, unlike standard rolling window betas, hybrid betas carry a

  12. beta(2)-Glycoprotein I : evolution, structure and function

    NARCIS (Netherlands)

    de Groot, P. G.; Meijers, J. C. M.


    beta(2)-Glycoprotein I (beta(2)-GPI) is a protein that circulates in blood at high concentrations. The function of beta(2)-GPI has long been an enigma. More than 20 years ago, it was discovered that beta(2)-GPI is the major antigen for the circulating antibodies in the antiphospholipid syndrome. How

  13. Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats. (United States)

    Bulgheroni, Anna; Kinsner-Ovaskainen, Agnieszka; Hoffmann, Sebastian; Hartung, Thomas; Prieto, Pilar


    Acute systemic toxicity is one of the areas of particular concern due to the 2009 deadline set by the 7th Amendment of the Cosmetics Directive (76/768/EEC), which introduces a testing and marketing ban of cosmetic products with ingredients tested on animals. The scientific community is putting considerable effort into developing and validating non-animal alternatives in this area. However, it is unlikely that validated and regulatory accepted alternative methods and/or strategies will be available in March 2009. Following the initiatives undertaken in the pharmaceutical industry to waive the acute oral toxicity testing before going to clinical studies by using information from other in vivo studies, we proposed an approach to identify non-toxic compounds (LD50>2000mg/kg) using information from 28 days repeated dose toxicity studies. Taking into account the high prevalence of non-toxic substances (87%) in the New Chemicals Database, it was possible to set a NOAEL threshold of 200mg/kg that allowed the correct identification of 63% of non-toxic compounds, while testing of cosmetic ingredients.

  14. News on $\\beta$-delayed particle emission from $^{14}$Be

    CERN Document Server

    Jeppesen, H; Borge, M J G; Cederkäll, J; Fynbo, H O U; Fedoseyev, V N; Hansper, V Y; Jonson, B; Markenroth, K; Mishin, V I; Nilsson, T; Nyman, G; Riisager, K; Tengblad, O; Wilhelmsen Rolander, K


    $\\beta$-delayed charged particles from $^{14}$Be have been measured and give an upper limit on $\\beta$-delayed $\\alpha$-particles of B($\\beta\\alpha$) < $\\,6.7\\times\\!10^{-5}$ and a tentative branching ratio on $\\beta$-delayed tritons of $7.5\\times\\!10^{-5}$ < B($\\beta$t) < $\\,3.9\\times\\!10^{-4}$. We combine the knowledge on $\\beta$-delayed particles from $^{14}$Be to deduce information on the $\\beta$-strength distribution.

  15. Continuous and Jump Betas: Implications for Portfolio Diversification

    Directory of Open Access Journals (Sweden)

    Vitali Alexeev


    Full Text Available Using high-frequency data, we decompose the time-varying beta for stocks into beta for continuous systematic risk and beta for discontinuous systematic risk. Estimated discontinuous betas for S&P500 constituents between 2003 and 2011 generally exceed the corresponding continuous betas. We demonstrate how continuous and discontinuous betas decrease with portfolio diversification. Using an equiweighted broad market index, we assess the speed of convergence of continuous and discontinuous betas in portfolios of stocks as the number of holdings increase. We show that discontinuous risk dissipates faster with fewer stocks in a portfolio compared to its continuous counterpart.

  16. The cellular toxicity of aluminium. (United States)

    Exley, C; Birchall, J D


    Aluminium is a serious environmental toxicant and is inimical to biota. Omnipresent, it is linked with a number of disorders in man including Alzheimer's disease, Parkinson's dementia and osteomalacia. Evidence supporting aluminium as an aetiological agent in such disorders is not conclusive and suffers principally from a lack of consensus with respect to aluminium's toxic mode of action. Obligatory to the elucidation of toxic mechanisms is an understanding of the biological availability of aluminium. This describes the fate of and response to aluminium in any biological system and is thus an important influence of the toxicity of aluminium. A general theme in much aluminium toxicity is an accelerated cell death. Herein mechanisms are described to account for cell death from both acute and chronic aluminium challenges. Aluminium associations with both extracellular surfaces and intracellular ligands are implicated. The cellular response to aluminium is found to be biphasic having both stimulatory and inhibitory components. In either case the disruption of second messenger systems is observed and GTPase cycles are potential target sites. Specific ligands for aluminium at these sites are unknown though are likely to be proteins upon which oxygen-based functional groups are orientated to give exceptionally strong binding with the free aluminium ion.

  17. DMPD: Immunoreceptor-like signaling by beta 2 and beta 3 integrins. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17913496 Immunoreceptor-like signaling by beta 2 and beta 3 integrins. Jakus Z, Fod...or S, Abram CL, Lowell CA, Mocsai A. Trends Cell Biol. 2007 Oct;17(10):493-501. (.png) (.svg) (.html) (.csml) Show Immunore...ceptor-like signaling by beta 2 and beta 3 integrins. PubmedID 17913496 Title Immunoreceptor-

  18. Des-Lys58-beta 2m and native beta 2m in rheumatoid arthritis serum and synovial fluid

    DEFF Research Database (Denmark)

    Williams, R C; Malone, C C; Nissen, Mogens Holst;


    OBJECTIVE. Levels of beta 2-microglobulin and modified beta 2-microglobulin (Des-Lys58-beta 2m) were measured in serum and synovial fluids from patients with rheumatoid arthritis (RA) and other inflammatory joint disorders using rabbit antisera prepared against the beta 2m peptide VEHSDLSFS...

  19. Characterization of beta-R1, a gene that is selectively induced by interferon beta (IFN-beta) compared with IFN-alpha. (United States)

    Rani, M R; Foster, G R; Leung, S; Leaman, D; Stark, G R; Ransohoff, R M


    We report preliminary characterization of a gene designated beta-R1, which is selectively expressed in response to interferon beta (IFN-beta) compared with IFN-alpha. In human astrocytoma cells, beta-R1 was induced to an equivalent extent by 10 IU/mL IFN-beta or 2500 IU/mL IFN-alpha2. To address the mechanism of this differential response, we analyzed induction of the beta-R1 gene in fibrosarcoma cells and derivative mutant cells lacking components required for signaling by type I IFNs. beta-R1 was readily induced by IFN-beta in the parental 2fTGH cell line, but not by recombinant IFN-alpha2, IFN-alpha Con1, or a mixture of IFN-alpha subtypes. IFN-alpha8 induced beta-R1 weakly. beta-R1 was not induced by IFN-beta in mutant cell lines U2A, U3A, U4A, and U6A, which lack, respectively, p48, STAT1, JAK1, and STAT2. U5A cells, which lack the Ifnar 2.2 component of the IFN-alpha and -beta receptor, also failed to express beta-R1. U1A cells are partially responsive to IFN-beta and IFN-alpha8 but lacked beta-R1 expression, indicating that TYK2 protein is essential for induction of this gene. Taken together, these results suggest that the expression of beta-R1 in response to type I IFN requires IFN-stimulated gene factor 3 plus an additional component, which is more efficiently formed on induction by IFN-beta compared with IFN-alpha.

  20. Amyloid Beta as a Modulator of Synaptic Plasticity


    Parihar, Mordhwaj S.; Gregory J. Brewer


    Alzheimer’s disease is associated with synapse loss, memory dysfunction and pathological accumulation of amyloid beta in plaques. However, an exclusively pathological role for amyloid beta is being challenged by new evidence for an essential function of amyloid beta at the synapse. Amyloid beta protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Amyloid beta is pres...

  1. Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast. (United States)

    Treusch, Sebastian; Hamamichi, Shusei; Goodman, Jessica L; Matlack, Kent E S; Chung, Chee Yeun; Baru, Valeriya; Shulman, Joshua M; Parrado, Antonio; Bevis, Brooke J; Valastyan, Julie S; Han, Haesun; Lindhagen-Persson, Malin; Reiman, Eric M; Evans, Denis A; Bennett, David A; Olofsson, Anders; DeJager, Philip L; Tanzi, Rudolph E; Caldwell, Kim A; Caldwell, Guy A; Lindquist, Susan


    Aβ (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.

  2. Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis

    DEFF Research Database (Denmark)

    Zheng, Lin; Kågedal, Katarina; Dehvari, Nodi;


    There is increasing evidence for the toxicity of intracellular amyloid beta-protein (Abeta) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD, enhances macroautophagy and leads...... to intralysosomal accumulation of Abeta in cultured neuroblastoma cells. We hypothesized that oxidative stress promotes AD by stimulating macroautophagy of Abeta that further may induce cell death by destabilizing lysosomal membranes. To investigate such possibility, we compared the effects of hyperoxia (40...

  3. Gulf of Mexico mud toxicity limitations

    Energy Technology Data Exchange (ETDEWEB)

    Dunn, H.E.; Beardmore, D.H. (Phillips Petroleum Co., Bartlesville, OK (USA)); Stewart, W.S. (Drilling Specialties Co. (US))


    Because of the Environmental Protection Agency's recent toxicity limits on drilling mud discharges for offshore Gulf of Mexico, Phillips Petroleum conducted a mud toxicity study based on both field and lab tests. The study, discussed in this article, found the polyanionic cellulose-sulfomethylated quebracho-chrome lignosulfonate mud Phillips had been using would comfortably pass the toxicity limitations. The study also found barite and thinners were of low toxicity, and hydrocarbons and surfactants were highly toxic.

  4. Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols. (United States)

    Chen, Min-Yu; Ike, Michihiko; Fujita, Masanori


    Although abundant data are available on the toxicity of bisphenol-A (2,2-bis (4-hydroxydiphenyl)propane; BPA), little is known about the toxicities of the structurally similar compounds, namely bisphenols (BPs). A variety of BPs were examined for their acute toxicity against Daphnia magna, mutagenicity, and estrogenic activity using the Daphtoxkit (Creasel Ltd.), the umu test system, and the yeast two-hybrid system, respectively, in comparison with BPA. BPA was moderately toxic to D. magna (48-h EC50 was 10 mg/l) according to the current U.S. EPA acute toxicity evaluation standard, and it was weakly estrogenic with 5 orders of magnitude lower activity than that of the natural estrogen 17 beta-estradiol in the yeast screen, while no mutagenicity was observed. All seven BPs tested here showed moderate to slight acute toxicity, no mutagenicity, and weak estrogenic activity as well as BPA. Some of the BPs showed considerably higher estrogenic activity than BPA, and others exhibited much lower activity. Among the tested BPs, two compounds, i.e., bisphenol-S (bis(4-hydroxydiphenyl)sulfone) and bis(4-hydroxyphenyl)sulfide, have never been reported for their estrogenic activity previously.

  5. Beta-adrenoceptors in obstetrics and gynecology. (United States)

    Modzelewska, Beata


    One hundred and twenty years after the description of extracts from the adrenal medulla, the use of beta-blockers and beta-agonists evolved from antianginal drugs and tocolytics to ligand-directed signaling. Beta-blockers in the fields of obstetrics and gynecology have so far been limited to the consideration of continuing treatment of disorders of the cardiovascular system and other dysfunctions that started before pregnancy. Studies in recent years have shown that beta-adrenoceptor signaling might be crucial in carcinogenesis and metastasis, apoptosis and anoikis. On the other hand, the use of beta-adrenoceptor agonists in tocolysis is, as yet, the primary method for inhibiting premature uterine contractions. Unfortunately, the efficacy of current pharmacological treatment for the management of preterm labor is regularly questioned. Moreover, studies related to non-pregnant myometrium performed to date indicate that the rhythmic contractions of the uterus are required for menstruation and have an important role in human reproduction. In turn, abnormal uterine contractility has been linked to dysmenorrhea, a condition associated with painful uterine cramping. The benefits of the use of beta2-adrenoceptor agonists in dysmenorrhea are still unclear and should be balanced against a wide range of adverse effects recognized with this class of medication. The ideal tocolytic agent is one which is effective for the pregnant or non-pregnant woman but has no side effects on either the woman or the baby. Looking to the future with both caution and hope, the potential metamorphosis of beta3-adrenoceptor agonists from experimental tools into therapeutic drugs for tocolysis warrants attention.

  6. Beta Gyres in Global Analysis Fields

    Institute of Scientific and Technical Information of China (English)



    A three-component decomposition is applied to global analysis data to show the existence of a beta gyre,which causes Tropical Cyclone (TC) to drift from a large-scale environmental steering current.Analyses from the Global Data Assimilation and Prediction System (GDAPS) of the Korea Meteorological Administration (KMA),the Global Forecast System (GFS) of NCEP,and the Navy Operational Global Atmospheric Prediction System (NOGAPS) are used in this study.The structure of the beta gyre obtained in our analyses is in good agreement with the theoretical structure,with a cyclonic circulation to the southwest of the TC center,an anticyclonic circulation to the northeast,and a ventilation flow directed northwestward near the center.The circulation of the beta gyre is strongest at the 850-hPa level where the cyclonically swirling primary circulation is strongest,and decreases with height,in a pyramid shape similar to the primary circulation.The individual structure of the beta gyre is case- and model-dependent.At a certain analysis time,one model may clearly reveal a well-defined beta gyre,but the other models may not.Within one model,the beta gyre may be well defined at some analysis times,but not at other times.The structure of the beta gyre in the analysis field is determined by the nature of the vortex initialization scheme and the model behavior during the 6-h forecast in the operational data assimilation cycle.

  7. Molecular mechanisms of homocysteine toxicity. (United States)

    Boldyrev, A A


    Hyperhomocysteinemia is a risk factor for a number of cardiovascular and neurodegenerative processes as well as a complicating factor in normal pregnancy. Toxic effects of homocysteine and the product of its spontaneous oxidation, homocysteic acid, are based on their ability to activate NMDA receptors, increasing intracellular levels of ionized calcium and reactive oxygen species. Even a short-term exposure of cells to homocysteic acid at concentrations characteristic of hyperhomocysteinemia induces their apoptotic transformation. The discovery of NMDA receptors both in neuronal tissue and in several other tissues and organs (including immunocompetent cells) makes them a target for toxic action of homocysteine. The neuropeptide carnosine was found to protect the organism from homocysteine toxicity. Treatment of pregnant rats with carnosine under conditions of alimentary hyperhomocysteinemia increases viability and functional activity of their progeny.

  8. [Transforming growth factor-beta controls pathogenesis of Crohn disease]. (United States)

    Friess, H; di Mola, F F; Egger, B; Scheuren, A; Kleeff, J; Zimmermann, A; Büchler, M W


    The pathogenetic mechanisms which contribute to the progression of Crohn's disease are still not known. Transforming growth factor-beta (TGF-beta) and its subtypes are multifunctional polypeptides which regulate immunological processes as well as the synthesis of the extracellular matrix and fibrogenesis. In the present study, Crohn's disease tissue samples of 18 patients undergoing intestinal resection were analyzed by Northern blot analysis, in situ hybridization and immunostaining for TGF-beta 1-3 and the TGF-beta receptors type I-III (T beta R-I, T beta R-II, T beta R-III). There was a marked overexpression of TGF-beta 1, TGF-beta 3 and T beta R-II in 94% of the Crohn's disease tissue samples. TGF-beta 2 and T beta R-I ALK5 and T beta R-III were enhanced in 72%, 72% and 82% of the Crohn tissue samples, respectively. In situ hybridization and immunostaining revealed that there was frequent coexpression of TGF-beta with its signaling receptors. Our data indicate that TGF-beta and their receptors seem to be involved in the pathogenesis of Crohn's disease. Their enhanced expression might contribute to the increase in extracellular matrix resulting in fibrosis and subsequently in intestinal obstruction.

  9. Validation of analytical methods

    Directory of Open Access Journals (Sweden)

    Xavier Rius, F.


    Full Text Available In this paper we shall discuss the concept of method validation, describe the various elements and explain its close relationship with fitness for purpose. Method validation is based on the assumption that a series of requirements are fulfilled and we shall explain how these requirements are selected, the way in which evidence is supplied and what work has to be carried out in the laboratory. The basic principles of method validation and the different ways to validate a methodology, by inter-laboratory comparison or performing an in-house validation, are also described.En este artículo se discute el concepto de validación del método, se describen los elementos que la componen y se explica la fuerte relación entre la validación y las características de ajuste. El método de validación se basa en el cumplimiento de una serie de requerimientos, se explica como seleccionar esos requerimientos, la forma en que se suministran evidencias, y que trabajo se debe llevar a cabo en el laboratorio. También se describen, los principios básicos del método de validación y los diferentes caminos para validar una metodología, tanto en la comparación entre laboratorios o como cuando se lleva a cabo una validación dentro del laboratorio.

  10. Validation of Serious Games

    Directory of Open Access Journals (Sweden)

    Katinka van der Kooij


    Full Text Available The application of games for behavioral change has seen a surge in popularity but evidence on the efficacy of these games is contradictory. Anecdotal findings seem to confirm their motivational value whereas most quantitative findings from randomized controlled trials (RCT are negative or difficult to interpret. One cause for the contradictory evidence could be that the standard RCT validation methods are not sensitive to serious games’ effects. To be able to adapt validation methods to the properties of serious games we need a framework that can connect properties of serious game design to the factors that influence the quality of quantitative research outcomes. The Persuasive Game Design model [1] is particularly suitable for this aim as it encompasses the full circle from game design to behavioral change effects on the user. We therefore use this model to connect game design features, such as the gamification method and the intended transfer effect, to factors that determine the conclusion validity of an RCT. In this paper we will apply this model to develop guidelines for setting up validation methods for serious games. This way, we offer game designers and researchers handles on how to develop tailor-made validation methods.

  11. Detrimental effects of beta-blockers in COPD - A concern for nonselective beta-blockers

    NARCIS (Netherlands)

    van der Woude, HJ; Zaagsma, J; Postma, DS; Winter, TH; van Hulst, M; Aalbers, R


    Introduction: beta-Blockers are known to worsen FEV1 and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring beta-blocker treatment. Design: A double-blind, placebo-controlled, randomized,

  12. Substitution of isoleucine-31 by helical-breaking proline abolishes oxidative stress and neurotoxic properties of Alzheimer's amyloid beta-peptide. (United States)

    Kanski, Jaroslaw; Aksenova, Marina; Schöneich, Christian; Butterfield, D Allan


    Alzheimer's disease (AD) brain is characterized by excess deposition of the 42-amino acid amyloid beta-peptide [A(beta)(1-42)]. AD brain is under intense oxidative stress, and we have previously suggested that A(beta)(1-42) was associated with this increased oxidative stress. In addition, we previously demonstrated that the single methionine residue of A(beta)(1-42), residue 35, was critical for the oxidative stress and neurotoxic properties of this peptide. Others have shown that the C-terminal region of A(beta)(1-42) is helical in aqueous micellar solutions, including that part of the protein containing Met35. Importantly, Cu(II)-binding induces alpha-helicity in A(beta) in aqueous solution. Invoking the i + 4 rule of helices, we hypothesized that the carbonyl oxygen of Ile31 would interact with the S atom of Met35 to change the electronic environment of the sulfur such that molecular oxygen could lead to the production of a sulfuramyl free radical on Met35. If this hypothesis is correct, a prediction would be that breaking the helical interaction of Ile31 and Met35 would abrogate the oxidative stress and neurotoxic properties of A(beta)(1-42). Accordingly, we investigated A(beta)(1-42) in which the Ile31 residue was replaced with the helix-breaking amino acid, proline. The alpha-helical environment around Met35 was completely abolished as indicated by circular dichroism (CD)-spectroscopy. As a consequence, the aggregation, oxidative stress, Cu(II) reduction, and neurotoxic properties of A(beta)(1-42)I31P were completely altered compared to native A(beta)(1-42). The results presented here are consistent with the notion that interaction of Ile31 with Met35 may play an important role in the oxidative processes of Met35 contributing to the toxicity of the peptide.

  13. Evaluation of beta-naphthoxyacetic acid for mutagenic activity in the Salmonella/mammalian microsome assay. (United States)

    Rashid, K A; Mumma, R O


    Beta-naphthoxyacetic acid (BNOA) is used as a plant growth regulator on tomatoes and strawberries. It is the active ingredient in Blossom-Set and Berry-Set, two plant hormone sprays for fruit-set. The mutagenic activity of BNOA was evaluated in four strains of Salmonella typhimurium (TA97, TA98, TA100 and TA1535) in the presence and absence of liver microsomal and cytosolic enzymes derived from Aroclor induced rats. BNOA did not produce any significant increase (p less than 0.05) in the reversion of any of the four tester strains in the standard plate incorporation assay. Results of the agar overlay toxicity tests indicates that the chemical shows toxic effects at concentrations above 500 micrograms/plate. It was concluded that under the conditions of these tests, BNOA did not exhibit any mutagenic activity.

  14. Ceftriaxone-induced toxic hepatitis

    Institute of Scientific and Technical Information of China (English)

    Erdal Peker; Eren Cagan; Murat Dogan


    Toxic hepatitis or drug-induced liver injury encompasses a spectrum of clinical disease ranging from mild biochemical abnormalities to acute liver failure. The advantages of a long half-life, wide spectrum, high tissue penetration rate, and a good safety profile,make ceftriaxone, a third-generation cephalosporin,a frequent choice in the treatment of childhood infections. Previous studies have reported a few cases of high aspartate aminotransferase and alanine aminotransferase levels, along with three cases ofhepatitis caused by ceftriaxone. Here, we report a case of drug-induced toxic hepatitis in a patient who was treated with ceftriaxone for acute tonsillitis.

  15. Lung toxicity of biodegradable nanoparticles. (United States)

    Fattal, Elias; Grabowski, Nadége; Mura, Simona; Vergnaud, Juliette; Tsapis, Nicolas; Hillaireau, Hervé


    Biodegradable nanoparticles exhibit high potentialities for local or systemic drug delivery through lung administration making them attractive as nanomedicine carriers. However, since particulate matter or some inorganic manufactured nanoparticles exposed to lung cells have provoked cytotoxic effects, inflammatory and oxidative stress responses, it becomes important to investigate nanomedicine toxicity towards the lungs. This is the reason why, in the present review, the behavior of biodegradable nanoparticles towards the different parts of the respiratory tract as well as the toxicological consequences, measured on several models in vitro, ex vivo or in vivo, are described. Taken all together, the different studies carried out so far conclude on no or slight toxicity of biodegradable nanoparticles.

  16. Rapid Robot Design Validation Project (United States)

    National Aeronautics and Space Administration — Energid Technologies will create a comprehensive software infrastructure for rapid validation of robot designs. The software will support push-button validation...

  17. Rapid Robot Design Validation Project (United States)

    National Aeronautics and Space Administration — Energid Technologies will create a comprehensive software infrastructure for rapid validation of robotic designs. The software will support push-button validation...

  18. Experimental studies of the early effects of inhaled beta-emitting radionuclides for nuclear accident risk assessment: Phase 2 report

    Energy Technology Data Exchange (ETDEWEB)

    Scott, B.R.; Hahn, F.F.; Newton, G.J.; Snipes, M.B.; Damon, E.G.; Mauderly, J.L.; Boecker, B.B.; Gray, D.H.


    This report summarizes a series of experiments concerning the effect of linear energy transfer and temporal radiation dose pattern to the lung from inhaled beta-emitting radionuclides. The results were used to test the validity of a hazard-function mathematical model for predicting death from radiation pneumonitis. Both morbidity and mortality within 18 months after exposure were examined in rats exposed to beta-emitting radionuclides, giving brief or protracted irradiation of the lung or having weak or strong beta emissions. Protraction of the radiation dose to the lung from a half-time in the lung of less than three days to a half-time with a long-term component of about 150 days has a sparing effect. The median lethal dose for the protracted irradiation is about 1.7 times the median lethal dose for the brief irradiation. Low energy beta emissions from /sup 147/Pm have a similar effectiveness in producing lethal injury as high energy beta emissions from /sup 90/Sr. Changes in three parameters of morbidity were measured: body weight, hematology and pulmonary function; only changes in pulmonary function correlated well with pulmonary radiation injury. The doses of radiation required to produce impaired function, however, were not significantly different from those that produced death. The hazard-function model for predicting death from radiation pneumonitis, which was developed from previously obtained data for inhalation exposures of dogs to beta-emitting radionuclides, adequately predicted the median lethal doses for rats receiving one of several different beta dose rate patterns to the lung, thus strengthening the validity of the mathematical model. 23 refs., 41 figs., 12 tabs.

  19. Shift Verification and Validation

    Energy Technology Data Exchange (ETDEWEB)

    Pandya, Tara M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Evans, Thomas M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Davidson, Gregory G [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Johnson, Seth R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Godfrey, Andrew T. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)


    This documentation outlines the verification and validation of Shift for the Consortium for Advanced Simulation of Light Water Reactors (CASL). Five main types of problems were used for validation: small criticality benchmark problems; full-core reactor benchmarks for light water reactors; fixed-source coupled neutron-photon dosimetry benchmarks; depletion/burnup benchmarks; and full-core reactor performance benchmarks. We compared Shift results to measured data and other simulated Monte Carlo radiation transport code results, and found very good agreement in a variety of comparison measures. These include prediction of critical eigenvalue, radial and axial pin power distributions, rod worth, leakage spectra, and nuclide inventories over a burn cycle. Based on this validation of Shift, we are confident in Shift to provide reference results for CASL benchmarking.

  20. Validation and Variability

    DEFF Research Database (Denmark)

    Carusi, Annamaria


    as inter-subject variability. This need is simultaneously social and epistemic: social as systems biologists attempt to engage with the interests and concerns of clinicians and others in applied medical research; epistemic as they attempt to develop new strategies to cope with variability in the validation...... and experimentally inclined modellers on one hand, and attempts to forge new collaborations with medical scientists on the other. Apart from the scientific interest of the population of models approach for tackling variability, the trial also offers a good illustration of the epistemology of experiment......-facing modelling. I claim that it shows the extent to which experiment-facing modelling and validation require the establishment of criteria for comparing models and experiments that enable them to be linked together. These 'grounds of comparability' are the broad framework in which validation experiments...

  1. Shift Verification and Validation

    Energy Technology Data Exchange (ETDEWEB)

    Pandya, Tara M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Evans, Thomas M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Davidson, Gregory G [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Johnson, Seth R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Godfrey, Andrew T. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)


    This documentation outlines the verification and validation of Shift for the Consortium for Advanced Simulation of LightWater Reactors (CASL). Fivemain types of problems were used for validation: small criticality benchmark problems; full-core reactor benchmarks for light water reactors; fixed source coupled neutron-photon dosimetry benchmarks; depletion/burnup benchmarks; and full-core reactor performance benchmarks. We compared Shift results to measured data and other simulated Monte Carlo radiation transport code results and found very good agreement in a variety of comparison measures. These include prediction of critical eigenvalue, radial and axial pin power distributions, rod worth, leakage spectra, and nuclide inventories over a burn cycle. Based on this validation of Shift, we are confident in Shift to provide reference results for CASL benchmarking.

  2. Space Shuttle navigation validation (United States)

    Ragsdale, A.

    The validation of the guidance, navigation, and control system of the Space Shuttle is explained. The functions of the ascent, on-board, and entry mission phases software of the navigation system are described. The common facility testing, which evaluates the simulations to be used in the navigation validation, is examined. The standard preflight analysis of the operational modes of the navigation software and the post-flight navigation analysis are explained. The conversion of the data into a useful reference frame and the use of orbit parameters in the analysis of the data are discussed. Upon entry the data received are converted to flags, ratios, and residuals in order to evaluate performance and detect errors. Various programs developed to support navigation validation are explained. A number of events that occurred with the Space Shuttle's navigation system are described.

  3. Identification of a Glycogen Synthase Kinase-3[beta] Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice

    Energy Technology Data Exchange (ETDEWEB)

    Kozikowski, Alan P.; Gunosewoyo, Hendra; Guo, Songpo; Gaisina, Irina N.; Walter, Richard L.; Ketcherside, Ariel; McClung, Colleen A.; Mesecar, Andrew D.; Caldarone, Barbara (Psychogenics); (Purdue); (UIC); (UTSMC)


    Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5 million people in the United States. Current treatment regimes include the so-called 'mood-stabilizing drugs', such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase-3{beta} (GSK-3{beta}) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3{beta}. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC{sub 50} values in the range of 4 to 680 nM against human GSK-3{beta}. One of these compounds exhibits reasonable kinase selectivity and promising preliminary absorption, distribution, metabolism, and excretion (ADME) data. The administration of this compound at doses of 10 to 25 mg kg{sup -1} resulted in the attenuation of hyperactivity in amphetamine/chlordiazepoxide-induced manic-like mice together with enhancement of prepulse inhibition, similar to the effects found for valproate (400 mg kg{sup -1}) and the antipsychotic haloperidol (1 mg kg{sup -1}). We also tested this compound in mice carrying a mutation in the central transcriptional activator of molecular rhythms, the CLOCK gene, and found that the same compound attenuates locomotor hyperactivity in response to novelty. This study further demonstrates the use of inhibitors of GSK-3{beta} in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3{beta} as a relevant therapeutic target in the identification of new therapies for bipolar patients.

  4. Undetected Toxicity Risk in Pharmacogenetic Testing for Dihydropyrimidine Dehydrogenase

    Directory of Open Access Journals (Sweden)

    Felicia Stefania Falvella


    Full Text Available Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD, a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T, fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C, conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.

  5. The validation of metaphors


    Verhulst, F.


    In this paper we introduce models as metaphors for the description of reality We consider a number of case studies of contemporary research pollution of the NorthSea the ow eld of theWadden Sea drillstring dynamics the use of metaphors in psychoanalysis In all these cases validation of the results takes a very dierent form Also this validation is certainly not in agreement with the picture of scienti c research projected by textbook examples In the discussion we draw some conclusions on the u...

  6. Validating Animal Models

    Directory of Open Access Journals (Sweden)

    Nina Atanasova


    Full Text Available In this paper, I respond to the challenge raised against contemporary experimental neurobiology according to which the field is in a state of crisis because of the multiple experimental protocols employed in different laboratories and strengthening their reliability that presumably preclude the validity of neurobiological knowledge. I provide an alternative account of experimentation in neurobiology which makes sense of its experimental practices. I argue that maintaining a multiplicity of experimental protocols and strengthening their reliability are well justified and they foster rather than preclude the validity of neurobiological knowledge. Thus, their presence indicates thriving rather than crisis of experimental neurobiology.

  7. The dialogic validation

    DEFF Research Database (Denmark)

    Musaeus, Peter


    This paper is inspired by dialogism and the title is a paraphrase on Bakhtin's (1981) "The Dialogic Imagination". The paper investigates how dialogism can inform the process of validating inquiry-based qualitative research. The paper stems from a case study on the role of recognition in apprentic......This paper is inspired by dialogism and the title is a paraphrase on Bakhtin's (1981) "The Dialogic Imagination". The paper investigates how dialogism can inform the process of validating inquiry-based qualitative research. The paper stems from a case study on the role of recognition...

  8. Beta decay of {sup 103}Sn

    Energy Technology Data Exchange (ETDEWEB)

    Kavatsyuk, O.; Kavatsyuk, M. [GSI, Darmstadt (Germany); National Taras Shevcjenko Univ. of Kyiv (Australia); Batist, L. [St. Petersburg Nuclear Physics Inst. (Russian Federation); Univ. di Napoli (Italy); INFN, Napoli (Italy); Banu, A.; Becker, F.; Bruechle, W.; Doering, J.; Gorska, M.; Grawe, H.; Kirchner, R.; Mandal, S.; Mazzocchi, C.; Plettner, C.; Roeckl, E.; Schaedel, M. [GSI, Darmstadt (Germany); Blazhev, A. [GSI, Darmstadt (Germany); Univ. Sofia (Bulgaria); Faestermann, T. [Technische Universitaet Muenchen (Germany); Janas, Z.; Karny, M.; Plochocki, A.; Zylicz, J. [University of Warsaw (Poland); Jungclaus, A. [Universidad Autonoma de Madrid, Departamento de Fisica Teorica (Spain); La Commara, M.; Romoli, M. [INFN, Napoli (Italy); Mukha, I. [GSI, Darmstadt (Germany); Kurchatov Inst. Moscow (Russian Federation); Muralithar, S. [GSI, Darmstadt (Germany); Forschungszentrum Rossendorf (Germany); Schwengner, R. [Forschungszentrum Rossendorf (Germany)


    The {beta} decay of {sup 103}Sn, a three-neutron-particle nucleus with respect to the {sup 100}Sn core, was investigated at the GSI on-line mass separator using an array of 17 germanium crystals and a total absorption spectrometer. A total of 31 {beta}-delayed {gamma}-rays (29 new) of the {sup 103}Sn{yields}{sup 103}In decay were observed and, on the basis of {beta}-{gamma}-{gamma} coincidences, the {sup 103}Sn decay scheme was established for the first time. By means of total absorption spectroscopy, {beta} intensities, the Gamow-Teller strength distribution and the summed Gamow-Teller strength value of 3.5{+-}0.5 were determined for this decay. Its half-life and Q{sub EC} value were found to be 7.0{+-}0.2 s and 7.64{+-}0.7 MeV, respectively. The {beta}-delayed proton branching ratio was measured to be 1.2{+-}0.1%. The results are discussed in comparison with shell-model predictions based on realistic and empirical interactions. (orig.)

  9. Beta-thalassemia and beta[A] globin gene haplotypes in Mexican mestizos. (United States)

    Villalobos-Arámbula, A R; Bustos, R; Casas-Castañeda, M; Gutiérrez, E; Perea, F J; Thein, S L; Ibarra, B


    B-globin haplotypes of 20 beta-thalassemia (beta-thal) and 87 beta(A) Mexican mestizo chromosomes were analyzed to ascertain the origin of the beta-thal alleles and the frequencies and distribution of the beta(A) haplotypes among northwestern Mexican mestizos. Sixteen beta-thal chromosomes carried six Mediterranean alleles [five codon 39 C-->T; two IVS1:1 G-->A; two IVS1:5 G-->A; three IVS1:110 G(A; one codon 11 (-T) and three (deltabeta)zero-thal]; the remaining four were linked to three rare alleles (two -28 A-->C and one each: -87 C-->T and initiation codon ATG-->GTG). Among the 87 beta(A) chromosomes, 17 different 5' haplotypes with frequencies for 1, 3, 2 and 5 of 39.0%, 17. 2%, 9.2% and 6.9%, respectively, were observed. The beta-haplotype analysis showed that 13 out of 16 Mediterranean chromosomes could easily be explained by gene migration; however, one codon 39 associated with haplotype 4 (----+ +-), one IVS1:1 with haplotype 1(+----++) and one IVS1:5 G-->A, may represent separate mutational events. Analysis of the rare alleles showed that the -28 A-->C mutation was associated with the commonest beta(A) haplotype in Mexican mestizos, Mediterraneans and the total world population; therefore an independent origin cannot be ruled out. The -87 C-->T and initiation codon ATG-->GTG were found with beta-haplotypes different from the reported ones, suggesting an indigenous origin.

  10. Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure

    Energy Technology Data Exchange (ETDEWEB)

    Altman, Robin [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine; Ly, Sonny [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Science Directorate; Hilt, Silvia [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine; Petrlova, Jitka [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine; Maezawa, Izumi [Univ. of California Davis, Sacramento, CA (United States). MIND Inst. and Dept. of Pathology and Laboratory Medicine; Kálai, Tamás [Univ. of Pecs (Hungary). Inst. of Organic and Medicinal Chemistry; Hideg, Kálmán [Univ. of Pecs (Hungary). Inst. of Organic and Medicinal Chemistry; Jin, Lee-Way [Univ. of California Davis, Sacramento, CA (United States). MIND Inst. and Dept. of Pathology and Laboratory Medicine; Laurence, Ted A. [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine; Voss, John C. [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine


    Alzheimer’s disease is characterized by the presence of extracellular plaques comprised of amyloid beta (Aβ) peptides. Soluble oligomers of the Aβ peptide underlie a cascade of neuronal loss and dysfunction associated with Alzheimer's disease. Single particle analyses of Aβ oligomers in solution by fluorescence correlation spectroscopy (FCS) were used to provide real-time descriptions of how spin-labeled fluorenes (SLFs; bi-functional small molecules that block the toxicity of Aβ) prevent and disrupt oligomeric assemblies of Aβ in solution. The FCS results, combined with electron paramagnetic resonance spectroscopy and circular dichroism spectroscopy, demonstrate SLFs can inhibit the growth of Aβ oligomers and disrupt existing oligomers while retaining Aβ in a largely disordered state. Furthermore, while the ability of SLF to block Aβ toxicity correlates with a reduction in oligomer size, our results suggest the conformation of Aβ within the oligomer determines the toxicity of the species. Attenuation of Aβ toxicity, which has been associated primarily with the soluble oligomeric form, can be achieved through redistribution of the peptides into smaller oligomers and arrest of the fractional increase in beta secondary structure.

  11. Chronic Dermal Toxicity of Epoxy Resins I. Skin Carcinogenic Potency and General Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Holland, J.M.


    Epoxy resins are a diverse class of chemicals that differ in structure, physical properties, and, presumably, biological activity. The purpose of these experiments was to compare the chronic dermal toxicity and carcinogenicity of selected commercial epoxy resins and to determine the potential for positive synergistic carcinogenic interactions between different resins. This work is an extension and continuation of a Department of Energy sponsored program to evaluate epoxy resins for potential occupational health risks. The materials examined were chosen on the basis of their interest to the U.S. government. They are representative of the manufacturer's production at the time, and therefore the data are completely valid only for the specific production period. Results of the experimental exposures will be reported in two parts. This report describes the test materials, their chemical and physical characteristics and the experimental design. General (systemic) toxicity will be evaluated and the skin carcinogenicity of the materials compared. A subsequent report will provide morphological descriptions of skin and significant internal pathology induced by the various treatments.

  12. Toxicity of some bis Mannich bases and corresponding piperidinols in the brine shrimp (Artemia salina) bioassay. (United States)

    Gul, H Inci; Gul, Mustafa; Erciyas, Ercin


    Some acetophenone-derived bis Mannich bases were synthesized: bis[beta-benzoylethyl]ethylamine hydrochloride (IIa), bis[beta-(p-methylbenzoyl)ethyl]ethylamine hydrochloride (IIb), bis[beta-(p-chlorobenzoyl)ethyl]ethy- lamine hydrochloride (IId), bis[(2-thienylcarbonyl)ethyl]ethylamine hydrochloride (IIe); some corresponding piperidinol derivatives: 3-benzoyl-1-ethyl-4-phenyl-4-piperidinol hydrochloride (IIIa), 1-ethyl-3-(p-methyl- benzoyl)-4-(p-methylphenyl)-4-piperidinol hydrochloride (IIIb), 1-ethyl-3-(p-methoxybenzoyl)-4-(p-methoxy- phenyl)-4-piperidinol hydrochloride (IIIc), 1-ethyl-3-(p-chlorobenzoyl)-4-(p-chlorophenyl)-4-piperidinol hydrochloride (IIId), 1-ethyl-4-(2-thienyl)-3-(2-thienylcarbonyl)-4-piperidinol hydrochloride (IIIe); and some representative quaternary piperidinols: 3-benzoyl-1-ethyl-4-hydroxy-1-methyl-4-phenylpiperidinium iodide (IIIf), 1-ethyl-4-hydroxy-1-methyl-3-(p-methylbenzoyl)-4-(p-methylphenyl)piperidinium iodide (IIIg). Toxicity was tested by the brine shrimp bioassay as an intermediate test before further in vivo animal experiments. Piperidine derivatives were found to be more potent than bis Mannich bases. Quaternary piperidine derivatives IIIf and IIIg and also non-quaternary piperidine derivatives IIIb, IIIe, IIIc and IIId were more toxic than 5-fluorouracil in brine shrimp bioassay. Except for IIe, bis Mannich bases were not effective. Quaternization and conversion of bis Mannich bases to corresponding piperidines improved the toxicity. The lipid solubility of the compounds may not affect the toxicity. From these findings the quaternary piperidine derivatives IIIf and IIIg could be used in further drug development and also for in vivo experiments.

  13. In vitro comparison of O4-benzylfolate modulated, BCNU-induced toxicity in human bone marrow using CFU-GM and tumor cell lines. (United States)

    Behrsing, Holger Peter; Furniss, Michael J; Robillard, Kristine A; Tomaszewski, Joseph E; Parchment, Ralph E


    2-Amino-O4-benzylpteridine derivatives inactivate the human DNA repair protein O6-alkylguanine-DNA alkyltransferase and have been tested as modulators of alkylating agent chemotherapy. Recently, the therapeutic potential of O4-benzylfolate (O4BF) in modulating bis-chloroethylnitrosourea (BCNU) toxicity was demonstrated in vitro using human HT29 and KB tumor lines. The current studies replicated the previous findings in HT29 and KB cells using ATP as an endpoint. However, the effective treatment conditions were severely toxic to human neutrophil progenitors called CFU-granulocyte/macrophage (CFU-GM), which could not tolerate > or =40 microM BCNU at any O4BF concentration. A lower BCNU concentration (10 microM) in combination with O4BF (2-100 microM) was only moderately tumoricidal. To screen for conditions tolerated by CFU-GM, bone marrow (BM) cells were pre-incubated (5 h) with O4BF, co-treated with O4BF and BCNU (42 h), washed, and plated to quantify CFU-GM survival. O4BF at 2 or 5 microM progressively lowered the inhibitory concentrations (ICs) for BCNU, but further increases in O4BF concentrations did not. Increasing O4BF concentrations with constant BCNU (10 microM) under the same prolonged exposure as in the human marrow study achieved only modest tumoricidal effects. In summary, the unexpected finding that normal BM cells are impacted by an agent developed to target malignant tissue refutes speculation that normal beta-folate receptor expressing hematopoietic cells will be spared. Further, the validated IC90 endpoint from the huCFU-GM assay has provided a reference point for judging the potential therapeutic effectiveness of this investigational combination in man using in vitro assays.

  14. Borocaptate sodium (BSH) toxicity issues

    Energy Technology Data Exchange (ETDEWEB)

    LaHann, T.


    ISU`s Center for Toxicology Research has been conducting toxicity testing of borocaptate sodium (BSH) to aid in assessing if proposed human studies of BSH are likely to be acceptably safe. This report describes BSH interactions with other biological agents.

  15. Gossypol Toxicity from Cottonseed Products

    Directory of Open Access Journals (Sweden)

    Ivana Cristina N. Gadelha


    Full Text Available Gossypol is a phenolic compound produced by pigment glands in cotton stems, leaves, seeds, and flower buds (Gossypium spp.. Cottonseed meal is a by-product of cotton that is used for animal feeding because it is rich in oil and proteins. However, gossypol toxicity limits cottonseed use in animal feed. High concentrations of free gossypol may be responsible for acute clinical signs of gossypol poisoning which include respiratory distress, impaired body weight gain, anorexia, weakness, apathy, and death after several days. However, the most common toxic effects is the impairment of male and female reproduction. Another important toxic effect of gossypol is its interference with immune function, reducing an animal’s resistance to infections and impairing the efficiency of vaccines. Preventive procedures to limit gossypol toxicity involve treatment of the cottonseed product to reduce the concentration of free gossypol with the most common treatment being exposure to heat. However, free gossypol can be released from the bound form during digestion. Agronomic selection has produced cotton varieties devoid of glands producing gossypol, but these varieties are not normally grown because they are less productive and are more vulnerable to attacks by insects.

  16. The Effect of Toxic Leadership (United States)


    for everything their organizations do or fail to do. However, does centralizing power in this manner lead to abuses and toxicity? According to Edmund ... Burke , ―Power, in whatever hands, is rarely guilty of too strict limitations on itself.‖115 The U.S. Government is strengthened by a system of

  17. Sparfloxacin induced toxic epidermal necrolysis

    Directory of Open Access Journals (Sweden)

    Ramesh M


    Full Text Available Toxic epidermal necrolysis (TEN is a life-threatening cutaneous adverse drug reaction. TEN is known to occur with the fluoroquinolone class of antibiotics, but only four cases of sparfloxacin induced TEN have been reported to the WHO database. This is another case report of sparfloxacin induced TEN.

  18. Iodine toxicity and its amelioration. (United States)

    Baker, David H


    Iodine (I) toxicity is rare in animals and humans, but nuclear explosions that give off radioactive I and excessive stable I ingestion in parts of the world where seaweed is consumed represent specialized I toxicity concerns. Chronic overconsumption of I reduces organic binding of I by the thyroid gland, which results in hypothyroidism and goiter. Bromine can replace I on position 5 of both T(3) and T(4) with no loss of thyroid hormone activity. Avian work has also demonstrated that oral bromide salts can reverse the malaise and growth depressions caused by high doses of I (as KI) added as supplements to the diet. Newborn infants by virtue of having immature thyroid glands are most susceptible to I toxicity, whether of stable or radioactive origin. For the latter, the 1986 Chernobyl nuclear accident in Belarus has provided evidence that KI blockage therapy for exposed individuals 18 years of age and younger is effective in minimizing the development of thyroid cancer. Whether bromide therapy has a place in I toxicity situations remains to be determined.

  19. Brain beta-amyloid accumulation in transgenic mice expressing mutant superoxide dismutase 1. (United States)

    Turner, Bradley J; Li, Qiao-Xin; Laughton, Katrina M; Masters, Colin L; Lopes, Elizabeth C; Atkin, Julie D; Cheema, Surindar S


    Oxidative stress is implicated in both the deposition and pathogenesis of beta-amyloid (Abeta) protein in Alzheimer's disease (AD). Accordingly, overexpression of the antioxidant enzyme superoxide dismutase 1 (SOD1) in neuronal cells and transgenic AD mice reduces Abeta toxicity and accumulation. In contrast, mutations in SOD1 associated with amyotrophic lateral sclerosis (ALS) confer enhanced pro-oxidative enzyme activities. We therefore examined whether ALS-linked mutant SOD1 overexpression in motor neuronal cells or transgenic ALS mice modulates Abeta toxicity or its accumulation in the brain. Aggregated, but not freshly solubilised, substrate-bound Abeta peptides induced degenerative morphology and cytotoxicity in motor neuron-like NSC-34 cells. Transfection of NSC-34 cells with human wild-type SOD1 attenuated Abeta-induced toxicity, however this neuroprotective effect was also observed for ALS-linked mutant SOD1. Analysis of the cerebral cortex, brainstem, cerebellum and olfactory bulb from transgenic SOD1G93A mice using enzyme-linked immunosorbent assay of acid-guanidine extracts revealed age-dependent elevations in Abeta levels, although not significantly different from wild-type mouse brain. In addition, brain amyloid protein precursor (APP) levels remained unaltered as a consequence of mutant SOD1 expression. We therefore conclude that mutant SOD1 overexpression promotes neither Abeta toxicity nor brain accumulation in these ALS models.

  20. Estimating beta-mixing coefficients via histograms

    CERN Document Server

    McDonald, Daniel J; Schervish, Mark


    The literature on statistical learning for time series often assumes asymptotic independence or "mixing" of data sources. Beta-mixing has long been important in establishing the central limit theorem and invariance principle for stochastic processes; recent work has identified it as crucial to extending results from empirical processes and statistical learning theory to dependent data, with quantitative risk bounds involving the actual beta coefficients. There is, however, presently no way to actually estimate those coefficients from data; while general functional forms are known for some common classes of processes (Markov processes, ARMA models, etc.), specific coefficients are generally beyond calculation. We present an l1-risk consistent estimator for the beta-mixing coefficients, based on a single stationary sample path. Since mixing coefficients involve infinite-order dependence, we use an order-d Markov approximation. We prove high-probability concentration results for the Markov approximation and show...

  1. Beta decay of {sup 61}Ga

    Energy Technology Data Exchange (ETDEWEB)

    Oinonen, M.; Dendooven, P.; Jokinen, A.; Penttilae, H.; Aeystoe, J. [Jyvaeskylae Univ. (Finland). Dept. of Physics; Baumann, P.; Knipper, A.; Ramdhane, M.; Walter, G. [Institut de Recherches Subatomiques, F-67037 Strasbourg (France); Fujita, Y. [Department of Physics, Osaka University, Toyonaka, Osaka 560-0043 (Japan); Gorska, M.; Grawe, H.; Hu, Z.; Kirchner, R.; Klepper, O.; Liu, W.; Roeckl, E. [Gesellschaft fuer Schwerionenforschung, Postfach 110552, D-64220 Darmstadt (Germany); Janas, Z.; Plochocki, A. [Institute of Experimental Physics, Warsaw University, PL-00681 Warsaw (Poland)


    The {beta} decay of {sup 61}Ga to its mirror nucleus {sup 61}Zn has been measured for the first time by using on-line mass separation and {beta}-delayed gamma-ray spectroscopy. The observed decay strength to the ground state implies superallowed character in accordance with the systematics of the mirror decays in the sd and fp shell. The {beta} feedings observed to four excited states in {sup 61}Zn are consistent with earlier spin-parity assignments based on in-beam experiments. The ground-state spin and parity for {sup 61}Ga were determined to be 3/2{sup -}. (orig.) With 3 figs., 2 tabs., 37 refs.

  2. Neutrinoless double beta decay from lattice QCD

    CERN Document Server

    Nicholson, Amy; Chang, Chia Cheng; Clark, M A; Joo, Balint; Kurth, Thorsten; Rinaldi, Enrico; Tiburzi, Brian; Vranas, Pavlos; Walker-Loud, Andre


    While the discovery of non-zero neutrino masses is one of the most important accomplishments by physicists in the past century, it is still unknown how and in what form these masses arise. Lepton number-violating neutrinoless double beta decay is a natural consequence of Majorana neutrinos and many BSM theories, and many experimental efforts are involved in the search for these processes. Understanding how neutrinoless double beta decay would manifest in nuclear environments is key for understanding any observed signals. In these proceedings we present an overview of a set of one- and two-body matrix elements relevant for experimental searches for neutrinoless double beta decay, describe the role of lattice QCD calculations, and present preliminary lattice QCD results.

  3. Presynaptic snake beta-neurotoxins produce tetanic fade and endplate potential run-down during neuromuscular blockade in mouse diaphragm. (United States)

    Wilson, H I; Nicholson, G M


    The present study investigated the ability of a number of presynaptic snake neurotoxins (snake beta-neurotoxins) to produce nerve-evoked train-of-four fade, tetanic fade and endplate potential run-down during the development of neuromuscular blockade in the isolated mouse phrenic-hemidiaphragm nerve-muscle preparation. All the snake beta-neurotoxins tested, with the exception of notexin, produced train-of-four and tetanic fade of nerve-evoked isometric muscle contractions. Train-of-four fade was not present during the initial depressant or facilitatory phases of muscle tension produced by the snake beta-neurotoxins but developed progressively during the final depressant phase that precedes complete neuromuscular blockade. The 'non-neurotoxic' bovine pancreatic phospholipase A2 and the 'low-toxicity' phospholipase A2 from Naja naja atra venom failed to elicit train-of-four fade, indicating that the phospholipase activity of the snake beta-neurotoxins is not responsible for the development of fade. Intracellular recording of endplate potentials (EPPs) elicited by nerve-evoked trains of stimuli showed a progressive run-down in EPP amplitude during the train following incubation with all snake beta-neurotoxins except notexin. Again this run-down in EPP amplitude was confined to the final depressant phase of snake beta-neurotoxin action. However when EPP amplitude fell to near uniquantal levels (fade was reduced. Unlike postjunctional snake alpha-neurotoxins, prejunctional snake beta-neurotoxins interfere with acetylcholine release at the neuromuscular junction during the development of neuromuscular blockade. This study provides further support for the hypothesis that fade in twitch and tetanic muscle tension is due to an underlying rundown in EPP amplitude resulting from a prejunctional alteration of transmitter release rather than a use-dependent block of postjunctional nicotinic receptors.

  4. Neurofilament ELISA validation.

    NARCIS (Netherlands)

    Petzold, A.; Altintas, A.; Andreoni, L.; Bartos, A.; Berthele, A.; Blankenstein, M.A.; Buee, L.; Castellazzi, M.; Cepok, S.; Comabella, M.; Constantinescu, C.S.; Deisenhammer, F.; Deniz, G.; Erten, G.; Espino, M.; Fainardi, E.; Franciotta, D.; Freedman, M.S.; Giedraitis, V.; Gilhus, N.E.; Giovannoni, G.; Glabinski, A.; Grieb, P.; Hartung, H.P.; Hemmer, B.; Herukka, S.K.; Hintzen, R.; Ingelsson, M.; Jackson, S.; Jacobsen, S.; Jafari, N.; Jalosinski, M.; Jarius, S.; Kapaki, E.; Kieseier, B.C.; Koel-Simmelink, M.J.; Kornhuber, J.; Kuhle, J.; Kurzepa, J.; Lalive, P.H.; Lannfelt, L.; Lehmensiek, V.; Lewczuk, P.; Livrea, P.; Marnetto, F.; Martino, D.; Menge, T.; Norgren, N.; Papuc, E.; Paraskevas, G.P.; Pirttila, T.; Rajda, C.; Rejdak, K.; Ricny, J.; Ripova, D.; Rosengren, L.; Ruggieri, M.; Schraen, S.; Shaw, G.; Sindic, C.; Siva, A.; Stigbrand, T.; Stonebridge, I.; Topcular, B.; Trojano, M.; Tumani, H.; Twaalfhoven, H.A.; Vecsei, L.; Pesch, V. Van; Stichele, H. van der; Vedeler, C.; Verbeek, M.M.; Villar, L.M.; Weissert, R.; Wildemann, B.; Yang, C.; Yao, K.; Teunissen, C.E.


    BACKGROUND: Neurofilament proteins (Nf) are highly specific biomarkers for neuronal death and axonal degeneration. As these markers become more widely used, an inter-laboratory validation study is required to identify assay criteria for high quality performance. METHODS: The UmanDiagnostics NF-light

  5. A valid licence

    NARCIS (Netherlands)

    Spoolder, H.A.M.; Ingenbleek, P.T.M.


    A valid licence Tuesday, April 20, 2010 Dr Hans Spoolder and Dr Paul Ingenbleek, of Wageningen University and Research Centres, share their thoughts on improving farm animal welfare in Europe At the presentation of the European Strategy 2020 on 3rd March, President Barroso emphasised the need for Eu

  6. The validation of metaphors

    NARCIS (Netherlands)

    Verhulst, F.


    In this paper we introduce models as metaphors for the description of reality We consider a number of case studies of contemporary research pollution of the NorthSea the ow eld of theWadden Sea drillstring dynamics the use of metaphors in psychoanalysis In all these cases validation of the resu

  7. Validation and test report

    DEFF Research Database (Denmark)

    Pedersen, Jens Meldgaard; Andersen, T. Bull


    . As a consequence of extensive movement artefacts seen during dynamic contractions, the following validation and test report consists of a report that investigates the physiological responses to a static contraction in a standing and a supine position. Eight subjects performed static contractions of the ankle...

  8. Statistical Analysis and validation

    NARCIS (Netherlands)

    Hoefsloot, H.C.J.; Horvatovich, P.; Bischoff, R.


    In this chapter guidelines are given for the selection of a few biomarker candidates from a large number of compounds with a relative low number of samples. The main concepts concerning the statistical validation of the search for biomarkers are discussed. These complicated methods and concepts are

  9. {sup 213}Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

    Energy Technology Data Exchange (ETDEWEB)

    Kratochwil, C.; Giesel, F.L.; Mier, W.; Haberkorn, U. [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Bruchertseifer, F.; Apostolidis, C.; Morgenstern, A. [European Commission, Institute for Transuranium Elements, Karlsruhe (Germany); Boll, R.; Murphy, K. [Oak Ridge National Laboratory, Oak Ridge, TN (United States)


    Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as {sup 90}Y/{sup 177}Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with {sup 213}Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with {sup 90}Y/{sup 177}Lu-DOTATOC were treated with an intraarterial infusion of {sup 213}Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of {sup 213}Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and {sup 68}Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. The biodistribution of {sup 213}Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. (orig.)

  10. BETASCAN: probable beta-amyloids identified by pairwise probabilistic analysis.

    Directory of Open Access Journals (Sweden)

    Allen W Bryan


    Full Text Available Amyloids and prion proteins are clinically and biologically important beta-structures, whose supersecondary structures are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Recent work has indicated the utility of pairwise probabilistic statistics in beta-structure prediction. We develop here a new strategy for beta-structure prediction, emphasizing the determination of beta-strands and pairs of beta-strands as fundamental units of beta-structure. Our program, BETASCAN, calculates likelihood scores for potential beta-strands and strand-pairs based on correlations observed in parallel beta-sheets. The program then determines the strands and pairs with the greatest local likelihood for all of the sequence's potential beta-structures. BETASCAN suggests multiple alternate folding patterns and assigns relative a priori probabilities based solely on amino acid sequence, probability tables, and pre-chosen parameters. The algorithm compares favorably with the results of previous algorithms (BETAPRO, PASTA, SALSA, TANGO, and Zyggregator in beta-structure prediction and amyloid propensity prediction. Accurate prediction is demonstrated for experimentally determined amyloid beta-structures, for a set of known beta-aggregates, and for the parallel beta-strands of beta-helices, amyloid-like globular proteins. BETASCAN is able both to detect beta-strands with higher sensitivity and to detect the edges of beta-strands in a richly beta-like sequence. For two proteins (Abeta and Het-s, there exist multiple sets of experimental data implying contradictory structures; BETASCAN is able to detect each competing structure as a potential structure variant. The ability to correlate multiple alternate beta-structures to experiment opens the possibility of computational investigation of prion strains and structural heterogeneity of amyloid

  11. Species used for drug testing reveal different inhibition susceptibility for 17beta-hydroxysteroid dehydrogenase type 1.

    Directory of Open Access Journals (Sweden)

    Gabriele Möller

    Full Text Available Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1 for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17beta-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17beta-HSD types 1, 2, 4, 5 and 7 but also against 17beta-HSD 1 of several other species including marmoset, pig, mouse, and rat. The latter are used in the processes of pharmacophore screening. We present the quantification of inhibitor preferences between human and animal models. Profound differences in the susceptibility to inhibition of steroid conversion among all 17beta-HSDs analyzed were observed. Especially, the rodent 17beta-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17beta-HSD 1 was obtained with the marmoset enzyme. Molecular docking experiments predicted estrone as the most potent inhibitor. The best performing compound in enzymatic assays was also highly ranked by docking scoring for the human enzyme. However, species-specific prediction of inhibitor performance by molecular docking was not possible. We show that experiments with good candidate compounds would out-select them in the rodent model during preclinical optimization steps. Potentially active human-relevant drugs, therefore, would no longer be further developed. Activity and efficacy screens in heterologous species systems must be evaluated with caution.

  12. Predicting the risk of toxic blooms of golden alga from cell abundance and environmental covariates (United States)

    Patino, Reynaldo; VanLandeghem, Matthew M.; Denny, Shawn


    Golden alga (Prymnesium parvum) is a toxic haptophyte that has caused considerable ecological damage to marine and inland aquatic ecosystems worldwide. Studies focused primarily on laboratory cultures have indicated that toxicity is poorly correlated with the abundance of golden alga cells. This relationship, however, has not been rigorously evaluated in the field where environmental conditions are much different. The ability to predict toxicity using readily measured environmental variables and golden alga abundance would allow managers rapid assessments of ichthyotoxicity potential without laboratory bioassay confirmation, which requires additional resources to accomplish. To assess the potential utility of these relationships, several a priori models relating lethal levels of golden alga ichthyotoxicity to golden alga abundance and environmental covariates were constructed. Model parameters were estimated using archived data from four river basins in Texas and New Mexico (Colorado, Brazos, Red, Pecos). Model predictive ability was quantified using cross-validation, sensitivity, and specificity, and the relative ranking of environmental covariate models was determined by Akaike Information Criterion values and Akaike weights. Overall, abundance was a generally good predictor of ichthyotoxicity as cross validation of golden alga abundance-only models ranged from ∼ 80% to ∼ 90% (leave-one-out cross-validation). Environmental covariates improved predictions, especially the ability to predict lethally toxic events (i.e., increased sensitivity), and top-ranked environmental covariate models differed among the four basins. These associations may be useful for monitoring as well as understanding the abiotic factors that influence toxicity during blooms.


    Directory of Open Access Journals (Sweden)

    Jirge Supriya


    Full Text Available A new simple, precise, rapid and selective high-performance thin-layer chromatography (HPTLC method has been developed for determination of beta-sitosterol-D-glucoside in Karela (Momordica charantia Linn. extracts as well as in plant based formulations containing Ashwagandha (Withania somnifera L. Dunal. The mobile phase consisted of toluene: ethyl acetate: formic acid (5: 5: 0.5 (v/v and TLC plates precoated with 60F254 silica gel were used as the stationary phase. Detection was carried out densitometrically using a UV detector at 540 nm after spraying with Anisaldehyde – Sulphuric acid Reagent (ASR. The retention factor of beta-sitosterol-D-glucoside was 0.47. Linearity was obtained in the range of 1.0 to 3.5 µg per spot for beta sitosterol -D-glucoside. The method was précise and accurate as the RSD was < 2 %. The method was found to be sensitive, selective and robust. The developed and validated HPTLC method was employed for standardization of methanol and petroleum ether extracts of Karela and seven different formulations containing Ashwagandha for the content of the beta-sitosterol-D-glucoside..

  14. Synthesis of {beta}-haloacids by radiation

    Energy Technology Data Exchange (ETDEWEB)

    Albarran, G.; Negron-Mendoza, A. [Instituto de Ciencias y Artes, Chiapas (Mexico). Escuela de Biologia


    Hydrogen halides add to alkenes yielding the corresponding haloalkane. The addition of HX ordinally follows the course of Markownikoff`s rule. In this paper we analyze the HBr addition reaction to unsaturated carboxylic acids. The course of the addition is anti-Markownikoff. This implies that the reaction goes through free radical mechanism and the haloacid formed is in the {beta}-position. The acids under study are fumaric, itaconic, citraconic acids and the methyl ester of fumaric acid. The {beta}-haloacids formed are easily purified from the bulk solutions. (author).

  15. Volume Effects in Discrete beta functions

    CERN Document Server

    Liu, Yuzhi; Zou, Haiyuan


    We calculate discrete beta functions corresponding to the two-lattice matching for the 2D O(N) models and Dyson's hierarchical model. We describe and explain finite-size effects such as the appearance of a nontrivial infrared fixed point that goes to infinity at infinite volume or the merging of an infrared and an ultraviolet fixed point. We present extensions of the RG flows to the complex coupling plane. We discuss the possibility of constructing a continuous beta function from the discrete one by using functional conjugation methods. We briefly discuss the relevance of these findings for the search of nontrivial fixed points in multiflavor lattice gauge theory models.

  16. Population screening for beta-thalassaemia. (United States)

    Flatz, S D; Flatz, G


    The graphic recording of time to 50% haemolysis in a glycerine-saline solution is a simple, reproducible method of determining erythrocyte osmotic fragility. Studies on a normal population yielded an upper limit of normal of 90 s. In 250 healthy males from Northern Thailand all 19 with beta-thalassaemia minor had abnormal osmotic indices, and the value of the test was confirmed in beta-thalassaemia heterozygotes in Europe. Of 23 patients with iron deficiency 18 had abnormal osmotic indices. However, this is not thought likely to be a significant source of false positives in the screening of populations at risk of haemoglobinopathies but in whom iron deficiency is rare.

  17. Detecting Double Beta Decays Using Nuclear Emulsions

    CERN Document Server

    Dracos, Marcos


    Neutrino nature and absolute mass scale are major questions in particle physics which cannot be addressed by the present neutrino oscillation program. To answer these two questions, several neutrinoless double beta decay experiments are underway or planed for the near future. These experiments, mainly use bolometric techniques or gaseous counters coupled with scintillator detectors. The energy resolution is better in bolometric experiments but experiments coupling tracking with calorimetry have the advantage of observing the two electron tracks and remove many background sources. Here, we present a proposal of using nuclear emulsions to observe double beta decays. This technique has the advantage of precise tracking and vertexing even for low energy electrons.

  18. American ginseng modulates pancreatic beta cell activities

    Directory of Open Access Journals (Sweden)

    Luo Luguang


    Full Text Available Abstract The mechanism of the beneficial effects of Panax quinquefolius (Xiyangshen, American ginseng on diabetes is yet to be elucidated. Recent studies show that Panax quinquefolius increases insulin production and reduces the death of pancreatic beta cells. Mechanism studies indicate that Panax quinquefolius improves cell's immuno-reactivity and mitochondrial function through various factors. Clinical studies show that Panax quinquefolius improves postprandial glycemia in type 2 diabetic patients. Further studies to identify the component(s of Panax quinquefolius linked with pancreatic islets/beta cells in vitro and in vivo are warranted for better understanding of the full effects of Panax quinquefolius.

  19. The NEXT double beta decay experiment (United States)

    Laing, A.; NEXT Collaboration


    NEXT (Neutrino Experiment with a Xenon TPC) is a neutrinoless double-beta (ββ0v) decay experiment at Laboratorio Subterraneo de Canfranc (LSC). It is an electroluminescent Time Projection Chamber filled with high pressure 136Xe gas with separated function capabilities for calorimetry and tracking. Energy resolution and background suppression are the two key features of any neutrinoless double beta decay experiment. NEXT has both good energy resolution (review NEXT R&D results, the status of detector commissioning at LSC and the NEXT physics case.

  20. Helicity and nuclear $\\beta$ decay correlations

    CERN Document Server

    Hong, Ran; García, Alejandro


    We present simple derivations of nuclear $\\beta$-decay correlations with an emphasis on the special role of helicity. This provides a good opportunity to teach students about helicity and chirality in particle physics through exercises using simple aspects of quantum mechanics. In addition, this paper serves as an introduction to nuclear $\\beta$-decay correlations from both a theoretical and experimental vantage. This article can be used to introduce students to ongoing experiments searching for hints of new physics in the low-energy precision frontier.

  1. Beta-decay of {sup 56}Cu

    Energy Technology Data Exchange (ETDEWEB)

    Ramdhane, M.; Baumann, P.; Knipper, A.; Walter, G. [Institute de Recherches Subatomiques, 67 - Strasbourg (France); Janas, Z.; Plochocki, A. [Warsaw Univ. (Poland). Inst. of Experimental Physics; Aeystoe, J.; Dendooven, P.; Jokinen, A.; Oinonen, M.; Pentilae, H. [Jyvaeskylae Univ. (Finland); Liu, W.; Grawe, H.; Hu, Z.; Kirchner, R.; Klepper, O.; Roeckl, E. [Gesellschaft fuer Schwerionenforschung mbH, Darmstadt (Germany); Gorska, M. [Warsaw Univ. (Poland). Inst. of Experimental Physics]|[Gesellschaft fuer Schwerionenforschung mbH, Darmstadt (Germany); Fujita, Y. [Osaka Univ. (Japan); Brown, B.A. [Michigan State Univ., East Lansing, MI (United States)


    By measuring positrons and {beta}-delayed {gamma}-rays emitted from mass-separated sources, the decay of {sup 56}Cu(4{sup +},T{sub z}=-1,T=1) to states in the doubly-magic nucleus {sup 56}Ni was studied for the first time. The half-life of {sup 56}Cu was measured to be 78(15) ms, and four {beta}-delayed {gamma}-rays were assigned to its decay. The resulting experimental data on Fermi and Gamow-Teller strength are compared with shell-model predictions. (orig.)

  2. Simulated progress in double-beta decay

    Energy Technology Data Exchange (ETDEWEB)

    Miley, H.S. (Pacific Northwest Laboratory, Battelle Blvd., Richland, WA 99352 (United States)); Arthur, R.J. (Pacific Northwest Laboratory, Battelle Blvd., Richland, WA 99352 (United States)); Avignone, F.T. (University of South Carolina, Columbia, SC 29208 (United States)); Barabash, A.S. (Institute for Theoretical and Experimental Physics, 117 259 Moscow (Russian Federation)); Brodzinski, R.L. (Pacific Northwest Laboratory, Battelle Blvd., Richland, WA 99352 (United States)); Collar, J.I. (University of South Carolina, Columbia, SC 29208 (United States)); Courant, H. (University of Minnesota, Minneapolis, MN 55455 (United States)); Garcia, E. (University of Zaragoza, Zaragoza (Spain)); Guerard, C.K. (University of South Carolina, Columbia, SC 29208 (United States)); Hensley, W.K. (Pacific Northwest Laboratory, Battelle Blvd., Richland, WA 99352 (United States)); Kirpichnikov, I.V. (Institute for Theoretical and Experimental Physics, 117 259 Moscow (Russian Federation)); Kl


    A Monte Carlo code has been developed to accurately simulate double-beta decay measurements. Coincident gamma rays, beta spectra, and angular correlations have been added to adequately simulate a complete [sup 100]Mo nuclear decay and provide corrections to experimentally determined detector efficiencies. This code has been used to strip certain low-background spectra obtained in the Homestake gold mine in Lead, SD, for the purpose of extremely sensitive materials assay for the construction of new, large, enriched germanium detectors. Assays as low as 9[mu]Bq/g of [sup 210]Pb in lead shielding were obtained. ((orig.))

  3. Simulated progress in double-beta decay (United States)

    Miley, H. S.; Arthur, R. J.; Avignone, F. T.; Barabash, A. S.; Brodzinski, R. L.; Collar, J. J.; Courant, H.; Garcia, E.; Guerard, C. K.; Hensley, W. K.; Kirpichnikov, I. V.; Klimenko, A. A.; Morales, A.; Morales, J.; Nunez-Lagos, R.; Osetrov, S. B.; Pogosov, V. S.; Puimedon, J.; Reeves, J. H.; Ruddick, K.; Saenz, C.; Salinas, A.; Sarsa, M. L.; Smolnikov, A. A.; Starostin, A. S.; Tamanyan, A. G.; Umatov, V. I.; Vasiliev, S. I.; Villar, J. A.


    A Monte Carlo code has been developed to accurately simulate double-beta decay measurements. Coincident gamma rays, beta spectra, and angular correlations have been added to adequately simulate a complete 100Mo nuclear decay and provide corrections to experimentally determined detector efficiencies. This code has been used to strip certain low-background spectra obtained in the Homestake gold mine in Lead, SD, for the purpose of extremely sensitive materials assay for the construction of new, large, enriched germanium detectors. Assays as low as 9 μBq/g of 210Pb in lead shielding were obtained.

  4. Atypical beta(s) haplotypes are generated by diverse genetic mechanisms. (United States)

    Zago, M A; Silva, W A; Dalle, B; Gualandro, S; Hutz, M H; Lapoumeroulie, C; Tavella, M H; Araujo, A G; Krieger, J E; Elion, J; Krishnamoorthy, R


    The majority of the chromosomes with the beta(S) gene have one of the five common haplotypes, designated as Benin, Bantu, Senegal, Cameroon, and Arab-Indian haplotypes. However, in every large series of sickle cell patients, 5-10% of the chromosomes have less common haplotypes, usually referred to as "atypical" haplotypes. In order to explore the genetic mechanisms that could generate these atypical haplotypes, we extended our analysis to other rarely studied polymorphic markers of the beta(S)-gene cluster, in a total of 40 chromosomes with uncommon haplotypes from Brazil and Cameroon. The following polymorphisms were examined: seven restriction site polymorphisms of the epsilongammadeltabeta-cluster, the pre-(G)gamma framework sequence including the 6-bp deletion/insertion pattern, HS-2 LCR (AT)xR(AT)y and pre-beta (AT)xTy repeat motifs, the GC/TT polymorphism at -1105-1106 of (G)gamma-globin gene, the C/T polymorphism at -551 of the beta-globin gene, and the intragenic beta-globin gene framework. Among the Brazilian subjects, the most common atypical structure (7/16) was a Bantu 3'-subhaplotype associated with different 5'-sequences, while in two chromosomes a Benin 3'-subhaplotype was associated with two different 5'-subhaplotypes. A hybrid Benin/Bantu configuration was also observed. In three chromosomes, the atypical haplotype differed from the typical one by the change of a single restriction site. In 2/134 chromosomes identified as having a typical Bantu RFLP-haplotype, a discrepant LCR repeat sequence was observed, probably owing to a crossover 5' to the epsilon-gene. Among 80 beta(S) chromosomes from Cameroon, 22 were associated with an atypical haplotype. The most common structure was represented by a Benin haplotype (from the LCR to the beta-gene) with a non-Benin segment 3' to the beta-globin gene. In two cases a Bantu LCR was associated with a Benin haplotype and a non-Benin segment 3' to the beta-globin gene. In three other cases, a more complex

  5. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. (United States)

    May, C; Rivella, S; Callegari, J; Heller, G; Gaensler, K M; Luzzatto, L; Sadelain, M


    The stable introduction of a functional beta-globin gene in haematopoietic stem cells could be a powerful approach to treat beta-thalassaemia and sickle-cell disease. Genetic approaches aiming to increase normal beta-globin expression in the progeny of autologous haematopoietic stem cells might circumvent the limitations and risks of allogeneic cell transplants. However, low-level expression, position effects and transcriptional silencing hampered the effectiveness of viral transduction of the human beta-globin gene when it was linked to minimal regulatory sequences. Here we show that the use of recombinant lentiviruses enables efficient transfer and faithful integration of the human beta-globin gene together with large segments of its locus control region. In long-term recipients of unselected transduced bone marrow cells, tetramers of two murine alpha-globin and two human betaA-globin molecules account for up to 13% of total haemoglobin in mature red cells of normal mice. In beta-thalassaemic heterozygous mice higher percentages are obtained (17% to 24%), which are sufficient to ameliorate anaemia and red cell morphology. Such levels should be of therapeutic benefit in patients with severe defects in haemoglobin production.

  6. Nuclear Matrix Elements for the $\\beta\\beta$ Decay of the $^{76}$Ge

    CERN Document Server

    Brown, B A; Horoi, M


    The nuclear matrix elements for two-neutrino double-beta (2 n$\\beta\\beta$ ) and zero-neutrino double-beta (0 n$\\beta\\beta$) decay of 76 Ge are evaluated in terms of the configuration interaction (CI), quasiparticle random phase approximation (QRPA) and interacting boson model (IBM) methods. We show that the decomposition of the matrix elements in terms of interemediate states in 74 Ge is dominated by ground state of this nucleus. We consider corrections to the CI results that arise from configurations admixtures involving orbitals out-side of the CI configuration space by using results from QRPA, many-body-perturbation theory, and the connections to related observables. The CI two-neutrino matrix element is reduced due to the inclusion of spin-orbit partners, and to many-body correlations connected with Gamow-Teller beta decay. The CI zero-neutrino matrix element for the heavy neutrino is enhanced due to particle-particle correlations that are connected with the odd-even oscillations in the nuclear masse...

  7. Transforming growth factor-beta (TGF-beta) and programmed cell death in the vertebrate retina. (United States)

    Duenker, Nicole


    Programmed cell death (PCD) is a precisely regulated phenomenon essential for the homeostasis of multicellular organisms. Developmental systems, particularly the nervous system, have provided key observations supporting the physiological role of PCD. We have recently shown that transforming growth factor-beta (TGF-beta) plays an important role in mediating ontogenetic PCD in the nervous system. As part of the central nervous system the developing retina serves as an ideal model system for investigating apoptotic processes during neurogenesis in vivo as it is easily accessible experimentally and less complex due to its limited number of different neurons. This review summarizes data indicating a pivotal role of TGF-beta in mediating PCD in the vertebrate retina. The following topics are discussed: expression of TGF-beta isoforms and receptors in the vertebrate retina, the TGF-beta signaling pathway, functions and molecular mechanisms of PCD in the nervous system, TGF-beta-mediated retinal apoptosis in vitro and in vivo, and interactions of TGF-beta with other pro- and anti-apoptotic factors.

  8. The nature and structure of correlations among Big Five ratings: the halo-alpha-beta model. (United States)

    Anusic, Ivana; Schimmack, Ulrich; Pinkus, Rebecca T; Lockwood, Penelope


    In light of consistently observed correlations among Big Five ratings, the authors developed and tested a model that combined E. L. Thorndike's (1920) general evaluative bias (halo) model and J. M. Digman's (1997) higher order personality factors (alpha and beta) model. With 4 multitrait-multimethod analyses, Study 1 revealed moderate convergent validity for alpha and beta across raters, whereas halo was mainly a unique factor for each rater. In Study 2, the authors showed that the halo factor was highly correlated with a validated measure of evaluative biases in self-ratings. Study 3 showed that halo is more strongly correlated with self-ratings of self-esteem than self-ratings of the Big Five, which suggests that halo is not a mere rating bias but actually reflects overly positive self-evaluations. Finally, Study 4 demonstrated that the halo bias in Big Five ratings is stable over short retest intervals. Taken together, the results suggest that the halo-alpha-beta model integrates the main findings in structural analyses of Big Five correlations. Accordingly, halo bias in self-ratings is a reliable and stable bias in individuals' perceptions of their own attributes. Implications of the present findings for the assessment of Big Five personality traits in monomethod studies are discussed.

  9. Macrocyclic beta-sheet peptides that mimic protein quaternary structure through intermolecular beta-sheet interactions. (United States)

    Khakshoor, Omid; Demeler, Borries; Nowick, James S


    This paper reports the design, synthesis, and characterization of a family of cyclic peptides that mimic protein quaternary structure through beta-sheet interactions. These peptides are 54-membered-ring macrocycles comprising an extended heptapeptide beta-strand, two Hao beta-strand mimics [JACS 2000, 122, 7654] joined by one additional alpha-amino acid, and two delta-linked ornithine beta-turn mimics [JACS 2003, 125, 876]. Peptide 3a, as the representative of these cyclic peptides, contains a heptapeptide sequence (TSFTYTS) adapted from the dimerization interface of protein NuG2 [PDB ID: 1mio]. 1H NMR studies of aqueous solutions of peptide 3a show a partially folded monomer in slow exchange with a strongly folded oligomer. NOE studies clearly show that the peptide self-associates through edge-to-edge beta-sheet dimerization. Pulsed-field gradient (PFG) NMR diffusion coefficient measurements and analytical ultracentrifugation (AUC) studies establish that the oligomer is a tetramer. Collectively, these experiments suggest a model in which cyclic peptide 3a oligomerizes to form a dimer of beta-sheet dimers. In this tetrameric beta-sheet sandwich, the macrocyclic peptide 3a is folded to form a beta-sheet, the beta-sheet is dimerized through edge-to-edge interactions, and this dimer is further dimerized through hydrophobic face-to-face interactions involving the Phe and Tyr groups. Further studies of peptides 3b-3n, which are homologues of peptide 3a with 1-6 variations in the heptapeptide sequence, elucidate the importance of the heptapeptide sequence in the folding and oligomerization of this family of cyclic peptides. Studies of peptides 3b-3g show that aromatic residues across from Hao improve folding of the peptide, while studies of peptides 3h-3n indicate that hydrophobic residues at positions R3 and R5 of the heptapeptide sequence are important in oligomerization.

  10. The ChemScreen project to design a pragmatic alternative approachto predict reproductive toxicity of chemicals

    NARCIS (Netherlands)

    Van der Burg, B.; Wedebye, E.B.; Dietrich, D.R.; Jaworska, J.; Mangelsdorf, I.; Paune, E.; Schwarz, M.; Piersma, A.H.; Kroese, E.D.


    There is a great need for rapid testing strategies for reproductive toxicity testing, avoiding animal use.The EU Framework program 7 project ChemScreen aimed to fill this gap in a pragmatic manner prefer-ably using validated existing tools and place them in an innovative alternative testing strategy

  11. beta-Scission of C-3 (beta-carbon) alkoxyl radicals on peptides and proteins

    DEFF Research Database (Denmark)

    Headlam, H A; Mortimer, A; Easton, C J


    of new reactive groups, including hydroperoxides. These processes can result in the loss of structural or enzymatic activity. Backbone fragmentation is known to occur via a number of mechanisms, most of which involve hydrogen abstraction from the alpha-carbon site on the backbone. In this study, we...... demonstrate that initial attack at a side chain site, the beta-position (C-3), can give rise to formation of alpha-carbon radicals, and hence backbone cleavage, via the formation and subsequent beta-scission of C-3 alkoxyl radicals. This beta-scission reaction is rapid (k estimated to be >10(7) s(-)(1)) even...

  12. Spectroscopy with {beta}2p and {beta}-{nu} recoil shifts

    Energy Technology Data Exchange (ETDEWEB)

    Fynbo, H.O.U. E-mail:; Axelsson, L.; Aeystoe, J.; Bergmann, U.C.; Borge, M.J.G.; Fraile, L.M.; Honkanen, A.; Hornshoej, P.; Jading, Y.; Jokinen, A.; Jonson, B.; Martel, I.; Mukha, I.; Nilsson, T.; Nyman, G.; Oinonen, M.; Riisager, K.; Siiskonen, T.; Smedberg, M.H.; Thaysen, J.; Tengblad, O.; Wenander, F


    The beta-delayed proton emission from the lightest Ar-isotopes has been measured with a high-granularity, large solid-angle Si-detector setup. Although designed for the detection of beta-delayed two-proton and three-proton events, the setup also permitted measurement of proton energy shifts due to the beta-neutrino recoil. We discuss how spectroscopic information can be extracted from such measurements, even at the drip line. For the case of {sup 31}Ar, the ground-state spin could be determined as 5/2.

  13. Modeling the toxicity of aromatic compounds to tetrahymena pyriformis: the response surface methodology with nonlinear methods. (United States)

    Ren, Shijin


    Response surface models based on multiple linear regression had previously been developed for the toxicity of aromatic chemicals to Tetrahymena pyriformis. However, a nonlinear relationship between toxicity and one of the molecular descriptors in the response surface model was observed. In this study, response surface models were established using six nonlinear modeling methods to handle the nonlinearity exhibited in the aromatic chemicals data set. All models were validated using the method of cross-validation, and prediction accuracy was tested on an external data set. Results showed that response surface models based on locally weighted regression scatter plot smoothing (LOESS), multivariate adaptive regression splines (MARS), neural networks (NN), and projection pursuit regression (PPR) provided satisfactory power of model fitting and prediction and had similar applicabilities. The response surface models based on nonlinear methods were difficult to interpret and conservative in discriminating toxicity mechanisms.

  14. QSAR studies for the acute toxicity of nitrobenzenes to the Tetrahymena pyriformis

    Directory of Open Access Journals (Sweden)

    Wang Dan-Dan


    Full Text Available Quantitative structure-activity relationship (QSAR models play a key role in finding the relationship between molecular structures and the toxicity of nitrobenzenes to Tetrahymena pyriformis. In this work, genetic algorithm, along with partial least square (GA-PLS was employed to select optimal subset of descriptors that have significant contribution to the toxicity of nitrobenzenes to Tetrahymena pyriformis. A set of five descriptors, namely G2, HOMT, G(Cl…Cl, Mor03v and MAXDP, was used for the prediction of the toxicity of 45 nitrobenzene derivatives and then were used to build the model by multiple linear regression (MLR method. It turned out that the built model, whose stability was confirmed using the leave-one-out validation and external validation test, showed high statistical significance (R2=0.963, Q2LOO=0.944. Moreover, Y-scrambling test indicated there was no chance correlation in this model.

  15. Strain-dependent differences in sensitivity of rat beta-cells to interleukin 1 beta in vitro and in vivo

    DEFF Research Database (Denmark)

    Reimers, J I; Andersen, H U; Mauricio, D


    The aim of this study was to investigate whether strain-dependent differences in beta-cell sensitivity to interleukin (IL) 1 beta exist in vitro and in vivo and if so, whether these differences correlate to variations in IL-1 beta-induced islet inducible nitric oxide synthase (iNOS) mRNA expression....../kg) or vehicle for 5 days. All the strains investigated were susceptible to IL-1 beta-induced changes in body weight, food intake, temperature, and plasma glucagon and corticosterone. However, IL-1 beta induced hyperglycemia and impairment of beta-cell glucose responsiveness in WK/Mol and LS/Mol rats...

  16. QSTR modeling for qualitative and quantitative toxicity predictions of diverse chemical pesticides in honey bee for regulatory purposes. (United States)

    Singh, Kunwar P; Gupta, Shikha; Basant, Nikita; Mohan, Dinesh


    Pesticides are designed toxic chemicals for specific purposes and can harm nontarget species as well. The honey bee is considered a nontarget test species for toxicity evaluation of chemicals. Global QSTR (quantitative structure-toxicity relationship) models were established for qualitative and quantitative toxicity prediction of pesticides in honey bee (Apis mellifera) based on the experimental toxicity data of 237 structurally diverse pesticides. Structural diversity of the chemical pesticides and nonlinear dependence in the toxicity data were evaluated using the Tanimoto similarity index and Brock-Dechert-Scheinkman statistics. Probabilistic neural network (PNN) and generalized regression neural network (GRNN) QSTR models were constructed for classification (two and four categories) and function optimization problems using the toxicity end point in honey bees. The predictive power of the QSTR models was tested through rigorous validation performed using the internal and external procedures employing a wide series of statistical checks. In complete data, the PNN-QSTR model rendered a classification accuracy of 96.62% (two-category) and 95.57% (four-category), while the GRNN-QSTR model yielded a correlation (R(2)) of 0.841 between the measured and predicted toxicity values with a mean squared error (MSE) of 0.22. The results suggest the appropriateness of the developed QSTR models for reliably predicting qualitative and quantitative toxicities of pesticides in honey bee. Both the PNN and GRNN based QSTR models constructed here can be useful tools in predicting the qualitative and quantitative toxicities of the new chemical pesticides for regulatory purposes.

  17. Time Until Neuron Death After Initial Puncture From an Amyloid-Beta Oligomer

    CERN Document Server

    Horton, Tanner


    Hardy and Higgins first proposed the amyloid cascade hypothesis in 1992, stating that the decrease in neuronal function observed in Alzheimer's Disease (AD) is due to a process initiated by the oligomerization of amyloid-beta peptides. One hypothesis states that toxicity arises from the aggregation of amyloid-beta into a pore structure, which can then puncture the brain cell membrane; this allow toxic calcium ions to flood through the opening, causing eventual cell death. In 2007, neurobiologist Ruth Nussinov calculated the three pore sizes most likely to occur within the brain. Based on her findings, we constructed a method to determine the time it takes for a cell to die after the cell is punctured by the pore. Our findings have shown that cell death occurs within one second after the oligomer makes contact with the cell. We believe this is important because instant cell death has been one criticism of Nussinov's model, and we have calculated a concrete time value for that criticism. We identify two potenti...

  18. Lipid raft disruption protects mature neurons against amyloid oligomer toxicity. (United States)

    Malchiodi-Albedi, Fiorella; Contrusciere, Valentina; Raggi, Carla; Fecchi, Katia; Rainaldi, Gabriella; Paradisi, Silvia; Matteucci, Andrea; Santini, Maria Teresa; Sargiacomo, Massimo; Frank, Claudio; Gaudiano, Maria Cristina; Diociaiuti, Marco


    A specific neuronal vulnerability to amyloid protein toxicity may account for brain susceptibility to protein misfolding diseases. To investigate this issue, we compared the effects induced by oligomers from salmon calcitonin (sCTOs), a neurotoxic amyloid protein, on cells of different histogenesis: mature and immature primary hippocampal neurons, primary astrocytes, MG63 osteoblasts and NIH-3T3 fibroblasts. In mature neurons, sCTOs increased apoptosis and induced neuritic and synaptic damages similar to those caused by amyloid beta oligomers. Immature neurons and the other cell types showed no cytotoxicity. sCTOs caused cytosolic Ca(2+) rise in mature, but not in immature neurons and the other cell types. Comparison of plasma membrane lipid composition showed that mature neurons had the highest content in lipid rafts, suggesting a key role for them in neuronal vulnerability to sCTOs. Consistently, depletion in gangliosides protected against sCTO toxicity. We hypothesize that the high content in lipid rafts makes mature neurons especially vulnerable to amyloid proteins, as compared to other cell types; this may help explain why the brain is a target organ for amyloid-related diseases.

  19. Volatile substance misuse: an updated review of toxicity and treatment. (United States)

    Ford, Jonathan B; Sutter, Mark E; Owen, Kelly P; Albertson, Timothy E


    Educational campaigns and legislative actions may have led to an overall decrease in the prevalence of volatile substance misuse (VSM) in many countries; however, it is still a common practice throughout the world. Studies currently suggest that girls are misusing volatile substances more than before and at a prevalence rate equal to or exceeding that of boys in several countries. Products that may be misused are ubiquitous and relatively easy to acquire. The most commonly misused substances in recent studies are fuels such as butane or petrol and compressed gas dusters and deodorants that may contain fluorocarbons and/or butane. Detection of VSM is challenging, therefore physicians must maintain a high level of suspicion based on history and clinical presentation. Clues to misuse are often subtle and may include the patient's proximity to a volatile substance or paraphernalia when found intoxicated, dermal burns, blisters, pigments, or rashes, and chemical odors. The primary targets of toxicity are the brain and the heart. The leading cause of death from VSM is from ventricular dysrhythmias. Treatment of toxicity begins with support of airway, breathing, and circulation. Exogenous catecholamines should be avoided if possible due to the theoretical "sensitized" and irritable myocardium. In the case of ventricular dysrhythmias, direct current defibrillation and/or beta-adrenergic receptor antagonism should be used. New evidence demonstrates the addictive potential of VSM yet effective therapy remains uncertain. Further research is needed in developing methods for preventing, detecting, and treating the harmful effects of VSM.

  20. Toxic effects of domestic sewage on zooplankton

    Digital Repository Service at National Institute of Oceanography (India)

    Gajbhiye, S.N.; Nair, V.R.; Desai, B.N.

    The toxic effects of raw domestic sewage on different groups of zooplank-ton, was tested in the laboratory for evaluating acute toxicity. 24 hr., LC-50 values for larvae of stomatopods, gastropods and chaetognaths (2-7% concentration) indicated...