Mutagenicity study of the urinary metabolites of 2-aminonaphthalene

The mutagenicity study of the urinary metabolites of 2-aminonaphthalene was conducted to determine whether differences in metabolism between different acetylator phenotypes could account for a proposed mechanism of bladder carcinogenesis. This required the use of fast and slow acetylator rabbits with phenotypic similarities to humans. In the absence of available slow acetylators, it was necessary to inhibit fast acetylators. The proposed mechanism was that slow acetylators were at greater potential risk of bladder carcinogenesis due to low rates of acetylation, a detoxification mechanism for certain aromatic amines. The alternate metabolic pathway will be hydroxylation. The fast acetylators were proposed to exhibit lower risk of bladder carcinogenicity as a result of higher acetylation rates and less mutagenic metabolites.^ This hypothesis was approached by determining from in vitro mutagenicity assays with Salmonella typhimurium strains TA98 and TA100 whether different metabolites were mutagenic. The acetylation rate of each rabbit and a suitable method of acetylation inhibition were determined through oral exposure to dapsone and the acetylation inhibitor, K-p-aminosalicylic acid. Residues of dapsone and its acetylated metabolite were extracted from blood samples and analyzed by ultra-violet spectrometry using standard curves for each metabolite. The urine samples were concentrated on XAD-2 resin and analyzed both as whole urine concentrates and as isolated metabolites from spots on high performance thin layer chromatography plates. The major isolated spots were identified and quantified through extraction and analysis by high performance liquid chromatography when possible.^ Acetylation rate determination and inhibition were successfully demonstrated in rabbits. Significant mutagenicity was noted for several critical metabolites. None of the mutagenic metabolites were detected in higher concentration in the inhibited acetylators and thus, no clear relationship of metabolite concentration to bladder carcinogenesis was evident for the compounds analyzed. There was some evidence that the inhibitor may have affected critical enzyme systems other than acetylation alone. This would account for the lower concentrations of mutagenic hydroxylated compounds observed. ^

Rifaximin-mediated changes to the epithelial cell proteome: 2-D gel analysis

Diarrhea remains a significant cause of worldwide morbidity and mortality. Over 4 million children die of diarrhea annually. Although antibiotics can be used as prophylaxis or for treatment of diarrhea, concern remains over antibiotic resistance. Rifaximin is a semi-synthetic rifamycin derivative that can be used to treat symptoms of infectious diarrhea, inflammatory bowel syndrome, bacterial overgrowth of the small bowel, pouchitis, and fulminant ulcerative colitis. Rifaximin is of particular interest because it is poorly adsorbed in the intestines, shows no indication of inducing bacterial resistance, and has minimal effect on intestinal flora. In order to better understand how rifaximin functions, we sought to compare the protein expression profile of cells pretreated with rifaximin, as compared to cells treated with acetone, rifamycin (control antibiotic), or media (untreated). 2-D gel electrophoresis identified 38 protein spots that were up- or down-regulated by over 2-fold in rifaximin treated cells compared to controls. 16 of these spots were down-regulated, including keratin, annexin A5, intestinal-type alkaline phosphatase, histone h4, and histone-binding protein RbbP4. 22 spots were up-regulated, including heat shock protein HSP 90 alpha, alkaline phosphatase, and fascin. Many of the identified proteins are associated with cell structure and cytoskeleton, transcription and translation, and cellular metabolism. A better understanding of the functionality of rifaximin will identify additional potential uses for rifaximin and determine for whom the drug is best suited. ^

Targeting TRAF6 for Cancer Therapeutical Development

Tumor necrosis factor (TNF)-Receptor Associated Factors (TRAFs) are a family of signal transducer proteins. TRAF6 is a unique member of this family in that it is involved in not only the TNF superfamily, but the toll-like receptor (TLR)/IL-1R (TIR) superfamily. The formation of the complex consisting of Receptor Activator of Nuclear Factor κ B (RANK), with its ligand (RANKL) results in the recruitment of TRAF6, which activates NF-κB, JNK and MAP kinase pathways. TRAF6 is critical in signaling with leading to release of various growth factors in bone, and promotes osteoclastogenesis. TRAF6 has also been implicated as an oncogene in lung cancer and as a target in multiple myeloma. In the hopes of developing small molecule inhibitors of the TRAF6-RANK interaction, multiple steps were carried out. Computational prediction of hot spot residues on the protein-protein interaction of TRAF6 and RANK were examined. Three methods were used: Robetta, KFC2, and HotPoint, each of which uses a different methodology to determine if a residue is a hot spot. These hot spot predictions were considered the basis for resolving the binding site for in silico high-throughput screening using GOLD and the MyriaScreen database of drug/lead-like compounds. Computationally intensive molecular dynamics simulations highlighted the binding mechanism and TRAF6 structural changes upon hit binding. Compounds identified as hits were verified using a GST-pull down assay, comparing inhibition to a RANK decoy peptide. Since many drugs fail due to lack of efficacy and toxicity, predictive models for the evaluation of the LD50 and bioavailability of our TRAF6 hits, and these models can be used towards other drugs and small molecule therapeutics as well. Datasets of compounds and their corresponding bioavailability and LD50 values were curated based, and QSAR models were built using molecular descriptors of these compounds using the k-nearest neighbor (k-NN) method, and quality of these models were cross-validated.

Volumetric Modulated Arc Therapy Evaluation with the Radiological Physics Center Head and Neck Phantom

Validation of treatment plan quality and dose calculation accuracy is essential for new radiotherapy techniques, including volumetric modulated arc therapy (VMAT). VMAT delivers intensity modulated radiotherapy treatments while simultaneously rotating the gantry, adding an additional level of complexity to both the dose calculation and delivery of VMAT treatments compared to static gantry IMRT. The purpose of this project was to compare two VMAT systems, Elekta VMAT and Varian RapidArc, to the current standard of care, IMRT, in terms of both treatment plan quality and dosimetric delivery accuracy using the Radiological Physics Center (RPC) head and neck (H&N) phantom. Clinically relevant treatment plans were created for the phantom using typical prescription and dose constraints for Elekta VMAT (planned with Pinnacle3 Smart Arc) and RapidArc and IMRT (both planned with Eclipse). The treatment plans were evaluated to determine if they were clinically comparable using several dosimetric criteria, including ability to meet dose objectives, hot spots, conformity index, and homogeneity index. The planned treatments were delivered to the phantom and absolute doses and relative dose distributions were measured with thermoluminescent dosimeters (TLDs) and radiochromic film, respectively. The measured and calculated doses of each treatment were compared to determine if they were clinically acceptable based upon RPC criteria of ±7% dose difference and 4 mm distance-to-agreement. Gamma analysis was used to assess dosimetric accuracy, as well. All treatment plans were able to meet the dosimetric objectives set by the RPC and had similar hot spots in the normal tissue. The Elekta VMAT plan was more homogenous but less conformal than the RapidArc and IMRT plans. When comparing the measured and calculated doses, all plans met the RPC ±7%/4 mm criteria. The percent of points passing the gamma analysis for each treatment delivery was acceptable. Treatment plan quality of the Elekta VMAT, RapidArc and IMRT treatments were comparable for consistent dose prescriptions and constraints. Additionally, the dosimetric accuracy of the Elekta VMAT and RapidArc treatments was verified to be within acceptable tolerances.

Investigation of I -compounds (newly discovered indigenous DNA modifications) by different approaches

I-compounds are newly discovered covalent DNA modifications detected by the $\sp{32}$P-postlabeling assay. They are age-dependent, tissue-specific and sex-different. The origin(s), chemistry and function(s) of I-compounds are unknown. The total level of I-compounds in 8-10 month old rat liver is 1 adduct in 10$\sp7$ nucleotides, which is not neglectable. It is proposed that I-compounds may play a role in spontaneous tumorigenesis and aging.^ In the present project, I-compounds were investigated by several different approaches. (1) Dietary modulation of I-compounds. (2) Comparison of I-compounds with persistent carcinogen DNA adducts and 5-methylcytosine. (3) Strain differences of I-compounds in relation to organ site spontaneous tumorigenesis. (4) Effects of nongenotoxic hepatocarcinogenes on I-compounds.^ It was demonstrated that the formation of I-compounds is diet-related. Rats fed natural ingredient diet exhibited more complex I-spot patterns and much higher levels than rats fed purified diet. Variation of major nutrients (carbohydrate, protein and fat) in the diet, produced quantitative differences in I-compounds of rat liver and kidney DNAs. Physiological level of vitamin E in the diet reduced intensity of one I-spot compared with vitamin E deficient diet. However, extremely high level of vitamin E in the diet gave extra spot and enhanced the intensities of some I-spots.^ In regenerating rat liver, I-compounds levels were reduced, as carcinogen DNA adducts, but not 5-methylcytosine, i.e. a normal DNA modification.^ Animals with higher incidences of spontaneous tumor or degenerative diseases tended to have a lower level of I-compounds.^ Choline devoid diet induced a drastic reduction of I-compound level in rat liver compared with choline supplemented diet. I-compound levels were reduced after multi-doses of carbon tetrachloride (CCl$\sb4$) exposure in rats and single dose exposure in mice. An inverse relationship was observed between I-compound level and DNA replication rate. CCl$\sb4$-related DNA adduct was detected in mice liver and intensities of some I-spots were enhanced 24 h after a single dose exposure.^ The mechanisms and explanations of these observations will be discussed. I-compounds are potentially useful indicators in carcinogenesis studies. ^

Recent distribution and accumulation of organic carbon on the continental margin west off Spitsbergen

The study compiles the controlling factors for organic matter sedimentation patterns from a suite of organogeochemical parameters in surface sediments off Spitsbergen and direct seabed observations using a Remotely Operated Vehicle (ROV). In addition we assess its storage rates as well as the potential of carbon sinks on the northwestern margin of the Barents Sea with short sediment cores from a selected fjord environment (Storfjord). While sedimentation in the fjords is mainly controlled by river/meltwater discharge and coastal erosion by sea ice/glaciers resulting in high supply of terrigenous organic matter, Atlantic water inflow, and thus enhanced marine organic matter supply, characterizes the environment on the outer shelf and slope. Local deviations from this pattern, particularly on the shelf, are due to erosion and out washing of fine-grained material by bottom currents. Spots dominated by marine productivity close to the island have been found at the outer Isfjord and west off Prins Karls Forland as well as off the Kongsfjord/Krossfjord area and probably reflect local upwelling of nutrient-rich Atlantic water-derived water masses. Accumulation rates of marine organic carbon as well as reconstructed primary productivities decreased since the middle of the last century. Negative correlation of the Isfjord temperature record with reconstructed productivities in the Storfjord could be explained by a reduced annual duration of the marginal ice zone in the area due to global warming. Extremely high accumulation rates of marine organic carbon between 5.4 and 17.2 g/m**2/yr mark the Storfjord area, and probably high-latitude fjord environments in general, as a sink for carbon dioxide.

(Table 1) Bulk geochemistry of some lavas at DSDP Hole 55-433C

According to Wilson's (1963a, b) hypothesis, the volcanoes of the Hawaiian-Emperor Chain are formed as the Pacific lithospheric plate moves over a source of magma in the mantle. Morgan (1971, 1972) proposed that these "hot spots" resulted from "mantle plumes" that rise vertically from the core/mantle boundary and that are fixed about the deep mantle and rotating globe poles. The age of volcanoes increases with distance away from the recent "hot spot" beneath Kilauea volcano. The Hawaiian-Emperor bend indicates that the direction of motion of the Pacific plate changed about 40 m.y. ago.

Oidiopsis taurica : nuevo patógeno de pimiento (Capsicum annum L.) y ají (Capsicum frutescens L.) en Mendoza (Argentina)

En febrero de 1998 se observó en cultivos de pimiento y ají de Mendoza (Argentina) muerte anticipada de plantas con severos daños en la producción. La magnitud del problema motivó una prospección en los principales oasis de la provincia, a fin de describir la sintomatología, conocer su dispersión, estimar los daños causados y recolectar material para realizar estudios en laboratorio tendientes a confirmar su etiología. Se constató que la afección se encontraba distribuida en todos los oasis del centro y norte. La sintomatología en hojas se caracterizó por la presencia en la cara adaxial de manchas amarillentas, de forma circular de 15 a 20 mm de diámetro, con puntuaciones necróticas, con tendencia a presentarse en anillos concéntricos. En la cara abaxial, generalmente las lesiones eran acompañadas de un micelio blanco tenue. Posteriormente siguió una severa defoliación. La producción disminuyó notablemente y además en pimiento los frutos fueron afectados por escaldaduras de sol y perdieron su valor comercial. A partir de aislamientos de pimiento y ají, mantenidos en plantas de brincos (Impatiens balsamina L.), se inocularon plantas sanas y se logró reproducir la enfermedad en condiciones de invernáculo.

Detección de Xanthomonas cucurbitae (Bryan) Vauterin et al. afectando frutos de zapallo coreano en Mendoza y San Juan, Argentina

Durante las campañas 2007/08 y 2008/09, en explotaciones comerciales de zapallo coreano (Cucurbita moschata Duch) de las zonas hortícolas de Mendoza y San Juan, se observaron sobre los frutos numerosas lesiones circulares, de 3 a 6 mm de diámetro, de aspecto húmedo, algo deprimidas hacia el centro, con un exudado gomoso color ámbar. Cuando las lesiones superficiales se unían, se desarrollaba una podredumbre gelatinosa hacia el interior de los tejidos, que podía profundizar hasta la cavidad seminal. El resultado final de la afección era una podredumbre seca y costrosa, que abarcaba gran parte del fruto, inutilizándolo para ser comercializado. En follaje también se observaron síntomas de la enfermedad, como manchas cloróticas angulares de 2 a 3 mm de lado, que en ocasiones se fusionaban. El objetivo del presente trabajo fue determinar la etiología de la enfermedad. Para ello, se tomaron y analizaron muestras de frutos y hojas afectadas, durante ambas temporadas. Se concluyó que la sintomatología es causada por una bacteria, que de acuerdo con los estudios morfobioquímicos y patogénicos es Xanthomonas cucurbitae (Bryan) Vauterin et al. Esta investigación constituye la primera cita de este patógeno afectando frutos en Argentina.

Efectividad de la implementación de una campaña de promoción de la salud radiodifundida por enfermería

La humanidad actual se encuentra inmersa en un mundo compuesto por lo tecnológico y lo virtual. Progresivamente se ha ido perdiendo el interés por lo innegable que significa tener calidad de vida. Para tal fin se necesita contar con un tesoro llamado “Salud" y que un porcentaje importante del total de las personas se encuentra despojado de ella. La mayoría de los pueblos apunta a la promoción y prevención para preservar la salud de las personas y evitar mayores costos en asistencialismo, solo que hay algo muy difícil de conseguir y es crear hábitos saludables en la comunidad. La enfermería siendo parte importante del equipo de salud, debe utilizar estrategias que ayuden a educar a la sociedad, con herramientas que le permitan llegar a un número mayor de personas y no solamente estar sujeta al núcleo del paciente internado. Esta realidad, motivó al grupo para investigar sobre el tema, y hacer uso de un medio masivo de comunicación; como es la radio, con el fin de promocionar la salud y prevenir enfermedades. Mediante campañas radiales, se intentarán promocionar a lo largo del tiempo, temas de importancia que ayuden a adquirir conocimientos primordiales para vivir mejor. Los objetivos de este trabajo son: determinar la efectividad de una campaña de promoci ón de la salud radiodifundida por enfermería, en la mejora de conductas y hábitos saludables en la población de la ciudad de Malargüe durante octubre de 2010 a mayo de 2011; identificar el tipo de población que escuchó la campaña de salud por radio en la ciudad de Malargüe; comparar el grado de conocimiento sobre el cuidado de la salud antes de la campaña y luego de realizada; lograr que los pobladores de la ciudad de Malargüe que escucharon la campaña, incorporen los conocimientos necesarios para el cuidado de su salud; lograr que los “spots" de la campaña “Manos limpias, cuerpo sano, más vida" perduren en el tiempo.

Robust trends of landscape dynamics in the Arctic Lena Delta with temporally dense Landsat time-series stacks, with links to GeoTIFFs

Arctic permafrost landscapes are among the most vulnerable and dynamic landscapes globally, but due to their extent and remoteness most of the landscape changes remain unnoticed. In order to detect disturbances in these areas we developed an automated processing chain for the calculation and analysis of robust trends of key land surface indicators based on the full record of available Landsat TM, ETM +, and OLI data. The methodology was applied to the ~ 29,000 km**2 Lena Delta in Northeast Siberia, where robust trend parameters (slope, confidence intervals of the slope, and intercept) were calculated for Tasseled Cap Greenness, Wetness and Brightness, NDVI, and NDWI, and NDMI based on 204 Landsat scenes for the observation period between 1999 and 2014. The resulting datasets revealed regional greening trends within the Lena Delta with several localized hot-spots of change, particularly in the vicinity of the main river channels. With a 30-m spatial resolution various permafrost-thaw related processes and disturbances, such as thermokarst lake expansion and drainage, fluvial erosion, and coastal changes were detected within the Lena Delta region, many of which have not been noticed or described before. Such hotspots of permafrost change exhibit significantly different trend parameters compared to non-disturbed areas. The processed dataset, which is made freely available through the data archive PANGAEA, will be a useful resource for further process specific analysis by researchers and land managers. With the high level of automation and the use of the freely available Landsat archive data, the workflow is scalable and transferrable to other regions, which should enable the comparison of land surface changes in different permafrost affected regions and help to understand and quantify permafrost landscape dynamics.

Transformar las ondas de radio: información segura sobre aborto seguro, Brasil

O presente relatório tem como objetivo apresentar os resultados finais do projeto “Transformar as ondas do rádio: informações seguras sobre aborto inseguro”. O projeto foi executado pelo Grupo Curumim e teve como objetivos: Fomentar entre as mulheres jovens um debate acerca do impacto da ilegalidade do aborto na saúde e vida das mulheres e na efetivação de direitos e políticas públicas relacionadas aos direitos sexuais e direitos reprodutivos; Produzir spots de rádio sobre aborto e os serviços de atendimento ao aborto legal; Articular comunicadores/as populares e divulgar informações sobre o aborto e os serviços de atendimento ao abortamento legal

Isotope composition of dolomite, calcite and pore-waters of ODP Leg 210 samples

Early diagenetic dolomite beds were sampled during the Ocean Drilling Programme (ODP) Leg 201 at four reoccupied ODP Leg 112 sites on the Peru continental margin (Sites 1227/684, 1228/680, 1229/681 and 1230/685) and analysed for petrography, mineralogy, d13C, d18O and 87Sr/86Sr values. The results are compared with the chemistry, and d13C and 87Sr/86Sr values of the associated porewater. Petrographic relationships indicate that dolomite forms as a primary precipitate in porous diatom ooze and siliciclastic sediment and is not replacing the small amounts of precursor carbonate. Dolomite precipitation often pre-dates the formation of framboidal pyrite. Most dolomite layers show 87Sr/86Sr-ratios similar to the composition of Quaternary seawater and do not indicate a contribution from the hypersaline brine, which is present at a greater burial depth. Also, the d13C values of the dolomite are not in equilibrium with the d13C values of the dissolved inorganic carbon in the associated modern porewater. Both petrography and 87Sr/86Sr ratios suggest a shallow depth of dolomite formation in the uppermost sediment (<30 m below the seafloor). A significant depletion in the dissolved Mg and Ca in the porewater constrains the present site of dolomite precipitation, which co-occurs with a sharp increase in alkalinity and microbial cell concentration at the sulphate-methane interface. It has been hypothesized that microbial 'hot-spots', such as the sulphate-methane interface, may act as focused sites of dolomite precipitation. Varying d13C values from -15 per mil to +15 per mil for the dolomite are consistent with precipitation at a dynamic sulphate-methane interface, where d13C of the dissolved inorganic carbon would likewise be variable. A dynamic deep biosphere with upward and downward migration of the sulphate-methane interface can be simulated using a simple numerical diffusion model for sulphate concentration in a sedimentary sequence with variable input of organic matter. Thus, the study of dolomite layers in ancient organic carbon-rich sedimentary sequences can provide a useful window into the palaeo-dynamics of the deep biosphere.