The cellular and molecular responses to a novel nucleotide analogue, GS-9219

GS-9219 is a cell-permeable double-prodrug of the acyclic nucleotide analogue 9-(2-phosphonylmethoxyethyl)guanine (PMEG). The conversion of GS-9219 to its active metabolite, PMEG diphosphate (PMEGpp), involves several intracellular enzymatic reactions which reduces the concentration of nephrotoxic PMEG in plasma. PMEGpp competes with the natural substrate, dGTP, for incorporation by DNA polymerases. The lack of a 3'-hydroxyl moiety makes PMEGpp a de facto DNA chain-terminator. The incorporation of PMEGpp into DNA during DNA replication causes DNA chain-termination and stalled replication forks. Thus, the primary mechanism of action of GS-9219 in replicating cells is via DNA synthesis inhibition. GS-9219 has substantial antiproliferative activity against activated lymphocytes and tumor cell lines of hematological malignancies. Tumor cell proliferation was significantly reduced as measured by PET/CT scans in dogs with advanced-stage, spontaneously occurring non-Hodgkin's lymphoma (NHL).^ The hypothesis of this dissertation is that the incorporation of PMEGpp into DNA during repair re-synthesis would result in the inhibition of DNA repair and accumulation of DNA damage in chronic lymphocytic leukemia (CLL) cells and activate signaling pathways to cell death.^ To test this hypothesis, CLL cells were treated with DNA-damaging agents to stimulate nucleotide excision repair (NER) pathways, enabling the incorporation of PMEGpp into DNA. When NER was activated by UV, PMEGpp was incorporated into DNA in CLL cells. Following PMEGpp incorporation, DNA repair was inhibited and led to the accumulation of DNA strand breaks. The combination of GS-9219 and DNA-damaging agents resulted in more cell death than the sum of the single agents alone. The presence of DNA strand breaks activated the phosphatidylinositol 3-kinase-like protein kinase (PIKK) family members ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK). The activated ATM initiated signaling to the downstream target, p53, which was subsequently phosphorylated and accumulated to exert its apoptotic functions. P53-targeted pro-apoptotic genes, Puma and Bax, were upregulated and activated when DNA repair was inhibited, likely contributing to cell death. ^

Assessing maintenance of evaporative cooling systems in Legionellosis outbreaks

Evaporative cooling systems continue to be associated with outbreaks of Legionnaires’ disease despite widely available maintenance guidelines intended to reduce these outbreaks. Yet, the guidelines vary widely regarding the recommendations that are made to maintain evaporative cooling systems and it is unclear whether guidelines were in place or, if they were, whether they were being followed when the outbreaks of Legionnaires’ disease occurred. Thus, this study was designed to conduct two systematic reviews of (1) evaporative cooling system maintenance guidelines; and (2) published Legionnaires’ disease outbreaks. For each maintenance guideline identified in the systematic review, recommended maintenance practices were abstracted and similarities and/or differences in the reported recommendations were assessed. Following the systematic review of outbreak investigations that meet the inclusion criteria established for the study, information about the state of the evaporative cooling system during the outbreak investigation was abstracted to summarize, when reported, which maintenance practices were implemented. As expected, the recommended maintenance procedures varied greatly across the guidelines and were not always specific. Overall, the outbreak investigations tended to report similar maintenance issues that were unclear in the maintenance guidelines. Generally, these maintenance issues were biocide use, microbiological testing, frequency of general inspections, and protocols and frequency of total system cleanings. The role in which non-standardized and generalized maintenance guidelines plays in the continued association between Legionnaires’ disease and evaporative cooling systems is still not fully understood. However, this study suggests that more specific and standardized maintenance guidelines, that have been scientifically established to be effective in controlling Legionella bacteria, are needed and then these guidelines must be properly implemented in order to help reduce further Legionnaires’ disease outbreaks associated with evaporative cooling systems.^

Geochemical analyses of secondary minerals from ODP Leg 115 basalts (Tables 1+2)

Basalts recovered along the Reunion hotspot track on Ocean Drilling Program (ODP) Leg 115 range in age from 34 Ma at Site 706 to 64 Ma at Site 707. They have undergone various degrees of secondary alteration. Within single holes the amount of alteration can vary from a few percent to near complete replacement of phenocrysts and groundmass by secondary minerals. Olivine appears to be the most susceptible to alteration and in some sections it is the only mineral altered. In other sections, olivine, pyroxene and plagioclase phenocrysts, and groundmass have been completely replaced by secondary minerals. Clays are the predominant form of secondary mineralization. In addition to replacing olivine, pyroxene, glass, and groundmass, clays have filled veins, vesicles, and voids. Minor amounts of calcite, zeolites, and K-feldspar were also detected. The clays that filled vesicles and veins often show color zonations of dark, opaque bands near the edges that grade into tan or green transparent regions in the centers of the veins. The electron microprobe was used to obtain chemical analyses of these veins as well as to characterize isolated clays that replaced specific minerals and filled voids and vesicles.

Modern and fossil corals from Palmyra and Christmas islands

The relationship between decadal to centennial changes in ocean circulation and climate is difficult to discern using the sparse and discontinuous instrumental record of climate and, as such, represents a large uncertainty in coupled ocean-atmosphere general circulation models. We present new modern and fossil coral radiocarbon (D14C) records from Palmyra (6°N, 162°W) and Christmas (2°N, 157°W) islands to constrain central tropical Pacific ocean circulation changes during the last millennium. Seasonally to annually resolved coral D14C measurements from the 10th, 12th-17th, and 20th centuries do not contain significant interannual to decadal-scale variations, despite large changes in coral d18O on these timescales. A centennial-scale increase in coral radiocarbon from the Medieval Climate Anomaly (~900-1200 AD) to the Little Ice Age (~1500-1800) can be largely explained by changes in the atmospheric D14C, as determined with a box model of Palmyra mixed layer D14C. However, large 12th century depletions in Palmyra coral D14C may reflect as much as a 100% increase in upwelling rates and/or a significant decrease in the D14C of higher-latitude source waters reaching the equatorial Pacific during this time. SEM photos reveal evidence for minor dissolution and addition of secondary aragonite in the fossil corals, but our results suggest that coral D14C is only compromised after moderate to severe diagenesis for these relatively young fossil corals.

(Table 2) Chemical composition of gases in basalts from DSDP Leg 65 Holes

Basalts from different structural provinces in the ocean basins, such as mid-ocean ridges, island arcs, and oceanic plateaus, show marked differences in major and minor element composition stemming from differences in magma source. In addition, there are variations even within individual provinces, based on such processes as crystal fractionation, secondary alteration, and hydrothermal alteration. It is also known that hydrothermal processes can cause changes in the gas composition of submarine basalts. For example, Zolotarev et al. (1978) have established that hydrothermal alteration frequently causes an increase in the CO2 content of basalts. If the homogeneity in composition and concentration of organic gases in oceanic basalts is associated with degassing during epimagmatic alteration, it would be interesting to investigate the relative abundance of gas phases in young basalts from midoceanic ridges. This chapter deals with the distribution of organic gases and CO2 in young basalts recovered on Leg 65 from the Gulf of California. Our aim was to establish the relationship between gas composition and degree of alteration.

Major and trace element analyses from DSDP Hole 26-253 at the Ninetyeast Ridge in the Indian Ocean

A basaltic sequence of Eocene submarine-erupted pyroclastic sediments totals at least 388 m at DSDP Site 253 on the Ninetyeast Ridge. These fossiliferous hyaloclastic sediments have been erupted and fragmented by explosive volcanism (hydroexplosions) in shallow water. The occurrence of interbedded basaltic ash-fall tuffs within the younger horizons of the hyaloclastic sequence marks the emergence of some Ninetyeast Ridge volcanic vents above sea level. Considerable textural variation allows subdivision of the sequence into six informal lithostratigraphic units. Hydrothermal and diagenetic alteration has caused the complete replacement of all original glass by smectites, and the introduction of abundant zeolite and calcite cements. The major and trace element contents of the hyaloclastites vary due to the alteration, and the admixture of biogenous calcite. On a calcium carbonate-free basis systematic variations are recognisable. Mg, Ni, Cr and Cu are enriched, and Li and Zn depleted in the three older units relative to the younger three. The chemical variability is reflected by the development of saponite in the older part of the sequence and montmorillonite in the younger; and by the presence of a quartz-normative basalt flow occurring in Unit II, in contrast to the Mg-rich highly olivine-normative basalt at the base of the sequence. The younger and older parts of the sequence therefore appear to have been derived from magmas of different chemistry. The sequence, like other basaltic rocks recovered from the Ninetyeast Ridge, is enriched in the light relative to the heavy rare earth elements (REE) although the REE contents vary unsystematically with depth, probably because of the high-temperature subaqueous alteration and the presence of biogenous calcite. This REE data indicates that the Ninetyeast Ridge volcanism was different from that which produces mid-ocean ridge basalts.

Céspedes de estadios de fútbol : Mendoza (Argentina)

Se considera los estados de desarrollo de los céspedes de estadios de fútbol en Mendoza (Argentina). Desde un punto de vista fitosociológico se determinan dos grupos de plantas: Molinio-Arrhenatheretea R. Tx. 1937 (campos húmedos y pisoteados, con vegetación subnitrófila e higrófita) y Stellarietea mediae R. Tx. 1950 (vegetación arvense de los cultivos). Se indican las etapas dinámicas que se producen por sobrepisoteo y labores culturales. Del análisis se desprende que: 1. El sobrepisoteo y falta de cuidados culturales conducen a la pérdida de la cubierta vegetal y a la formación de peladeros sin vegetación. 2. La comunidad de Cynodon dactylon L., junto con elementos de la Molinio-Arrhenatheretea, es la más aceptada. Su cobertura representa el mejor estado del campo. 3. Adecuadas prácticas culturales asegurarían el mantenimiento y/o conservación de los céspedes favoreciendo la práctica del deporte y aportando belleza escénica.

Physical properties and elastic constants of ODP Holes 137-504B and 140-504B upper crustal rocks

Seismic velocities have been measured at confining pressures of 100 MPa and 600 MPa for sheeted dike samples recovered during Ocean Drilling Program Legs 137 and 140. The compressional- and shear-wave velocities show an increase with depth at Hole 504B, which is in sharp contrast to the atmospheric pressure velocity measurements performed as part of the shipboard analyses. Rocks exposed to different types of alteration and fracture patterns show distinct changes in their physical properties. The seismic reflectors observed on the vertical seismic profile (VSP) experiment performed during Leg 111 may have been caused by low velocity zones resulting from alteration. The amount of fracturing and hydrothermal alteration in several zones also may have contributed to the acoustic impedance contrast necessary to produce the E5 reflector. Poisson's ratios calculated from laboratory velocity measurements show several low values at depths ranging from 1600 mbsf to 2000 mbsf, which tends to follow similar trends obtained from previous oceanic refraction experiments. A comparison of physical properties between samples recovered from Hole 504B and ophiolite studies in the Bay of Islands and Oman shows a good correlation with the Bay of Islands but significant differences from the measurements performed in the Oman complex.

Organic matter, isotopic composition of calcite veins in basement basalt and pore water at DSDP Leg 78A Holes

Sediments of the Barbados Ridge complex, cored on DSDP Leg 78A, contain low concentrations of acid-insoluble carbon (0.05-0.25%) and nitrogen (C/N 1.5-5) and dispersed C1-C6 hydrocarbons (100-800 ppb). The concentrations of organic carbon and 13C in organic carbon decrease with depth, whereas the concentration of dispersed hydrocarbons increases slightly with depth. These trends may reflect the slow oxidation of organic matter, with selective removal of 13C and slow conversion of the residual organic matter to hydrocarbons. Very minor indications of nitrogen gas were observed at about 250 meters sub-bottom at two of the drilling sites. Basement basalts have calcite veins with d13C values in the range of 2.0 to 3.2 per mil and d18O-SMOW values ranging from 28.5 to +30.6 per mil. Interstitial waters have d18O-SMOW of 0.2 to -3.5 per mil and dD-SMOW of -2 to -15 per mil. The oxygen isotopic composition of the calcite veins in the basement basalts gives estimated equilibrium fractionation temperatures in the range of 11 to 24°C, assuming precipitation from water with d18O-SMOW in the range of +0.1 to -1.0 per mil. This suggests that basalt alteration and precipitation of vein calcite occurred in contact either with warmer Campanian seawater or, later, with pore water, after burial to depths of 200- 300 meters. Pore waters from all three sites are depleted in deuterium and 18O, and dissolved sulfate is enriched in 34S at Sites 541 and 542, but not at Site 543.

Chemical, isotope and mineral composition of hydrothermally altered upper oceanic crust drilled at ODP Site 129-801C

ODP Hole 801C penetrates >400 m into 170-Ma oceanic basement formed at a fast-spreading ridge. Most basalts are slightly (10-20%) recrystallized to saponite, calcite, minor celadonite and iron oxyhydroxides, and trace pyrite. Temperatures estimated from oxygen isotope data for secondary minerals are 5-100°C, increasing downward. At the earliest stage, dark celadonitic alteration halos formed along fractures and celadonite, and quartz and chalcedony formed in veins from low-temperature (<100°C) hydrothermal fluids. Iron oxyhydroxides subsequently formed in alteration halos along fractures where seawater circulated, and saponite and pyrite developed in the host rock and in zones of restricted seawater flow under more reducing conditions. Chemical changes include variably elevated K, Rb, Cs, and H2O; local increases in FeT, Ba, Th, and U; and local losses of Mg and Ni. Secondary carbonate veins have 87Sr/86Sr = 0.706337 - 0.707046, and a negative correlation with d18O results from seawater-basalt interaction. Carbonates could have formed at any time since the formation of Site 801 crust. Variable d13C values (-11.2? to 2.9?) reflect the incorporation of oxidized organic carbon from intercalated sediments and changes in the d13C of seawater over time. Compared to other oceanic basements, a major difference at Site 801 is the presence of two hydrothermal silica-iron deposits that formed from low-temperature hydrothermal fluids at the spreading axis. Basalts associated with these horizons are intensely altered (60-100%) to phyllosilicates, calcite, K-feldspar, and titanite; and exhibit large increases in K, Rb, Cs, Ba, H2O, and CO2, and losses of FeT, Mn, Mg, Ca, Na, and Sr. These effects may be common in crust formed at fast-spreading rates, but are not ubiquitous. A second important difference is that the abundance of brown oxidation halos along fractures at Site 801 is an order of magnitude less than at some other sites (2% vs. 20-30%). Relatively smooth basement topography (<100 m) and high sedimentation rate (8 m/Ma) probably restricted the access of oxygenated seawater. Basement lithostratigraphy and early low-temperature hydrothermal alteration and mineral precipitation in fractures at the spreading axis controlled permeability and limited later flow of oxygenated seawater to restricted depth intervals.

Distribution of polycyclic aromatic hydrocarbons in eolian and eolian-deluvial sediments from the North Iceland

This work considers results of a study of Holocene cover sediments in Iceland. They are largely composed of wind-transported palagonitized hyaloclastite particles and coeval horizons of acid and basic tephras. It is established that polyciclic aromatic hydrocarbons (PAH) are released from basaltic glass in natural environments only in case of intense physicochemical alteration and destruction of its structure. This process does not influence PAH composition and their quantitative proportions. No new PAH formed during several thousands of years in Holocene section. Hydrocarbons are transferred from fixed state in basaltic glass into free state in palagonites practically without any changes. PAH were mainly redeposited by winds, derived together with palagonite from weathered hyaloclastites, and precipitated from atmosphere with tephra during eruptions.

Late Cretaceous volcaniclastic rocks at DSDP Holes 74-525A and 74-528

Volcaniclastic rocks of Late Cretaceous age occur in four out of five sites (525, 527, 528, 529) drilled on the crest and the northwest flank of the Walvis Ridge during Leg 74. They are mostly interlayered with and overlie basement in the lowermost 10-100 m of the sedimentary section. Rocks from Holes 525A and 528 were studied megascopically and microscopically, by XRD, and XRF chemical analyses of whole-rock major and trace elements were undertaken. The dominant rock of Hole 528 volcaniclastics is a fine-grained (silt to fine sand), mostly matrix-bearing (partly matrix-rich) vitric "tuff," occurring as 5-110 cm thick, partly graded layers, some of which are distinctly bedded. Volcaniclastics of Hole 525A are generally richer in sanidine crystals. Most rocks contain some nonvolcanic clasts, chiefly foraminifers and lesser amounts of shallow-water fossil debris. Scoria shards, clasts of tachylite, and fine-grained basalts as well as chemical analyses suggest a basaltic to intermediate composition for most rocks of Hole 528, whereas volcaniclastics of Hole 525A are more silicic. The occurrence of tachylite and epiclastic, coarse-grained, basaltic clasts throughout the volcaniclastic sequence at Site 528 indicates shallow-water eruptions and perhaps even ocean island volcanism. The minor occurrence in Hole 528 of trachytic? pumice shards with phenocrysts of K-feldspar and the abundance of such shards in rocks from Hole 525A indicate Plinian eruptions characteristic of more mature stages of ocean island evolution. The sedimentary structures of volcaniclastic layers and their occurrence within deep sea calcareous oozes indicate a mass flow origin. Diagenetic alteration of the volcaniclastic rocks is pronounced, and four major stages of glass shard alteration are distinguished. Despite the effects of alteration and small-scale redistribution of elements and the admixture of nonvolcanic components, there were no drastic changes in the chemical composition of the rocks, except for pronounced increases in K and Rb and decreases in Ca and Fe. The basaltic volcaniclastic rocks very much resemble basement basalts in that they are moderately evolved tholeiites derived from an LIL-enriched mantle source with Zr/Nb ratios (Hole 528) of 5 to 6. This, in conjunction with the interbedding of volcaniclastic rocks and basement lavas, indicates contemporaneous seamount or island and basement volcanic activity involving magmas derived from similar sources.