Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1

Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag−/− mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.National Institutes of Health (U.S.) (NIH grant R01-CA075576)National Institutes of Health (U.S.) (NIH grant R01-CA055042)National Institutes of Health (U.S.) (NIH grant R01-CA149261)National Institutes of Health (U.S.) (NIH grant P30-ES00002)National Institutes of Health (U.S.) (NIH grant P30-ES02109)National Center for Research Resources (U.S.) (grant number M01RR-01066)National Center for Research Resources (U.S.) (grant number UL1 RR025758, Harvard Clinical and Translational Science Center

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Lidar measurements of Bora wind effects on aerosol loading

The Vipava valley in Slovenia is well known for the appearance of strong, gusty North-East Bora winds, which occur as a result of air flows over an adjacent orographic barrier. There are three revealing wind directions within the valley which were found to give rise to specific types of atmospheric structures. These structures were investigated using a Mie scattering lidar operating at 1064 nm, which provided high temporal and spatial resolution backscatter data on aerosols, which were used as tracers for atmospheric flows. Wind properties were monitored at the bottom of the valley and at the rim of the barrier using two ultrasonic anemometers. Twelve time periods between February and April 2015 were selected when lidar data was available. The periods were classified according to the wind speed and direction and investigated in terms of appearance of atmospheric structures. In two periods with strong or moderate Bora, periodic atmospheric structures in the lidar data were observed at heights above the mountain barrier and are believed to be Kelvin–Helmholtz waves, induced by wind shear. No temporal correlation was found between these structures and wind gusts at the ground level. The influence of the wind on the height of the planetary boundary layer was studied as well. In periods with low wind speeds, the vertical evolution of the planetary boundary layer was found to be governed by solar radiation and clouds. In periods with strong or moderate Bora wind, convection within the planetary boundary layer was found to be much weaker due to strong turbulence close to the ground, which inhibited mixing through the entire layer

The influence of human exploration on the microbial community structure and ammonia oxidizing potential of the Su Bentu limestone cave in Sardinia, Italy

The bacterial diversity in the Su Bentu Cave in Sardinia was investigated by means of 16S rRNA gene-based analysis. This 15 km long cave, carved in Jurassic limestone, hosts a variety of calcite speleothems, and a long succession of subterranean lakes with mixed granite and carbonate sands. The lower level is occasionally flooded by a rising groundwater level, but with only scarce input of organic remains (leaves and charcoal fragments). On the quiet cave pools there are visible calcite rafts, whereas walls are locally coated with manganese deposits. In the drier upper levels, where organic input is much more subdued, moonmilk—a hydrated calcium-magnesium carbonate speleothem—can be found. Relative humidity approaches 100% and the measured mean annual cave air temperature is 14.8°C. Samples were obtained in 2014 from calcite rafts, moonmilk, manganese oxide deposits and soil (limestone and granite grains). Microclimatic conditions in the cave near the sampling sites, sample properties, physico-chemical parameters of water, and sediment composition were determined. The microbial community of this system is predominately composed of the phyla Proteobacteria, Actinobacteria, Acidobacteria, Nitrospirae, and Firmicutes. Sampling sites near the entrance of the cave and in close proximity of the underground campsite–located 500 meters deep into the cave—revealed the highest diversity as well as the highest number of human associated microorganisms. Two samples obtained in very close proximity of each other near the campsite, indicate that the human impact is localized and is not distributed freely within the system. Analysis of the abundance of bacterial and archaeal amoA genes revealed a far greater abundance of archaeal amoA genes compared to bacterial representatives. The results of this study highlight that human impact is confined to locations that are utilized as campsites and that exploration leaves little microbial trails. Furthermore, we uncovered a highly specialized microbiome, which is perfectly adapted to survive and thrive in an environment with low nutrient availability