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CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and earabnormalities (1). Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood (2). Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p[53.sup.25,26,53,54]) (3), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p[53.sup.25,26,53,54/-] mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p[53.sup.25,26,53,54/-] embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome., Unrestrained p53 activity induced by loss of the negative regulators MDM2 or MDM4 causes early embryonic lethality (4). To explore the role of transcriptional activation by p53 in promoting developmental [...]

The ability to measure [sup.238]U/[sup.235]U to high precision presents an important new opportunity to study the fate and transport of uranium in the environment. The ratio of [sup.238]U/[sup.235]U was determined by multicollector--inductively coupled plasma--mass spectrometer in six uranium ore samples representing two different classes of deposits. Significant offsets in [sup.238]U/[sup.235]U are observed between uranium ores precipitated from groundwaters at low temperature versus hydrothermal deposits precipitated at high temperatures, reinforcing an observation made previously but lacking the needed precision. Specifically, tabular sandstone-type uranium deposits were found to be depleted in [sup.235]U, with a total offset between low-temperature deposits and higher temperature deposits of [approximately equal to] 1.0 [per thousand]. We attribute this offset to reflect a temperature-dependent fractionation related to the nuclear field shift effect during chemical reduction of uranium in ambient temperature groundwaters.

The contribution of transcriptional activation to the p53 effector functions critical for tumor suppression, apoptosis and cellular senescence, remains unclear because of p53's ability to regulate diverse cellular processes in a transactivation-independent manner. Dissociating the importance of transactivation from other p53 functions, including regulating transcriptional repression, DNA replication, homologous recombination, centrosome duplication, and mitochondrial function, has been difficult because of overlapping motifs for these functions in the amino terminus. To determine the relative contribution of these activities and transactivation to p53 function, we generated knockin mice expressing a p53 mutant lacking domains involved in these transactivation-independent functions, while remaining competent for transactivation through fusion to the Herpes Simplex Virus VP16 transactivation domain. This chimeric mutant, termed [p53.sup.VP16], robustly activates the transcription of a range of p53 targets involved in both apoptosis and senescence. Intriguingly, despite being transactivation-competent, this chimeric protein shows selectivity in p53 effector function in mouse fibroblasts, with a capacity to trigger senescence but not apoptosis under a variety of conditions. Our study highlights the central role of p53 transactivation for senescence while suggesting that transactivation is insufficient for apoptosis, and provides insight into the mechanisms by which p53 serves as a tumor suppressor. mouse model | transactivation | tumor suppression

Groundwater in aquifers is generally older than expected on the basis of flow velocity, and this observation has important implications for interpreting radiometric age determinations. Hydrologists commonly account for the aging of water as it flows along streamtubes, but not for the effects of mixing old water from aquitards (or confining layers) into aquifers, because the rate of mass exchange between aquifers and aquitards can in many cases be assumed to be small. We show, however, that the effect on age of such mixing does not depend on the mixing rate; this is the paradox of groundwater age. Surprisingly, the contribution of aquitards to the age of groundwater in aquifers depends only on the ratio of fluid volume in aquitards to aquifers. This result has broad importance for understanding the relationship between groundwater flow and the distribution of radiometric age. Keywords: groundwater age, residence time, radiometric age dating.

Groundwater in aquifers is generally older than expected on the basis of flow velocity, and this observation has important implications for interpreting radiometric age determinations. Hydrologists commonly account for the aging of water as it flows along streamtubes, but not for the effects of mixing old water from aquitards (or confining layers) into aquifers, because the rate of mass exchange between aquifers and aquitards can in many cases be assumed to be small. We show, however, that the effect on age of such mixing does not depend on the mixing rate; this is the paradox of groundwater age. Surprisingly, the contribution of aquitards to the age of groundwater in aquifers depends only on the ratio of fluid volume in aquitards to aquifers. This result has broad importance for understanding the relationship between groundwater flow and the distribution of radiometric age. Keywords: groundwater age, residence time, radiometric age dating.

Researchers from the Lawrence Berkeley National Laboratory, U.S. Geological Survey and University of Illinois studied ratios of selenium stable isotopes found from samples taken at the San Francisco Bay Estuary to investigate the dynamics and anthropogenic inputs of selenium.

Reactive oxygen species (ROS) have been implicated as potential modulators of apoptosis. Conversely, experiments under hypoxic conditions have suggested that apoptosis could occur in the absence of ROS. We sought to determine whether a central modulator of apoptosis, p53, regulates the levels of intracellular ROS and whether a rise in ROS levels is required for the induction of p53-dependent apoptosis. We transiently overexpressed wild-type p53, using adenoviral gene transfer, and identified cell types that were sensitive or resistant to p53-mediated apoptosis. Cells sensitive to p53-mediated apoptosis produced ROS concomitantly with p53 overexpression, whereas cells resistant to p53 failed to produce ROS. In sensitive cells, both ROS production and apoptosis were inhibited by antioxidant treatment. These results suggest that p53 acts to regulate the intracellular redox state and induces apoptosis by a pathway that is dependent on ROS production.

Introduction As ground water hydrologists, we make few calculations more significant than figuring the distribution of ground water age (or residence time) in a flow regime. Ground water age tells [...]

Measurements of chromium (Cr) stable-isotope fractionation in laboratory experiments and natural waters show that lighter isotopes reacted preferentially during Cr(VI) reduction by magnetite and sediments. The [sup.53]Cr/[sup.52]Cr ratio of the product was 3.4 ± 0.1 per mil less than that of the reactant. [sup.53]Cr/[.sup.52]Cr shifts in water samples indicate the extent of reduction, a critical process that renders toxic Cr(VI) in the environment immobile and less toxic., Chromium is a common contaminant in surface water and groundwater (1, 2) because it is used widely in electroplating and other industries and occurs naturally at high concentration in ultramafic [...]

A reexamination of the concept of groundwater age by hydrologists is discussed. Revised models and methods for groundwater age dating are presented, and their implications on future groundwater age dating studies are analyzed.

The isotopic composition and concentration of uranium and strontium in groundwater, combined with solute concentration data, provide important details regarding groundwater geochemical evolution and flow-pathways in the eastern Snake River Plain aquifer. The study was conducted in the vicinity of the Idaho National Engineering and Environmental Laboratory (INEEL), Idaho, which has a long history of storing and disposing of radioactive waste, some of which has entered the aquifer. Uranium concentrations in INEEL groundwater range from 0.3 to 3.6 ppb, and [sup.234]U/[sup.238]U atomic ratios range between 0.000085 and 0.000168 (activity ratios of 1.5 to 3.1). All of the samples have natural [sup.235]U/ [sup.238]U ratios, and [sup.236]U was not detected; thus, the trends delineated by the [sup.234]U/[sup.238]U ratios reflect natural variations in the aquifer. Groundwater nearest the valleys that provides focused recharge to the Snake River Plain aquifer from the northwest has high [sup.234]U/[sup.238]U ratios when compared to values of regional groundwater flowing southwestward in the aquifer. Mixing of these water masses can account for the intermediate uranium isotope ratios of some of the samples; however, water-rock interaction must also be invoked to account for the observed trends in isotopic data. Uranium and [sup.87]Sr/ [sup.86]Sr isotope ratios are positively correlated and define a trend toward isotope ratios of the aquifer host rock. These relations indicate that dissolution and/or ion exchange are more important than alpha recoil or selective leaching in controlling [sup.234]U/[sup.238]U ratios. As a result, [sup.234]U/[sup.238]U ratios decrease along flow pathways toward the secular equilibrium values of the aquifer host rock. Uranium and strontium isotopic modification can be explained by incongruent dissolution of the host basalt. Lateral distributions of [sup.234]U/[sup.238]U ratios indicate elongate zones of high [sup.234]U/[sup.238]U ratios extending southward from the mouths of Birch Creek and the Little Lost River. These elongate zones are interpreted as preferential flow paths. Two isolated pockets of groundwater located in the central and western parts of the study area have lower [sup.234]U/[sup.238]U ratios than the adjacent aquifer water. Both of these zones are interpreted to contain stagnant waters that are relatively isolated from flow in the regional aquifer due to lower permeability. Physical and chemical evidence strongly suggests that the stagnant zones are dominated by water from the Big Lost River that infiltrated via flood control ponds (spreading areas), playas, and the riverbed. Keywords: flow, groundwater, Snake River plain, strontium, uranium disequilibrium.

Preferential flow paths are expected in many groundwater systems and must be located because they can greatly affect contaminant transport. The fundamental characteristics of radiogenic isotope ratios in chemically evolving waters make them highly effective as preferential flow path indicators. These ratios tend to be more easily interpreted than solute-concentration data because their response to water-rock interaction is less complex. We demonstrate this approach with groundwater [sup.87]Sr/[sup.86]Sr ratios in the Snake River Plain aquifer within and near the Idaho National Engineering and Environmental Laboratory. These data reveal slow-flow zones as lower [sup.87]Sr/[sup.86]Sr areas created by prolonged interaction with the host basalts and a relatively fast flowing zone as a high [sup.87]Sr/[sup.86]Sr area. Keywords: groundwater tracers, isotope ratios, Snake River Plain, aquifer properties, aqueous solutions.