Explore the vast range of titles available.

Two environmental tracer methods are applied to the Ti‐Tree Basin in central Australia to shed light on the importance of recharge from floodouts of ephemeral rivers in this arid environment. Ground water carbon‐14 concentrations from boreholes are used to estimate the average recharge rate over the interval between where the ground water sample first entered the saturated zone and the bore. Environmental chloride concentrations in ground water samples provide estimates of the recharge rate at the exact point in the landscape where the sample entered the saturated zone. The results of the two tracer approaches indicate that recharge rates around one of the rivers and an extensive flood‐plain are generally higher than rates of diffuse recharge that occurs in areas of lower topographic relief. Ground water 2H/1H and 18O/16O compositions are all depleted in the heavier isotopes (δ2H = ‐67%0 to ‐50%0; 518O = ‐9.2%0 to ‐5.7%0) compared with the long‐term, amount‐weighted mean isotopic composition of rainfall in the area (δ2H = ‐33.8%0; δ18O = ‐6.3%0). This indicates that recharge throughout the basin occurs only after intense rainfall events of at least 150 to 200 mm/month. Finally, a recharge map is developed to highlight the spatial extent of the two recharge mechanisms. Floodout recharge to the freshest ground water (TDS <1000 mg/L) is ∼1.9 mm/year compared with a mean recharge rate of ∼0.2 mm/year to the remainder of the basin. These findings have important implications for management of the ground water resource.

A workflow is described to estimate specific storage (Sₛ) and hydraulic conductivity (K) from a profile of vibrating wire piezometers embedded into a regional aquitard in Australia. The loading efficiency, compressibility and Sₛwere estimated from pore pressure response to atmospheric pressure changes, and K was estimated from the earliest part of the measurement record following grouting. Results indicate that Sₛand K were, respectively, 8.8 × 10⁻⁶to 1.2 × 10⁻⁵ m⁻¹and 2 × 10⁻¹² m s⁻¹for a claystone/siltstone, and 4.3 × 10⁻⁶to 9.6 × 10⁻⁶ m⁻¹and 1 × 10⁻¹²to 5 × 10⁻¹² m s⁻¹for a thick mudstone. K estimates from the pore pressure response are within one order of magnitude when compared to direct measurement in a laboratory and inverse modelled flux rates determined from natural tracer profiles. Further analysis of the evolution and longevity of the properties of borehole grout (e.g. thermal and chemical effects) may help refine the estimation of formation hydraulic properties using this workflow. However, the convergence of K values illustrates the benefit of multiple lines of evidence to support aquitard characterization. An additional benefit of in situ pore pressure measurement is the generation of long-term data to constrain groundwater flow models, which provides a link between laboratory scale data and the formation scale.

We present a new technique for identifying and quantifying the discharge of long residence time, regional groundwater to rivers using naturally occurring tracers measured within the river. Terrigenic 4He and 222Rn, synoptically sampled along a 100 km reach in the Fitzroy River in northern Western Australia, are used to identify areas of groundwater inflow to the river and to distinguish shallow, local and deep, regional groundwater. Models of tracer transport in the river can be numerically optimized to calculate total groundwater discharge and to separate regional and local discharge fractions. Discharge of regional groundwater composes close to 15% of the total groundwater discharge along the entire reach, varying spatially along the reach from 0% to 100% of total groundwater discharge. This method should be applicable in river systems where groundwater with elevated terrigenic helium could be discharging to the river. The ability to separate locally from regionally derived groundwater discharge has significant implications for calculating catchment water budgets, for predicting catchment response to changes in precipitation, and for sustainable management of the catchment. Key Points Elevated helium in river water indicates discharge of regional groundwater Regional discharge can be separated from locally derived groundwater discharge Total, local and regional groundwater discharge volumes can be calculated

We present a new technique for identifying and quantifying the discharge of long residence time, regional groundwater to rivers using naturally occurring tracers measured within the river. Terrigenic 4 He and 222 Rn, synoptically sampled along a 100 km reach in the Fitzroy River in northern Western Australia, are used to identify areas of groundwater inflow to the river and to distinguish shallow, local and deep, regional groundwater. Models of tracer transport in the river can be numerically optimized to calculate total groundwater discharge and to separate regional and local discharge fractions. Discharge of regional groundwater composes close to 15% of the total groundwater discharge along the entire reach, varying spatially along the reach from 0% to 100% of total groundwater discharge. This method should be applicable in river systems where groundwater with elevated terrigenic helium could be discharging to the river. The ability to separate locally from regionally derived groundwater discharge has significant implications for calculating catchment water budgets, for predicting catchment response to changes in precipitation, and for sustainable management of the catchment. Elevated helium in river water indicates discharge of regional groundwater Regional discharge can be separated from locally derived groundwater discharge Total, local and regional groundwater discharge volumes can be calculated

CERES is a new computational method to estimate gene-dependency levels from CRISPR–Cas9 essentiality screens while accounting for copy number effects and variable sgRNA activity. Applying CERES to new genome-scale CRISPR–Cas9 essentiality screen data from 342 cancer cell lines and other published data sets shows that CERES decreases false-positive results and provides consistent estimates of sgRNA activity. The CRISPR–Cas9 system has revolutionized gene editing both at single genes and in multiplexed loss-of-function screens, thus enabling precise genome-scale identification of genes essential for proliferation and survival of cancer cells 1 , 2 . However, previous studies have reported that a gene-independent antiproliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, thereby leading to false-positive results in copy number–amplified regions 3 , 4 . We developed CERES, a computational method to estimate gene-dependency levels from CRISPR–Cas9 essentiality screens while accounting for the copy number–specific effect. In our efforts to define a cancer dependency map, we performed genome-scale CRISPR–Cas9 essentiality screens across 342 cancer cell lines and applied CERES to this data set. We found that CERES decreased false-positive results and estimated sgRNA activity for both this data set and previously published screens performed with different sgRNA libraries. We further demonstrate the utility of this collection of screens, after CERES correction, for identifying cancer-type-specific vulnerabilities.

Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X) receptor agonist) produces modest hypertension in patients (2-3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P₁,₅ agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P₁ mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P₃ receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P₁ receptors mediate bradycardia while hypertension is mediated by S1P₃ receptor activation.

To provide evidence for quantitative magnetic resonance (qMR) biomarkers in Duchenne muscular dystrophy by investigating the relationship between qMR measures of lower extremity muscle pathology and functional endpoints in a large ambulatory cohort using a multicenter study design. MR spectroscopy and quantitative imaging were implemented to measure intramuscular fat fraction and the transverse magnetization relaxation time constant (T2) in lower extremity muscles of 136 participants with Duchenne muscular dystrophy. Measures were collected at 554 visits over 48 months at one of three imaging sites. Fat fraction was measured in the soleus and vastus lateralis using MR spectroscopy, while T2 was assessed using MRI in eight lower extremity muscles. Ambulatory function was measured using the 10m walk/run, climb four stairs, supine to stand, and six minute walk tests. Significant correlations were found between all qMR and functional measures. Vastus lateralis qMR measures correlated most strongly to functional endpoints (|ρ| = 0.68-0.78), although measures in other rapidly progressing muscles including the biceps femoris (|ρ| = 0.63-0.73) and peroneals (|ρ| = 0.59-0.72) also showed strong correlations. Quantitative MR biomarkers were excellent indicators of loss of functional ability and correlated with qualitative measures of function. A VL FF of 0.40 was an approximate lower threshold of muscle pathology associated with loss of ambulation. Lower extremity qMR biomarkers have a robust relationship to clinically meaningful measures of ambulatory function in Duchenne muscular dystrophy. These results provide strong supporting evidence for qMR biomarkers and set the stage for their potential use as surrogate outcomes in clinical trials.

The future of coral reefs under increasing CO2 depends on their capacity to recover from disturbances. To predict the recovery potential of coral communities that are fully acclimatized to elevated CO2, we compared the relative success of coral recruitment and later life stages at two volcanic CO2 seeps and adjacent control sites in Papua New Guinea. Our field experiments showed that the effects of ocean acidification (OA) on coral recruitment rates were up to an order of magnitude greater than the effects on the survival and growth of established corals. Settlement rates, recruit and juvenile densities were best predicted by the presence of crustose coralline algae, as opposed to the direct effects of seawater CO2. Offspring from high CO2 acclimatized parents had similarly impaired settlement rates as offspring from control parents. For most coral taxa, field data showed no evidence of cumulative and compounding detrimental effects of high CO2 on successive life stages, and three taxa showed improved adult performance at high CO2 that compensated for their low recruitment rates. Our data suggest that severely declining capacity for reefs to recover, due to altered settlement substrata and reduced coral recruitment, is likely to become a dominant mechanism of how OA will alter coral reefs.

Habitat recognition and selective settlement by dispersive propagules greatly increases the post-settlement survival chances of sessile organisms. To better understand the key role some species can play in the structure of highly complex coral reef ecosystems, we compare the role of two independent, but sequential, processes: settlement choice and post-settlement survival. This study describes the chemical and physical recognition and ranking of specific settlement substrata by coral larvae. Several species of crustose coralline algae (CCA) are known to induce coral settlement; however they also employ physical and biological anti-settlement defense strategies that vary greatly in effectiveness. We examine the interactions between settling larvae of two common reef building coral species (Acropora tenuis and A. millepora) and five species of CCA (Neogoniolithon fosliei, Porolithon onkodes, Hydrolithon reinboldii, Titanoderma prototypum, and Lithoporella melobesioides) that co-occur on reef crests and slopes of the Great Barrier Reef, Australia. Distinct settlement patterns were observed when coral larvae were provided with a choice of settlement substrata. Settlement on the most preferred substratum, the CCA species T. prototypum, was 15 times higher than on N. fosliei, the least preferred substratum. The rates of post-settlement survival of the corals also varied between CCA species in response to their anti-settlement strategies (shedding of surface cell layers, overgrowth, and potential chemical deterrents). Rates of larval settlement, post-settlement survival, and the sensitivity of larvae to chemical extracts of CCA were all positively correlated across the five species of CCA. Nonliving settlement substrata on coral reefs is sparse; consequently the fact that only a few CCA species (notably T. prototypum) facilitate coral recruitment, has important implications for structuring the reef ecosystem.

Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.