Assessing the effects of exposure timing on biomarker expression using β-estradiol

Temporal and spatial variability in estrogenicity has been documented formanytreated wastewater effluents with the consequences of this variability on the expression of biomarkers of endocrine disruption being largely unknown. Laboratory exposure studies usually utilize constant exposure concentrations which may produce biological effects that differ from those observed in organisms exposed in natural environments. In this study, we investigated the effects of differential timing of exposures with 17β - estradiol (E2) on a range of fathead minnow biomarkers to simulate diverse environmentally relevant exposure profiles. Two 21-day, replicate experiments were performed exposing mature male fathead minnows to E2 at time-weighted mean concentrations (similar average exposure to the contaminant during the 21-day exposure period; 17 ng E2/L experiment 1; 12 ng E2/L experiment 2) comparable to E2 equivalency values (EEQ) reported for several anthropogenically altered environments. A comparable time-weighted mean concentration of E2 was applied to five treatments which varied in the daily application schema: E2 was either applied at a steady rate (ST), in a gradual decreasing concentration (HI), a gradual increasing concentration (LO), applied intermittently (IN), or at a randomly varying concentration (VA). We assessed a range of widely used physiological (vitellogenin mRNA induction and plasma concentrations), anatomical (body and organ indices, secondary sex characteristics, and histopathology), and behavioral (nest holding) biomarkers reported to change following exposure to endocrine active compounds (EACs). All treatments responded with a rise in plasma vitellogenin concentration when compared with the ethanol carrier control. Predicatively, vitellogenin mRNA induction, which tracked closely with plasma vitellogenin concentrations in most treatments was not elevated in the HI treatment, presumably due to the lack of E2 exposure immediately prior to analysis. The ability of treatment male fish to hold nest sites in direct competition with control males was sensitive to E2 exposure and did yield statistically significant differences between treatments and carrier control. Other biological endpoints assessed in this study (organosomatic indices, secondary sex characteristics) varied little between treatments and controls. This study indicates that a broad suite of endpoints is necessary to fully assess the biological consequences of fish exposure to estrogens and that for at least field studies, a combination of vitellogenin mRNA and plasma vitellogenin analysis are most promising in deciphering exposure histories of wild-caught and caged fishes

The fate of fluids released from subducting slab in northern Cascadia

Large amounts of water carried down in subduction zones are driven upward into the overlying forearc upper mantle and crust as increasing temperatures and pressure dehydrate the subducting crust. Through seismic tomography velocities we show (a) the overlying forearc mantle in northern Cascadia is hydrated to serpentinite, and (b) there is low Poisson's ratio at the base of the forearc lower crust that may represent silica deposited from the rising fluids. From the velocities observed in the forearc mantle, the volume of serpentinite estimated is ∼30 %. This mechanically weak hydrated forearc region has important consequences in limits to great earthquakes and to collision tectonics. An approximately 10 km thick lower crustal layer of low Poisson's ratio (σ = 0.22) in the forearc is estimated to represent a maximum addition of ∼14 % by volume of quartz (σ = 0.09). If this quartz is removed from rising silica-saturated fluids over long times, it represents a significant addition of silica to the continental crust and an important contributor to its average composition

Forecasting the price of gold

This article seeks to evaluate the appropriateness of a variety of existing forecasting techniques (17 methods) at providing accurate and statistically significant forecasts for gold price. We report the results from the nine most competitive techniques. Special consideration is given to the ability of these techniques to provide forecasts which outperforms the random walk (RW) as we noticed that certain multivariate models (which included prices of silver, platinum, palladium and rhodium, besides gold) were also unable to outperform the RW in this case. Interestingly, the results show that none of the forecasting techniques are able to outperform the RW at horizons of 1 and 9 steps ahead, and on average, the exponential smoothing model is seen providing the best forecasts in terms of the lowest root mean squared error over the 24-month forecasting horizons. Moreover, we find that the univariate models used in this article are able to outperform the Bayesian autoregression and Bayesian vector autoregressive models, with exponential smoothing reporting statistically significant results in comparison with the former models, and classical autoregressive and the vector autoregressive models in most cases

Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney.

BackgroundExcess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by drug-drug interactions and off-target toxicity, respectively. Here, we define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for treatment of chronic gout.MethodssUA levels, fractional excretion of uric acid (FEUA), lesinurad plasma levels, and urinary excretion of lesinurad were measured in healthy volunteers treated with lesinurad. In addition, lesinurad, probenecid, and benzbromarone were compared in vitro for effects on urate transporters and the organic anion transporters (OAT)1 and OAT3, changes in mitochondrial membrane potential, and human peroxisome proliferator-activated receptor gamma (PPARγ) activity.ResultsAfter 6 hours, a single 200-mg dose of lesinurad elevated FEUA 3.6-fold (p < 0.001) and reduced sUA levels by 33 % (p < 0.001). At concentrations achieved in the clinic, lesinurad inhibited activity of URAT1 and OAT4 in vitro, did not inhibit GLUT9, and had no effect on ABCG2. Lesinurad also showed a low risk for mitochondrial toxicity and PPARγ induction compared to benzbromarone. Unlike probenecid, lesinurad did not inhibit OAT1 or OAT3 in the clinical setting.ConclusionThe pharmacodynamic effects and in vitro activity of lesinurad are consistent with inhibition of URAT1 and OAT4, major apical transporters for uric acid. Lesinurad also has a favorable selectivity and safety profile, consistent with an important role in sUA-lowering therapy for patients with gout

Bargaining with a residual claimant: An experimental study

We experimentally investigate a bargaining environment in which players negotiate over a fixed payment to one player, while the other player receives the residual from a random pie realization after subtracting the fixed payment. Contrary to the intuition that risk exposure is detrimental, we show that residual claimants are able to extract a risk premium, which is increasing in risk exposure. In some cases the premium is so high that it is advantageous to bargain over a risky pie rather than a risk-less pie. Contrary to theory, the comparatively less risk averse residual claimants benefit the most. Moreover, bargaining frictions increase as risk increases, and we document more frequent disagreements as risk increases. When given the chance to choose a less or more risky distribution over which to bargain, residual claimants tend to choose the more risky distribution only when there is the possibility of an equal-split ex-post. Our results suggest that theoretical bargaining models require some separation between the determinants of bargaining power and fair compensation for risk exposure

Stochastic Feedback and the Regulation of Biological Rhythms

We propose a general approach to the question of how biological rhythms spontaneously self-regulate, based on the concept of ``stochastic feedback''. We illustrate this approach by considering the neuroautonomic regulation of the heart rate. The model generates complex dynamics and successfully accounts for key characteristics of cardiac variability, including the $1/f$ power spectrum, the functional form and scaling of the distribution of variations, and correlations in the Fourier phases. Our results suggest that in healthy systems the control mechanisms operate to drive the system away from extreme values while not allowing it to settle down to a constant output.Comment: 15 pages, latex2e using rotate and epsf, with 4 ps figures. Submitted to PR

Meta-transcriptomic discovery of a divergent circovirus and a chaphamaparvovirus in captive reptiles with proliferative respiratory syndrome

Viral pathogens are being increasingly described in association with mass morbidity and mortality events in reptiles. However, our knowledge of reptile viruses remains limited. Herein, we describe the meta-transcriptomic investigation of a mass morbidity and mortality event in a colony of central bearded dragons (Pogona vitticeps) in 2014. Severe, extensive proliferation of the respiratory epithelium was consistently found in affected dragons. Similar proliferative lung lesions were identified in bearded dragons from the same colony in 2020 in association with increased intermittent mortality. Total RNA sequencing identified two divergent DNA viruses: a reptile-infecting circovirus, denoted bearded dragon circovirus (BDCV), and the first exogeneous reptilian chaphamaparvovirus—bearded dragon chaphamaparvovirus (BDchPV). Phylogenetic analysis revealed that BDCV was most closely related to bat-associated circoviruses, exhibiting 70% amino acid sequence identity in the Replicase (Rep) protein. In contrast, in the nonstructural (NS) protein, the newly discovered BDchPV showed approximately 31%–35% identity to parvoviruses obtained from tilapia fish and crocodiles in China. Subsequent specific PCR assays revealed BDCV and BDchPV in both diseased and apparently normal captive reptiles, although only BDCV was found in those animals with proliferative pulmonary lesions and respiratory disease. This study expands our understanding of viral diversity in captive reptiles

Cross-continental emergence of Nannizziopsis barbatae disease may threaten wild Australian lizards

Members of the genus Nannizziopsis are emerging fungal pathogens of reptiles that have been documented as the cause of fatal mycoses in a wide range of reptiles in captivity. Cases of severe, proliferative dermatitis, debility and death have been detected in multiple free-living lizard species from locations across Australia, including a substantial outbreak among Eastern water dragons (Intellagama lesueurii) in Brisbane, Queensland. We investigated this disease in a subset of severely affected lizards and identified a clinically consistent syndrome characterized by hyperkeratosis, epidermal hyperplasia, dermal inflammation, necrosis, ulceration, and emaciation. Using a novel fungal isolation method, histopathology, and molecular techniques, we identified the etiologic agent as Nannizziopsis barbatae, a species reported only once previously from captive lizards in Australia. Here we report severe dermatomycosis caused by N. barbatae in five species of Australian lizard, representing the first cases of Nannizziopsis infection among free-living reptiles, globally. Further, we evaluate key pathogen and host characteristics that indicate N. barbatae-associated dermatomycosis may pose a concerning threat to Australian lizards

Heterogeneous coupling of the Sumatran megathrust constrained by geodetic and paleogeodetic measurements

Geodetic and paleogeodetic measurements of interseismic strain above the Sumatran portion of the Sunda subduction zone reveal a heterogeneous pattern of coupling. Annual banding in corals provides vertical rates of deformation spanning the last half of the 20th century, and repeated GPS surveys between 1991 and 2001 and continuous measurements at GPS stations operated since 2002 provide horizontal velocities. Near the equator, the megathrust is locked over a narrow width of only a few tens of kilometers. In contrast, the locked fault zone is up to about 175 km wide in areas where great interplate earthquakes have occurred in the past. Formal inversion of the data reveals that these strongly coupled patches are roughly coincident with asperities that ruptured during these events. The correlation is most spectacular for rupture of the M_w 8.7 Nias-Simeulue earthquake of 2005, which released half of the moment deficit that had accumulated since its previous rupture in 1861, suggesting that this earthquake was overdue. Beneath the Mentawai islands, strong coupling is observed within the overlapping rupture areas of the great earthquakes of 1797 and 1833. The accumulated slip deficit since these events is slowly reaching the amount of slip that occurred during the 1833 earthquake but already exceeds the slip that occurred during the 1797 earthquake. Thus, rerupture of part of the Mentawai patch in September 2007 was not a surprise. In contrast, coupling is low below the Batu islands near the equator and around Enggano island at about 5°S, where only moderate earthquakes (M_w < 8.0) have occurred in the past two centuries. The correlation of large seismic asperities with patches that are locked during the interseismic period suggests that they are persistent features. This interpretation is reinforced by the fact that the large locked patches and great ruptures occur beneath persistent geomorphologic features, the largest outer arc islands. Depth- and convergence-rate-dependent temperature might influence the pattern of coupling, through its effect on the rheology of the plate interface, but other influences are required to account for the observed along-strike heterogeneity of coupling. In particular, subduction of the Investigator Fracture Zone could be the cause for the low coupling near the equator