The estrogenic activity of phthalate esters in vitro

A large number of phthalate esters were screened for estrogenic activity using a recombinant yeast screen. a selection of these was also tested for mitogenic effect on estrogen-responsive human breast cancer cells. A small number of the commercially available phthalates tested showed extremely weak estrogenic activity. The relative potencies of these descended in the order butyl benzyl phthalate (BBP) > dibutyl phthalate (DBP) > diisobutyl phthalate (DIBP) > diethyl phthalate (DEP) > diisiononyl phthalate (DINP). Potencies ranged from approximately 1 x 10(6) to 5 x 10(7) times less than 17beta-estradiol. The phthalates that were estrogenic in the yeast screen were also mitogenic on the human breast cancer cells. Di(2-ethylhexyl) phthalate (DEHP) showed no estrogenic activity in these in vitro assays. A number of metabolites were tested, including mono-butyl phthalate, mono-benzyl phthalate, mono-ethylhexyl phthalate, mon-n-octyl phthalate; all were wound to be inactive. One of the phthalates, ditridecyl phthalate (DTDP), produced inconsistent results; one sample was weakly estrogenic, whereas another, obtained from a different source, was inactive. analysis by gel chromatography-mass spectometry showed that the preparation exhibiting estrogenic activity contained 0.5% of the ortho-isomer of bisphenol A. It is likely that the presence of this antioxidant in the phthalate standard was responsible for the generation of a dose-response curve--which was not observed with an alternative sample that had not been supplemented with o,p'-bisphenol A--in the yeast screen; hence, DTDP is probably not weakly estrogenic. The activities of simple mixtures of BBP, DBP, and 17beta-estradiol were assessed in the yeast screen. No synergism was observed, although the activities of the mixtures were approximately additive. In summary, a small number of phthalates are weakly estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vivo; this will require tests using different classes of vertebrates and different routes of exposure

Regional differences in the response of rainfall to convectively coupled Kelvin waves over tropical Africa

The representation of convection remains one of the most important sources of bias in global models and evaluation methods are needed that show that models provide the correct mean state and variability; both for the correct reasons. Here we develop a novel approach for evaluating rainfall variability due to CCKWs in this region. A phase cycle was defined for the CCKW cycle in OLR and used to composite rainfall anomalies. We characterize the observed (TRMM) rainfall response to CCKWs over tropical Africa in April and evaluate the performance of regional climate model (RCM) simulations: a parameterized convection simulation (P25) and the first pan-Africa convection permitting simulation (CP4). TRMM mean rainfall is enhanced and suppressed by CCKW activity and the occurrence of extreme rainfall and dry days is coupled with CCKW activity. Focusing on regional differences, we show for the first time that: there is a dipole between West Africa and the Gulf of Guinea involving onshore/offshore shifts in rainfall; and the transition to enhanced rainfall over west equatorial Africa occurs one phase before the transition over east equatorial Africa. The global model used to drive the RCMs simulated CCKWs with mean amplitudes of 75%-82% of observations. The RCMs simulated coherent responses to the CCKWs and captured the large-scale spatial patterns and phase relationships in rainfall although the simulated rainfall response is weaker than observations and there are regional biases which are bigger away from the equator. P25 produced a closer match to TRMM mean rainfall anomalies than CP4 although the response in dry days was more closely simulated by CP4

Robotic Extrusion of Algae-Laden Hydrogels for Large-Scale Applications

A bioprinting technique for large‐scale, custom‐printed immobilization of microalgae is developed for potential applications within architecture and the built environment. Alginate‐based hydrogels with various rheology modifying polymers and varying water percentages are characterized to establish a window of operation suitable for layer‐by‐layer deposition on a large scale. Hydrogels formulated with methylcellulose and carrageenan, with water percentages ranging from 80% to 92.5%, demonstrate a dominant viscoelastic solid–like property with G′ > G″ and a low phase angle, making them the most suitable for extrusion‐based printing. A custom multimaterial pneumatic extrusion system is developed to be attached on the end effector of an industrial multiaxis robot arm, allowing precision‐based numerically controlled layered deposition of the viscous hydrogel. The relationship between the various printing parameters, namely air pressure, material viscosity, viscoelasticity, feed rate, printing distance, nozzle diameter, and the speed of printing, are characterized to achieve the desired resolution of the component. Printed prototypes are postcured in CaCl2 via crosslinking. Biocompatibility tests show that cells can survive for 21 days after printing the constructs. To demonstrate the methodology for scale‐up, a 1000 × 500 mm fibrous hydrogel panel is additively deposited with 3 different hydrogels with varying water percentages

Pulmonary artery wave propagation and reservoir function in conscious man: impact of pulmonary vascular disease, respiration and dynamic stress tests

Detailed haemodynamic analysis may provide novel insights into the pulmonary circulation. Therefore, wave intensity and reservoir-excess pressure analyses were applied in the pulmonary artery to characterize changes in wave propagation and reservoir function during spontaneous respiration and dynamic stress tests. Right heart catheterization was performed using a pressure and Doppler flow sensor tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in control subjects and patients with pulmonary arterial hypertension (PAH) at rest. In controls, recordings were also obtained during Valsalva manoeuvre and handgrip exercise. The asymptotic pressure at which the flow through the microcirculation ceases, the reservoir pressure related to arterial compliance and the excess pressure caused by arterial waves increased in PAH patients compared to controls. The systolic and diastolic rate constants also increased, while the diastolic time constant decreased. The forward compression wave energy decreased by ∼8% in controls and ∼6% in PAH patients during expiration compared to inspiration, while the wave speed remained unchanged throughout the respiratory cycle. Wave energy decreased during Valsalva manoeuvre (by ∼45%) and handgrip exercise (by ∼27%) with unaffected wave speed. Moreover, the reservoir and excess pressures decreased during Valsalva manoeuvre but remained unaltered during handgrip exercise. In conclusion, reservoir-excess pressure analysis applied to the pulmonary artery revealed distinctive differences between controls and PAH patients. Variations in the ventricular preload and afterload influence pulmonary arterial wave propagation as demonstrated by changes in wave energy during spontaneous respiration and dynamic stress tests

What Drives the Intensification of Mesoscale Convective Systems over the West African Sahel under Climate Change?

Extreme rainfall is expected to increase under climate change, carrying potential socioeconomic risks. However, the magnitude of increase is uncertain. Over recent decades, extreme storms over the West African Sahel have increased in frequency, with increased vertical wind shear shown to be a cause. Drier midlevels, stronger cold pools, and increased storm organization have also been observed. Global models do not capture the potential effects of lower- to midtropospheric wind shear or cold pools on storm organization since they parameterize convection. Here we use the first convection-permitting simulations of African climate change to understand how changes in thermodynamics and storm dynamics affect future extreme Sahelian rainfall. The model, which simulates warming associated with representative concentration pathway 8.5 (RCP8.5) until the end of the twenty-first century, projects a 28% increase of the extreme rain rate of MCSs. The Sahel moisture change on average follows Clausius–Clapeyron scaling, but has regional heterogeneity. Rain rates scale with the product of time-of-storm total column water (TCW) and in-storm vertical velocity. Additionally, prestorm wind shear and convective available potential energy both modulate in-storm vertical velocity. Although wind shear affects cloud-top temperatures within our model, it has no direct correlation with precipitation rates. In our model, projected future increase in TCW is the primary explanation for increased rain rates. Finally, although colder cold pools are modeled in the future climate, we see no significant change in near-surface winds, highlighting avenues for future research on convection-permitting modeling of storm dynamics

The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

Proactive and politically skilled professionals: What is the relationship with affective occupational commitment?

The aim of this study is to extend research on employee affective commitment in three ways: (1) instead of organizational commitment the focus is on occupational commitment; (2) the role of proactive personality on affective occupational commitment is examined; and (3) occupational satisfaction is examined as a mediator and political skills as moderator in the relationship between proactive personality and affective occupational commitment. Two connected studies, one in a hospital located in the private sector and one in a university located in the public sector, are carried out in Pakistan, drawing on a total sample of over 400 employees. The results show that proactive personality is positively related to affective occupational commitment, and that occupational satisfaction partly mediates the relationship between proactive personality and affective occupational commitment. No effect is found for a moderator effect of political skills in the relationship between proactive personality and affective occupational commitment. Political skills however moderate the relationship between proactive personality and affective organizational commitment

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido