Influence of ERβ selective agonism during the neonatal period on the sexual differentiation of the rat hypothalamic-pituitary-gonadal (HPG) axis

<p>Abstract</p> <p>Background</p> <p>It is well established that sexual differentiation of the rodent hypothalamic-pituitary-gonadal (HPG) axis is principally orchestrated by estrogen during the perinatal period. Here we sought to better characterize the mechanistic role the beta form of the estrogen receptor (ERβ) plays in this process.</p> <p>Methods</p> <p>To achieve this, we exposed neonatal female rats to three doses (0.5, 1 and 2 mg/kg) of the ERβ selective agonist diarylpropionitrile (DPN) using estradiol benzoate (EB) as a positive control. Measures included day of vaginal opening, estrous cycle quality, GnRH and Fos co-localization following ovariectomy and hormone priming, circulating luteinizing hormone (LH) levels and quantification of hypothalamic kisspeptin immunoreactivity. A second set of females was then neonatally exposed to DPN, the ERα agonist propyl-pyrazole-triol (PPT), DPN+PPT, or EB to compare the impact of ERα and ERβ selective agonism on kisspeptin gene expression in pre- and post-pubescent females.</p> <p>Results</p> <p>All three DPN doses significantly advanced the day of vaginal opening and induced premature anestrus. GnRH and Fos co-labeling, a marker of GnRH activation, following ovariectomy and hormone priming was reduced by approximately half at all doses; the magnitude of which was not as large as with EB or what we have previously observed with the ERα agonist PPT. LH levels were also correspondingly lower, compared to control females. No impact of DPN was observed on the density of kisspeptin immunoreactive (-ir) fibers or cell bodies in the arcuate (ARC) nucleus, and kisspeptin-ir was only significantly reduced by the middle (1 mg/kg) DPN dose in the preoptic region. The second experiment revealed that EB, PPT and the combination of DPN+PPT significantly abrogated preoptic Kiss1 expression at both ages but ARC expression was only reduced by EB.</p> <p>Conclusion</p> <p>Our results indicate that selective agonism of ERβ is not sufficient to completely achieve male-typical HPG organization observed with EB or an ERα agonist.</p

Mixing in density- and viscosity-stratified flows

The lock-exchange problem is used extensively to study the flow dynamics of density-driven flows, such as gravity currents, and as a canonical problem to mixing in stratified flows. Opposite halves of a domain are filled with two fluids of different densities and held in place by a lock-gate. Upon release, the density difference drives the flow causing the fluids to slosh back and forth. In many scenarios, density stratification will also impose a viscosity stratification (e.g., if there are suspended sediments or the two fluids are distinct). However, numerical models often neglect variable viscosity. This paper characterizes the effect of both density and viscosity stratification in the lock-exchange configuration. The governing Navier-Stokes equations are solved using direct numerical simulation. Three regimes are identified in terms of the viscosity ratio μ 2 / μ 1 = (1 + γ) between the dense and less dense fluids: when γ ≪ 1, the flow dynamics are similar to the equal-viscosity case; for intermediate values (γ ∼ 1), viscosity inhibits interface-scale mixing leading to a global reduction in mixing and enhanced transfer between potential and kinetic energy. Increasing the excess viscosity ratio further (γ ≫ 1) results in significant viscous dissipation. Although many gravity or turbidity current models assume constant viscosity, our results demonstrate that viscosity stratification can only be neglected when γ ≪ 1. The initial turbidity current composition could enhance its ability to become self-sustaining or accelerating at intermediate excess viscosity ratios. Currents with initially high excess viscosity ratio may be unable to dilute and propagate long distances because of the decreased mixing rates and increased dissipation

Pulse propagation in gravity currents

Real world gravity current flows rarely exist as a single discrete event, but are instead made up of multiple surges. This paper examines the propagation of surges as pulses in gravity currents. Using theoretical shallow-water modeling, we analyze the structure of pulsed flows created by the sequential release of two lock-boxes. The first release creates a gravity current, while the second creates a pulse that eventually propagates to the head of the first current. Two parameters determine the flow structure: the densimetric Froude number at the head of the current, Fr, and a dimensionless time between releases, tre. The shallow-water model enables the flow behavior to be mapped in (Fr, tre) space. Pulse speed depends on three critical characteristic curves: two that derive from the first release and correspond to a wavelike disturbance which reflects between the head of the current and the back of the lock-box and a third that originates from the second release and represents the region of the flow affected by the finite supply of source material. Pulses have non-negative acceleration until they intersect the third characteristic, after which they decelerate. Variations in pulse speed affect energy transfer and dissipation. Critically for lahars, landslides, and avalanches, pulsed flows may change from erosional to depositional, further affecting their dynamics. Gravity current hazard prediction models for such surge-prone flows may underpredict risk if they neglect internal flow dynamics

Should Any Workplace Be Exempt from Smoke-Free Law: The Irish Experience

Background. In 2004, the Irish Government introduced national legislation banning smoking in workplaces; with exemptions for “a place of residence”. This paper summarises three Irish studies of exempted premises; prisons, psychiatric hospitals and nursing homes. Methods. PM2.5 and nicotine were measured in nursing homes and psychiatric hospitals, in addition to ultrafine particles in the hospitals. In the prisons, officers (n = 30) completed exhaled breath Carbon Monoxide (CO) measurements. Questionnaires determined officers' opinion on introducing smoking prohibitions in prisons. Nursing home smoking policies were examined and questionnaires completed by staff regarding workplace secondhand smoke (SHS) exposure. Findings. Ultrafine particle concentrations in psychiatric hospitals averaged 130,000  cm3, approximately 45% higher than Dublin pub (35.5 μg/m3) pre ban. PM2.5 levels in psychiatric hospitals (39.5 μg/m3) were similar to Dublin pubs (35.5 μg/m3) pre ban. In nursing homes permitting smoking, similar PM2.5 levels (33 μg/m3) were measured, with nicotine levels (0.57 μg/m3) four times higher than “non-smoking” nursing homes (0.13 μg/m3). In prisons, 44% of non-smoking officers exhibited exhaled breath CO criteria for light to heavy smokers. Conclusions. With SHS exposure levels in some exempted workplaces similar to Dublin pubs levels pre ban, policies ensuring full protection must be developed and implemented as a right for workers, inmates and patients

Dissolving microneedles for DNA vaccination: Improving functionality via polymer characterisation and RALA complexation

DNA vaccination holds the potential to treat or prevent nearly any immunogenic disease, including cancer. To date, these vaccines have demonstrated limited immunogenicity in vivo due to the absence of a suitable delivery system which can protect DNA from degradation and improve transfection efficiencies in vivo. Recently, microneedles have been described as a novel physical delivery technology to enhance DNA vaccine immunogenicity. Of these devices, dissolvable microneedles promise a safe, pain-free delivery system which may simultaneously improve DNA stability within a solid matrix and increase DNA delivery compared to solid arrays. However, to date little work has directly compared the suitability of different dissolvable matrices for formulation of DNA-loaded microneedles. Therefore, the current study examined the ability of 4 polymers to formulate mechanically robust, functional DNA loaded dissolvable microneedles. Additionally, complexation of DNA to a cationic delivery peptide, RALA, prior to incorporation into the dissolvable matrix was explored as a means to improve transfection efficacies following release from the polymer matrix. Our data demonstrates that DNA is degraded following incorporation into PVP, but not PVA matrices. The complexation of DNA to RALA prior to incorporation into polymers resulted in higher recovery from dissolvable matrices, and increased transfection efficiencies in vitro. Additionally, RALA/DNA nanoparticles released from dissolvable PVA matrices demonstrated up to 10-fold higher transfection efficiencies than the corresponding complexes released from PVP matrices, indicating that PVA is a superior polymer for this microneedle application

The inherent instability of leveed seafloor channels

New analytical models demonstrate that under 2 aggradational flow conditions seafloor channel-levee systems are inherently unstable; both channel area and stability necessarily decrease at long timescales. In time such systems must avulse purely through internal (autogenic) forcing. Although autogenic instabilities likely arise over long enough time for additional allogenic forcing to be expected, channel-levee sensitivity to variations in flow character depends on the prior degree of system evolution. Recalibrated modern Amazon Fan avulsion timings are consistent with this model, challenging accepted interpretations of avulsion triggering