A novel mechanism of non- feminizing estrogens in neuroprotection

Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in an in vitro assay using a panel of more than 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large bulky group at the C2 or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C or D rings either reduced or did not markedly change neuroprotection. Collectively, there was a negative correlation between binding to ERs and neuroprotection with the more potent compounds showing no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. We demonstrated that these non-feminizing estrogens engage in a redox cycle with glutathione, using the hexose monophosphate shunt to apply cytosolic reducing potential to cellular membranes. Together, these results demonstrate that non-feminizing estrogens are neuroprotective and protect brain from the induction of ischemic- and Alzheimer’s disease (AD)-like neuropathology in an animal model. These features of non-feminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, as they are not expected to show the side effects of chronic estrogen therapy that are mediated by ER actions in the liver, uterus and breast

An implicit unsteady hydraulic solver for suspended cuttings transport in managed pressure wells

We present a simulation tool for transient events in complex hydraulic networks. The code includes modelling of the transport of suspended cuttings in near-vertical wells. An unstructured finite volume formulation with implicit time integration has been chosen. The unconditional stability of the integrator makes the method suitable for the simulation of transient events over a wide range of characteristic timescales. It handles both very fast transients (e.g. fluid hammer events) and the long-term evolution of the well (e.g. hole cleaning operations). The software has been developed to address the need of the oil industry for a robust and efficient predictive tool allowing effective well control in managed pressure drilling operations. The physical modelling follows the standard practices accepted by the industry (e.g. mud rheology computations). The mathematical foundation of the algorithm is described followed by validation cases that illustrate its capabilities and accuracy. Finally, a practical industrial application example is provided to demonstrate the real-world performance of the software.Peer ReviewedPostprint (author's final draft

Evaluation of tillage and crop rotation effects on groundwater quality—Nashua project

Sampling shows that agricultural chemicals are occurring increasingly in ground- and surface water in Iowa. The same trend has been reported throughout the United States; one study reported finding 73 pesticides in the groundwater of 34 states. Even pesticides known to be adsorbed to soil particles (and thus relatively immobile) have been found in a few sampled wells in trace concentrations. Nitrate-nitrogen (NO3-N) is the most common agricultural chemical found in groundwater. Nitrogen fertilizers and pesticides applied to the soil surface prior to and immediately following crop planting are particularly susceptible to surface runoff or leaching to groundwater through the soil profile.</p

Neuroprotection with non-feminizing estrogen analogues: an overlooked possible therapeutic strategy

Although many of the effects of estrogens on the brain are mediated through estrogen receptors (ERs), there is evidence that neuroprotective activity of estrogens can be mediated by non-ER mechanisms. Herein, we review the substantial evidence that estrogens neuroprotection is in large part non-ER mediated and describe in vitro and in vivo studies that support this conclusion. Also, we described our drug discovery strategy for capitalizing on enhancement in neuroprotection while at the same time, reducing ER binding of a group of synthetic non-feminizing estrogens. Finally, we offer evidence that part of the neuroprotection of these non-feminizing estrogens is due to enhancement in redox potential of the synthesized compounds

An implicit unsteady hydraulic solver for suspended cuttings transport in managed pressure wells

We present a simulation tool for transient events in complex hydraulic networks. The code includes modelling of the transport of suspended cuttings in near-vertical wells. An unstructured finite volume formulation with implicit time integration has been chosen. The unconditional stability of the integrator makes the method suitable for the simulation of transient events over a wide range of characteristic timescales. It handles both very fast transients (e.g. fluid hammer events) and the long-term evolution of the well (e.g. hole cleaning operations). The software has been developed to address the need of the oil industry for a robust and efficient predictive tool allowing effective well control in managed pressure drilling operations. The physical modelling follows the standard practices accepted by the industry (e.g. mud rheology computations). The mathematical foundation of the algorithm is described followed by validation cases that illustrate its capabilities and accuracy. Finally, a practical industrial application example is provided to demonstrate the real-world performance of the software.Peer Reviewe