Coupled CFD/CSD Analysis of an Active-Twist Rotor in a Wind Tunnel with Experimental Validation

An unsteady Reynolds averaged Navier-Stokes analysis loosely coupled with a comprehensive rotorcraft code is presented for a second-generation active-twist rotor. High fidelity Navier-Stokes results for three configurations: an isolated rotor, a rotor with fuselage, and a rotor with fuselage mounted in a wind tunnel, are compared to lifting-line theory based comprehensive rotorcraft code calculations and wind tunnel data. Results indicate that CFD/CSD predictions of flapwise bending moments are in good agreement with wind tunnel measurements for configurations with a fuselage, and that modeling the wind tunnel environment does not significantly enhance computed results. Actuated rotor results for the rotor with fuselage configuration are also validated for predictions of vibratory blade loads and fixed-system vibratory loads. Varying levels of agreement with wind tunnel measurements are observed for blade vibratory loads, depending on the load component (flap, lag, or torsion) and the harmonic being examined. Predicted trends in fixed-system vibratory loads are in good agreement with wind tunnel measurements

Coupled CFD/CSD Computation of Airloads of an Active-Twist Rotor

An unsteady Reynolds averaged Navier-Stokes analysis loosely coupled with a comprehensive rotorcraft code for blade trim and aeroelastic effects is presented for a second-generation Active-Twist Rotor. Mesh and temporal sensitives of computed airloads are evaluated. In the final paper, computed airloads will be compared with wind tunnel data for the Active-Twist Rotor test that is currently underway

Context-Dependent Cell Cycle Checkpoint Abrogation by a Novel Kinase Inhibitor

Checkpoint kinase 1 and 2 (Chk1/Chk2), and the Aurora kinases play a critical role in the activation of the DNA damage response and mitotic spindle checkpoints. We have identified a novel inhibitor of these kinases and utilized this molecule to probe the functional interplay between these two checkpoints.Fragment screening, structure guided design, and kinase cross screening resulted in the identification of a novel, potent small molecule kinase inhibitor (VER-150548) of Chk1 and Chk2 kinases with IC(50)s of 35 and 34 nM as well as the Aurora A and Aurora B kinases with IC(50)s of 101 and 38 nM. The structural rationale for this kinase specificity could be clearly elucidated through the X-ray crystal structure. In human carcinoma cells, VER-150548 induced reduplication and the accumulation of cells with >4N DNA content, inhibited histone H3 phosphorylation and ultimately gave way to cell death after 120 hour exposure; a phenotype consistent with cellular Aurora inhibition. In the presence of DNA damage induced by cytotoxic chemotherapeutic drugs, VER-150548 abrogated DNA damage induced cell cycle checkpoints. Abrogation of these checkpoints correlated with increased DNA damage and rapid cell death in p53 defective HT29 cells. In the presence of DNA damage, reduplication could not be observed. These observations are consistent with the Chk1 and Chk2 inhibitory activity of this molecule.In the presence of DNA damage, we suggest that VER-150548 abrogates the DNA damage induced checkpoints forcing cells to undergo a lethal mitosis. The timing of this premature cell death induced by Chk1 inhibition negates Aurora inhibition thereby preventing re-entry into the cell cycle and subsequent DNA reduplication. This novel kinase inhibitor therefore serves as a useful chemical probe to further understand the temporal relationship between cell cycle checkpoint pathways, chemotherapeutic agent induced DNA damage and cell death

Within-river phosphorus retention: accounting for a missing piece in the watershed phosphorus puzzle

The prevailing "puzzle" in watershed phosphorus (P) management is how to account for the nonconservative behavior (retention and remobilization) of P along the land-freshwater continuum. This often hinders our attempts to directly link watershed P sources with their water quality impacts. Here, we examine aspects of within-river retention of wastewater effluent P and its remobilization under high flows. Most source apportionment methods attribute P loads mobilized under high flows (including retained and remobilized effluent P) as nonpoint agricultural sources. We present a new simple empirical method which uses chloride as a conservative tracer of wastewater effluent, to quantify within-river retention of effluent P, and its contribution to river P loads, when remobilized under high flows. We demonstrate that within-river P retention can effectively mask the presence of effluent P inputs in the water quality record. Moreover, we highlight that by not accounting for the contributions of retained and remobilized effluent P to river storm-flow P loads, existing source apportionment methods may significantly overestimate nonpoint agricultural sources and underestimate wastewater sources in mixed land-use watersheds. This has important implications for developing effective watershed remediation strategies, where remediation needs to be equitably and accurately apportioned among point and nonpoint P contributors

Kinetic and structure–activity studies of the triazolium ion-catalysed benzoin condensation

Steady-state kinetic and structure–activity studies of a series of six triazolium-ion pre-catalysts 2a–2f were investigated for the benzoin condensation. These data provide quantitative insight into the role of triazolium N-aryl substitution under synthetically relevant catalytic conditions in a polar solvent environment. Kinetic behaviour was significantly different to that previously reported for a related thiazolium-ion pre-catalyst 1, with the observed levelling of initial rate constants to νmax at high aldehyde concentrations for all triazolium catalysts. Values for νmax for 2a–2f increase with electron withdrawing N-aryl substituents, in agreement with reported optimal synthetic outcomes under catalytic conditions, and vary by 75-fold across the series. The levelling of rate constants supports a change in rate-limiting step and evidence supports the assignment of the Breslow-intermediate forming step to the plateau region. Correlation of νmax reaction data yielded a positive Hammett ρ-value (ρ = +1.66) supporting the build up of electron density adjacent to the triazolium N-Ar in the rate-limiting step favoured by electron withdrawing N-aryl substituents. At lower concentrations of aldehyde, both Breslow-intermediate and benzoin formation are partially rate-limiting

P-Rex1 Controls Sphingosine 1-Phosphate Receptor Signalling, Morphology, and Cell-Cycle Progression in Neuronal Cells.

P-Rex1 is a guanine-nucleotide exchange factor (GEF) that activates Rac-type small G proteins in response to the stimulation of a range of receptors, particularly G protein-coupled receptors (GPCRs), to control cytoskeletal dynamics and other Rac-dependent cell responses. P-Rex1 is mainly expressed in leukocytes and neurons. Whereas its roles in leukocytes have been studied extensively, relatively little is known about its functions in neurons. Here, we used CRISPR/Cas9-mediated P-Rex1 deficiency in neuronal PC12 cells that stably overexpress the GPCR S1PR1, a receptor for sphingosine 1-phosphate (S1P), to investigate the role of P-Rex1 in neuronal GPCR signalling and cell responses. We show that P-Rex1 is required for the S1P-stimulated activation of Rac1 and Akt, basal Rac3 activity, and constitutive cAMP production in PC12-S1PR1 cells. The constitutive cAMP production was not due to increased expression levels of major neuronal adenylyl cyclases, suggesting that P-Rex1 may regulate adenylyl cyclase activity. P-Rex1 was required for maintenance of neurite protrusions and spreading in S1P-stimulated PC12-S1PR1 cells, as well as for cell-cycle progression and proliferation. In summary, we identified novel functional roles of P-Rex1 in neuronal Rac, Akt and cAMP signalling, as well as in neuronal cell-cycle progression and proliferation

The foot-health of people with diabetes in regional and rural Australia:Baseline results from an observational cohort study

Background: There is limited Australian epidemiological research that reports on the foot-health characteristics ofpeople with diabetes, especially within rural and regional settings. The objective of this study was to explore theassociations between demographic, socio-economic and diabetes-related variables with diabetes-related footmorbidity in people residing in regional and rural Australia.Methods: Adults with diabetes were recruited from non-metropolitan Australian publicly-funded podiatry services. Theprimary variable of interest was the University of Texas diabetic foot risk classification designated to each participant atbaseline. Independent risk factors for diabetes-related foot morbidity were identified using multivariable analysis.Results: Eight-hundred and ninety-nine participants enrolled, 443 (49.3%) in Tasmania and 456 (50.7%) in Victoria.Mean age was 67 years (SD 12.7), 9.2% had type 1 diabetes, 506 (56.3%) were male, 498 (55.4%) had diabetes for longerthan 10 years and 550 (61.2%) either did not know the ideal HbA1c target or reported that it was ≥7.0. A majority hadperipheral neuropathy or worse foot morbidity (61.0%). Foot morbidity was associated with male sex (OR 2.42, 95% CI1.82–3.22), duration of diabetes > 20 years (OR 3.25, 95% CI 2.22–4.75), and Tasmanian residence (OR 3.38, 95% CI 2.35–4.86).Conclusions: A high proportion of the regional Australian clinical population with diabetes seen by the publiclyfunded podiatric services in this study were at high risk of future limb threatening foot morbidity, and participantsresiding in Northern Tasmania are more likely to have worse diabetes-related foot morbidity than those from regionalVictoria. Service models should be reviewed to ensure that diabetes-related foot services are appropriately developedand resourced to deliver interdisciplinary evidence-based care