Probabilistic analysis of bladed turbine disks and the effect of mistuning

Probabilistic assessment of the maximum blade response on a mistuned rotor disk is performed using the computer code NESSUS. The uncertainties in natural frequency, excitation frequency, amplitude of excitation and damping are included to obtain the cumulative distribution function (CDF) of blade responses. Advanced mean value first order analysis is used to compute CDF. The sensitivities of different random variables are identified. Effect of the number of blades on a rotor on mistuning is evaluated. It is shown that the uncertainties associated with the forcing function parameters have significant effect on the response distribution of the bladed rotor

Effect of Berberine on in vitro metabolism of Sulfonylureas: a herb-drug interactions study

Rationale: Patients with type 2 diabetes may co-ingest herbal and prescription medicine to control their blood sugar levels. Competitive binding of drug and herb may mutually affect their metabolism. This can alter the level of drug and its kinetics in the body, potentially causing toxicities or loss of efficacy. Understanding how metabolism of sulfonylureas like glyburide and gliclazide can be affected by the presence of berberine and vice versa can provide valuable information on the possible risk of toxicities caused by co-ingestion of drugs. Methods: Berberine and sulfonylureas (glyburide and gliclazide) were co-incubated with rat liver microsomes in the presence of NADPH regenerating system. The metabolites of berberine and sulfonylureas were analysed using liquid chromatography with high resolution mass spectrometry in the positive ion mode. The role of individual isozymes in the metabolism of berberine, glyburide and gliclazide was investigated by using specific inhibitors. Results: In vitro metabolism of berberine lead to the formation of demethyleneberberine (B1a) and B1b through demethylenation. Berberrubine (B2a) and its isomer (B2b) was formed through demethylation. The isozymes CYP3A and CYP2D were found to be involved in the metabolism of berberine. In vitro metabolism of glyburide and gliclazide lead to the formation of hydroxylated metabolites. The isozymes CYP3A and CYP2C were found to be involved in the metabolism of glyburide. Gliclazide was metabolised by CYP2C. In vitro co-incubation of glyburide or gliclazide with berberine showed that each drugs metabolism was compromised as both share a common isozymes. A strong negative linear correlation of glyburide or gliclazide metabolites levels and the concentration of berberine confirmed the effect of berberine on the metabolism of sulfonylurea

Local origins impart conserved bone type-related differences in human osteoblast behaviour

Osteogenic behaviour of osteoblasts from trabecular, cortical and subchondral bone were examined to determine any bone type-selective differences in samples from both osteoarthritic (OA) and osteoporotic (OP) patients. Cell growth, differentiation; alkaline phosphatase (TNAP) mRNA and activity, Runt-related transcription factor-2 (RUNX2), SP7-transcription factor (SP7), bone sialoprotein-II (BSP-II), osteocalcin/bone gamma-carboxyglutamate (BGLAP), osteoprotegerin (OPG, TNFRSF11B), receptor activator of nuclear factor-κβ ligand (RANKL, TNFSF11) mRNA levels and proangiogenic vascular endothelial growth factor-A (VEGF-A) mRNA and protein release were assessed in osteoblasts from paired humeral head samples from age-matched, human OA/OP (n = 5/4) patients. Initial outgrowth and increase in cell number were significantly faster (p < 0.01) in subchondral and cortical than trabecular osteoblasts, in OA and OP, and this bone type-related differences were conserved despite consistently faster growth in OA. RUNX2/SP7 levels and TNAP mRNA and protein activity were, however, greater in trabecular than subchondral and cortical osteoblasts in OA and OP. BSP-II levels were significantly greater in trabecular and lowest in cortical osteoblasts in both OA and OP. In contrast, BGLAP levels showed divergent bone type-selective behaviour; highest in osteoblasts from subchondral origins in OA and trabecular origins in OP. We found virtually identical bone type-related differences, however, in TNFRSF11B:TNFSF11 in OA and OP, consistent with greater potential for paracrine effects on osteoclasts in trabecular osteoblasts. Subchondral osteoblasts (OA) exhibited highest VEGF-A mRNA levels and release. Our data indicate that human osteoblasts in trabecular, subchondral and cortical bone have inherent, programmed diversity, with specific bone type-related differences in growth, differentiation and pro-angiogenic potential in vitro

Epistemic Schmagency?

Constructivist approaches in epistemology and ethics offer a promising account of normativity. But constructivism faces a powerful Schmagency Objection, raised by David Enoch. While Enoch’s objection has been widely discussed in the context of practical norms, no one has yet explored how the Schmagency Objection might undermine epistemic constructivism. In this paper, I rectify that gap. First, I develop the objection against a prominent form of epistemic constructivism, Belief Constitutivism. Belief Constitutivism is susceptible to a Schmagency Objection, I argue, because it locates the source of normativity in the belief rather than the agent. In the final section, I propose a version of epistemic constructivism that locates epistemic normativity as constitutive of agency. I argue that this version has the resources to respond to the Schmagency Objection

Pilot Sensitivity to Simulator Flight Dynamics Model Formulation for Stall Training

A piloted simulation study was performed in the Cockpit Motion Facility at the National Aeronautics and Space Administration Langley Research Center. The research was motivated by the desire to reduce the commercial transport airplane fatal accident rate due to in-flight loss of control. The purpose of this study, which focused on a generic T-tail transport airplane, was to assess pilot sensitivity to flight dynamics model formulation used during a simulator stall recognition and recovery training/demonstration profile. To accomplish this, the flight dynamics model was designed with many configuration options. The model options were based on recently acquired static and dynamic stability and control data from sources that included wind tunnel, water tunnel, and computational fluid dynamics. The results, which are specific to a transport airplane stall recognition and recovery guided demonstration scenario, showed the two most important aerodynamic effects (other than stick pusher) to model were stall roll- off and the longitudinal static stability characteristic associated with the pitch break