427 research outputs found
Scoping study on the significance of mesh resolution vs. scenario uncertainty in the CFD modelling of residential smoke control systems
Computational fluid dynamics (CFD) modelling is a commonly applied tool adopted to support the specification and design of common corridor ventilation systems in UK residential buildings. Inputs for the CFD modelling of common corridor ventilation systems are typically premised on a āreasonable worst caseā, i.e. no specific uncertainty quantification process is undertaken to evaluate the safety level. As such, where the performance of a specific design sits on a probability spectrum is not defined. Furthermore, mesh cell sizes adopted are typically c. 100 ā 200 mm. For a large eddy simulation (LES) based CFD code, this is considered coarse for this application and creates a further uncertainty in respect of capturing key behaviours in the CFD model. Both co-existing practices summarised above create uncertainty, either due to parameter choice or the (computational fire and smoke) model. What is not clear is the relative importance of these uncertainties.
This paper summarises a scoping study that subjects the noted common corridor CFD application to a probabilistic risk assessment (PRA), using the MaxEnt method. The uncertainty associated with the performance of a reference design is considered at different grid scales (achieving different āa posterioriā mesh quality indicators), with the aim of quantifying the relative importance of uncertainties associated with inputs and scenarios, vs. the fidelity of the CFD model. For the specific case considered herein, it is found that parameter uncertainty has a more significant impact on the confidence of a given design solution relative to that arising from grid resolution, for grid sizes of 100 mm or less. Above this grid resolution, it was found that uncertainty associated with the model dictates. Given the specific ventilation arrangement modelled in this work care should be undertaken in generalising such conclusions
Safety factors: Can they be inherently captured in modelling assumptions? A short scoping study
Transient reliability evaluation of a stochastic structural system in fire : application of a probability density evolution method supported by evacuation models
Structural fire resistance is a fundamental component of the overall fire safety strategy for buildings. Specifically, with respect to life safety, the structural fire resistance is intended to allow for the safe evacuation of the occupants and access for the fire & rescue service. With the proliferation of performance-based design (PBD)
methodologies, the efficiency of fire safety measures is increasingly being challenged. For low-rise buildings, with limited travel distances to a place of ultimate safety, evacuation may be very efficient, and from the perspective of life safety only limited structural fire resistance needed. For high-rise buildings with long evacuation times the opposite may be true. However, such interactions between structural and human response in fire are currently not clearly quantified, nor by extension explicitly considered in guidance. In support of rational decision making and cost-optimisation for (fire)
life safety investments, the current paper tentatively explores the relationship between evacuation times in model office buildings on the one hand, and the time-dependent failure probability of critical structural components on the other hand. As a case study, the timedependent failure probability of an insulated steel beam is evaluated, and the expected number of fatalities assessed for different model office building heights (i.e. affecting evacuation duration)
Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial.
Trial designThis analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.MethodsMales aged 5-18 years with complete Ī±-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine).ResultsPlasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0-27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.ConclusionsThese data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.Trial registrationClinicalTrials.gov NCT00701415
Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli
Modulation of bacterial chromosomal supercoiling is a function of DNA gyrase-catalyzed strand breakage and rejoining. This reaction is exploited by both antibiotic and proteic gyrase inhibitors, which trap the gyrase molecule at the DNA cleavage stage. Owing to this interaction, double-stranded DNA breaks are introduced and replication machinery is arrested at blocked replication forks. This immediately results in bacteriostasis and ultimately induces cell death. Here we demonstrate, through a series of phenotypic and gene expression analyses, that superoxide and hydroxyl radical oxidative species are generated following gyrase poisoning and play an important role in cell killing by gyrase inhibitors. We show that superoxide-mediated oxidation of ironāsulfur clusters promotes a breakdown of iron regulatory dynamics; in turn, iron misregulation drives the generation of highly destructive hydroxyl radicals via the Fenton reaction. Importantly, our data reveal that blockage of hydroxyl radical formation increases the survival of gyrase-poisoned cells. Together, this series of biochemical reactions appears to compose a maladaptive response, that serves to amplify the primary effect of gyrase inhibition by oxidatively damaging DNA, proteins and lipids
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Severe Biallelic Loss-of-function Mutations in Nicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2) in Two Fetuses with Fetal Akinesia Deformation Sequence
The three nicotinamide mononucleotide adenylyltransferase (NMNAT) family members synthesize the electron carrier nicotinamide adenine dinucleotide (NAD+) and are essential for cellular metabolism. In mammalian axons, NMNAT activity appears to be required for axon survival and is predominantly provided by NMNAT2. NMNAT2 has recently been shown to also function as a chaperone to aid in the refolding of misfolded proteins. Nmnat2 deficiency in mice, or in its ortholog dNmnat in Drosophila, results in axon outgrowth and survival defects. Peripheral
nerve axons in NMNAT2-deficient mice fail to extend and innervate
targets, and skeletal muscle is severely underdeveloped. In addition,
removing NMNAT2 from established axons initiates axon death by Wallerian degeneration. We report here on two stillborn siblings with fetal
akinesia deformation sequence (FADS), severely reduced skeletal muscle
mass and hydrops fetalis. Clinical exome sequencing identified compound
heterozygous NMNAT2 variant alleles in both cases. Both protein variants
are incapable of supporting axon survival in mouse primary neuron cultures when overexpressed. In vitro assays demonstrate altered protein
stability and/or defects in NAD+ synthesis and chaperone functions. Thus,
both patient NMNAT2 alleles are null or severely hypo-morphic. These data indicate a previously unknown role for NMNAT2 in human neurological development and provide the first direct molecular evidence to support the involvement of Wallerian degeneration in a human axonal disorder.Funding for the project comes from the NIH (R.W.S. R01NS085023; R.G.Z. R56NS095893), the UK Medical Research Council grant (J.G. MR/N004582/1), the John and Lucille van Geest Foundation (M.C.) and the Taishan Scholar Project of Shandong Province, China (R.G.Z.)
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