This graduate-level 2006 text incorporates these advances in a comprehensive treatment of the fundamental principles of combustion physics. The presentation emphasises analytical proficiency and ...physical insight, with the former achieved through complete, though abbreviated, derivations at different levels of rigor, and the latter through physical interpretations of analytical solutions, experimental observations, and computational simulations. Exercises are mostly derivative in nature in order to further strengthen the student's mastery of the theory. Implications of the fundamental knowledge gained herein on practical phenomena are discussed whenever appropriate. These distinguishing features provide a solid foundation for an academic program in combustion science and engineering.
The need and prospect of incorporating realistic fuel chemistry in large-scale simulations of combustion phenomena and combustor performance are reviewed. The review first demonstrates the ...intricacies of chemical kinetics in homogeneous and diffusive systems, and emphasizes the essential importance of the comprehensiveness of chemical fidelity for mechanisms at the detailed and reduced levels. A systematic approach towards developing detailed reaction mechanisms is then outlined, followed by an extensive discussion on the development of reduced mechanisms and the associated strategies towards facilitated computation. Topics covered include skeletal reduction especially through directed relation graph; time-scale reduction based on the concepts of quasi-steady species enabled through computational singular perturbation; the lumping of isomers and of species with similar diffusivities; on-the-fly stiffness removal; the relative merits of implicit versus explicit solvers; and computation cost minimization achieved through tabulation and the judicious re-sequencing of the computational steps in arithmetic evaluations. Examples are given for laminar flames and direct numerical simulations of turbulent combustion to demonstrate the utility of the integrated strategy and the component methods in incorporating realistic chemistry of practical fuels in large-scale simulations, recognizing that the detailed mechanisms of these fuels may consist of hundreds to thousands of species and thousands to tens of thousands of reactions. Directions for further research are suggested.
α-Synuclein (α-syn) is a synaptic protein in which four mutations (A53T, A30P, E46K and gene triplication) have been found to cause an autosomal dominant form of Parkinson's disease (PD). It is also ...the major component of intraneuronal protein aggregates, designated as Lewy bodies (LBs), a prominent pathological hallmark of PD. How α-syn contributes to LB formation and PD is still not well-understood. It has been proposed that aggregation of α-syn contributes to the formation of LBs, which then leads to neurodegeneration in PD. However, studies have also suggested that aggregates formation is a protective mechanism against more toxic α-syn oligomers. In this study, we have generated α-syn mutants that have increased propensity to form aggregates by attaching a CL1 peptide to the C-terminal of α-syn. Data from our cellular study suggest an inverse correlation between cell viability and the amount of α-syn aggregates formed in the cells. In addition, our animal model of PD indicates that attachment of CL1 to α-syn enhanced its toxicity to dopaminergic neurons in an age-dependent manner and induced the formation of Lewy body-like α-syn aggregates in the substantia nigra. These results provide new insights into how α-syn-induced toxicity is related to its aggregation.
The integrated processes of flame acceleration, deflagration-to-detonation transition (DDT), and the resulting detonation propagation in micro- and macro-scale channels are simulated. It is found ...that the modes of flame acceleration and DDT in these two channels are different, being primarily controlled by viscosity and turbulent flame development, respectively. Furthermore, while boundary layer ignition is crucial for DDT in both channels, viscous wall friction is the key to self-sustained propagation in micro-channels, leading to momentum loss and consequently deficit of the detonation velocity. In macro-channels, the strong overdriven detonation decays and gradually evolves into the Chapman–Jouguet detonation.
Chronic obstructive pulmonary disease is a leading global cause of morbidity and mortality that is characterised by inexorable deterioration of small airways obstruction with emphysema associated ...with cellular inflammation and structural remodelling. Other features include apoptosis as well as proliferation of cells, and both tissue repair and lack of tissue repair. Metalloprotease release, together with that of apoptotic factors, may underlie the emphysema, and, conversely, fibrosis of the small airways may be accounted for by the effects of growth factor activation. In advanced disease, influential factors include the development of autoimmunity, with activation of dendritic cells and T-helper cells of both type 1 and 2, and the senescence response. An inability of macrophages to ingest apoptosed cells and bacteria may exacerbate inflammatory responses. Systemic inflammation with concomitant cardiovascular disease and metabolic syndrome may reflect the effect of cigarette smoke on nonpulmonary cells. Corticosteroid resistance may be secondary to oxidative stress mechanisms, such as inactivation of histone deacetylases. The mechanisms of chronic obstructive pulmonary disease may be heterogeneous, according to severity, and clinical phenotypes need to be correlated with cellular and pathological processes. Treatments may be targeted to patients with specific mechanisms.
Using n-heptane as a representative fuel exhibiting NTC (negative temperature coefficient) chemistry, a comprehensive computational and mechanism study was conducted on the role and controlling ...chemistry of the first-stage ignition delay in the superficially dissimilar systems of the auto-ignition of homogeneous mixtures and the nonpremixed counterflow ignition of fuel versus heated air. It is first shown that the first-stage auto-ignition delay time, τ1, possesses a minimum value, τ1,min, with increasing temperature, and that for temperatures below the range corresponding to τ1,min, τ1 is largely insensitive to the equivalence ratio (ϕ) and pressure (p) of the mixture. Furthermore, in this regime the global reaction order was found to be close to unity, hence supporting the notion that the limiting steps in this temperature regime are the RO2 isomerization reactions, which in turn explains the insensitivity of τ1 on ϕ and p in this temperature regime. However, when the temperature approaches that of τ1,min, competition of QOOH decomposition and the β scission reactions of the alkyl radicals with the low-temperature chemistry chain reactions, as well as the equilibrium shift of the oxygen addition reactions, increases τ1 and consequently results in τ1,min. The corresponding global reaction order also increases, to about two, indicating the progressive importance of the oxygen addition reactions. Extracted values of the global activation energy are also close to those of the controlling reactions in these temperature regimes. Results from the counterflow show the same global kinetic responses by identifying the reciprocal of the counterflow strain rate as the relevant ignition delay time and the temperature of the heated air stream as the homogeneous mixture temperature. It is further found that in the temperature range corresponding to τ1,min, the diminished heat release causes the counterflow to lose its characteristic, non-monotonic S-curve response and consequently distinct, abrupt ignition–extinction transition events.
Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated ...in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.
Aims/hypothesis
As microRNA-21 (miR-21) plays a pathological role in fibrosis, we hypothesised that it may be a therapeutic target for diabetic nephropathy.
Methods
Abundance of miR-21 was examined ...in diabetic kidneys from
db/db
mice. The therapeutic potential of miR-21 in diabetic kidney injury was examined in
db/db
mice by an ultrasound-microbubble-mediated miR-21 small hairpin RNA transfer. In addition, the role and mechanisms of miR-21 in diabetic renal injury were examined in vitro under diabetic conditions in rat mesangial and tubular epithelial cell lines by overexpressing or downregulating miR-21.
Results
In
db/db
mice, a mouse model of type 2 diabetes, renal miR-21 at age 20 weeks was increased twofold compared with
db/m
+
mice at the same age, and this increase was associated with the development of microalbuminuria and renal fibrosis and inflammation. More importantly, gene transfer of miR-21 knockdown plasmids into the diabetic kidneys of
db/db
mice at age 10 weeks significantly ameliorated microalbuminuria and renal fibrosis and inflammation at age 20 weeks, revealing a therapeutic potential for diabetic nephropathy by targeting miR-21. Overexpression of miR-21 in kidney cells enhanced, but knockdown of miR-21 suppressed, high-glucose-induced production of fibrotic and inflammatory markers. Targeting
Smad7
may be a mechanism by which miR-21 regulates renal injury because knockdown of renal miR-21 restored Smad7 levels and suppressed activation of the TGF-β and NF-κB signalling pathways.
Conclusions/interpretation
Inhibition of miR-21 might be an effective therapy for diabetic nephropathy.
Since 2000 there have been major advances in our understanding of the genetic and genomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based on existing ...knowledge, around 25-30% of patients diagnosed with idiopathic PAH have an underlying Mendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, we summarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches. In addition, factors determining the incomplete penetrance observed in HPAH are discussed. The currently available approaches to genetic testing and counselling, and the impact of a genetic diagnosis on clinical management of the patient with PAH, are presented. Advances in DNA sequencing technology are rapidly expanding our ability to undertake genomic studies at scale in large cohorts. In the future, such studies will provide a more complete picture of the genetic contribution to PAH and, potentially, a molecular classification of this disease.
This work studies the real gas effects on the autoignition of hydrocarbon fuels under high pressures, using normal dodecane (n-dodecane) as the representative fuel and the Redlich–Kwong equation of ...state (EoS) as the real gas description. It is demonstrated that the real gas description yields a shorter ignition delay time (IDT) compared with the ideal gas description, especially in low-temperature regimes which could encompass the negative temperature coefficient (NTC) phenomena and has a stronger dependence on the molecular volume than the attractive potential. The study further shows that high pressure facilitates low-temperature reaction pathways, where the compressibility factors of key reactants contribute to real gas effects. Moreover, the results suggest that accounting for real gas behavior leads to an increase in the formation of polycyclic aromatic hydrocarbons (PAHs), which, in turn, promotes soot generation.
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