Dry reforming catalysts, especially those with activity at moderate temperatures, have been intensely investigated to enhance the conversion of biogas. Here, Ru is evaluated as a promoter for Ni-Mg ...based catalysts. Catalysts based on 1.4 wt%Ni-1.0 wt%Mg-Ce0.6Zr0.4O2 with Ru (0.02–0.32 wt%) were prepared using incipient wetness. The reducibility of the catalysts and conversions increased with increasing Ru content. Increases in conversions with increasing Ru loading was attributed to the additional active sites and synergistic effect between Ru and Ni, which weakened Ni-Mg interactions. Samples showed dry reforming activity at low temperatures (450–510 °C). Reaction rates and activation energies of higher loading Ru samples (1.4 wt%Ni-1.0 wt%Mg/Ce0.6Zr0.4 O2 with 0.16 and 0.32 wt%Ru) decreased when the reduction temperature was raised from 300 to 400 °C. A 20 h TOS study showed stable catalytic activity with minimal coke deposition. The results suggest that Ru is an alternative to Pt in promoting low temperature dry reforming of methane.
This thesis studies the evolution and current purpose of the political offence exception for the purpose of determining whether there is a continuing role for the exception. It concludes that there ...is a continuing need for the exception. The thesis examines the coexistence in international law and policy between the demand for international public order, as characterized by the system of extradition laws and treaties, and the need to safeguard the rights of the individual, as reflected in the political offence exception to extradition, international refugee protection and the practice of asylum. There are a number of concerns with the political offence exception as currently applied, namely: (1) Designation of inappropriate acts as political offences; (2) Excessive rigidity and formality by some courts; (3) Excessive judicial discretion; (4) Over-emphasis on efficacy of the act in question; (5) Excessive political influence on decision-making. The thesis proposes an alternative political offence exception test with the following five criteria: (1) the individual should be involved in a dispute concerning political control over the state; (2) the individual should be part of a group which is involved in such a struggle and the act in question must be done in furtherance of that struggle; (3) the exception should not apply to heinous crimes such as crimes against humanity; (4) certain acts such as hijacking should be automatically excluded; (5) there should be proportionality between means and ends. (Abstract shortened by UMI.)
This thesis studies the evolution and current purpose of the political offence exception for the purpose of determining whether there is a continuing role for the exception. It concludes that there ...is a continuing need for the exception. The thesis examines the coexistence in international law and policy between the demand for international public order, as characterized by the system of extradition laws and treaties, and the need to safeguard the rights of the individual, as reflected in the political offence exception to extradition, international refugee protection and the practice of asylum. There are a number of concerns with the political offence exception as currently applied, namely: (1) Designation of inappropriate acts as political offences; (2) Excessive rigidity and formality by some courts; (3) Excessive judicial discretion; (4) Over-emphasis on efficacy of the act in question; (5) Excessive political influence on decision-making. The thesis proposes an alternative political offence exception test with the following five criteria: (1) the individual should be involved in a dispute concerning political control over the state; (2) the individual should be part of a group which is involved in such a struggle and the act in question must be done in furtherance of that struggle; (3) the exception should not apply to heinous crimes such as crimes against humanity; (4) certain acts such as hijacking should be automatically excluded; (5) there should be proportionality between means and ends. (Abstract shortened by UMI.)
The accurate prediction of multiphase flow when particles are differentiated by a set of “internal” variables, such as size or temperature, can pose modelling and numerical challenges. Although ...Lagrangian particle methods can provide predictive simulations of a wide spectrum of complex multiphase problems, they can become prohibitively expensive as the number of particles becomes large. Alternatively, Eulerian approaches have the potential to improve the computational efficiency of multiphase flows, but classical methods produce modelling artifacts or do not properly treat the local statistical dependence between the particle velocities and internal variables, or between the internal variables themselves. In this paper an extension is proposed of the classical Gaussian ten-moment model from gaskinetic theory to a model for the treatment of a dilute particle phase with an arbitrary number of internal variables based on an entropy-maximization argument. Unlike previous formulations, this new model provides a set of first-order robustly-hyperbolic balance laws that include a direct treatment for the local statistical variance of each variable, as well as the covariance between the internal variables or the internal variables and particle velocity. A study of the wave speeds of the general hyperbolic system is presented. To demonstrate an example application, the model is then specialized for polydisperse flows that are subject to viscous fluid drag as well as gravitational and buoyancy forces. The complete eigenstructure of this fifteen-moment polydisperse Gaussian model (PGM) is presented and the PGM is shown to maintain a physically realizable distribution function for all admissible initial conditions. Finally, several illustrative low-dimensional problems are studied to demonstrate the predictive capabilities of the new model.
•New Eulerian-based model for particle-laden flows with arbitrary internal variables.•Resulting PDEs are closed form, robustly hyperbolic, entropy stable and well-posed.•The polydisperse Gaussian model (PGM) gives better predictions over classical model.•Polydisperse sedimentation flow is predicted very accurately and efficiently by PGM.•The model allows use of efficient classical discretizations on modern architectures.
Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome ...proliferator–activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up‐regulate BA‐glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13‐15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145‐160 mg/day) as standard of care. Serum BA and BA‐glucuronide concentrations were measured by liquid chromatography–mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (−76%, P < 0.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (−54%), and increased serum BA‐glucuronides (+2.1‐fold, P < 0.01) versus ursodiol monotherapy. The major serum BA‐glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid–6G (+3.7‐fold, P < 0.01), hyocholic acid–6G (+2.6‐fold, P < 0.05), chenodeoxycholic acid (CDCA)–3G (−36%), and lithocholic acid (LCA)–3G (−42%) versus ursodiol monotherapy. Fenofibrate also up‐regulated the expression of uridine 5′‐diphospho‐glucuronosyltransferases and multidrug resistance–associated protein 3 messenger RNA in primary human hepatocytes. Pearson’s correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA‐3G (r2 = 0.62, P < 0.0001), deoxycholic acid (DCA)‐3G (r2 = 0.48, P < 0.0001), and LCA‐3G (r2 = 0.40, P < 0.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA‐glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA‐glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα‐mediated anti‐cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA‐glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.
Combination therapy with fenofibrate favorably alters BA‐glucuronidation as a PPARa‐mediated mechanism to reduce elevated serum BAs in patients with PBC and PSC who are incomplete responders to Ursodiol monotherapy. This study also identifies serum BA‐glucuronides and their respective metabolic ratios as indicators of response to therapy. Serum BA‐glucuronides may serve as mechanistically relevant secondary endpoints in clinical trials for PBC and PSC with anti‐cholestatic agents.
Huntington's disease is triggered by misfolding of fragments of mutant forms of the huntingtin protein (mHTT) with aberrant polyglutamine expansions. The C4 single-chain Fv antibody (scFv) binds to ...the first 17 residues of huntingtin HTT(1-17) and generates substantial protection against multiple phenotypic pathologies in situ and in vivo. We show in this paper that C4 scFv inhibits amyloid formation by exon1 fragments of huntingtin in vitro and elucidate the structural basis for this inhibition and protection by determining the crystal structure of the complex of C4 scFv and HTT(1-17). The peptide binds with residues 3–11 forming an amphipathic helix that makes contact with the antibody fragment in such a way that the hydrophobic face of this helix is shielded from the solvent. Residues 12–17 of the peptide are in an extended conformation and interact with the same region of another C4 scFv:HTT(1-17) complex in the asymmetric unit, resulting in a β-sheet interface within a dimeric C4 scFv:HTT(1-17) complex. The nature of this scFv–peptide complex was further explored in solution by high-resolution NMR and physicochemical analysis of species in solution. The results provide insights into the manner in which C4 scFv inhibits the aggregation of HTT, and hence into its therapeutic potential, and suggests a structural basis for the initial interactions that underlie the formation of disease-associated amyloid fibrils by HTT.
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•C4 scFv specific for HTT(1-17) inhibits mHTT aggregation in vitro.•HTT(1-17) binds to C4 scFv in a partly helical, partly extended conformation.•C4 scFv increases the solubility of HTT(1-17) and sterically hinders mHTT aggregation.•C4 scFv:HTT(1-17) crystallizes in a dimeric assembly forming an extended β-sheet network.
Lipoprotein(a) (Lpa) is the preferential lipoprotein carrier of oxidized phospholipids (OxPLs) and a well-established genetic risk factor for calcific aortic valve stenosis (CAVS). Whether Lp(a) ...predicts aortic valve microcalcification in individuals without CAVS is unknown. Our objective was to estimate the prevalence of elevated Lp(a) and OxPL levels in patients with CAVS and to determine if individuals with elevated Lp(a) but without CAVS have higher aortic valve microcalcification.
We recruited 214 patients with CAVS from Montreal and 174 patients with CAVS and 108 controls from Québec City, Canada. In a second group of individuals with high (≥75 nmol/L, n = 27) or low (<75 nmol/L, n = 28) Lp(a) levels, 18F-sodium fluoride positron emission tomography/computed tomography was performed to determine the difference in mean tissue-to-background ratio (TBR) of the aortic valve.
Patients with CAVS had 62.0% higher Lp(a) (median = 28.7, interquartile range 8.2-116.6 vs 10.9 3.6-28.8 nmol/L,
0.0001), 50% higher OxPL-apolipoprotein-B (2.2 1.3-6.0 vs 1.1 0.7-2.6 nmol/L,
0.0001), and 69.9% higher OxPL-apolipoprotein(a) (7.3 1.8-28.4 vs 2.2 0.8-8.4 nmol/L,
0.0001) levels compared with individuals without CAVS (all
0.0001). Individuals without CAVS but elevated Lp(a) had 40% higher mean TBR compared with individuals with low Lp(a) levels (mean TBR = 1.25 ± 0.23 vs 1.15 ± 0.11,
= 0.02).
Elevated Lp(a) and OxPL levels are associated with prevalent CAVS in patients studied in an echocardiography laboratory setting. In individuals with elevated Lp(a), evidence of aortic valve microcalcification by 18F-sodium fluoride positron emission tomography/computed tomography is present before the development of clinically manifested CAVS.
Genetic variants at the LPA locus are associated with both calcific aortic valve stenosis (CAVS) and coronary artery disease (CAD). Whether these variants are associated with CAVS in patients with ...CAD vs those without CAD is unknown.
To study the associations of LPA variants with CAVS in a cohort of patients undergoing heart surgery and LPA with CAVS in patients with CAD vs those without CAD and to determine whether first-degree relatives of patients with CAVS and high lipoprotein(a) (Lpa) levels showed evidence of aortic valve microcalcification.
This genetic association study included patients undergoing cardiac surgery from the Genome-Wide Association Study on Calcific Aortic Valve Stenosis in Quebec (QUEBEC-CAVS) study and patients with CAD, patients without CAD, and control participants from 6 genetic association studies: the UK Biobank, the European Prospective Investigation of Cancer (EPIC)-Norfolk, and Genetic Epidemiology Research on Aging (GERA) studies and 3 French cohorts. In addition, a family study included first-degree relatives of patients with CAVS. Data were collected from January 1993 to September 2018, and analysis was completed from September 2017 to September 2018.
Case-control studies.
Presence of CAVS according to a weighted genetic risk score based on 3 common Lp(a)-raising variants and aortic valve microcalcification, defined as the mean tissue to background ratio of 1.25 or more, measured by fluorine 18-labeled sodium fluoride positron emission tomography/computed tomography.
This study included 1009 individuals undergoing cardiac surgery and 1017 control participants in the QUEBEC-CAVS cohort; 3258 individuals with CAVS and CAD, 41 100 controls with CAD, 2069 individuals with CAVS without CAD, and 380 075 control participants without CAD in the UK Biobank, EPIC-Norfolk, and GERA studies and 3 French cohorts combined; and 33 first-degree relatives of 17 patients with CAVS and high Lp(a) levels (≥60 mg/dL) and 23 control participants with normal Lp(a) levels (<60 mg/dL). In the QUEBEC-CAVS study, each SD increase of the genetic risk score was associated with a higher risk of CAVS (odds ratio OR, 1.35 95% CI, 1.10-1.66; P = .003). Each SD increase of the genetic risk score was associated with a higher risk of CAVS in patients with CAD (OR, 1.30 95% CI, 1.20-1.42; P < .001) and without CAD (OR, 1.33 95% CI, 1.14-1.55; P < .001). The percentage of individuals with a tissue to background ratio of 1.25 or more or CAVS was higher in first-degree relatives of patients with CAVS and high Lp(a) (16 of 33 49%) than control participants (3 of 23 13%; P = .006).
In this study, a genetically elevated Lp(a) level was associated with CAVS independently of the presence of CAD. These findings support further research on the potential usefulness of Lp(a) cascade screening in CAVS.
Durable efficacy and long-term safety of antiretroviral therapy are important goals in the management of treatment-experienced patients. The 96-week efficacy and safety of the non-nucleoside reverse ...transcriptase inhibitor (NNRTI) etravirine were evaluated in the Phase III DUET trials.
HIV type-1-infected treatment-experienced adults with viral loads >5,000 copies/ml and NNRTI and protease inhibitor resistance were randomized to receive etravirine 200 mg or placebo, each twice daily and in combination with a background regimen of darunavir/ritonavir twice daily, nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. The primary end point was the proportion of patients with viral load <50 copies/ml (intent-to-treat analysis, time-to-loss of virological response algorithm) at week 24. Results from both trials were combined in the pre-specified pooled 96-week analysis.
In total, 599 patients received etravirine and 604 received placebo. At week 96, 57% of patients in the etravirine group versus 36% in the placebo group had a viral load <50 copies/ml (P<0.0001); 91% and 88% of patients, respectively, had maintained this response from week 48. Mean increases in CD4(+) T-cell count from baseline at week 96 were 128 cells/mm(3) with etravirine versus 86 cells/mm(3) with placebo (P<0.0001). With the exception of rash, which was reported more frequently with etravirine than placebo (21% versus 12%, respectively; P<0.0001), the safety and tolerability profile of etravirine was similar to placebo over the treatment period.
Etravirine, in combination with an antiretroviral background regimen, provided durable virological and immunological responses with no new safety concerns in treatment-experienced patients over 96 weeks in the DUET trials.
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