We report the preparation of 5,10,15,20-tetraphenyl-2,3,7,8,12,13,17,18-octakis(phenylethynyl)porphinato complexes of Ni(II), H2, Zn(II), Mg(II), and Cu(II), as well as select trimethylsilanylethynyl ...derivatives. The X-ray structures of the octakis(phenylethynyl) compounds show systematic deviations from planarity (Ni(II), 0.2851 Å; Zn(II), 0.0304 Å) as a function of the central cation. These geometric distortions are reflected in bathochromic shifts of the Soret and Q bands (Ni(II), 497, 604, and 650 nm; Mg(II), 515, 595, 642, and 705 nm) which loosely correlate with increasing planarity of the structure. Similarly, vibrational modes involving the octasubstituted porphyrin core exhibit shifts to lower frequency as a function of increasing planarity in the solution-state resonance Raman spectra (λexc = 501.7 nm) of these compounds. Analogous trends are also observed in their solid-state electronic and resonance Raman spectra, indicating that the structural distortions within the octakis(phenylethynyl) series are preserved in solution. Comparison of the saddle distortion of the octasubstituted Ni(II) compound with the ruffle/saddle distortions of the pentakis and hexakis Ni(II) derivatives reveals some influence of asymmetric peripheryl substitution on geometric structure. These Ni(II) derivatives also exhibit systematic red shifts in their electronic spectra as a function of the number of conjugated alkyne units (∼13 nm/alkyne), revealing participation of the enediyne units in the electronic ground and excited states. The solid-state Bergman cyclization temperatures of the phenylethynyl compounds vary markedly as a function of planarity, and correlate loosely with alkyne termini separation (Ni(PA)8, 4.00 Å, 281 °C; MgP(PA)8, 3.77 Å, 244 °C). In solution, both thermal and photochemical activation of the free-base octakis(phenylethynyl) compound lead to formal reduction of the porphyrin backbone via H-atom addition at opposing meso-positions. Generation of a common product suggests that both thermal and photochemical pathways to Bergman cyclization in solution contain significant activation barriers to formation of the 1,4-phenyl diradical intermediate, and under these solution conditions, alternate reaction channels are more thermodynamically favorable.
Cobalt catalysts supported on silica aerogel have been prepared using sol–gel chemistry followed by drying under supercritical ethanol conditions. Three different loadings of cobalt were synthesized: ...2, 6, and 10% by weight. Transmission electron micrographs indicate that the metallic cobalt exists as discrete particles 50–70
nm in diameter for the 2 and 6% loadings. The 10% catalyst shows long needles of cobalt. BET and BJH measurements indicate that the catalysts retain the silica aerogel properties of high surface area (∼800
m
2/g), large pore volume (∼5
cm
3/g), and an average pore diameter in the mesoporous regime (∼25
nm). The catalysts were evaluated for Fischer–Tropsch activity in a laboratory-scale packed bed reactor. All three catalysts were active with the 10% Co catalyst achieving more than 20% CO conversion which corresponds to a rate of 1.53
g CO per g-cat per hour. The catalysts were selective for the C
10+ hydrocarbons with more than 50% of the carbon contained within this fraction. A significant portion of the C
9–C
15 hydrocarbon product was observed as 1-olefins which reflects the enhanced mass transport within the very porous aerogel support.
Four-coordinate vanadium complexes containing a terminal neopentylidyne functionality have been prepared by two consecutive α-hydrogen abstraction reactions both of which were induced by one-electron ...oxidations. Among these vanadium−alkylidyne complexes are the neutral and the cation (Nacnac)V⋮CtBu(OTf) and (Nacnac)V⋮CtBu(THF)+, respectively (Nacnac- = ArNC(CH3)CHC(CH3)NAr, Ar = 2,6-(CHMe2)2C6H3). The vanadium−alkylidynes have been characterized by 1H, 13C, 51V NMR spectroscopy and single-crystal X-ray diffraction and are consistent with a short V⋮C bond. These alkylidynes were found to transform to azametalacyclohexatriene systems via an intramolecular cross-metathesis reaction. Kinetic studies of the transformation of (Nacnac)V⋮CtBu(OTf) in C7D8 reveal the formation of the azametalacyclohexatriene to be independent of solvent (toluene vs THF) and the reaction to be first order in vanadium (k = 3.30(5) × 10-5 s-1 at 80 °C, with activation parameters ΔH ⧧= 25.4(3) kcal/mol, ΔS ⧧ = −6(3) cal/molK). High-level DFT calculations on the full model suggest an intramolecular mechanism invoking only one transition state. The overall thermodynamic driving force for the reaction (ΔG) in solution phase was estimated to be −21.3 kcal/mol.
A family of high activity catalysts for the vinyl addition polymerization of norbornene-type monomers based on cationic η-allylpalladium complexes coordinated by phosphine ligands has been ...discovered. The palladium complex (η3-allyl)Pd(tricyclohexylphosphine)(ether)B(3,5-(CF3)2C6H3)4 (2) was found to copolymerize 5-butylnorbornene and 5-triethoxysilylnorbornene (95:5 molar ratio) with truly high activity and is capable of producing more than a metric ton of copolymer per mole Pd per hour. Multicomponent catalyst systems based on the addition of salts of weakly coordinating anions (e.g., NaB(3,5-(CF3)2C6H3)4 or LiB(C6F5)4·2.5Et2O) to (η3-allyl)Pd(X)(PR3) (X = chloride, acetate, nitrate, trifluoroacetate, and triflate) in the presence of norbornene-type monomers were developed. NMR tube experiments confirm that NaB(3,5-(CF3)2C6H3)4 abstracts the Cl ligand from the palladium complex forming the cationic complex in situ. Control experiments confirmed that a high activity polymerization system requires a palladium cation containing an allyl ligand, a neutral, two-electron-donor phosphine ligand, and a weakly coordinating counterion. Those complexes where X contained electron-withdrawing groups such as trifluoroacetate or triflate were found to be the most active catalyst precursors. η3-Allylpalladium catalyst precursors with larger cone angle phosphine ligands yield lower molecular weight polymers. The poly(norbornene) molecular weights can be further tuned by addition of α-olefin chain transfer agents to the reaction mixture. The catalyst systems were also found to polymerize norbornene-type monomers in aqueous media to high conversion at very low catalyst loadings. The effect of molecular weight on thermomechanical properties was explored.
Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with ...increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk.
To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol.
Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.
Background
Multi‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. ...This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.
Objectives
To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.
Methods
Summary statistics from genome wide‐association studies (GWAS) from seven hemostatic traits (factor VII FVII, factor VIII FVIII, von Willebrand factor VWF factor XI FXI, fibrinogen, tissue plasminogen activator tPA, plasminogen activator inhibitor 1 PAI‐1) and three major cardiovascular (CV) events (venous thromboembolism VTE, coronary artery disease CAD, ischemic stroke IS), were combined in 27 multi‐trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi‐trait combinations performed (n = 27).
Results
Across the 27 multi‐trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes.
Conclusions
The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
Objectives: Physical activity (PA) has the potential to improve outcomes in both arthritis and diabetes, but these conditions are rarely examined together. Our objective was to explore whether ...persons with arthritis alone or those with both arthritis and diabetes could improve amounts of PA with a home-based counselling intervention.
Methods: As part of the Veterans LIFE (Learning to Improve Fitness and Function in Elders) Study, veterans aged 70-92 were randomized to usual care or a 12-month PA counselling programme. Arthritis and diabetes were assessed by self-report. Mixed models were used to compare trajectories for minutes of endurance and strength training PA for persons with no arthritis (n = 85), arthritis (n = 178), and arthritis plus diabetes (n = 84).
Results: Recipients of PA counselling increased minutes of PA per week independent of disease status (treatment arm by time interaction p < 0.05 for both; endurance training time p = 0.0006 and strength training time p < 0.0001). Although PA was lower at each wave among persons with arthritis, and even more so among persons with arthritis plus diabetes, the presence of these conditions did not significantly influence response to the intervention (arthritis/diabetes group × time interactions p > 0.05 for both outcomes) as each group experienced a nearly twofold or greater increase in PA.
Conclusions: A home-based PA intervention was effective in increasing minutes of weekly moderate intensity endurance and strength training PA in older veterans, even among those with arthritis or arthritis plus diabetes. This programme may serve as a useful model to improve outcomes in older persons with these pervasive diseases.
Remifentanil hydrochloride is an ultra-short-acting opioid that undergoes rapid metabolism by tissue and plasma esterases. We aimed to characterize the pharmacokinetics and determine the hemodynamic ...profile of remifentanil after a single-bolus dose in children aged 0 to 18 yr. Forty-two children undergoing elective surgical procedures received remifentanil 5 microg/kg infused over 1 min. Patients were divided into age groups as follows: young infants (< or =2 mo), older infants (> 2 mo to < 2 yr), young children (2 to < 7 yr), older children (7 to < 13 yr), adolescents (13 to < 16 yr), and young adults (16 to < 18 yr). Arterial blood samples were collected and analyzed by mass spectroscopy to determine remifentanil pharmacokinetic profiles. Hemodynamic measurements for remifentanil's effect were made after the infusion. Methods of statistical analysis included analysis of variance and linear regression, with significance at P < or = 0.05. Complete remifentanil pharmacokinetic data were obtained from 34 patients. The volume of distribution was largest in the infants < 2 mo (mean, 452 mL/kg) and decreased to means of 223 to 308 mL/kg in the older patients. There was a more rapid clearance in the infants < 2 mo of age (90 mL. kg(-1). min(-1)) and infants 2 mo to 2 yr (92 mL. kg(-1). min(-1)) than in the other groups (means, 46 to 76 mL. kg(-1). min(-1)). The half-life was similar in all age groups, with means of 3.4 to 5.7 min. Seven subjects (17%) developed hypotension related to the remifentanil bolus. Remifentanil showed an extremely rapid elimination similar to that in adults. The fast clearance rates observed in neonates and infants, as well as the lack of age-related changes in half-life, are in sharp contrast to the pharmacokinetic profile of other opioids. Remifentanil in a bolus dose of 5 microg/kg may cause hypotension in anesthetized children.
The pharmacokinetics of remifentanil were studied in children from birth to 18 yr. Remifentanil was found to have age-related changes in clearance and volume of distribution, but not half-life. The increased clearance observed in young infants is in contrast to other opioids.
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