Ring-opening metathesis polymerization (ROMP) of norbornene by a Group VIII carbene complex in protic media

During the past two decades, intense research efforts have enabled an in-depth understanding of the olefin metathesis reaction as catalyzed by early transition metal complexes. In contrast, the nature of the intermediates and the reaction mechanism for group VIII transition metal metathesis catalysts remain elusive. Such knowledge is important in view of the promise group VIII metals show in polymerizing a wide variety of functionalized cyclic olefins in protic solvents. Highly active late transition metal catalysts should also open the way to the metathesis of functionalized acyclic olefins. Previous studies in our group have focused on the chemistry of highly active, functional-group-tolerant catalysts prepared from aquoruthenium(II) olefin complexes. In these systems, characterization of the catalytic intermediates is difficult due to their very low concentrations and high activity in the reaction mixtures. Although it is reasonable to assume that the active species are ruthenacyclobutanes and ruthenium carbenes (ruthenaolefins), the oxidation state and ligation of these intermediates are not known. Furthermore, the discrete ruthenium carbene complexes that have been isolated to date do not exhibit both metathesis activity and stability to protic/aqueous solvents. We report here the reaction of an Ru(II) complex with a strained olefin to produce a carbene species that polymerizes norbornene in organic media both in the absence and presence of protic/aqueous solvents. In both solvent systems, a stable propagating carbene complex can be observed throughout the course of the polymerization, as has been previously found with titanium, tantalum, tungsten, molybdenum, and ruthenium complexes

Facile tungsten alkylidene synthesis: alkylidene transfer from a phosphorane to a tungsten imido complex

A number of transition-metal complexes catalyze the ring-opening metathesis polymerization (ROMP) of a variety of cyclic olefins. Notable among these catalysts are the titanacyclobutane derivatives and certain alkylidene complexes of tungsten: molybdenum, tantalum, and rhenium. The highly reactive tungsten alkylidene complexes developed by Schrock, Osborn, and Basset are particularly useful for the synthesis of unsaturated polymers such as novel conducting polymers and soluble precursors and derivatives of polyacetylene. Recent applications of these catalytic systems involve the polymerization of acyclic alkynes and dienes In addition, the use of tungsten alkylidene complexes as Wittig-type reagents in organic synthesis holds considerable promise

Methods for the synthesis of tungsten alkylidenes : ring-opening of cyclopropenes and alkylidene transfer from phosphoranes

In the research reported in this thesis, two methods for synthesizing alkylidene complexes were investigated: (1) ring-opening of cyclopropenes to give vinyl alkylidene complexes and (2) alkylidene transfer from phosphorus ylides to metal centers. Tungsten(IV) imido precursors of the form WX_2(NAr)L_n (X = Cl or OR; Ar = Ph, 2,6-C_6H_3-Me_2, 2,6-C_6H_3-(i-PR)_2, L_n = PR3, P(OR)_3 or ether donor ligands) were used throughout the investigation. A brief overview of the syntheses and uses of high-valent alkylidene complexes is given in Chapter 1. The reactions of WCl_2(NAr)(PX_3)_3 (X = R or OR) precursors with 3,3-diphenylcyclopropene and 4,8-dioxaspiro[2.5]oct-1-ene are reported in Chapter 2. η^2-Cyclopropene complexes [W(η2-cyclopropene)Cl_2(NAr)(PX_3)_2] were synthesized from precursors containing the smaller imido ligands; increasing the steric bulk of the imido ligand favored the ring-opening of the cyclopropenes to yield the vinyl alkylidene compounds [W(=CH-CH=CR'_2)Cl_2(NAr)(PX_3)_2]. Conversion of thermally stable η^2-cyclopropene complexes to give the corresponding vinyl alkylidene compounds was observed upon photolysis or addition of catalytic amounts of H_gCl_2. The transfer of alkylidenes from Ph_3P=CHAr' and Ph_3P=CH-CH=CMe_2 to WCI_2(NPh)(PMePh_2)_3 to give W(=CHR')CI_2(NPh)(PMePh_2)_2 is reported in the first half of Chapter 3, and the effects of varying the solvent, the ylides, and the tungsten precursors are discussed. The remainder of Chapter 3 deals with the in situ reduction and trapping of WCl_2(NAr)[OCMe(CF3_ 3) _ 2] _ 2(THF) precursors by Ph_3P=CHAr' to give W(=CHAr')(NAr)[OCMe(CF_3)_2]_2(PPh_3). The use of the chelating o-methoxybenzylidene was especially effective here, as coordination by the o-methoxy group greatly aided the transfer reaction and, in addition, stabilized the resulting product. Chapter 4 documents initial studies involving the reactions of WCI_2(NAr)(PX_3) _3 precursors with exo-5,6-dimethoxymethyl-7-oxanorbornene. For reactions involving tungsten precursors with the smaller imido ligands, fonnation of η2-olefin complexes W[η_2-(7-oxanorbomene]Cl2(NAr)(PX3h was observed. Oxygen abstraction to give 5,6- dimethoxymethylcyclohexadiene occurred upon reaction of this olefin with WCl_2[N-2,6-C_6H_3-(i-Pr) _2] [P(OMe) _3] _3.</p

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Facile tungsten alkylidene synthesis: alkylidene transfer from a phosphorane to a tungsten imido complex

A number of transition-metal complexes catalyze the ring-opening metathesis polymerization (ROMP) of a variety of cyclic olefins. Notable among these catalysts are the titanacyclobutane derivatives and certain alkylidene complexes of tungsten: molybdenum, tantalum, and rhenium. The highly reactive tungsten alkylidene complexes developed by Schrock, Osborn, and Basset are particularly useful for the synthesis of unsaturated polymers such as novel conducting polymers and soluble precursors and derivatives of polyacetylene. Recent applications of these catalytic systems involve the polymerization of acyclic alkynes and dienes In addition, the use of tungsten alkylidene complexes as Wittig-type reagents in organic synthesis holds considerable promise

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Immunopotentiation of Trivalent Influenza Vaccine When Given with VAX102, a Recombinant Influenza M2e Vaccine Fused to the TLR5 Ligand Flagellin

BACKGROUND: Currently controversy exists about the immunogenicity of seasonal trivalent influenza vaccine in certain populations, especially the elderly. STF2.4×M2e (VAX102) is a recombinant fusion protein that links four copies of the ectodomain of influenza virus matrix protein 2 (M2e) antigen to Salmonella typhimurium flagellin, a TLR5 ligand. The objectives of this study were to assess the feasibility of giving VAX102 and TIV in combination in an effort to achieve greater immunogenicity and to provide cross-protection. METHODOLOGY/PRINCIPAL FINDINGS: Eighty healthy subjects, 18-49 years old, were enrolled in May and June 2009 in a double-blind, randomized, controlled trial at two clinical sites. Subjects were randomized to receive either TIV + VAX102 or TIV + placebo. Both arms tolerated the vaccines. Pain at the injection site was more severe with TIV + VAX102. Two weeks after immunization the HAI responses to the H1 and H3 antigens of TIV were higher in those that received TIV + VAX102 than in TIV + placebo (309 vs 200 and 269 vs 185, respectively), although statistically non-significant. There was no difference in the HAI of the B antigen. In the TIV + VAX102 arm, the geometric mean M2e antibody concentration was 0.5 µg/ml and 73% seroconverted. CONCLUSIONS/SIGNIFICANCE: The combination of TIV + VAX102 has the potential to increase the immune response to the influenza A components of TIV and to provide M2e immunity which may protect against influenza A strains not contained in seasonal TIV. TRIAL REGISTRATION: ClinicalTrials.gov NCT00921973

Associations between the legal context of HIV, perceived social capital, and HIV antiretroviral adherence in North America

Background Human rights approaches to manage HIV and efforts to decriminalize HIV exposure/transmission globally offer hope to persons living with HIV (PLWH). However, among vulnerable populations of PLWH, substantial human rights and structural challenges (disadvantage and injustice that results from everyday practices of a well-intentioned liberal society) must be addressed. These challenges span all ecosocial context levels and in North America (Canada and the United States) can include prosecution for HIV nondisclosure and HIV exposure/transmission. Our aims were to: 1) Determine if there were associations between the social structural factor of criminalization of HIV exposure/transmission, the individual factor of perceived social capital (resources to support one’s life chances and overcome life’s challenges), and HIV antiretroviral therapy (ART) adherence among PLWH and 2) describe the nature of associations between the social structural factor of criminalization of HIV exposure/transmission, the individual factor of perceived social capital, and HIV ART adherence among PLWH. Methods We used ecosocial theory and social epidemiology to guide our study. HIV related criminal law data were obtained from published literature. Perceived social capital and HIV ART adherence data were collected from adult PLWH. Correlation and logistic regression were used to identify and characterize observed associations. Results Among a sample of adult PLWH (n = 1873), significant positive associations were observed between perceived social capital, HIV disclosure required by law, and self-reported HIV ART adherence. We observed that PLWH who have higher levels of perceived social capital and who live in areas where HIV disclosure is required by law reported better average adherence. In contrast, PLWH who live in areas where HIV transmission/exposure is a crime reported lower 30-day medication adherence. Among our North American participants, being of older age, of White or Hispanic ancestry, and having higher perceived social capital, were significant predictors of better HIV ART adherence. Conclusions Treatment approaches offer clear advantages in controlling HIV and reducing HIV transmission at the population level. These advantages, however, will have limited benefit for adherence to treatments without also addressing the social and structural challenges that allow HIV to continue to spread among society’s most vulnerable populations