Reactions of metal complexes with Lewis bases and their utilisation in the selective filtration of smoke

This thesis is concerned with internal redox reactions of metal complexes and the application of such reactions in the selective filtration of tobacco smoke. The reactions of Fe(II), Fe(III) and Cu(II) quinoneoximic complexes and of some other complexes of these metals with Lewis bases (e.g. Ph3P and py) have been investigated. From the results obtained and from a critical consideration of analogous reactions reported in the literature the behaviour of metal chelates towards Lewis bases has been assessed. It has been established that the reaction between a metal chelate and a Lewis base may lead to: (i) Adduct formation, (ii) condensation and (iii) to an internal redox reaction, M(chel)n LB[over arrow] M(chel)n-1(LB)x + chel* The latter is favoured when the metal in M(chel)n has a stable lower oxidation state, by Lewis bases capable of E[eta]—bonding and by chelating ligands exerting a strong ligand field. The type of behaviour shown by chel* has been considered. The dissociated radical may: (i) Abstract a hydrogen atom to give the protonated ligand, (ii) dimerise, (iii) undergo coupling or degradation. A detailed investigation of the reactions of Fe(l-nqo)3 and Fe(2-nqo)3 with Ph3P (including kinetic studies) showed that these complexes undergo internal redox reactions to give iron(II) complexes and products arising from the deoxygenation of the nqo* radical. Mechanisms for these resctions have been proposed. The behaviour of quinoneoximic complexes of iron towards the Lewis base CO has been examined both directly and indirectly by studying the behaviour of nqoH towards Fe(CO)5 or Fe(CO)5/PhNH2. Fe(CO)5 and 1-nqoH or 2-nqoH afforded complexes of the type Fe(nqo)2, without formation of CO adducts or deoxygenation products. In the presence of PhNH2 complexes of type Fe(nqo)2 and Fe(nqo-A)2 resulted, where nqo-A is a species arising from the coupling of the nqo ligand with PhNH2. Both systems also afforded various organic products. On the basis of Mossbauer and other techniques oligomeric structures have been suggested for the complexes Fe(nqo)2 and Fe(nqo-A)2. Whereas CO did not react with Fe(nqo)2 or Fe(nqo)2.2py, it reacted with Fe(nqo)3, possibly via an internal redox process. For Fe(2-nqo)3 products arising from a deoxygenated ligand and a complex tentatively formulated as the nitrene species, Fe(2-nq)2, were isolated. The reactivity of the Fe(nqo), complexes towards CO has been successfully utilised in the selective filtration of tobacco smoke. Both Fe(1-nqo)3, and Fe(2-nqo)3 were shown to be capable of significantly reducing the level of CO in tobacco smoke under smoking conditions when supported on suitable filters. Reduction of the levels of other Lewis bases in tobacco smoke, e.g. nicotine and furfural, was observed. The complexes Fe(nqo)2, Fe(nqo)2.2py and Fe(nqo)3 reacted readily with NO to give complicated mixtures, but their effectiveness in removing NO from tobacco smoke has not been unambiguously established

Controlling product selectivity with nanoparticle composition in tandem chemo-biocatalytic styrene oxidation

The combination of heterogeneous catalysis and biocatalysis into one-pot reaction cascades is a potential approach to integrate enzymatic transformations into existing chemical infrastructure. Peroxygenases, which can achieve clean C-H activation, are ideal candidates for incorporation into such tandem systems; however a constant supply of low-level hydrogen peroxide (H2O2) is required. The use of such enzymes at industrial scale will likely necessitate the in situ generation of the oxidant from cheap and widely available reactants. We show that combing heterogeneous catalysts (AuxPdy/TiO2) to produce H2O2 in situ from H2 and air, in the presence of an evolved unspecific peroxygenase from Agrocybe aegerita (PaDa-I variant) yields a highly active cascade process capable of oxidizing alkyl and alkenyl substrates under mild conditions. When alkenes such as styrene are subjected to this tandem oxidation process, divergent reaction pathways are observed due to the competing hydrogenation of the alkene by palladium rich nanoparticles in the presence of H2. Each pathway presents opportunities for value added products. Product selectivity was highly sensitive to the rate of reduction compared to hydrogen peroxide delivery. Here we show that some control over product selectivity may be exerted by careful selection of nanoparticle composition

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year