Reclaiming the Docile Body: An Autoethnography of Illness and Adult Education.

I am presenting an autoethnography on my experiences of illness and my return to education, in an adult education context. I first became ill with acute kidney failure in January 2011, a few months after giving birth to my son. It happened so suddenly and unexpectedly. I was thrown into a completely different world, questioning and reflecting on my life up to that point. In this thesis, I will show how my experiences of illness led me to return to education and how adult education enabled me to reclaim myself through agency. I have used the work of Foucault to help me interpret my experiences. I chose to do this topic for other to gain insight into the experiences of those with illness and how adult education can be used as a catalyst for change

2,5-Dioxopyrrolidin-1-yl adamantane-1-carboxyl­ate

The title compound, C15H19NO4, contains one crystallographically independent mol­ecule in the asymmetric unit. The N—O—C—O torsion angle is 1.97 (9)°. The two pairs of vicinal H atoms that lie above or below the plane defined by the five-membered pyrrolidine-2,5-dione ring are an average of 6.57 (5)° from being eclipsed. The average absolute C—C—C—C torsion angle in the adamantane skeleton, in which each fused cyclo­hexane ring is in a chair configuration, is 59.99 (5)°. The crystal packing is unremarkable

Engineering a cleavable disulfide bond into a natural product siderophore using precursor-directed biosynthesis

An analogue of the bacterial siderophore desferrioxamine B (DFOB) containing a disulfide motif in the backbone was produced from Streptomyces pilosus cultures supplemented with cystamine. Cystamine competed against native 1,5-diaminopentane during assembly. DFOB(SS)1[001] and its complexes with Fe(III) or Ga(III) were cleaved upon incubation with dithiothreitol. Compounds such as DFOB-(SS)1[001] and its thiol-containing cleavage products could expand antibiotic strategies and Au-S-based nanotechnologies

Fluorinated Analogues of Desferrioxamine B from Precursor-Directed Biosynthesis Provide New Insight into the Capacity of DesBCD

The siderophore desferrioxamine B (DFOB, 1) native to Streptomyces pilosus is biosynthesized by the DesABCD enzyme cluster. DesA-mediated decarboxylation of l-lysine gives 1,5-diaminopentane (DP) for processing by DesBCD. S. pilosus culture medium was supplemented with rac-1,4-diamino-2-fluorobutane (rac-FDB) to compete against DP to generate fluorinated analogues of DFOB, as agents of potential clinical interest. LC-MS/MS analysis identified fluorinated analogues of DFOB with one, two, or three DP units (binary notation: 0) exchanged for one (DFOA-F1[001] (2), DFOA-F1[010] (3), DFOA-F1[100] (4)), two (DFOA-F2[011] (5), DFOA-F2[110] (6), DFOA-F2[101] (7)), or three (DFOA-F3[111] (8)) rac-FDB units (binary notation: 1). The two sets of constitutional isomers 2–4 and 5–7 arose from the position of the substrates in the N-acetyl, internal, or amine-containing regions of the DFOB trimer. N-Acetylated fluorinated DFOB analogues were formed where the rac-FDB substrate was positioned in the amine region (e.g., N-Ac-DFOA-F1[001] (2a)). Other analogues contained two hydroxamic acid groups and three amide bonds. Experiments using rac-FDB, R-FDB, or S-FDB showed a similar species profile between rac-FDB and R-FDB. These data are consistent with the following. (i) DesB can act on rac-FDB. (ii) DesC can act directly on rac-FDB. (iii) The products of DesBC or DesC catalysis of rac-FDB can undergo a second round of DesC catalysis at the free amine. (iv) DesD catalysis of these products gives N,N′-diacetylated compounds. (v) A minimum of two hydroxamic acid groups is required to form a viable DesD-substrate(s) precomplex. (vi) One or more DesBCD-catalyzed steps in DFOB biosynthesis is enantioselective. This work has provided a potential path to access fluorinated analogues of DFOB and new insight into its biosynthesis

Immobilized Metal Affinity Chromatography as a Drug Discovery Platform for Metalloenzyme Inhibitors

Immobilized metal-ion affinity chromatography (IMAC) used to purify recombinant proteins features a resin-bound 1:1 Ni(II)-iminodiacetic acid (IDA) complex. This hemi-saturated Ni(II)-IDA system containing exchangeable sites at the metal ion is re-cast as a surrogate of a coordinatively-unsaturated metalloenzyme active site, with utility for selecting compounds with metal-binding groups from mixtures as potential metalloenzyme inhibitors. Exchanging Ni(II) for other metal ions could broaden the scope of metalloenzyme target. This work examined the performance of Cu(II)-, Fe(III)-, Ga(III)-, Ni(II)-, or Zn(II)-IMAC resins to reversibly bind experimental or clinical metalloenzyme inhibitors of Zn(II)-ACE1, Zn(II)-HDAC, Fe(II)/(III)-5-LO or Cu(II)-tyrosinase from a curated mixture (1-17). Each IMAC system gave a distinct selection profile. The Zn(II)-IMAC system selectively bound the thiol-containing Zn(II)-ACE1 inhibitors captopril and omapatrilat, and the Fe(III)-IMAC system selectively bound the Fe(II)/(III)-5-LO inhibitor licofelone, demonstrating a remarkable IMAC-metalloenzyme metal ion match. IMAC provides a simple, water-compatible platform, which could accelerate metalloenzyme inhibitor discovery

Reduction-cleavable desferrioxamine B pulldown system enriches Ni( ii )-superoxide dismutase from a Streptomyces proteome

Two resins with the hydroxamic acid siderophore desferrioxamine B (DFOB) immobilised as a free ligand or its Fe(iii) complex were prepared to screen the Streptomyces pilosus proteome for proteins involved in siderophore-mediated Fe(iii) uptake. The resin design included a disulfide bond to enable the release of bound proteins under mild reducing conditions. Proteomics analysis of the bound fractions did not identify proteins associated with siderophore-mediated Fe(iii) uptake, but identified nickel superoxide dismutase (NiSOD), which was enriched on the apo-DFOB-resin but not the Fe(iii)-DFOB-resin or the control resin. While DFOB is unable to sequester Fe(iii) from sites deeply buried in metalloproteins, the coordinatively unsaturated Ni(ii) ion in NiSOD is present in a surface-exposed loop region at the N-terminus, which might enable partial chelation. The results were consistent with the notion that the apo-DFOB-resin formed a ternary complex with NiSOD, which was not possible for either the coordinatively saturated Fe(iii)-DFOB-resin or the non-coordinating control resin systems. In support, ESI-TOF-MS measurements from a solution of a model Ni(ii)-SOD peptide and DFOB showed signals that correlated with a ternary Ni(ii)-SOD peptide–DFOB complex. Although any biological implications of a DFOB–NiSOD complex are unclear, the work shows that the metal coordination properties of siderophores might influence an array of metal-dependent biological processes beyond those established in iron uptake

Complexes Formed in Solution Between Vanadium(IV)/(V) and the Cyclic Dihydroxamic Acid Putrebactin or Linear Suberodihydroxamic Acid

The ability of microbial siderophores to coordinate metal ions, particularly Fe(III), continues to generate interest in the poten-tial applications of these bioligands in the environment and medicine.13 Siderophores produced by terrestrial and marin

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

Genetic Knock-Down of HDAC7 Does Not Ameliorate Disease Pathogenesis in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is an inherited, progressive neurological disorder caused by a CAG/polyglutamine repeat expansion, for which there is no effective disease modifying therapy. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression. Administration of histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) have consistently shown therapeutic potential in models of HD, at least partly through increasing the association of acetylated histones with down-regulated genes and by correcting mRNA abnormalities. The HDAC enzyme through which SAHA mediates its beneficial effects in the R6/2 mouse model of HD is not known. Therefore, we have embarked on a series of genetic studies to uncover the HDAC target that is relevant to therapeutic development for HD. HDAC7 is of interest in this context because SAHA has been shown to decrease HDAC7 expression in cell culture systems in addition to inhibiting enzyme activity. After confirming that expression levels of Hdac7 are decreased in the brains of wild type and R6/2 mice after SAHA administration, we performed a genetic cross to determine whether genetic reduction of Hdac7 would alleviate phenotypes in the R6/2 mice. We found no improvement in a number of physiological or behavioral phenotypes. Similarly, the dysregulated expression levels of a number of genes of interest were not improved suggesting that reduction in Hdac7 does not alleviate the R6/2 HD-related transcriptional dysregulation. Therefore, we conclude that the beneficial effects of HDAC inhibitors are not predominantly mediated through the inhibition of HDAC7

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer