Approaches to the synthesis of peptide substituted frameworks

The 1,3 dipolar cycloaddition between carbonyl ylids (generated from cyclobutene epoxides flanked by esters) and norbornyl alkenes – the ACE reaction – offers a facile method for the construction of polynorbornyl molecular frameworks. This reaction has, as described in this dissertation, underpinned the construction of molecular frameworks that have peptides and amino acids attached. Such highly rigid peptide-frameworks are of use in the field of peptidomimetics; the template molecule governs the final positioning of any attached groups such that a precise arrangement of amino acids can be achieved without the need to construct entire proteins. In the course of any ACE reaction the ester flanked cyclobutene epoxide is transformed to a 1,3 dipole, the esters serve to stablise this reactive intermediate and are as a consequence incorporated in the reaction product. Modification of these esters provides pseudo-equatorial points for peptide attachment. These methyl esters were replaced with tert-butyl esters to provide pseudo-axial attachment points that could be selectively addressed. The optimal strategy for peptide-framework construction involved direct condensation of carboxyl protected amino acids to bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid as well as condensation of amino acids to cyclobutene epoxides derived from this acid. The ACE reaction of (±) bicycloheptene-2-endo-carboxylic acid derivatives with cyclobutene epoxides synthesised from such racemic acid derivatives provided a mixture of enantiomers and meso compounds. In order to control the position of the attachment points – and hence the final location of the attached peptides – the ACE reaction required chiral starting materials. Accordingly, all peptidoframeworks were derived from the chiral (2S)-(-)-bicycloheptene carboxylic acid. The ACE reaction of this (S)-norbornene with the (S)-epoxide provided a peptide framework in which the attached amino acids were positioned pseudo-axially. Deprotection of the amino acid allowed peptide chain building in the pseudo-axial direction. Using this strategy a framework with an alanine residue and a triglycine peptide was synthesised. By combining this strategy with the ter-butyl ester variant a framework with pseudo-axial alanine and pseudo-equatorial glycine residues was manufactured

Friedrich Sieburg, a twentieth-century German francophile

Friedrich Sieburg achieved renown as a German literary critic in the years following World War II. His career in journalism and diplomacy prior to 1945, largely ignored in the 1950s and 1960s, has come under a new scrutiny since 1980. The connection between Sieburg\u27s writings, many of which dealt with France, and his work with the German Foreign Office in wartime Paris has been a particular object of this scrutiny. The study Friedrich Sieburg. A Twentieth-Century German Francophile builds on the work of Joachim Fest, Margot Taureck and others, and argues that Sieburg was a romantic nationalist who became a National Socialist. He constructed a theory, from elements in the German literary tradition, which posited French form in opposition to German mass. This theory makes intelligible his praise of the German 1933 as a national awakening and as the workings of a mythic destiny. Journalism and diplomacy served Sieburg\u27s historic role as national publicist. After 1945, Sieburg was generally silent about the Hitler regime; his was a common response in a nation unwilling to assess its past. Attached to this study is a translation of the greater part of the memoir of Paris, Our Most Beautiful Years, which Sieburg published in 1950

The core collapse supernova rate in the sdss-ii supernova survey

The Sloan Digital Sky Survey II Supernova Survey (SDSS-II SN), though designed as a type Ia supernova search for cosmology, also discovered a large sample of core collapse supernovae (CCSN). I use the SDSS-II SN data to measure the volumetric CCSN rate in the redshift range (0.03 \u3c z \u3c 0.09), finding a volume-averaged rate of 0.98±0.18 ×10⊃−4⊃h⊂70⊂⊃3⊃yr⊃−1⊃Mpc⊃−3⊃. The CCSN luminosity function is also extracted from the data, and its implications on the cosmic star formation history are considered

INCREASED STRIATAL VULNERABILITY TO 3-NITROPROPIONIC ACID IN MALE, BUT NOT FEMALE, MICE LACKING INTERLEUKIN-1R1

Interleukin-1β (IL-1β), classically considered as a pro-inflammatory cytokine, has proven essential to cellular defense in nearly all tissues (Kaur et al., 2014, Ren and Torres, 2009). In brain, studies suggest that IL-1β has pleiotrophic effects. It acts as a neuromodulator, has been implicated in the pathogenic processes associated with a number of CNS diseases, but has also been shown to provide protection to the injured CNS. With respect to the latter, IL-1β signalling appears to mitigate pathology and motor symptoms in a mouse model of Huntington’s disease (HD), a progressive neurodegenerative condition that targets the striatum. Specifically, HD mice bred onto an IL-1R1 null background demonstrate greater pathological striatal HTT aggregation that coincides with increased severity of motor symptoms (Wang et al., 2010). Of interest for this thesis, mitochondrial dysfunction and subsequent reactive oxygen species (ROS) generation appear to precipitate neuropathology in HD (Emerit et al., 2004). Also of interest, is research from this laboratory demonstrating that IL-1β can protect neural cells against oxidant-induced injury (He et al., 2015) (Chowdhury, unpublished observations). Thus, in this thesis, I explored whether IL-1β signalling could protect against oxidative stress-generated brain damage in vivo by employing a chemical model of HD. Toward this end, both male and female mice (16-18 wks) that were either null or wild-type for the IL-1β signalling receptor, IL-1R1, were treated systemically with 3-nitropropionic acid (3-NP), a phyto/fungal mitochondrial toxin (Pedraza-Chaverrí et al., 2009), for a total cumulative dose of 920mg/kg. Comparisons of the histological striatal injury and extent of behavioral symptomatology were made. Motor symptoms —including reduced general locomotor activity, hind limb and truncal dystonia, and postural instability —increased progressively with increasing days of dosage with 3-NP, in both sexes regardless of genotype, demonstrating no observable difference in response during treatment. Despite this, histological analysis of the striatum, measured over seven levels ranging from +1.22 to -0.18 from bregma, revealed that IL-1R1 null male, but not female, mice had a greater incidence of striatal lesions that were also larger in size compared to their wild-type littermate controls. These results indicate that endogenous IL-1β signalling mitigated 3-NP induced structural, but not functional, striatal injury in male but not female mice