Polycyclic- and sulfurcontaining-compounds: from polycyclic hydrocarbons to thiaspherophane

This thesis contains the examination of four, in first glance, unrelated topics. However, the overarching motivation behind these subjects are the same: The Art and Challenge of Organic Chemistry. I. The first chapter deals with the design, based on theoretical principles, and preparation of unsaturated spirocyclic compounds bearing sulfur functionalities with the aim of elucidating the charge-transport properties of such molecules on the level of single molecules. In collaboration with the Group of Professor Herre van der Zant from the Delft University of Technology preliminary conductance measurements of such spirocyclic structures could be gathered. The motivation for this joint endeavor is the prospect of using such spirocyclic structures as a molecular switch for the construction of molecular electronic devices. II. The second part shows our engagement in the long tradition among organic chemist to challenge our abilities to synthesize inspiring, complex and aesthetical pleasing structures. One such structure was identified by employing predictive computational methods by the group of Professor Jean-Louis Reymond. The structure of interest was recognized as one of the last three remaining and not yet synthesized fully-cyclic C11 isomers without strain. Encouraged by this finding, we accepted the challenge to synthesize this tetracyclic saturated hydrocarbon with the molecular formula C11H16 with the proposed trivial name of trinorbornane. III. Thirdly, Thiaspherophane: A highly symmetrical structure consisting of eight benzene rings bridged over twelve sulfur atoms describing a cuboctahedron: one of the 13 Archimedean solids. This elusive molecule, predicted over 25 years ago, bears the potential of being transformed into a cryptatium. Our efforts and progress on the synthesis of thiaspherophane will be discussed. IV. Unsymmetrical disulfides are ubiquitous in the field of chemistry and at the interface with physics, where nanotechnology emerges. In this chapter, our investigation of an efficient method for the preparation of unsymmetrical disulfides will be presented Whereby the potential of this method for the formation of functional units bearing multiple unsymmetrical disulfides was assessed with the aim of using these compounds for functionalization of gold surfaces

La recuperación de la memoria en la redefinición de la identidad: la narración como estrategia literaria en When We Were Orphans y Never Let Me Go, de Kazuo Ishiguro

In his novels, Kazuo Ishiguro uses the narrators as storytellers, both in a Benjaminian and in an Arendtian sense. He uses this literary strategy in order to connect his characters’ construction of identity to their fragmented memory, a process which allows them to recover from their phantasmal and unresolved past. The central aim of this paper is to demonstrate that Ishiguro deploys the use of the literary strategy of the narrators’ storytelling differently in his first four novels and that it plays a more active role in When We Were Orphans (2000) and Never Let Me Go (2005). In these later novels the storytelling is closer to a dynamic subject agency and is used to demonstrate the narrator’s rejection of falling into a paralyzing sense of victimization. Self-knowledge is more actively related to a process of critical understanding of the narrators’ life experiences, as in their tales they leave aside the Benjaminian apocalyptic vision of the historical experience as paralysis and enter Hanna Arendt’s domain of storytelling as action.En sus novelas, Kazuo Ishiguro utiliza la técnica de la narración, entendida desde las perspectivas de Hanna Arendt y Walter Benjamin, como una estrategia literaria que relaciona la construcción de la identidad de sus personajes con un proceso fragmentario de recuperación de los recuerdos para negociar con los fantasmas irresueltos del pasado. Sin embargo, el objetivo central de este trabajo es el de demostrar que la narración como estrategia literaria no se utiliza de la misma manera en las seis novelas del autor, ya que en When We Were Orphans (2000) y Never Let Me Go (2005) el relato en primera persona define a unos personajes que rechazan ser victimizados por su pasado. El proceso de auto-conocimiento al que se someten a través de la recuperación de sus recuerdos los define como sujetos que se enfrentan a su historia vital dejando de lado la atmósfera apocalíptica benjaminiana de la experiencia histórica entendida como parálisis y entran en los dominios de Hanna Arendt, en la narración concebida como acción y progreso hacia el futuro

The Enantiomers of Trinorbornane and Derivatives Thereof

Herein, we report the synthesis of the enantiomers of trinorbornane, a tetracyclic saturated hydrocarbon with the chemical formula C11H16. The preparation of these rigid carbon scaffolds was enabled by the successful chiral separation of its tricyclic precursor, thus allowing the enantiomers to be synthesized through a reductive radical cyclization reaction. Assignment of the absolute conformation of the enantiomers was achieved through VCD experiments. Further, we report an alternative cyclization procedure providing access to hydroxyl and phenyl sulfone functionalized trinorbornanes

Loss of penicillin tolerance by inactivating the carbon catabolite repression determinant CcpA in Streptococcus gordonii

Objectives Antibiotic tolerance is a phenomenon allowing bacteria to withstand drug-induced killing. Here, we studied a penicillin-tolerant mutant of Streptococcus gordonii (Tol1), which was shown to be deregulated in the expression of the arginine deiminase operon (arc). arc was not directly responsible for tolerance, but is controlled by the global regulator CcpA. Therefore, we sought whether CcpA might be implicated in tolerance. Methods The ccpA gene was characterized and subsequently inactivated by PCR ligation mutagenesis in both the susceptible wild-type (WT) and Tol1. The minimal inhibitory concentration and time-kill curves for the strains were determined and the outcome of penicillin treatment in experimental endocarditis assessed. Results ccpA sequence and expression were similar between the WT and Tol1 strains. In killing assays, the WT lost 3.5 ± 0.6 and 5.3 ± 0.6 log10 cfu/mL and Tol1 lost 0.4 ± 0.2 and 1.4 ± 0.9 log10 cfu/mL after 24 and 48 h of penicillin exposure, respectively. Deletion of ccpA almost totally restored Tol1 kill susceptibility (loss of 2.5 ± 0.7 and 4.9 ± 0.7 log10 cfu/mL at the same endpoints). In experimental endocarditis, penicillin treatment induced a significant reduction in vegetation bacterial densities between Tol1 (4.1 log10 cfu/g) and Tol1ΔccpA (2.4 log10 cfu/g). Restitution of ccpA re-established the tolerant phenotype both in vitro and in vivo. Conclusions CcpA, a global regulator of the carbon catabolite repression system, is implicated in penicillin tolerance both in vitro and in vivo. This links antibiotic survival to bacterial sugar metabolism. However, since ccpA sequence and expression were similar between the WT and Tol1 strains, other factors are probably involved in toleranc

Vancomycin-intermediate Staphylococcus aureus selected during vancomycin therapy of experimental endocarditis are not detected by culture-based diagnostic procedures and persist after treatment arrest

Objectives Laboratory detection of vancomycin-intermediate Staphylococcus aureus (VISA) and their heterogeneous VISA (hVISA) precursors is difficult. Thus, it is possible that vancomycin failures against supposedly vancomycin-susceptible S. aureus are due to undiagnosed VISA or hVISA. We tested this hypothesis in experimental endocarditis. Methods Rats with aortic valve infection due to the vancomycin-susceptible (MIC 2 mg/L), methicillin-resistant S. aureus M1V2 were treated for 2 days with doses of vancomycin that mimicked the pharmacokinetics seen in humans following intravenous administration of 1 g of the drug every 12 h. Half of the treated animals were killed 8 h after treatment arrest and half 3 days thereafter. Population analyses were done directly on vegetation homogenates or after one subculture in drug-free medium to mimic standard diagnostic procedures. Results Vancomycin cured 14 of 26 animals (54%; P < 0.05 versus controls) after 2 days of treatment. When vegetation homogenates were plated directly on vancomycin-containing plates, 6 of 13 rats killed 8 h after treatment arrest had positive cultures, 1 of which harboured hVISA. Likewise, 6 of 13 rats killed 3 days thereafter had positive valve cultures, 5 of which harboured hVISA. However, one subculture of vegetations in drug-free broth was enough to revert all the hVISA phenotypes to the susceptible pattern of the parent. Thus, vancomycin selected for hVISA during therapy of experimental endocarditis due to vancomycin-susceptible S. aureus. These hVISA were associated with vancomycin failure. The hVISA phenotype persisted in vivo, even after vancomycin arrest, but was missed in vitro after a single passage of the vegetation homogenate on drug-free medium. Conclusions hVISA might escape detection in clinical samples if they are subcultured before susceptibility test

Evaluation of a new serological test for the detection of anti-Coxiella and anti-Rickettsia antibodies.

Coxiella burnetii and members of the genus Rickettsia are obligate intracellular bacteria. Since cultivation of these organisms requires dedicated techniques, their diagnosis usually relies on serological or molecular biology methods. Immunofluorescence is considered the gold standard to detect antibody-reactivity towards these organisms. Here, we assessed the performance of a new automated epifluorescence immunoassay (InoDiag) to detect IgM and IgG against C. burnetii, Rickettsia typhi and Rickettsia conorii. Samples were tested with the InoDiag assay. A total of 213 sera were tested, of which 63 samples from Q fever, 20 from spotted fever rickettsiosis, 6 from murine typhus and 124 controls. InoDiag results were compared to micro-immunofluorescence. For acute Q fever, the sensitivity of phase 2 IgG was only of 30% with a cutoff of 1 arbitrary unit (AU). In patients with acute Q fever with positive IF IgM, sensitivity reached 83% with the same cutoff. Sensitivity for chronic Q fever was 100% whereas sensitivity for past Q fever was 65%. Sensitivity for spotted Mediterranean fever and murine typhus were 91% and 100%, respectively. Both assays exhibited a good specificity in control groups, ranging from 79% in sera from patients with unrelated diseases or EBV positivity to 100% in sera from healthy patients. In conclusion, the InoDiag assay exhibits an excellent performance for the diagnosis of chronic Q fever but a very low IgG sensitivity for acute Q fever likely due to low reactivity of phase 2 antigens present on the glass slide. This defect is partially compensated by the detection of IgM. Because it exhibits a good negative predictive value, the InoDiag assay is valuable to rule out a chronic Q fever. For the diagnosis of rickettsial diseases, the sensitivity of the InoDiag method is similar to conventional immunofluorescence