Chemical Probes for the Treatment of Castration-Resistant Prostate Cancer and Necrotizing Enterocolitis

This thesis describes the synthesis of several small molecules, structurally related to SID3712502, which have shown promise as inhibitors of castration-resistant prostate cancer by preventing nuclear translocation of the androgen receptor. This thesis also describes the preparation of a small library of α- and β-glycoslyated analogs of N-acetylglucosamine and N-acetylgalactosamine, which were prepared from an oxazoline intermediate or by an acid catalyzed isomerization with the desired glycosyl acceptors. The configuration of the lead compound, C34, was confirmed by synthesis and NMR studies. Four glucosamine analogs and two galactosamine analogs showed promising in vitro anti-inflammatory effects. These analogs were shown to be probes for reducing cytokine over-expression through inhibition of TLR4 and able to reduce the gross disease of necrotizing enterocolitis

Proper Motion Dispersions of Red Clump Giants in the Galactic Bulge: Observations and Model Comparisons

Red clump giants in the Galactic bulge are approximate standard candles and hence they can be used as distance indicators. We compute the proper motion dispersions of RCG stars in the Galactic bulge using the proper motion catalogue from the second phase of the Optical Gravitational Microlensing Experiment (OGLE-II, Sumi et al. 2004) for 45 fields. The proper motion dispersions are measured to a few per cent accuracy due to the large number of stars in the fields. The observational sample is comprised of 577736 stars. These observed data are compared to a state-of-the-art particle simulation of the Galactic bulge region. The predictions are in rough agreement with observations, but appear to be too anisotropic in the velocity ellipsoid. We note that there is significant field-to-field variation in the observed proper motion dispersions. This could either be a real feature, or due to some unknown systematic effect.Comment: 12 pages, 13 figures, accepted for publication in MNRA

Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Film VerORTen: Film als Forschungs- und Kommunikationsmedium in der Geographie

In this “positioning” we discuss current developments, possibilities and challenges around working with film in and for geography. We describe possibilities that certain conscious and collaborative ways of employing film offer: They point beyond film analysis and are more than a mere add-on to communicate research results, but rather can stimulate new forms of reflexivity and creativity along different steps of research and teaching processes. We further show how the emergence of new digital and physical platforms can enable and support exchange on film and other digital media, using the example of our new media laboratory (mLab) at the University of Bern

Social regulation of ageing by young workers in the honey bee, Apis mellifera

Organisms' lifespans are modulated by both genetic and environmental factors. The lifespan of eusocial insects is determined by features of the division of labor, which itself is influenced by social regulatory mechanisms. In the honey bee, Apis mellifera, the presence of brood and of old workers carrying out foraging tasks are important social drivers of ageing, but the influence of young adult workers is unknown, as it has not been experimentally teased apart from that of brood. In this study, we test the role of young workers in the ageing of their nestmates. We measured the impact of different social contexts characterized by the absence of brood and/or young adults on the lifespan of worker nestmates in field colonies. To acquire insight into the physiological processes occurring under these contexts, we analyzed the expression of genes known to affect honey bee ageing. The data showed that young workers significantly reduced the lifespan of nestmate workers, similar to the effect of brood on its own. Differential expression of vitellogenin, major royal jelly protein-1, and methylase transferase, but not methyl farneosate epoxidase genes suggests that young workers and brood influence ageing of adult nestmate workers via different physiological pathways. We identify young workers as an essential part of the social regulation of ageing in honey bee colonies

A Laboratory Word Memory Test Analogue Differentiates Intentional Feigning from True Responding Using the P300 Event-Related Potential

Symptom exaggeration and feigned cognitive impairment occur commonly in forensic and medicolegal evaluations. As a result, methods to detect feigned cognitive impairment are an indispensable component of neuropsychological assessments. This study reports the results of two neurophysiological experiments using a forced-choice recognition task built from the stimuli of the Word Memory Test and Medical Symptom Validity Test as well as a new linguistically informed stimulus set. Participant volunteers were instructed either to do their best or to feign cognitive impairment consistent with a mild traumatic brain injury while their brain activity was monitored using event-related potentials (ERP). Experiment 1 varied instructions across individuals, whereas Experiment 2 varied instructions within individuals. The target brain component was a positive deflection indicating stimulus recognition that occurs approximately 300 ms after exposure to a stimulus (i.e., the P300). Multimodal comparison (P300 amplitude to behavioral accuracy) allowed the detection of feigned cognitive impairment. Results indicate that, for correct responses, P300s were equivalent for the simulated malingering and good effort conditions. However, for incorrect responses, feigned impairment produced reliable but significantly reduced P300 amplitudes. Although the P300 is an automatic index of recognition—even when knowledge is hidden—its amplitude appears capable of modulation by feigning strategies. Implications of this finding are discussed for research and clinical applications