The Application of Metallated Enamines to the Synthesis of Morphine Alkaloids

Metallated enamines have been used to prepare a number of morphine-based analgesics, including efficient entry to the 4a-phenylisoquinolines and morphinans. Stereocontrolled formation of both cis and trans-fused perhydroisoquinolines has been accomplished by either kinetic or thermodynamic protonation of the corresponding octahydroisoquinoline. Reaction of 4a-phenyloctahydroisoquinolinium perchlorates with diazomethane afforded the expected aziridinium perchlorate with a component of direct cyclization to the morphinan structure also observed. Kornbloom oxidation to the α-amino-aldehyde was accomplished on treatment of the aziridinium salts with dimethyl-sulfoxide. The aldehydes were cyclized to the morphinan structure on reaction with boron trifluoride etherate, providing ready access to intermediates used by Gates in his pioneering total synthesis of morphine.</p

Cardiomyopathy Secondary to Thyroid and Parathyroid Dysfunction: Case Report and Literature Review

Heart failure due to metabolic derangements is not common in clinical practice. However, outcome is usually positive given that the precipitating factor is recognized and treatment is initiated in a timely fashion. We report an unusual case of reduced left ventricular systolic function as a result of hypocalcemia and long standing untreated primary hypothyroidism in a patient without structural heart disease. Delay in seeking appropriate medical attention for both disorders has culminated in cardiac dysfunction that was favorably altered with correction of underlying etiologies. Therefore, early recognition and expedient management of hypocalcemia and hypothyroidism can result in an imminent improvement of cardiac function

EEV CCD39 wavefront sensor cameras for AO and interferometry

SciMeasure, in collaboration with Emory University and the Jet Propulsion Laboratory (JPL), has developed an extremely versatile CCD controller for use in adaptive optics, optical interferometry, and other applications requiring high-speed readout rates and/or low read noise. The overall architecture of this controller system will be discussed and its performance using both EEV CCD39 and MIT/LL CCID-19 detectors will be presented. Initially developed for adaptive optics applications, this controller is used in the Palomar Adaptive Optics program (PALAO), the AO system developed by JPL for the 200' Hale telescope at Palomar Mountain. An overview of the PALAO system is discussed and diffraction-limited science results will be shown. Recently modified under NASA SBIR Phase II funding for use in the Space Interferometry Mission testbeds, this controller is currently in use on the Micro- Arcsecond Metrology testbed at JPL. Details of a new vacuum- compatible remote CCD enclosure and specialized readout sequence programming will also be presented

Design, Synthesis, and Evaluation of Hydroxamic Acid-Based Molecular Probes for In Vivo Imaging of Histone Deacetylase (HDAC) in Brain

Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging.Chemistry and Chemical Biolog

HIV Testing and Epidemiology in a Hospital-Based Surgical Cohort in Malawi

Despite the high prevalence of HIV in adults (11 %) in Malawi, testing among surgical patients is not routine. We examined the feasibility of universal opt-out HIV testing and counseling (HTC) on the surgical wards of Kamuzu Central Hospital in Lilongwe, Malawi, and sought to further delineate the role of HIV in surgical presentation and outcome

EEV CCD39 wavefront sensor cameras for AO and interferometry

SciMeasure, in collaboration with Emory University and the Jet Propulsion Laboratory (JPL), has developed an extremely versatile CCD controller for use in adaptive optics, optical interferometry, and other applications requiring high-speed readout rates and/or low read noise. The overall architecture of this controller system will be discussed and its performance using both EEV CCD39 and MIT/LL CCID-19 detectors will be presented. Initially developed for adaptive optics applications, this controller is used in the Palomar Adaptive Optics program (PALAO), the AO system developed by JPL for the 200' Hale telescope at Palomar Mountain. An overview of the PALAO system is discussed and diffraction-limited science results will be shown. Recently modified under NASA SBIR Phase II funding for use in the Space Interferometry Mission testbeds, this controller is currently in use on the Micro- Arcsecond Metrology testbed at JPL. Details of a new vacuum- compatible remote CCD enclosure and specialized readout sequence programming will also be presented

Original Article Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain

Abstract: Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging

Broad Down, Devon: archaeological and other stories

publication-status: PublishedThis is a post-print, author-produced version of an article accepted for publication Journal of Material Culture, 2010, Vol. 15, Issue 3, pp. 345 - 367. Copyright © 2010 SAGE Publications. The definitive publisher-authenticated version is available online at http://mcu.sagepub.com/content/15/3/345.shortThis article explores the knowledge construction process of an archaeological site in East Devon, UK. Bouncing off an oral historical account of the site that seems to run against scientific truth claims, the author investigates the story of how knowledge of the site has developed over the last two centuries. Building on previous work that explores the history and practice of archaeology, the article opens up questions of what counts as evidence. Then, taking a cue from more recent work that suggests a more dynamic and open-ended engagement with the landscape, the article turns to examine how the meaning of a site can be made and remade. As part of this endeavour, questions of what as well as who can ‘speak’ are examined and some space is opened up for the agency of ‘minor figures’, both human and non-human

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Comparison of reactions for the production of 258,257Db: 208Pb(51V,xn) and 209Bi(50Ti,xn)

Excitation functions for the 1n and 2n exit channels of the 208Pb(51V,xn)259-xDb reaction were measured. A maximum cross section of the 1n exit channel of 2070+1100/-760 pb was measured at an excitation energy of 16.0 +- 1.8 MeV. For the 2n exit channel, a maximum cross section of 1660+450/-370 pb was measured at 22.0 +- 1.8 MeV excitation energy. The 1n excitation function for the 209Bi(50Ti,n)258Db reaction was remeasured, resulting in a cross section of 5480+1750/-1370 pb at an excitation energy of 16.0 +- 1.6 MeV, in agreement with previous values [F. P. Hebberger, et al., Eur. Phys. J. A 12, 57 (2001)]. Differences in cross section maxima are discussed in terms of the fusion probability below the barrier