Asymmetric Chemical Synthesis of (R)- and (S)-Citramalate in High Enantiomeric Purity

Both enantiomers of dimethyl 2-acety1citramalate have been asymmetrically synthesized in over 96% enantiomeric excess and good overall chemical yield (500/0)from 2-keto-1,3-oxathianes 1a, and 1b

Chemical probes for methyl lysine reader domains

The primary intent of a chemical probe is to establish the relationship between a molecular target, usually a protein whose function is modulated by the probe, and the biological consequences of that modulation. In order to fulfill this purpose, a chemical probe must be profiled for selectivity, mechanism of action, and cellular activity, as the cell is the minimal system in which ‘biology’ can be explored. This review provides a brief overview of progress toward chemical probes for methyl lysine reader domains with a focus on recent progress targeting chromodomains

Peptide Technologies in the Development of Chemical Tools for Chromatin‐Associated Machinery

Discerning a mechanistic understanding of the cause‐and‐effect relationships between chromatin post‐translational modifications (PTMs) and DNA accessibility for replication, transcription, and repair is an elusive goal being pursued using molecular and cellular biology, biochemistry, and more recently chemical inhibition. Chemical intervention of the chromatin‐associated complexes that regulate PTM maintenance and chromatin structure faces numerous challenges due to the broad surface‐groove interactions between many of these proteins and histones; yet, the increasing interest in understanding chromatin‐modifying complexes suggests tractable lead compounds will be critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains. Peptides and peptidomimetics afford several advantages to efficient inhibitor development including a rational starting point, modular assembly, and retention of secondary structure. Numerous peptide technologies have been employed in the chromatin field to characterize substrate interactions, evaluate ligand selectivity, and optimize potent peptidomimetic inhibitors. We describe the progress and advantages of these efforts, and provide a perspective on their implications for future chemical probe and drug discovery efforts. Drug Dev Res 78 : 300–312, 2017. © 2017 Wiley Periodicals, Inc

Real-time tomography mooring

A real-time tomography system has been developed which combines ocean acoustic tomography with satellite-based time keeping and satellite telemetry. The basis of the system is the acoustic tomography transceiver and its associated acoustic navigation grid. To this basic system, a link to the surface has been added to provide a pathway for telemetry of the tomographic data to shore and a downlink for satellite-derived time which is used to correct the transceiver's clock. The surface buoy contains a GPS receiver, clock comparator, system controller and multiple ID Argos transmitters. Processed tomography signals, transceiver location data time, time drift and surface buoy engineering data are transmitted to satellite using a total of 32 data buffers transmitted every eight minutes. The report describes the real-time tomography system in detail, with particular emphasis on the modifications implemented to convert the standard tomography instrument to a real-time oceanographic tool.Funding was provided by the Office of Naval Technology under Contract No. N000-14-C-90-0098

Pharmacometabolomics reveals racial differences in response to atenolol treatment.

Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug

A Web 2.0 and OGC Standards Enabled Sensor Web Architecture for Global Earth Observing System of Systems

This paper will describe the progress of a 3 year research award from the NASA Earth Science Technology Office (ESTO) that began October 1, 2006, in response to a NASA Announcement of Research Opportunity on the topic of sensor webs. The key goal of this research is to prototype an interoperable sensor architecture that will enable interoperability between a heterogeneous set of space-based, Unmanned Aerial System (UAS)-based and ground based sensors. Among the key capabilities being pursued is the ability to automatically discover and task the sensors via the Internet and to automatically discover and assemble the necessary science processing algorithms into workflows in order to transform the sensor data into valuable science products. Our first set of sensor web demonstrations will prototype science products useful in managing wildfires and will use such assets as the Earth Observing 1 spacecraft, managed out of NASA/GSFC, a UASbased instrument, managed out of Ames and some automated ground weather stations, managed by the Forest Service. Also, we are collaborating with some of the other ESTO awardees to expand this demonstration and create synergy between our research efforts. Finally, we are making use of Open Geospatial Consortium (OGC) Sensor Web Enablement (SWE) suite of standards and some Web 2.0 capabilities to Beverage emerging technologies and standards. This research will demonstrate and validate a path for rapid, low cost sensor integration, which is not tied to a particular system, and thus be able to absorb new assets in an easily evolvable, coordinated manner. This in turn will help to facilitate the United States contribution to the Global Earth Observation System of Systems (GEOSS), as agreed by the U.S. and 60 other countries at the third Earth Observation Summit held in February of 2005

Effects of hypophysectomy and thyroidectomy on salt balance in the plethodontid salamanders, Desmognathus fuscus and Desmognathus monticola

Hypophysectomy significantly reduced serum sodium levels in Desmognathus fuscus and D. monticola . Prolactin, corticosterone or aldosterone replacement failed to restore serum sodium to control levels. Hypophysectomy also led to decreases in in vitro integumental potential difference and shortcircuit current, which were not restored to control levels by prolactin or corticosterone. Thyroidectomy significantly reduced the level of serum sodium in D. monticola , but it increased in vitro potential difference and short-circuit current. Thyroxine treatment of either hypophysectomized or thyroidectomized D. monticola completely restored serum sodium, potential difference and short-circuite current to control levels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47122/1/360_2004_Article_BF00799050.pd

TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaque

Acute coronary syndromes (ACS) are precipitated by a rupture of the atherosclerotic plaque, often at the site of T cell and macrophage infiltration. Here, we show that plaque-infiltrating CD4 T cells effectively kill vascular smooth muscle cells (VSMC). VSMCs sensitive to T cell–mediated killing express the death receptor DR5 (TNF-related apoptosis-inducing ligand [TRAIL] receptor 2), and anti-TRAIL and anti-DR5 antibodies block T cell–mediated apoptosis. CD4 T cells that express TRAIL upon stimulation are expanded in patients with ACS and more effectively induce VSMC apoptosis. Adoptive transfer of plaque-derived CD4 T cells into immunodeficient mice that are engrafted with human atherosclerotic plaque results in apoptosis of VSMCs, which was prevented by coadministration of anti-TRAIL antibody. These data identify that the death pathway is triggered by TRAIL-producing CD4 T cells as a direct mechanism of VSMC apoptosis, a process which may lead to plaque destabilization

Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds

Epigenetic alterations relate to various human diseases, and developing inhibitors of Kme regulatory proteins is considered to be a new frontier for drug discovery. We were inspired by the known multicyclic ligands, UNC669 and UNC926, which are the first reported small molecule ligands for a methyl-lysine binding domain. We hypothesized that reducing the conformational flexibility of the key amine moiety of UNC669 would result in a unique set of ligands. Twenty-five novel compounds containing a fused bi- or tricyclic amine or a spirocyclic amine were designed and synthesized. To gauge the potential of these amine-containing compounds to interact with Kme regulatory proteins, the compounds were screened against a panel of 24 protein methyltransferases. Compound 13 was discovered as a novel scaffold that interacts with SETD8 and could serve as a starting point for the future development of PKMT inhibitors