First-in-Class Inhibitors of Sulfur Metabolism with Bactericidal Activity against Non-Replicating M-tuberculosis

Development of effective therapies to eradicate persistent, slowly replicating M. tuberculosis (Mtb) represents a significant challenge to controlling the global TB epidemic. To develop such therapies, it is imperative to translate information from metabolome and proteome adaptations of persistent Mtb into the drug discovery screening platforms. To this end, reductive sulfur metabolism is genetically and pharmacologically implicated in survival, pathogenesis, and redox homeostasis of persistent Mtb. Therefore, inhibitors of this pathway are expected to serve as powerful tools in its preclinical and clinical validation as a therapeutic target for eradicating persisters. Here, we establish a first functional HTS platform for identification of APS reductase (APSR) inhibitors, a critical enzyme in the assimilation of sulfate for the biosynthesis of cysteine and other essential sulfur-containing molecules. Our HTS campaign involving 38?350 compounds led to the discovery of three distinct structural classes of APSR inhibitors. A class of bioactive compounds with known pharmacology displayed potent bactericidal activity in wild-type Mtb as well as MDR and XDR clinical isolates. Top compounds showed markedly diminished potency in a conditional Delta APSR mutant, which could be restored by complementation with Mtb APSR. Furthermore, ITC studies on representative compounds provided evidence for direct engagement of the APSR target. Finally, potent APSR inhibitors significantly decreased the cellular levels of key reduced sulfur-containing metabolites and also induced an oxidative shift in mycothiol redox potential of live Mtb, thus providing functional validation of our screening data. In summary, we have identified first-in-class inhibitors of APSR that can serve as molecular probes in unraveling the links between Mtb persistence, antibiotic tolerance, and sulfate assimilation, in addition to their potential therapeutic value.

Report of the 2005 Workshop on Ocean Ecodynamics Comparison in the Subarctic Pacific

I. Scientific Issues Posed by OECOS II. Participant Contributions to the OECOS Workshop A. ASPECTS OF PHYTOPLANKTON ECOLOGY IN THE SUBARCTIC PACIFIC Microbial community compositions by Karen E. Selph Subarctic Pacific lower trophic interactions: Production-based grazing rates and grazing-corrected production rates by Nicholas Welschmeyer Phytoplankton bloom dynamics and their physiological status in the western subarctic Pacific by Ken Furuya Temporal and spatial variability of phytoplankton biomass and productivity in the northwestern Pacific by Sei-ichi Saitoh, Suguru Okamoto, Hiroki Takemura and Kosei Sasaoka The use of molecular indicators of phytoplankton iron limitation by Deana Erdner B. IRON CONCENTRATION AND CHEMICAL SPECIATION Iron measurements during OECOS by Zanna Chase and Jay Cullen 25 The measurement of iron, nutrients and other chemical components in the northwestern North Pacific Ocean by Kenshi Kuma The measurement of iron, nutrients and other chemical components in the northwestern North Pacific Ocean by Kenshi Kuma C. PHYSICAL OCEANOGRAPHY, FINE-SCALE DISTRIBUTION PATTERNS AND AUTONOMOUS DRIFTERS The use of drifters in Lagrangian experiments: Positives, negatives and what can really be measured by Peter Strutton The interaction between plankton distribution patterns and vertical and horizontal physical processes in the eastern subarctic North Pacific by Timothy J. Cowles D. MICROZOOPLANKTON Microzooplankton processes in oceanic waters of the eastern subarctic Pacific: Project OECOS by Suzanne Strom Functional role of microzooplankton in the pelagic marine ecosystem during phytoplankton blooms in the western subarctic Pacific by Takashi Ota and Akiyoshi Shinada E. MESOZOOPLANKTON Vertical zonation of mesozooplankton, and its variability in response to food availability, density stratification, and turbulence by David L. Mackas and Moira Galbraith Marine ecosystem characteristics and seasonal abundance of dominant calanoid copepods in the Oyashio region by Atsushi Yamaguchi, Tsutomu Ikeda and Naonobu Shiga OECOS: Proposed mesozooplankton research in the Oyashio region, western subarctic Pacific by Tsutomu Ikeda Some background on Neocalanus feeding by Michael Dagg Size and growth of interzonally migrating copepods by Charles B. Miller Growth of large interzonal migrating copepods by Toru Kobari F. MODELING Ecosystem and population dynamics modeling by Harold P. Batchelder III. Reports from Workshop Breakout Groups A. PHYSICAL AND CHEMICAL ASPECTS WITH EMPHASIS ON IRON AND IRON SPECIATION B. PHYTOPLANKTON/MICROZOOPLANKTON STUDIES C. MESOZOOPLANKTON STUDIES IV. Issues arising during the workshop A. PHYTOPLANKTON STOCK VARIATIONS IN HNLC SYSTEMS AND TROPHIC CASCADES IN THE NANO AND MICRO REGIMES B. DIFFERENCES BETWEEN EAST AND WEST IN SITE SELECTION FOR OECOS TIME SERIES C. TIMING OF OECOS EXPEDITIONS D. CHARACTERIZATION OF PHYSICAL OCEANOGRAPHY V. Concluding Remarks VI. References (109 page document)

Submarine landslides : selected studies in the U.S. Exclusive Economic Zone

Submarine Landslides: An Introduction 1 By RIo Lee, W.C. Schwab, and J.S. Booth U.S. Atlantic Continental Slope Landslides: Their Distribution, General Anributes, and Implications 14 By J.S. Booth, D.W. O'Leary, Peter Popenoe, and W.W. Danforth Submarine Mass Movement, a Formative Process of Passive Continental Margins: The Munson-Nygren Landslide Complex and the Southeast New England Landslide Complex 23 By D.W. O'Leary The Cape Fear Landslide: Slope Failure Associated with Salt Diapirism and Gas Hydrate Decomposition 40 By Peter Popenoe, E.A. Schmuck, and W.P. Dillon Ancient Crustal Fractures Control the Location and Size of Collapsed Blocks at the Blake Escarpment, East of Florida 54 By W.P. Dillon, J.S. Risch, K.M. Scanlon, P.C. Valentine, and Q.J. Huggett Tectonic and Stratigraphic Control on a Giant Submarine Slope Failure: Puerto Rico Insular Slope 60 By W.C. Schwab, W.W. Danforth, and K.M. Scanlon Slope Failure of Carbonate Sediment on the West Florida Slope 69 By D.C. Twichell, P.C. Valentine, and L.M. Parson Slope Failures in an Area of High Sedimentation Rate: Offshore Mississippi River Delta 79 By J.M. Coleman, D.B. Prior, L.E. Garrison, and H.J. Lee Salt Tectonics and Slope Failure in an Area of Salt Domes in the Northwestern Gulf of Mexico 92 By B.A. McGregor, R.G. Rothwell, N.H. Kenyon, and D.C. Twichell Slope Stability in Regions 01 Sea-Floor Gas Hydrate: Beaufort Sea Continental Slope 97 By R.E. Kayen and H.J. Lee Mass Movement Related to Large Submarine Canyons Along the Beringian Margin, Alaska 104 By P.R. Carlson, H.A. Karl, B.D. Edwards, J.V. Gardner, and R. Hall Comparison of Tectonic and Stratigraphic Control of Submarine Landslides on the Kodiak Upper Continental Slope, Alaska 117 By M.A. Hampton Submarine Landslides That Had a Significant Impact on Man and His Activities: Seward and Valdez, Alaska 123 By M.A. Hampton, R.W. Lemke, and H.W. Coulter Processes Controlling the Style of Mass Movement in Glaciomarine Sediment: Northeastern Gulf of Alaska 135 By W.C. Schwab and H.J. Lee Contents V VI Contents Liquefaction of Continental Shelf Sediment: The Northern California Earthquake of 1980 143 By M.E. Field A Submarine Landslide Associated with Shallow Sea-Floor Gas and Gas Hydrates off Northern California 151 By M.E. Field and J.H. Barber, Jr. Sur Submarine Landslide, a Deep-Water Sediment Slope Failure 158 By C.E. Gutmacher and W.R. Normark Seismically Induced Mudflow in Santa Barbara Basin, California 167 By B.D. Edwards, H.J. Lee, and M.E. Field Submarine Landslides in a Basin and Ridge Setting, Southern California 176 By M.E. Field and B.D. Edwards Giant Volcano-Related Landslides and the Development of the Hawaiian Islands 184 By W.R. Normark, J.G. Moore, and M.E. Torresan Submarine Slope Failures Initiated by Hurricane Iwa, Kahe Point, Oahu, Hawaii 197 By W.R. Normark, Pat Wilde, J.F. Campbell, T.E. Chase, and Bruce Tsutsui (PDF contains 210 pages)

Report on estimating the size of dolphin schools, based on data obtained during a charter cruise of the M/V Gina Anne, October 11 -November 25, 1979

Estimates of dolphin school sizes made by observers and crew members aboard tuna seiners or by observers on ship or aerial surveys are important components of population estimates of dolphins which are involved in the yellowfin tuna fishery in the eastern Pacific. Differences in past estimates made from tuna seiners and research ships and aircraft have been noted by Brazier (1978). To compare various methods of estimating dolphin school sizes a research cruise was undertaken with the following major objectives: 1) compare estimates made by observers aboard a tuna seiner and in the ship's helicopter, from aerial photographs, and from counts made at the backdown channel, 2) compare estimates of observers who are told the count of the school size after making their estimate to the observer who is not aware of the count to determine if observers can learn to estimate more accurately, and 3) obtain movie and still photographs of dolphin schools of known size at various stages of chase, capture and release to be used for observer training. The secondary objectives of the cruise were to: 1) obtain life history specimens and data from any dolphins that were killed incidental to purse seining. These specimens and data were to be analyzed by the U.S. National Marine Fisheries Service ( NMFS ) , 2) record evasion tactics of dolphin schools by observing them from the helicopter while the seiner approached the school, 3) examine alternative methods for estimating the distance and bearing of schools where they were first sighted, 4) collect the Commission's standard cetacean sighting, set log and daily activity data and expendable bathythermograph data. (PDF contains 31 pages.)

Protecting a threatened coastal fish species through regional collaboration

Rainbow smelt (Osmerus mordax) are small anadromous fish that live in nearshore coastal waters during much of the year and migrate to tidal rivers to spawn during the spring. They are a key prey species in marine food webs, as they are consumed by larger organisms such as striped bass, bluefish, and seabirds. In addition, smelt are valued culturally and economically, as they support important recreational and commercial fisheries. The Atlantic Coast range of rainbow smelt has been contracting in recent decades. Historically, populations extended from the Delaware River to eastern Labrador and the Gulf of St. Lawrence (Buckley 1989). More recent observations indicate that rainbow smelt spawning populations have been extirpated south of Long Island Sound, and evidence of spawning activity is extremely limited between Long Island and Cape Cod, MA. In the Gulf of Maine region, spawning runs are still observed, but monitoring surveys as well as commercial and recreational catches indicate that these populations have also declined (e.g., Chase and Childs 2001). Many diverse factors could drive the recently noted declines in rainbow smelt populations, including spawning habitat conditions, fish health, marine environmental conditions, and fishing pressure. Few studies have assessed any of these potential threats or their joint implications. In 2004, the National Marine Fisheries Service (NMFS) listed rainbow smelt as a species of concern. Subsequently, the states of Maine, New Hampshire, and Massachusetts were awarded a grant through NMFS’s Proactive Conservation Program to gather new information on the status of rainbow smelt, identify factors that affect spawning populations, and develop a multi-state conservation program. This paper provides an overview of this collaborative project, highlighting key biological monitoring and threats assessment research that is being conducted throughout the Gulf of Maine. (PDF contains 4 pages)

Modelagem computacional aplicada na estimação de parâmetros cinéticos em processos químicos e cromatográficos

A estimação de parâmetros cinéticos em processos químicos e cromatográficos utilizando técnicas numéricas assistidas por computadores tem conduzido para melhoria da eficiência e o favorecimento da compreensão das fenomenologias envolvidas nos mesmos. Na primeira parte deste trabalho será realizada a modelagem computacional do processo de produção de biodiesel via esterificação, sendo que, o método de otimização estocástica Random Restricted Window (R2W) será correlacionado com os dados experimentais da produção de biodiesel a partir da esterificação do ácido láurico com etanol anidro na presença do catalisador ácido nióbico (Nb2O5). Na segunda parte do mesmo será realizada a modelagem computacional do processo de cromatografia de adsorção (batch process) onde serão correlacionados os dados provenientes dos modelos cinéticos de HASHIM, CHASE e IKM2 com os dados experimentais da adsorção de amoxicilina com quitosana, e também serão correlacionados os dados experimentais da adsorção de Bovine Serum Albumin (BSA) com Streamline DEAE com os dados provenientes de uma nova aplicação do método R2W mediante a implementação de um modelo cinético reversível. Ademais, as constantes cinéticas para cada processo supracitado serão estimadas levando em consideração o valor mínimo da função resíduos quadrados.