9 CFR 93.106 - Quarantine requirements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... other than ratites and hatching eggs of ratites. Each lot of pet birds, except as provided for in § 93... Whereas, it is the intention of the parties hereto that such cooperation shall be for their mutual benefit and the benefit of the people of the United States; Now therefore, for and in consideration of the...

9 CFR 93.106 - Quarantine requirements.

Code of Federal Regulations, 2012 CFR

2012-01-01

... other than ratites and hatching eggs of ratites. Each lot of pet birds, except as provided for in § 93... Whereas, it is the intention of the parties hereto that such cooperation shall be for their mutual benefit and the benefit of the people of the United States; Now therefore, for and in consideration of the...

9 CFR 93.106 - Quarantine requirements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... other than ratites and hatching eggs of ratites. Each lot of pet birds, except as provided for in § 93... Whereas, it is the intention of the parties hereto that such cooperation shall be for their mutual benefit and the benefit of the people of the United States; Now therefore, for and in consideration of the...

A novel transient structure with phylogenetic implications found in ratite spermatids

PubMed Central

2013-01-01

Background A novel transient structure was observed in the spermatids of three ratite species using transmission electron microscopy. Results The structure first appeared at the circular manchette stage of sperm development, was most prominent during the longitudinal manchette phase and disappeared abruptly prior to spermiation. It was composed of regularly-spaced finger-like projections which were closely associated with the outer nuclear membrane, giving the nucleus a cogwheel-like appearance. The projections were approximately 30 nm long and 14 nm wide. Although a similar structure has been described in certain lizard and crocodile species, this is the first report of a similar structure in the developing spermatids of birds. Conclusions The potential value of non-traditional characters, such as spermiogenesis and sperm ultrastructure, as phylogenetic markers has recently been advocated. The morphologically unique structure found in ratite spermatids provides additional evidence of a possible phylogenetic link between the reptiles and birds. It also endorses the basal positioning of the ratites as a monophyletic group within the avian phylogenetic tree. PMID:23705947

Ratite production as an agricultural enterprise.

PubMed

Gillespie, J M; Schupp, A R

1998-11-01

The ratite industry remains in the market introduction stage of evolution; basic information on markets and production is limited. It is uncertain when, or perhaps whether, either the ostrich or emu industries will progress to the market growth stage. Until significant expansion occurs, ratite operations are likely to be faced with low or even nonexistant profits. It is the authors' observation that the ostrich industry is making slow but significant progress toward introducing products into potential growth markets. The fact that ostrich products were in demand prior to the ostrich being introduced into North America has helped the industry. The future of the emu industry appears to be much less certain. In the authors' opinion, in order for the emu industry to become profitable and grow, significant promotion of emu meat and immediate resolution of the value of the oil must be achieved. Meat sales alone will not carry emu production as a profitable commercial enterprise. Veterinarians can derive significant conclusions from this information. Currently, ratite production is composed of firms generating losses or minimal profits. South African producers are receiving approximately the same amount for a slaughter ostrich as North American producers. It is unlikely that North American ostrich prices will increase significantly. Prices of ostrich breeders of $2,000 to $4,000 per pair and $400 to $450 for slaughter birds are likely to remain the same for some time. Given that world demand has increased at a slower rate than supply, prices may decrease further. Breeder and slaughter birds will continue to require significant veterinary care; however, the producer will be forced to perform more farm treatments, given the negligible margins. Based on the differences in efficiency of existing operations, there are ample opportunities for veterinarians and extension services to assist producers. Vertical coordination in the ratite industry may evolve slowly in the future, especially in the arid regions of the country; however, economies of size in ratite slaughter are likely to remain uncaptured in the short run, limiting the rate at which vertical coordination evolves. If significant opportunities develop for veterinarians in vertically integrated ratite firms, the emphasis, as with other intensive livestock operations, will be preventative rather than therapeutic medicine, and will involve the integration of nutrition, management, genetics, and the control of disease.

Bone growth marks reveal protracted growth in New Zealand kiwi (Aves, Apterygidae)

PubMed Central

Bourdon, Estelle; Castanet, Jacques; de Ricqlès, Armand; Scofield, Paul; Tennyson, Alan; Lamrous, Hayat; Cubo, Jorge

2009-01-01

The presence of bone growth marks reflecting annual rhythms in the cortical bone of non-avian tetrapods is now established as a general phenomenon. In contrast, ornithurines (the theropod group including modern birds and their closest relatives) usually grow rapidly in less than a year, such that no annual rhythms are expressed in bone cortices, except scarce growth marks restricted to the outer cortical layer. So far, cyclical growth in modern birds has been restricted to the Eocene Diatryma, the extant parrot Amazona amazonica and the extinct New Zealand (NZ) moa (Dinornithidae). Here we show the presence of lines of arrested growth in the long bones of the living NZ kiwi (Apteryx spp., Apterygidae). Kiwis take 5–6 years to reach full adult body size, which indicates a delayed maturity and a slow reproductive cycle. Protracted growth probably evolved convergently in moa and kiwi sometime since the Middle Miocene, owing to the severe climatic cooling in the southwest Pacific and the absence of mammalian predators. PMID:19515655

Quaternary record of aridity and mean annual precipitation based on δ15N in ratite and dromornithid eggshells from Lake Eyre, Australia.

PubMed

Newsome, Seth D; Miller, Gifford H; Magee, John W; Fogel, Marilyn L

2011-12-01

The cause(s) of the late Pleistocene megafauna extinction on the Australian continent remains largely unresolved. Unraveling climatic forcing mechanisms from direct or indirect human agents of ecosystem alteration has proven to be extremely difficult in Australia due to the lack of (1) well-dated vertebrate fossils and (2) paleo-environmental and -ecological records spanning the past approximately 100 ka when regional climatic conditions are known to have significantly varied. We have examined the nitrogen isotope composition (δ(15)N) of modern emu (Dromaius novaehollandiae) eggshells collected along a precipitation gradient in Australia, along with modern climatological data and dietary δ(15)N values. We then used modern patterns to interpret an approximately 130-ka record of δ(15)N values in extant Dromaius and extinct Genyornis newtoni eggshells from Lake Eyre to obtain a novel mean annual precipitation (MAP) record for central Australia spanning the extinction interval. Our data also provide the first detailed information on the trophic ecology and environmental preferences of two closely related taxa, one extant and one extinct. Dromaius eggshell δ(15)N values show a significant shift to higher values during the Last Glacial Maximum and Holocene, which we interpret to indicate more frequent arid conditions (<200 mm MAP), relative to δ(15)N from samples just prior to the megafauna extinction. Genyornis eggshells had δ(15)N values reflecting wetter nesting conditions overall relative to those of coeval Dromaius, perhaps indicating that Genyornis was more reliant on mesic conditions. Lastly, the Dromaius eggshell record shows a significant decrease in δ(13)C values prior to the extinction, whereas the Genyornis record does not. Neither species showed a concomitant change in δ(15)N prior to the extinction, which suggests that a significant change in vegetation surrounding Lake Eyre occurred prior to an increase in local aridity.

Ancient DNA provides new insights into the evolutionary history of New Zealand's extinct giant eagle.

PubMed

Bunce, Michael; Szulkin, Marta; Lerner, Heather R L; Barnes, Ian; Shapiro, Beth; Cooper, Alan; Holdaway, Richard N

2005-01-01

Prior to human settlement 700 years ago New Zealand had no terrestrial mammals--apart from three species of bats--instead, approximately 250 avian species dominated the ecosystem. At the top of the food chain was the extinct Haast's eagle, Harpagornis moorei. H. moorei (10-15 kg; 2-3 m wingspan) was 30%-40% heavier than the largest extant eagle (the harpy eagle, Harpia harpyja), and hunted moa up to 15 times its weight. In a dramatic example of morphological plasticity and rapid size increase, we show that the H. moorei was very closely related to one of the world's smallest extant eagles, which is one-tenth its mass. This spectacular evolutionary change illustrates the potential speed of size alteration within lineages of vertebrates, especially in island ecosystems.

Ancient DNA Provides New Insights into the Evolutionary History of New Zealand's Extinct Giant Eagle

PubMed Central

Szulkin, Marta; Lerner, Heather R. L; Barnes, Ian; Shapiro, Beth; Cooper, Alan; Holdaway, Richard N

2005-01-01

Prior to human settlement 700 years ago New Zealand had no terrestrial mammals—apart from three species of bats—instead, approximately 250 avian species dominated the ecosystem. At the top of the food chain was the extinct Haast's eagle, Harpagornis moorei. H. moorei (10–15 kg; 2–3 m wingspan) was 30%–40% heavier than the largest extant eagle (the harpy eagle, Harpia harpyja), and hunted moa up to 15 times its weight. In a dramatic example of morphological plasticity and rapid size increase, we show that the H. moorei was very closely related to one of the world's smallest extant eagles, which is one-tenth its mass. This spectacular evolutionary change illustrates the potential speed of size alteration within lineages of vertebrates, especially in island ecosystems. PMID:15660162

The evolution of giant flightless birds and novel phylogenetic relationships for extinct fowl (Aves, Galloanseres)

NASA Astrophysics Data System (ADS)

Worthy, Trevor H.; Degrange, Federico J.; Handley, Warren D.; Lee, Michael S. Y.

2017-10-01

The extinct dromornithids, gastornithids and phorusrhacids are among the most spectacular birds to have ever lived, with some giants exceeding 500 kg. The affinities and evolution of these and other related extinct birds remain contentious, with previous phylogenetic analyses being affected by widespread convergence and limited taxon sampling. We address these problems using both parsimony and tip-dated Bayesian approaches on an expansive taxon set that includes all key extinct flightless and flighted (e.g. Vegavis and lithornithids) forms, an extensive array of extant fowl (Galloanseres), representative Neoaves and palaeognaths. The Paleogene volant Lithornithidae are recovered as stem palaeognaths in the Bayesian analyses. The Galloanseres comprise four clades inferred to have diverged in the Late Cretaceous on Gondwana. In addition to Anseriformes and Galliformes, we recognize a robust new clade (Gastornithiformes) for the giant flightless Dromornithidae (Australia) and Gastornithidae (Eurasia, North America). This clade exhibits parallels to ratite palaeognaths in that flight presumably was lost and giant size attained multiple times. A fourth clade is represented by the Cretaceous Vegavis (Antarctica), which was strongly excluded from Anseriformes; thus, a crucial molecular calibration point needs to be reconsidered. The presbyornithids Wilaru (Australia) and Presbyornis (Northern Hemisphere) are robustly found to be the sister group to Anatoidea (Anseranatidae + Anatidae), a relatively more basal position than hitherto recognized. South America's largest bird, Brontornis, is not a galloansere, but a member of Neoaves related to Cariamiformes; therefore, giant Galloanseres remain unknown from this continent. Trait analyses showed that while gigantism and flightlessness evolved repeatedly in groups, diet is constrained by phylogeny: all giant Galloanseres and palaeognaths are herbivores or mainly herbivorous, and giant neoavians are zoophagous or omnivorous.

To excite a heart: a bird's view.

PubMed

Sommer, J R; Bossen, E; Dalen, H; Dolber, P; High, T; Jewett, P; Johnson, E A; Junker, J; Leonard, S; Nassar, R

1991-01-01

Ultrastructural investigations of avian cardiac muscle, including ratite hearts, have provided great insights into the mechanisms as to how excitation leads to contraction in the heart. The geometry of the conduction fibers of ratite hearts confirms earlier observations on birds showing that the geometry of the conduction system and its component cells is adapted to hearts of different sizes and rates of contraction so as to maintain a differential in conduction velocities between the conduction system and the working fibers. The study of the ratite conduction fibers bears out the idea of an inverse relationship between the size of the gap junctions and the input resistance of cardiac cells. The anomalous extended junctional SR typical of all avian hearts, proscribes the notion of direct contact transduction into calcium release for contraction of an excitatory signal propagating at the cell surface. Couplings appear well suited to maintain direct, if transitory, connections to the extracellular space in addition to harboring channels for intracellular calcium release.

Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence

PubMed Central

Meek, M E (Bette); Palermo, Christine M; Bachman, Ammie N; North, Colin M; Jeffrey Lewis, R

2014-01-01

The mode of action human relevance (MOA/HR) framework increases transparency in systematically considering data on MOA for end (adverse) effects and their relevance to humans. This framework continues to evolve as experience increases in its application. Though the MOA/HR framework is not designed to address the question of “how much information is enough” to support a hypothesized MOA in animals or its relevance to humans, its organizing construct has potential value in considering relative weight of evidence (WOE) among different cases and hypothesized MOA(s). This context is explored based on MOA analyses in published assessments to illustrate the relative extent of supporting data and their implications for dose–response analysis and involved comparisons for chemical assessments on trichloropropane, and carbon tetrachloride with several hypothesized MOA(s) for cancer. The WOE for each hypothesized MOA was summarized in narrative tables based on comparison and contrast of the extent and nature of the supporting database versus potentially inconsistent or missing information. The comparison was based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations of MOA taking into account increasing experience in their application internationally. This clarification of considerations for WOE determinations as a basis for comparative analysis is anticipated to contribute to increasing consistency in the application of MOA/HR analysis and potentially, transparency in separating science judgment from public policy considerations in regulatory risk assessment. Copyright © 2014. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd. The potential value of the mode of action (MOA)/human relevance (species concordance) framework in considering relative weight of evidence (WOE) amongst different cases and hypothesized MOA(s) is explored based on the content of several published assessments. The comparison is based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations for MOA based on experience internationally. PMID:24777878

Genetic characterization of moaB mutants of Escherichia coli

PubMed Central

Kozmin, Stanislav G.; Schaaper, Roel M.

2013-01-01

The moaABCDE operon of Escherichia coli encodes enzymes essential for the biosynthesis of the molybdenum cofactor (Moco). However, the role of the moaB gene within this operon has remained enigmatic. Here, we have investigated the effect of moaB defects on two phenotypes diagnostic for Moco-deficiency: chlorate-resistance and sensitivity to the base analog 6-N-hydroxylaminopurine (HAP). We found that transposon insertions in moaB caused partial Moco-deficiency associated with chlorate-resistance, but not for HAP-sensitivity. On the other hand, in-frame deletions of moaB, or moaB overexpression, had no effect on either phenotype. Our combined data are consistent with the lack of any role for MoaB in Moco biosynthesis in E. coli. PMID:23680484

A Bayesian network model for predicting aquatic toxicity mode ...

EPA Pesticide Factsheets

The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity, but development of predictive MoA classification models in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity MoA using a recently published dataset containing over one thousand chemicals with MoA assignments for aquatic animal toxicity. Two dimensional theoretical chemical descriptors were generated for each chemical using the Toxicity Estimation Software Tool. The model was developed through augmented Markov blanket discovery from the dataset of 1098 chemicals with the MoA broad classifications as a target node. From cross validation, the overall precision for the model was 80.2%. The best precision was for the AChEI MoA (93.5%) where 257 chemicals out of 275 were correctly classified. Model precision was poorest for the reactivity MoA (48.5%) where 48 out of 99 reactive chemicals were correctly classified. Narcosis represented the largest class within the MoA dataset and had a precision and reliability of 80.0%, reflecting the global precision across all of the MoAs. False negatives for narcosis most often fell into electron transport inhibition, neurotoxicity or reactivity MoAs. False negatives for all other MoAs were most often narcosis. A probabilistic sensitivity analysis was undertaken for each MoA to examine the sensitivity to individual and multiple descriptor findings. The results show that the Markov blank

Human bloodstains on bone artefacts: an SEM intra- and inter-sample comparative study using ratite bird tibiotarsus.

PubMed

Hortolà, Policarp

2016-11-01

Apart from their forensic significance in crime investigation, human bloodstains have an anthropological interest due to their occurrence on certain traditional weapons and ritual objects. Previously, a guiding study of erythrocytes in experimental samples including domestic sheep (Ovis aries) tibia was carried out using a scanning electron microscope (SEM). Here, a comparative SEM study to reveal the potential differences in bloodstain surface morphology as a function of intra-sample (smear region) and inter-sample (individual smear, smearing mechanism, bone origin) parameters is reported. A fragment of emu (Dromaius novaehollandiae) tibiotarsus was smeared with an adult man's peripheral blood. After air-drying and storing indoors, the boundary and neighbouring inner areas of the three individual bloodstains obtained were examined via secondary electrons in a variable-pressure SEM working in low-vacuum mode. As a whole, desiccation microcracks were present, the limits between the smear and the substrate appeared poorly defined, and no erythrocyte negative replicas were observed in the examined areas. In addition, a putative fibrin network, more or less embedded in the dried plasma matrix, was observed in the smears' boundary. Regarding the smear region in sliding smears, the periphery and boundary revealed to be different, while the head and tail were similar. Considering individual sliding smears, they had similar characteristics. Relating to the smear region as a function of the smearing mechanism, the periphery was different whether sliding or touching, while the boundary was similar in sliding and touching smears. Concerning the smear region as a function of the bone origin, the periphery revealed to be similar in both ratite and mammalian bone, while the boundary did different in ratite and mammalian bone. The results of this study show that SEM examination can be used fruitfully to detect bloodstains on ratite bone. Combined with previous SEM results in domestic sheep bone, they suggest, further, that blood remains can be detected on objects made of bone irrespectively of the mammalian or ratite origin of this raw material. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence.

PubMed

Meek, M E Bette; Palermo, Christine M; Bachman, Ammie N; North, Colin M; Jeffrey Lewis, R

2014-06-01

The mode of action human relevance (MOA/HR) framework increases transparency in systematically considering data on MOA for end (adverse) effects and their relevance to humans. This framework continues to evolve as experience increases in its application. Though the MOA/HR framework is not designed to address the question of "how much information is enough" to support a hypothesized MOA in animals or its relevance to humans, its organizing construct has potential value in considering relative weight of evidence (WOE) among different cases and hypothesized MOA(s). This context is explored based on MOA analyses in published assessments to illustrate the relative extent of supporting data and their implications for dose-response analysis and involved comparisons for chemical assessments on trichloropropane, and carbon tetrachloride with several hypothesized MOA(s) for cancer. The WOE for each hypothesized MOA was summarized in narrative tables based on comparison and contrast of the extent and nature of the supporting database versus potentially inconsistent or missing information. The comparison was based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations of MOA taking into account increasing experience in their application internationally. This clarification of considerations for WOE determinations as a basis for comparative analysis is anticipated to contribute to increasing consistency in the application of MOA/HR analysis and potentially, transparency in separating science judgment from public policy considerations in regulatory risk assessment. Copyright © 2014. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

A Bayesian network model for predicting aquatic toxicity mode ...

EPA Pesticide Factsheets

The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity but MoA classification in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity mode of action using a recently published dataset containing over one thousand chemicals with MoA assignments for aquatic animal toxicity. Two dimensional theoretical chemical descriptors were generated for each chemical using the Toxicity Estimation Software Tool. The model was developed through augmented Markov blanket discovery from the data set with the MoA broad classifications as a target node. From cross validation, the overall precision for the model was 80.2% with a R2 of 0.959. The best precision was for the AChEI MoA (93.5%) where 257 chemicals out of 275 were correctly classified. Model precision was poorest for the reactivity MoA (48.5%) where 48 out of 99 reactive chemicals were correctly classified. Narcosis represented the largest class within the MoA dataset and had a precision and reliability of 80.0%, reflecting the global precision across all of the MoAs. False negatives for narcosis most often fell into electron transport inhibition, neurotoxicity or reactivity MoAs. False negatives for all other MoAs were most often narcosis. A probabilistic sensitivity analysis was undertaken for each MoA to examine the sensitivity to individual and multiple descriptor findings. The results show that the Markov blanket of a structurally

A chronology for late prehistoric Madagascar.

PubMed

Burney, David A; Burney, Lida Pigott; Godfrey, Laurie R; Jungers, William L; Goodman, Steven M; Wright, Henry T; Jull, A J Timothy

2004-01-01

A database has been assembled with 278 age determinations for Madagascar. Materials 14C dated include pretreated sediments and plant macrofossils from cores and excavations throughout the island, and bones, teeth, or eggshells of most of the extinct megafaunal taxa, including the giant lemurs, hippopotami, and ratites. Additional measurements come from uranium-series dates on speleothems and thermoluminescence dating of pottery. Changes documented include late Pleistocene climatic events and, in the late Holocene, the apparently human-caused transformation of the environment. Multiple lines of evidence point to the earliest human presence at ca. 2300 14C yr BP (350 cal yr BC). A decline in megafauna, inferred from a drastic decrease in spores of the coprophilous fungus Sporormiella spp. in sediments at 1720+/-40 14C yr BP (230-410 cal yr AD), is followed by large increases in charcoal particles in sediment cores, beginning in the SW part of the island, and spreading to other coasts and the interior over the next millennium. The record of human occupation is initially sparse, but shows large human populations throughout the island by the beginning of the Second Millennium AD. Dating of the "subfossil" megafauna, including pygmy hippos, elephant birds, giant tortoises, and large lemurs, demonstrates that most if not all the extinct taxa were still present on the island when humans arrived. Many taxa overlapped chronologically with humans for a millennium or more. The extinct lemurs Hadropithecus stenognathus, Pachylemur insignis, Mesopropithecus pithecoides, and Daubentonia robusta, and the elephant birds Aepyornis spp. and Mullerornis spp., were still present near the end of the First Millennium AD. Palaeopropithecus ingens, Megaladapis edwardsi, and Archaeolemur sp. (cf. edwardsi) may have survived until the middle of the Second Millennium A.D. One specimen of Hippopotamus of unknown provenance dates to the period of European colonization.

Congressional Submission RDT&E Descriptive Summaries, FY 1994

DTIC Science & Technology

1993-04-01

U) Extremely High Frequency (EHF) lower cost, communication technologies ( ASTEC ) will be developed to support the ASD/C 3 1 MILSATCOM modernization...restructured and formalized into the ASTEC , CAMEO and IMPACT Programs. F. (U) PROGRAM DOCUMENTATION: * (U) U.S. Air Force/DARPA MOA dated 1988 * (U) U.S...Army/DARPA MOA dated 1990 * (U) SDIO/DARPA MOA dated 1990 * (U) DARPA/U.S. Air Force TAOS MOA dated 1992 * (U) DARPA/Joint Services ASTEC MOA (in

Discovery of new herbicide modes of action with natural phytotoxins

USDA-ARS?s Scientific Manuscript database

About 20 modes of action (MOAs) are utilized by commercial herbicides, and almost 30 years have passed since the last new MOA was introduced. Rapidly increasing evolution of resistance to herbicides with these MOAs has greatly increased the need for herbicides with new MOAs. Combinatorial chemistry ...

Enhanced amine and amino acid analysis using Pacific Blue and the Mars Organic Analyzer microchip capillary electrophoresis system.

PubMed

Chiesl, Thomas N; Chu, Wai K; Stockton, Amanda M; Amashukeli, Xenia; Grunthaner, Frank; Mathies, Richard A

2009-04-01

The fluorescent amine reactive probe Pacific Blue succinimidyl ester (PB) is used for the detection of trace amounts of amines and amino acids by microchip capillary electrophoresis on the Mars Organic Analyzer (MOA). The spectral and chemical properties of PB provide a 200-fold increase in sensitivity and improved resolution compared to fluorescamine derivatization. With the use of cross injection and PB labeling, the MOA detected amino acids at concentrations as low as 75 pM (sub-parts-per-trillion). Micellar electrokinetic chromatography (MEKC) which separates PB-labeled amino acids by their hydrophobicity is also demonstrated. The optimized MEKC conditions (45 mM CHAPSO, pH 6 at 5 degrees C) effectively separated amines and 25 amino acids with enantiomeric resolution of alanine, serine, and citrulline. Samples from the Yungay Hills region in the Atacama Desert, Chile, and from the Murchison meteorite are successfully analyzed using both techniques, and amino acids are found in the parts-per-billion range. Abiotic amino acids such as beta-alanine and epsilon-aminocaprioc acid are detected along with several neutral and acidic amino acids in the Murchison sample. The Atacama Desert sample is found to contain homochiral L-alanine and L-serine indicating the presence of extant or recently extinct life.

Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis

DOE PAGES

Hover, Bradley M.; Tonthat, Nam K.; Schumacher, Maria A.; ...

2015-05-04

The molybdenum cofactor (Moco) is essential for all kingdoms of life, plays central roles in various biological processes, and must be biosynthesized de novo. During Moco biosynthesis, the characteristic pyranopterin ring is constructed by a complex rearrangement of guanosine 5'-triphosphate (GTP) into cyclic pyranopterin (cPMP) through the action of two enzymes, MoaA and MoaC (molybdenum cofactor biosynthesis protein A and C, respectively). Conventionally, MoaA was considered to catalyze the majority of this transformation, with MoaC playing little or no role in the pyranopterin formation. Recently, this view was challenged by the isolation of 3',8-cyclo-7,8-dihydro-guanosine 5'-triphosphate (3',8-cH 2GTP) as the productmore » of in vitro MoaA reactions. To elucidate the mechanism of formation of Moco pyranopterin backbone, in this paper we performed biochemical characterization of 3',8-cH 2GTP and functional and X-ray crystallographic characterizations of MoaC. These studies revealed that 3',8-cH 2GTP is the only product of MoaA that can be converted to cPMP by MoaC. Our structural studies captured the specific binding of 3',8-cH 2GTP in the active site of MoaC. These observations provided strong evidence that the physiological function of MoaA is the conversion of GTP to 3',8-cH 2GTP (GTP 3',8-cyclase), and that of MoaC is to catalyze the rearrangement of 3',8-cH 2GTP into cPMP (cPMP synthase). Furthermore, our structure-guided studies suggest that MoaC catalysis involves the dynamic motions of enzyme active-site loops as a way to control the timing of interaction between the reaction intermediates and catalytically essential amino acid residues. In conclusion, these results reveal the previously unidentified mechanism behind Moco biosynthesis and provide mechanistic and structural insights into how enzymes catalyze complex rearrangement reactions.« less

Characterizing Lenses and Lensed Stars of High-magnification Single-lens Gravitational Microlensing Events with Lenses Passing over Source Stars

NASA Astrophysics Data System (ADS)

Choi, J.-Y.; Shin, I.-G.; Park, S.-Y.; Han, C.; Gould, A.; Sumi, T.; Udalski, A.; Beaulieu, J.-P.; Street, R.; Dominik, M.; Allen, W.; Almeida, L. A.; Bos, M.; Christie, G. W.; Depoy, D. L.; Dong, S.; Drummond, J.; Gal-Yam, A.; Gaudi, B. S.; Henderson, C. B.; Hung, L.-W.; Jablonski, F.; Janczak, J.; Lee, C.-U.; Mallia, F.; Maury, A.; McCormick, J.; McGregor, D.; Monard, L. A. G.; Moorhouse, D.; Muñoz, J. A.; Natusch, T.; Nelson, C.; Park, B.-G.; Pogge, R. W.; "TG" Tan, T.-G.; Thornley, G.; Yee, J. C.; μFUN Collaboration; Abe, F.; Barnard, E.; Baudry, J.; Bennett, D. P.; Bond, I. A.; Botzler, C. S.; Freeman, M.; Fukui, A.; Furusawa, K.; Hayashi, F.; Hearnshaw, J. B.; Hosaka, S.; Itow, Y.; Kamiya, K.; Kilmartin, P. M.; Kobara, S.; Korpela, A.; Lin, W.; Ling, C. H.; Makita, S.; Masuda, K.; Matsubara, Y.; Miyake, N.; Muraki, Y.; Nagaya, M.; Nishimoto, K.; Ohnishi, K.; Okumura, T.; Omori, K.; Perrott, Y. C.; Rattenbury, N.; Saito, To.; Skuljan, L.; Sullivan, D. J.; Suzuki, D.; Suzuki, K.; Sweatman, W. L.; Takino, S.; Tristram, P. J.; Wada, K.; Yock, P. C. M.; MOA Collaboration; Szymański, M. K.; Kubiak, M.; Pietrzyński, G.; Soszyński, I.; Poleski, R.; Ulaczyk, K.; Wyrzykowski, Ł.; Kozłowski, S.; Pietrukowicz, P.; OGLE Collaboration; Albrow, M. D.; Bachelet, E.; Batista, V.; Bennett, C. S.; Bowens-Rubin, R.; Brillant, S.; Cassan, A.; Cole, A.; Corrales, E.; Coutures, Ch.; Dieters, S.; Dominis Prester, D.; Donatowicz, J.; Fouqué, P.; Greenhill, J.; Kane, S. R.; Menzies, J.; Sahu, K. C.; Wambsganss, J.; Williams, A.; Zub, M.; PLANET Collaboration; Allan, A.; Bramich, D. M.; Browne, P.; Clay, N.; Fraser, S.; Horne, K.; Kains, N.; Mottram, C.; Snodgrass, C.; Steele, I.; Tsapras, Y.; RoboNet Collaboration; Alsubai, K. A.; Bozza, V.; Burgdorf, M. J.; Calchi Novati, S.; Dodds, P.; Dreizler, S.; Finet, F.; Gerner, T.; Glitrup, M.; Grundahl, F.; Hardis, S.; Harpsøe, K.; Hinse, T. C.; Hundertmark, M.; Jørgensen, U. G.; Kerins, E.; Liebig, C.; Maier, G.; Mancini, L.; Mathiasen, M.; Penny, M. T.; Proft, S.; Rahvar, S.; Ricci, D.; Scarpetta, G.; Schäfer, S.; Schönebeck, F.; Skottfelt, J.; Surdej, J.; Southworth, J.; Zimmer, F.; MiNDSTEp Consortium

2012-05-01

We present the analysis of the light curves of nine high-magnification single-lens gravitational microlensing events with lenses passing over source stars, including OGLE-2004-BLG-254, MOA-2007-BLG-176, MOA-2007-BLG-233/OGLE-2007-BLG-302, MOA-2009-BLG-174, MOA-2010-BLG-436, MOA-2011-BLG-093, MOA-2011-BLG-274, OGLE-2011-BLG-0990/MOA-2011-BLG-300, and OGLE-2011-BLG-1101/MOA-2011-BLG-325. For all of the events, we measure the linear limb-darkening coefficients of the surface brightness profile of source stars by measuring the deviation of the light curves near the peak affected by the finite-source effect. For seven events, we measure the Einstein radii and the lens-source relative proper motions. Among them, five events are found to have Einstein radii of less than 0.2 mas, making the lenses very low mass star or brown dwarf candidates. For MOA-2011-BLG-274, especially, the small Einstein radius of θE ~ 0.08 mas combined with the short timescale of t E ~ 2.7 days suggests the possibility that the lens is a free-floating planet. For MOA-2009-BLG-174, we measure the lens parallax and thus uniquely determine the physical parameters of the lens. We also find that the measured lens mass of ~0.84 M ⊙ is consistent with that of a star blended with the source, suggesting that the blend is likely to be the lens. Although we did not find planetary signals for any of the events, we provide exclusion diagrams showing the confidence levels excluding the existence of a planet as a function of the separation and mass ratio.

F/EF-111 Basing at Cannon Air Force Base, Curry County, New Mexico

DTIC Science & Technology

1992-04-01

construction on Base and at Melrose Rang6, Mount Dora Military Operations Area (MOA), and Pecos MOA are proposed actions associated with the realignment...Under the Mount Dora MOA, 1987 ....................................................................... 3-13 Table 3.1-5 Visitation at State and...National Parks Located in the Area Under the Mount Dora MOA ........................... 3-14 Table 3.2-1 Federal and State Ambient Air Quality Standards

Classifying compound mechanism of action for linking whole cell phenotypes to molecular targets

PubMed Central

Bourne, Christina R.; Wakeham, Nancy; Bunce, Richard A.; Berlin, K. Darrell; Barrow, William W.

2013-01-01

Drug development programs have proven successful when performed at a whole cell level, thus incorporating solubility and permeability into the primary screen. However, linking those results to the target within the cell has been a major set-back. The Phenotype Microarray system, marketed and sold by Biolog, seeks to address this need by assessing the phenotype in combination with a variety of chemicals with known mechanism of action (MOA). We have evaluated this system for usefulness in deducing the MOA for three test compounds. To achieve this, we constructed a database with 21 known antimicrobials, which served as a comparison for grouping our unknown MOA compounds. Pearson correlation and Ward linkage calculations were used to generate a dendrogram that produced clustering largely by known MOA, although there were exceptions. Of the three unknown compounds, one was definitively placed as an anti-folate. The second and third compounds’ MOA were not clearly identified, likely due to unique MOA not represented within the commercial database. The availability of the database generated in this report for S. aureus ATCC 29213 will increase the accessibility of this technique to other investigators. From our analysis, the Phenotype Microarray system can group compounds with clear MOA, but distinction of unique or broadly acting MOA at this time is less clear. PMID:22434711

Environmental Impact Statement. Preliminary Draft. Realignment of Cannon Air Force Base, Curry County, New Mexico

DTIC Science & Technology

1989-12-15

creation of the Mount Dora Military Operations Area are proposed actions associated with the realignment. Contact for Further Information: Captain...2.2.5 Establishment of the Mount Dora MOA ................. 2-1532.2.6 Pecos MOA Use ................................. 2-21 2.3 THE NO-ACTION...2-22 2.3.3 Establishment of the Mount Dora MOA ................. 2-22 2.3.4 Pecos MOA Use ................................. 2-2532.4

Ten factors for considering the mode of action of Cr(VI)-induced gastrointestinal tumors in rodents.

PubMed

Thompson, Chad M; Suh, Mina; Proctor, Deborah M; Haws, Laurie C; Harris, Mark A

2017-11-01

The determination of whether a chemical induces a specific cancer through a mutagenic or non-mutagenic mode of action (MOA) plays an important role in choosing between linear and nonlinear low-dose extrapolation to derive toxicity criteria. There is no formal framework from the U.S. EPA for determining whether environmental chemicals act through a mutagenic or non-mutagenic MOA; consequently, most such determinations are made on an ad hoc basis. Eastmond [Mutat Res 751 (2012)] recently conducted a systematic investigation of MOA determinations by U.S. and international regulatory agencies and organizations, and identified ten major factors that influence them, including toxicokinetics, in vivo genotoxicity in target organs, data quality, and evidence for alternative MOAs. We have used these ten factors to evaluate mutagenic vs. non-mutagenic MOA for gastrointestinal tumors induced by oral exposure to hexavalent chromium [Cr(VI)]. We also highlight similarities between Cr(VI) and other intestinal carcinogens previously determined to have non-genotoxic MOAs. Based on these analyses, we conclude that the MOA for Cr(VI) induced gastrointestinal tumors is non-mutagenic and that threshold risk assessment approaches are appropriate. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Mode of action in relevance of rodent liver tumors to human cancer risk.

PubMed

Holsapple, Michael P; Pitot, Henri C; Cohen, Samuel M; Cohen, Samuel H; Boobis, Alan R; Klaunig, James E; Pastoor, Timothy; Dellarco, Vicki L; Dragan, Yvonne P

2006-01-01

Hazard identification and risk assessment paradigms depend on the presumption of the similarity of rodents to humans, yet species specific responses, and the extrapolation of high-dose effects to low-dose exposures can affect the estimation of human risk from rodent data. As a consequence, a human relevance framework concept was developed by the International Programme on Chemical Safety (IPCS) and International Life Sciences Institute (ILSI) Risk Science Institute (RSI) with the central tenet being the identification of a mode of action (MOA). To perform a MOA analysis, the key biochemical, cellular, and molecular events need to first be established, and the temporal and dose-dependent concordance of each of the key events in the MOA can then be determined. The key events can be used to bridge species and dose for a given MOA. The next step in the MOA analysis is the assessment of biological plausibility for determining the relevance of the specified MOA in an animal model for human cancer risk based on kinetic and dynamic parameters. Using the framework approach, a MOA in animals could not be defined for metal overload. The MOA for phenobarbital (PB)-like P450 inducers was determined to be unlikely in humans after kinetic and dynamic factors were considered. In contrast, after these factors were considered with reference to estrogen, the conclusion was drawn that estrogen-induced tumors were plausible in humans. Finally, it was concluded that the induction of rodent liver tumors by porphyrogenic compounds followed a cytotoxic MOA, and that liver tumors formed as a result of sustained cytotoxicity and regenerative proliferation are considered relevant for evaluating human cancer risk if appropriate metabolism occurs in the animal models and in humans.

Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of approaches

EPA Science Inventory

The mode of toxic action (MOA) is recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, MOA classification has never been standardized in ecotoxicology, and a comprehensive comparison of classific...

Computational Chemistry-based Acute Aquatic Toxicity Mode of Action Assignment

EPA Science Inventory

The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertai...

Prediction of aquatic toxicity mode of action using linear discriminant and random forest models

EPA Science Inventory

The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertai...

Modeling-Oriented Assessment in K-12 Science Education: A synthesis of research from 1980 to 2013 and new directions

NASA Astrophysics Data System (ADS)

Namdar, Bahadir; Shen, Ji

2015-05-01

Scientific modeling has been advocated as one of the core practices in recent science education policy initiatives. In modeling-based instruction (MBI), students use, construct, and revise models to gain scientific knowledge and inquiry skills. Oftentimes, the benefits of MBI have been documented using assessments targeting students' conceptual understanding or affective domains. Fewer studies have used assessments directly built on the ideas of modeling. The purpose of this study is to synthesize and examine modeling-oriented assessments (MOA) in the last three decades and propose new directions for research in this area. The study uses a collection of 30 empirical research articles that report MOA from an initial library of 153 articles focusing on MBI in K-12 science education from 1980 to 2013. The findings include the variety of themes within each of the three MOA dimensions (modeling products, modeling practices, and meta-modeling knowledge) and the areas of MOA still in need of much work. Based on the review, three guiding principles are proposed for future work in MOA: (a) framing MOA in an ecology of assessment, (b) providing authentic modeling contexts for assessment, and (c) spelling out the connections between MOA items and the essential aspects of modeling to be assessed.

A Critical Review of Mode of Action (MOA) Assignment ...

EPA Pesticide Factsheets

There are various structure-based classification schemes to categorize chemicals based on mode of action (MOA) which have been applied for both eco and human health toxicology. With increasing calls to assess thousands of chemicals, some of which have little available information other than structure, clear understanding how each of these MOA schemes was devised, what information they are based on, and the limitations of each approach is critical. Several groups are developing low-tier methods to more easily classify or assess chemicals, using approaches such as the ecological threshold of concern (eco-TTC) and chemical-activity. Evaluation of these approaches and determination of their domain of applicability is partly dependent on the MOA classification that is used. The most commonly used MOA classification schemes for ecotoxicology include Verhaar and Russom (included in ASTER), both of which are used to predict acute aquatic toxicity MOA. Verhaar is a QSAR-based system that classifies chemicals into one of 4 classes, with a 5th class specified for those chemicals that are not classified in the other 4. ASTER/Russom includes 8 classifications: narcotics (3 groups), oxidative phosphorylation uncouplers, respiratory inhibitors, electrophiles/proelectrophiles, AChE inhibitors, or CNS seizure agents. Other methodologies include TEST (Toxicity Estimation Software Tool), a computational chemistry-based application that allows prediction to one of 5 broad MOA

76 FR 5394 - Notice of Proposed Information Collection for Public Comment; Memorandum of Agreement (MOA) and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-31

... Information Collection for Public Comment; Memorandum of Agreement (MOA) and Improvement Plan (IP) in...: Title of Proposal: Memorandum of Agreement (MOA), Progress Report and Improvement Plan (IP). OMB Control... 60% is required to submit an Improvement Plan (IP). These plans are designed to address deficiencies...

Effect of biomass concentration on methane oxidation activity using mature compost and graphite granules as substrata.

PubMed

Xie, S; O'Dwyer, T; Freguia, S; Pikaar, I; Clarke, W P

2016-10-01

Reported methane oxidation activity (MOA) varies widely for common landfill cover materials. Variation is expected due to differences in surface area, the composition of the substratum and culturing conditions. MOA per methanotrophic cell has been calculated in the study of natural systems such as lake sediments to examine the inherent conditions for methanotrophic activity. In this study, biomass normalised MOA (i.e., MOA per methanotophic cell) was measured on stabilised compost, a commonly used cover in landfills, and on graphite granules, an inert substratum widely used in microbial electrosynthesis studies. After initially enriching methanotrophs on both substrata, biomass normalised MOA was quantified under excess oxygen and limiting methane conditions in 160ml serum vials on both substrata and blends of the substrata. Biomass concentration was measured using the bicinchoninic acid assay for microbial protein. The biomass normalised MOA was consistent across all compost-to-graphite granules blends, but varied with time, reflecting the growth phase of the microorganisms. The biomass normalised MOA ranged from 0.069±0.006μmol CH4/mg dry biomass/h during active growth, to 0.024±0.001μmol CH4/mg dry biomass/h for established biofilms regardless of the substrata employed, indicating the substrata were equally effective in terms of inherent composition. The correlation of MOA with biomass is consistent with studies on methanotrophic activity in natural systems, but biomass normalised MOA varies by over 5 orders of magnitude between studies. This is partially due to different methods being used to quantify biomass, such as pmoA gene quantification and the culture dependent Most Probable Number method, but also indicates that long term exposure of materials to a supply of methane in an aerobic environment, as can occur in natural systems, leads to the enrichment and adaptation of types suitable for those conditions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Prediction of aquatic toxicity mode of action using linear discriminant and random forest models.

PubMed

Martin, Todd M; Grulke, Christopher M; Young, Douglas M; Russom, Christine L; Wang, Nina Y; Jackson, Crystal R; Barron, Mace G

2013-09-23

The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertainty, or rely on professional judgment. In this study, machine based learning algorithms (linear discriminant analysis and random forest) were used to develop models for assigning aquatic toxicity MOA. These methods were selected since they have been shown to be able to correlate diverse data sets and provide an indication of the most important descriptors. A data set of MOA assignments for 924 chemicals was developed using a combination of high confidence assignments, international consensus classifications, ASTER (ASessment Tools for the Evaluation of Risk) predictions, and weight of evidence professional judgment based an assessment of structure and literature information. The overall data set was randomly divided into a training set (75%) and a validation set (25%) and then used to develop linear discriminant analysis (LDA) and random forest (RF) MOA assignment models. The LDA and RF models had high internal concordance and specificity and were able to produce overall prediction accuracies ranging from 84.5 to 87.7% for the validation set. These results demonstrate that computational chemistry approaches can be used to determine the acute toxicity MOAs across a large range of structures and mechanisms.

A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors

EPA Science Inventory

The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity, but development of predictive MoA classification models in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity MoA using a recently pu...

A Cross-Species Mode of Action (Moa) Information Assessment: A Case Study of Bisphenol a (BPA)

EPA Science Inventory

EPA has released a report entitled, A Cross-Species Mode of Action Information Assessment: A Case Study of Bisphenol A [EPA/600/R-50/044F] . This report describes an approach to predict chemical effects and mode of action (MOA) for animal species without data from MOA i...

9 CFR 381.71 - Condemnation on ante mortem inspection.

Code of Federal Regulations, 2012 CFR

2012-01-01

... AGRICULTURE AGENCY ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY... slaughter an injured ratite at night or Sunday or a holiday, and the Agency veterinary medical officer...

9 CFR 381.71 - Condemnation on ante mortem inspection.

Code of Federal Regulations, 2013 CFR

2013-01-01

... AGRICULTURE AGENCY ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY... slaughter an injured ratite at night or Sunday or a holiday, and the Agency veterinary medical officer...

9 CFR 381.71 - Condemnation on ante mortem inspection.

Code of Federal Regulations, 2014 CFR

2014-01-01

... AGRICULTURE AGENCY ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY... slaughter an injured ratite at night or Sunday or a holiday, and the Agency veterinary medical officer...

9 CFR 381.71 - Condemnation on ante mortem inspection.

Code of Federal Regulations, 2011 CFR

2011-01-01

... AGRICULTURE AGENCY ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY... slaughter an injured ratite at night or Sunday or a holiday, and the Agency veterinary medical officer...

9 CFR 381.71 - Condemnation on ante mortem inspection.

Code of Federal Regulations, 2010 CFR

2010-01-01

... AGRICULTURE AGENCY ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY... slaughter an injured ratite at night or Sunday or a holiday, and the Agency veterinary medical officer...

Discriminating toxicant classes by mode of action. 1. (Eco)toxicity profiles.

PubMed

Nendza, Monika; Wenzel, Andrea

2006-05-01

Predictive toxicology, particularly quantitative structure-activity relationships (QSARs), require classification of chemicals by mode of action (MOA). MOA is, however, not a constant property of a compound but it varies between species and may change with concentration and duration of exposure. A battery of MOA-specific in-vitro and low-complexity assays, featuring biomolecular targets for major classes of environmental pollutants, provides characteristic responses for (1.) classification of chemicals by MOA, (2.) identification of (eco)toxicity profiles of chemicals, (3.) identification of chemicals with specific MOAs, (4.) indication of most sensitive species, (5.) identification of chemicals that are outliers in QSARs and (6.) selection of appropriate QSARs for predictions. Chemicals covering nine distinct modes of toxic action (non-polar non-specific toxicants (n=14), polar non-specific toxicants (n=18), uncouplers of oxidative phosphorylation (n=25), inhibitors of photosynthesis (n=15), inhibitors of acetylcholinesterase (n=14), inhibitors of respiration (n=3), thiol-alkylating agents (n=9), reactives (irritants) (n=8), estrogen receptor agonists (n=9)) were tested for cytotoxicity in the neutralred assay, oxygen consumption in isolated mitochondria, oxygen production in algae, inhibition of AChE, reaction with GSH and activity in the yeast estrogen receptor assay. Data on in-vivo aquatic toxicity (LC50, EC50) towards fish, daphnids, algae and bacteria were collected from the literature for reasons of comparison and reference scaling. In the MOA-specific in-vitro test battery, most test chemicals are specifically active at low concentrations, though multiple effects do occur. Graphical and statistical evaluation of the individual classes versus MOA 1 (non-polar non-specific toxicants) identifies interactions related to predominant MOA. Discriminant analyses (DA) on subsets of the data revealed correct classifications between 70% (in-vivo data) and >90% (in-vitro data). Functional similarity of chemical substances is defined in terms of their (eco)toxicity profiles. Within each MOA class, the compounds share some properties related to the rate-limiting interactions, e.g., steric fit to the target site and/or reactivity with target biomolecules, revealing a specific pattern (fingerprint) of characteristic effects. The successful discrimination of toxicant classes by MOA is based on comprehensive characterization of test chemicals' properties related to interactions with target sites. The suite of aquatic in-vivo tests using fish, daphnids, algae and bacteria covers most acute effects, whilst long-term (latent) impacts are generally neglected. With the MOA-specific in-vitro test battery such distinctions are futile, because it focuses on isolated targets, i.e. it indicates the possible targets of a chemical regardless of the timescale of effects. The data analysis indicates that the in-vitro battery covers most effects in vivo and moreover provides additional aspects of the compounds' MOA. Translating in-vitro effects to in-vivo toxicity requires combining physiological and chemical knowledge about underlying processes. Comparison of the specific in-vitro effects of a compound with the respective sensitivities of aquatic organisms indicates particularly sensitive species. Classifications of toxicants by MOA based on physicochemical descriptors provides insight to interactions and directs to mechanistic QSARs.

Stardust Blazes MOA Trail

NASA Technical Reports Server (NTRS)

Faris, Grant B.; Bryant, Larry W.

2010-01-01

Mission Operations Assurance (MOA) started at the Jet Propulsion Laboratory (JPL) with the Magellan and Galileo missions of the late 80's. It continued to develop and received a significant impetus with the failures of two successive missions to Mars in the late 90's. MOA continued to evolve with each successive project at JPL achieving its current maturity with the Stardust sample return to Earth.

The yield and nutritional value of meat from African ungulates, camelidae, rodents, ratites and reptiles.

PubMed

Hoffman, L C

2008-09-01

The current knowledge of the yield and nutritional (proximate and fatty acid) composition of meat derived from African ungulates, camelidae, rodents, ratites and reptiles is reviewed. Although most of the species discussed give low cholesterol levels consistent with their low meat lipid contents, the tegu lizard gives a very low level (18.2mg/100g tissue). The fatty acid profiles of the various species all have low saturated fatty acids and high polyunsaturated fatty acids resulting in favourable saturated to polyunsaturated fatty acid ratios. Although the springbok, camel, ostrich and crocodile are marketed and exported to sophisticated markets, the rodents are the species that show most promise in becoming large commercial commodities. Not only is their meat desirable and nutritional, but they are also highly adaptable to extensive and intensive production systems.

Evaluation of neural reflex activation as a mode of action for the acute respiratory effects of ozone.

PubMed

Prueitt, Robyn L; Goodman, Julie E

2016-09-01

Exposure to elevated levels of ozone has been associated with a variety of respiratory-related health endpoints in both epidemiology and controlled human exposure studies, including lung function decrements and airway inflammation. A mode of action (MoA) for these effects has not been established, but it has been proposed that they may occur through ozone-induced activation of neural reflexes. We critically reviewed experimental studies of ozone exposure and neural reflex activation and applied the International Programme on Chemical Safety (IPCS) mode-of-action/human relevance framework to evaluate the biological plausibility and human relevance of this proposed MoA. Based on the currently available experimental data, we found that the proposed MoA of neural reflex activation is biologically plausible for the endpoint of ozone-induced lung function decrements at high ozone exposures, but further studies are needed to fill important data gaps regarding the relevance of this MoA at lower exposures. A role for the proposed MoA in ozone-induced airway inflammation is less plausible, as the evidence is conflicting and is also of unclear relevance given the lack of studies conducted at lower exposures. The evidence suggests a different MoA for ozone-induced inflammation that may still be linked to the key events in the proposed MoA, such that neural reflex activation may have some degree of involvement in modulating ozone-induced neutrophil influx, even if it is not a direct role.

Critical concepts in elder abuse research.

PubMed

Goergen, Thomas; Beaulieu, Marie

2013-08-01

This paper identifies core elements in principal definitions of elder abuse or mistreatment of older adults (EA/MOA) and discusses the relevance of four crucial concepts: age, vulnerability, trust, and power balance in relationships. A critical analysis of selected literature in EA/MOA with a focus on works from the last 10 years. Current definitions of EA/MOA share commonalities regarding an understanding of elder abuse as a status offence, the inclusion of both acts and omissions, and the consideration of multiple levels of behavior and its effects. Definitions differ with regard to aspects as crucial as the intentionality of an abusive action and its actual or potential harmful effects. EA/MOA can be considered as a complex subtype of victimization in later life limited to victim-perpetrator relationships, where the perpetrator has assumed responsibility for the victim, the victim puts trust in the offender, or the role assigned to the offending person creates the perception and expectation that the victim may trust the perpetrator. Vulnerability is identified as a key variable in EA/MOA theory and research. With regard to neglect, the mere possibility of being neglected presupposes a heightened level of vulnerability. Power imbalance often characterizes victim - perpetrator relationships but is not a necessary characteristic of abuse. Research on EA/MOA needs conceptual development. Confining phenomena of EA/MOA to specific relationships and tying them to notions of vulnerability has implications for research design and sampling and points to the limits of population-based victimization surveys.

An integrated approach for prospectively investigating a mode-of-action for rodent liver effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

LeBaron, Matthew J., E-mail: MJLeBaron@dow.com; Geter, David R., E-mail: dave.geter@gmail.com; Rasoulpour, Reza J.

Registration of new plant protection products (e.g., herbicide, insecticide, or fungicide) requires comprehensive mammalian toxicity evaluation including carcinogenicity studies in two species. The outcome of the carcinogenicity testing has a significant bearing on the overall human health risk assessment of the substance and, consequently, approved uses for different crops across geographies. In order to understand the relevance of a specific tumor finding to human health, a systematic, transparent, and hypothesis-driven mode of action (MoA) investigation is, appropriately, an expectation by the regulatory agencies. Here, we describe a novel approach of prospectively generating the MoA data by implementing additional end pointsmore » to the standard guideline toxicity studies with sulfoxaflor, a molecule in development. This proactive MoA approach results in a more robust integration of molecular with apical end points while minimizing animal use. Sulfoxaflor, a molecule targeting sap-feeding insects, induced liver effects (increased liver weight due to hepatocellular hypertrophy) in an initial palatability probe study for selecting doses for subsequent repeat-dose dietary studies. This finding triggered the inclusion of dose-response investigations of the potential key events for rodent liver carcinogenesis, concurrent with the hazard assessment studies. As predicted, sulfoxaflor induced liver tumors in rats and mice in the bioassays. The MoA data available by the time of the carcinogenicity finding supported the conclusion that the carcinogenic potential of sulfoxaflor was due to CAR/PXR nuclear receptor activation with subsequent hepatocellular proliferation. This MoA was not considered to be relevant to humans as sulfoxaflor is unlikely to induce hepatocellular proliferation in humans and therefore would not be a human liver carcinogen. - Highlights: • We prospectively generated MoA data into standard guideline toxicity studies. • A proactive MoA approach integrates all end points while minimizing animal use. • MoA data predicted the rodent carcinogenicity of sulfoxaflor via CAR/PXR. • Liver MoA was considered not relevant to humans and hence not a human carcinogen.« less

Determinant of Household Business Scale of Moa Buffaloes at Moa Island Southwest Maluku Regency

NASA Astrophysics Data System (ADS)

Lainsamputty, J.; Roessali, W.; Santosa, S. I.; Eddy, B. T.

2018-02-01

The objective of this research was to analyze factors that affect the business scale of Moa buffaloes at Moa Island, Regency of Southwest Maluku. The research used a survey method with multistage random sampling. The location chosen was the District of Moa Lakor at Moa Island based on its largest buffalo population. Respondents were randomly drawn in a total of 120 respondents. The variables measured were years of experience in rearing animals, costs of production, farmer’s participation in group activities, animal housing systems, farmer’s income and farmer’s age. The statistical test used was the multiple linear regressions. The results showed that the mean of business scale in the area of high density of buffaloes population was 12.6 AU, in the moderate was 12.4 AU and in the low was 11.0 AU. The average of production cost was IDR 1.893.536.00/year, the average of revenue was IDR14.083.333.00/year, while the average of income was IDR 12.189.797.00/year. The independent variables simultaneously influence the business scale (P<0.01). Partially, experience, costs of production, participation and housing systems had highly significant influences on the business scale (P<0.01).

Bone cells in birds show exceptional surface area, a characteristic tracing back to saurischian dinosaurs of the late Triassic.

PubMed

Rensberger, John M; Martínez, Ricardo N

2015-01-01

Dinosaurs are unique among terrestrial tetrapods in their body sizes, which range from less than 3 gm in hummingbirds to 70,000 kg or more in sauropods. Studies of the microstructure of bone tissue have indicated that large dinosaurs, once believed to be slow growing, attained maturity at rates comparable to or greater than those of large mammals. A number of structural criteria in bone tissue have been used to assess differences in rates of osteogenesis in extinct taxa, including counts of lines of arrested growth and the density of vascular canals. Here, we examine the density of the cytoplasmic surface of bone-producing cells, a feature which may set an upper limit to the rate of osteogenesis. Osteocyte lacunae and canaliculi, the cavities in bone containing osteocytes and their extensions, were measured in thin-sections of primary (woven and parallel fibered) bone in a diversity of tetrapods. The results indicate that bone cell surfaces are more densely organized in the Saurischia (extant birds, extinct Mesozoic Theropoda and Sauropodomorpha) than in other tetrapods, a result of denser branching of the cell extensions. The highest postnatal growth rates among extant tetrapods occur in modern birds, the only surviving saurischians, and the finding of exceptional cytoplasmic surface area of the cells that produce bone in this group suggests a relationship with bone growth rate. In support of this relationship is finding the lowest cell surface density among the saurischians examined in Dinornis, a member of a group of ratites that evolved in New Zealand in isolation from mammalian predators and show other evidence of lowered maturation rates.

Bone Cells in Birds Show Exceptional Surface Area, a Characteristic Tracing Back to Saurischian Dinosaurs of the Late Triassic

PubMed Central

Rensberger, John M.; Martínez, Ricardo N.

2015-01-01

Background Dinosaurs are unique among terrestrial tetrapods in their body sizes, which range from less than 3 gm in hummingbirds to 70,000 kg or more in sauropods. Studies of the microstructure of bone tissue have indicated that large dinosaurs, once believed to be slow growing, attained maturity at rates comparable to or greater than those of large mammals. A number of structural criteria in bone tissue have been used to assess differences in rates of osteogenesis in extinct taxa, including counts of lines of arrested growth and the density of vascular canals. Methodology/Principal Findings Here, we examine the density of the cytoplasmic surface of bone-producing cells, a feature which may set an upper limit to the rate of osteogenesis. Osteocyte lacunae and canaliculi, the cavities in bone containing osteocytes and their extensions, were measured in thin-sections of primary (woven and parallel fibered) bone in a diversity of tetrapods. The results indicate that bone cell surfaces are more densely organized in the Saurischia (extant birds, extinct Mesozoic Theropoda and Sauropodomorpha) than in other tetrapods, a result of denser branching of the cell extensions. The highest postnatal growth rates among extant tetrapods occur in modern birds, the only surviving saurischians, and the finding of exceptional cytoplasmic surface area of the cells that produce bone in this group suggests a relationship with bone growth rate. In support of this relationship is finding the lowest cell surface density among the saurischians examined in Dinornis, a member of a group of ratites that evolved in New Zealand in isolation from mammalian predators and show other evidence of lowered maturation rates. PMID:25830561

Mitochondrial and nuclear DNA sequences support a Cretaceous origin of Columbiformes and a dispersal-driven radiation in the Paleocene .

PubMed

Pereira, Sergio L; Johnson, Kevin P; Clayton, Dale H; Baker, Allan J

2007-08-01

Phylogenetic relationships among genera of pigeons and doves (Aves, Columbiformes) have not been fully resolved because of limited sampling of taxa and characters in previous studies. We therefore sequenced multiple nuclear and mitochondrial DNA genes totaling over 9000 bp from 33 of 41 genera plus 8 outgroup taxa, and, together with sequences from 5 other pigeon genera retrieved from GenBank, recovered a strong phylogenetic hypothesis for the Columbiformes. Three major clades were recovered with the combined data set, comprising the basally branching New World pigeons and allies (clade A) that are sister to Neotropical ground doves (clade B), and the Afro-Eurasian and Australasian taxa (clade C). None of these clades supports the monophyly of current families and subfamilies. The extinct, flightless dodo and solitaires (Raphidae) were embedded within pigeons and doves (Columbidae) in clade C, and monophyly of the subfamily Columbinae was refuted because the remaining subfamilies were nested within it. Divergence times estimated using a Bayesian framework suggest that Columbiformes diverged from outgroups such as Apodiformes and Caprimulgiformes in the Cretaceous before the mass extinction that marks the end of this period. Bayesian and maximum likelihood inferences of ancestral areas, accounting for phylogenetic uncertainty and divergence times, respectively, favor an ancient origin of Columbiformes in the Neotropical portion of what was then Gondwana. The radiation of modern genera of Columbiformes started in the Early Eocene to the Middle Miocene, as previously estimated for other avian groups such as ratites, tinamous, galliform birds, penguins, shorebirds, parrots, passerine birds, and toucans. Multiple dispersals of more derived Columbiformes between Australasian and Afro-Eurasian regions are required to explain current distributions.

Machine learning algorithms for mode-of-action classification in toxicity assessment.

PubMed

Zhang, Yile; Wong, Yau Shu; Deng, Jian; Anton, Cristina; Gabos, Stephan; Zhang, Weiping; Huang, Dorothy Yu; Jin, Can

2016-01-01

Real Time Cell Analysis (RTCA) technology is used to monitor cellular changes continuously over the entire exposure period. Combining with different testing concentrations, the profiles have potential in probing the mode of action (MOA) of the testing substances. In this paper, we present machine learning approaches for MOA assessment. Computational tools based on artificial neural network (ANN) and support vector machine (SVM) are developed to analyze the time-concentration response curves (TCRCs) of human cell lines responding to tested chemicals. The techniques are capable of learning data from given TCRCs with known MOA information and then making MOA classification for the unknown toxicity. A novel data processing step based on wavelet transform is introduced to extract important features from the original TCRC data. From the dose response curves, time interval leading to higher classification success rate can be selected as input to enhance the performance of the machine learning algorithm. This is particularly helpful when handling cases with limited and imbalanced data. The validation of the proposed method is demonstrated by the supervised learning algorithm applied to the exposure data of HepG2 cell line to 63 chemicals with 11 concentrations in each test case. Classification success rate in the range of 85 to 95 % are obtained using SVM for MOA classification with two clusters to cases up to four clusters. Wavelet transform is capable of capturing important features of TCRCs for MOA classification. The proposed SVM scheme incorporated with wavelet transform has a great potential for large scale MOA classification and high-through output chemical screening.

Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent Chromium

PubMed Central

Thompson, Chad M.; Haws, Laurie C.; Harris, Mark A.; Gatto, Nicole M.; Proctor, Deborah M.

2011-01-01

Mode of action (MOA) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human health risk assessment. Uncertainties and data gaps identified in the MOA analysis may also be used to guide future research to improve understanding of the MOAs underlying a specific toxic response and foster development of toxicokinetic and toxicodynamic models. An MOA analysis, consistent with approaches outlined in the MOA Framework as described in the Guidelines for Carcinogen Risk Assessment, was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium (Cr(VI)) in drinking water. Based on review of the literature, key events in the MOA are hypothesized to include saturation of the reductive capacity of the upper gastrointestinal tract, absorption of Cr(VI) into the intestinal epithelium, oxidative stress and inflammation, cell proliferation, direct and/or indirect DNA modification, and mutagenesis. Although available data generally support the plausibility of these key events, several unresolved questions and data gaps were identified, highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range. Experimental assays that can address these data gaps are discussed along with strategies for comparisons between responsive and nonresponsive tissues and species. This analysis provides a practical application of MOA Framework guidance and is instructive for the design of studies to improve upon the information available for quantitative risk assessment. PMID:20947717

5-Methoxyl Aesculetin Abrogates Lipopolysaccharide-Induced Inflammation by Suppressing MAPK and AP-1 Pathways in RAW 264.7 Cells

PubMed Central

Wu, Lei; Li, Xueqin; Wu, Haifeng; Long, Wei; Jiang, Xiaojian; Shen, Ting; Qiang, Qian; Si, Chuanling; Wang, Xinfeng; Jiang, Yunyao; Hu, Weicheng

2016-01-01

For the first time, a pale amorphous coumarin derivative, 5-methoxyl aesculetin (MOA), was isolated from the dried bark of Fraxinus rhynchophylla Hance (Oleaceae). MOA modulates cytokine expression in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages, but the precise mechanisms are still not fully understood. We determined the effects of MOA on the production of inflammatory mediators and pro-inflammatory cytokines in the LPS-induced inflammatory responses of RAW 264.7 macrophages. MOA significantly inhibited the LPS-induced production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-6, and interleukin-1β. It also effectively attenuated inducible nitric oxide (NO) synthase, cyclooxygenase-2, and TNF-α mRNA expression and significantly decreased the levels of intracellular reactive oxygen species. It inhibited phosphorylation of the extracellular signal-regulated kinase (ERK1/2), thus blocking nuclear translocation of activation protein (AP)-1. In a molecular docking study, MOA was shown to target the binding site of ERK via the formation of three hydrogen bonds with two residues of the kinase, which is sufficient for the inhibition of ERK. These results suggest that the anti-inflammatory effects of MOA in RAW 264.7 macrophages derive from its ability to block both the activation of mitogen-activated protein kinases (MAPKs) and one of their downstream transcription factors, activator protein-1 (AP-1). Our observations support the need for further research into MOA as a promising therapeutic agent in inflammatory diseases. PMID:26938526

Ratite oils promote keratinocyte cell growth and inhibit leukocyte activation

PubMed Central

Bennett, Darin C.; Leung, Gigi; Wang, Eddy; Ma, Sam; Lo, Blanche K. K.; McElwee, Kevin J.; Cheng, Kimberly M.

2015-01-01

Traditionally, native Australian aborigines have used emu oil for the treatment of inflammation and to accelerate wound healing. Studies on mice suggest that topically applied emu oil may have anti-inflammatory properties and may promote wound healing. We investigated the effects of ratite oils (6 emu, 3 ostrich, 1 rhea) on immortalized human keratinocytes (HaCaT cells) in vitro by culturing the cells in media with oil concentrations of 0%, 0.5%, and 1.0%. Peking duck, tea tree, and olive oils were used as comparative controls. The same oils at 0.5% concentration were evaluated for their influence on peripheral blood mononuclear cell (PBMC) survival over 48 hr and their ability to inhibit IFNγ production in PBMCs activated by phytohemagglutinin (PHA) in ELISpot assays. Compared to no oil control, significantly shorter population doubling time durations were observed for HaCaT cells cultured in emu oil (1.51 × faster), ostrich oil (1.46 × faster), and rhea oil (1.64 × faster). Tea tree oil demonstrated significant antiproliferative activity and olive oil significantly prolonged (1.35 × slower) cell population doubling time. In contrast, almost all oils, particularly tea tree oil, significantly reduced PBMC viability. Different oils had different levels of inhibitory effect on IFNγ production with individual emu, ostrich, rhea, and duck oil samples conferring full inhibition. This preliminary investigation suggests that emu oil might promote wound healing by accelerating the growth rate of keratinocytes. Combined with anti-inflammatory properties, ratite oil may serve as a useful component in bandages and ointments for the treatment of wounds and inflammatory skin conditions. PMID:26217022

Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator

PubMed Central

Elcombe, Clifford R.; Peffer, Richard C.; Wolf, Douglas C.; Bailey, Jason; Bars, Remi; Bell, David; Cattley, Russell C.; Ferguson, Stephen S.; Geter, David; Goetz, Amber; Goodman, Jay I.; Hester, Susan; Jacobs, Abigail; Omiecinski, Curtis J.; Schoeny, Rita; Xie, Wen; Lake, Brian G.

2014-01-01

The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk. PMID:24180433

Combination of a proteomics approach and reengineering of meso scale network models for prediction of mode-of-action for tyrosine kinase inhibitors.

PubMed

Balabanov, Stefan; Wilhelm, Thomas; Venz, Simone; Keller, Gunhild; Scharf, Christian; Pospisil, Heike; Braig, Melanie; Barett, Christine; Bokemeyer, Carsten; Walther, Reinhard; Brümmendorf, Tim H; Schuppert, Andreas

2013-01-01

In drug discovery, the characterisation of the precise modes of action (MoA) and of unwanted off-target effects of novel molecularly targeted compounds is of highest relevance. Recent approaches for identification of MoA have employed various techniques for modeling of well defined signaling pathways including structural information, changes in phenotypic behavior of cells and gene expression patterns after drug treatment. However, efficient approaches focusing on proteome wide data for the identification of MoA including interference with mutations are underrepresented. As mutations are key drivers of drug resistance in molecularly targeted tumor therapies, efficient analysis and modeling of downstream effects of mutations on drug MoA is a key to efficient development of improved targeted anti-cancer drugs. Here we present a combination of a global proteome analysis, reengineering of network models and integration of apoptosis data used to infer the mode-of-action of various tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) cell lines expressing wild type as well as TKI resistance conferring mutants of BCR-ABL. The inferred network models provide a tool to predict the main MoA of drugs as well as to grouping of drugs with known similar kinase inhibitory activity patterns in comparison to drugs with an additional MoA. We believe that our direct network reconstruction approach, demonstrated on proteomics data, can provide a complementary method to the established network reconstruction approaches for the preclinical modeling of the MoA of various types of targeted drugs in cancer treatment. Hence it may contribute to the more precise prediction of clinically relevant on- and off-target effects of TKIs.

Combination of a Proteomics Approach and Reengineering of Meso Scale Network Models for Prediction of Mode-of-Action for Tyrosine Kinase Inhibitors

PubMed Central

Balabanov, Stefan; Wilhelm, Thomas; Venz, Simone; Keller, Gunhild; Scharf, Christian; Pospisil, Heike; Braig, Melanie; Barett, Christine; Bokemeyer, Carsten; Walther, Reinhard

2013-01-01

In drug discovery, the characterisation of the precise modes of action (MoA) and of unwanted off-target effects of novel molecularly targeted compounds is of highest relevance. Recent approaches for identification of MoA have employed various techniques for modeling of well defined signaling pathways including structural information, changes in phenotypic behavior of cells and gene expression patterns after drug treatment. However, efficient approaches focusing on proteome wide data for the identification of MoA including interference with mutations are underrepresented. As mutations are key drivers of drug resistance in molecularly targeted tumor therapies, efficient analysis and modeling of downstream effects of mutations on drug MoA is a key to efficient development of improved targeted anti-cancer drugs. Here we present a combination of a global proteome analysis, reengineering of network models and integration of apoptosis data used to infer the mode-of-action of various tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) cell lines expressing wild type as well as TKI resistance conferring mutants of BCR-ABL. The inferred network models provide a tool to predict the main MoA of drugs as well as to grouping of drugs with known similar kinase inhibitory activity patterns in comparison to drugs with an additional MoA. We believe that our direct network reconstruction approach, demonstrated on proteomics data, can provide a complementary method to the established network reconstruction approaches for the preclinical modeling of the MoA of various types of targeted drugs in cancer treatment. Hence it may contribute to the more precise prediction of clinically relevant on- and off-target effects of TKIs. PMID:23326482

Isoleucine epimerization and amino acid composition in molecular-weight separations of Pleistocene Genyornis eggshell

NASA Astrophysics Data System (ADS)

Kaufman, Darrell S.; Miller, Gifford H.

1995-07-01

This study explores the geochronological utility and analytical reproducibility of separating the high-molecular-weight fraction (HMW) from eggshells of the extinct late Pleistocene ratite, Genyornis, using disposable, prepacked gel-filtration columns. The superior integrity of ratite eggshell for the retention of amino acids indicates that this biomineral is better suited for this type of investigation than previously studied molluscan shell. To evaluate the reproducibility of the gel-filtration technique, we analyzed triplicate subsamples of three eggshells of different ages. The reproducibility, based on the average intrashell variation (coefficient of variation; CV) in the extent of isoleucine epimerization (aIle/Ile) in the HMW (enriched in molecules ca. >10,000 MW) is 3%, well within the range appropriate for geochronological purposes. The average intrashell variation in the total amino acid concentration (Σ[aa]) of the HMW is 5%, somewhat better than for the total acid hydrolysate (TOTAL) of the same samples (7%). To evaluate the relation between molecular weight and the rate of isoleucine epimerization, three molecular-weight fractions were separated using gel filtration, plus the naturally hydrolyzed free fraction (FREE), for each of four fossil eggshells. AIle/Ile increases with decreasing molecular weight in all shells, with a ca. sixfold to ninefold difference in ratios between the HMW andFREE, and a ca. fivefold difference between the HMW andTOTAL. Although linear correlations between aIle/Ile measured in each molecular-weight fraction and in theTOTAL are all highly significant (r ⩾ 0.951), the relation between the extent of epimerization in the HMW and in the TOTAL is best expressed as an exponential function (r = 0.951). This relation is consistent with the idea that, as the epimerization reaction approaches equilibrium in theTOTAL (ca. aIle/Ile > 1.1), its rate decreases beyond that of the HMW. The amino acid composition (relative percent of eight amino acids or combinations of amino acids) is more uniform in the HMW of the four samples compared to lower-molecular-weight fractions. The greater "compositional stability" of the HMW indicates that it contains a residuum of macromolecules that have not been affected by the diagenetically driven changes observed in lower-molecular-weight fractions.

Deciphering the complete mitochondrial genome and phylogeny of the extinct cave bear in the Paleolithic painted cave of Chauvet.

PubMed

Bon, Céline; Caudy, Nicolas; de Dieuleveult, Maud; Fosse, Philippe; Philippe, Michel; Maksud, Frédéric; Beraud-Colomb, Eliane; Bouzaid, Eric; Kefi, Rym; Laugier, Christelle; Rousseau, Bernard; Casane, Didier; van der Plicht, Johannes; Elalouf, Jean-Marc

2008-11-11

Retrieving a large amount of genetic information from extinct species was demonstrated feasible, but complete mitochondrial genome sequences have only been deciphered for the moa, a bird that became extinct a few hundred years ago, and for Pleistocene species, such as the woolly mammoth and the mastodon, both of which could be studied from animals embedded in permafrost. To enlarge the diversity of mitochondrial genomes available for Pleistocene species, we turned to the cave bear (Ursus spelaeus), whose only remains consist of skeletal elements. We collected bone samples from the Paleolithic painted cave of Chauvet-Pont d'Arc (France), which displays the earliest known human drawings, and contains thousands of bear remains. We selected a cave bear sternebra, radiocarbon dated to 32,000 years before present, from which we generated overlapping DNA fragments assembling into a 16,810-base pair mitochondrial genome. Together with the first mitochondrial genome for the brown bear western lineage, this study provides a statistically secured molecular phylogeny assessing the cave bear as a sister taxon to the brown bear and polar bear clade, with a divergence inferred to 1.6 million years ago. With the first mitochondrial genome for a Pleistocene carnivore to be delivered, our study establishes the Chauvet-Pont d'Arc Cave as a new reservoir for Paleogenetic studies. These molecular data enable establishing the chronology of bear speciation, and provide a helpful resource to rescue for genetic analysis archeological samples initially diagnosed as devoid of amplifiable DNA.

Deciphering the complete mitochondrial genome and phylogeny of the extinct cave bear in the Paleolithic painted cave of Chauvet

PubMed Central

Bon, Céline; Caudy, Nicolas; de Dieuleveult, Maud; Fosse, Philippe; Philippe, Michel; Maksud, Frédéric; Beraud-Colomb, Éliane; Bouzaid, Eric; Kefi, Rym; Laugier, Christelle; Rousseau, Bernard; Casane, Didier; van der Plicht, Johannes; Elalouf, Jean-Marc

2008-01-01

Retrieving a large amount of genetic information from extinct species was demonstrated feasible, but complete mitochondrial genome sequences have only been deciphered for the moa, a bird that became extinct a few hundred years ago, and for Pleistocene species, such as the woolly mammoth and the mastodon, both of which could be studied from animals embedded in permafrost. To enlarge the diversity of mitochondrial genomes available for Pleistocene species, we turned to the cave bear (Ursus spelaeus), whose only remains consist of skeletal elements. We collected bone samples from the Paleolithic painted cave of Chauvet-Pont d'Arc (France), which displays the earliest known human drawings, and contains thousands of bear remains. We selected a cave bear sternebra, radiocarbon dated to 32,000 years before present, from which we generated overlapping DNA fragments assembling into a 16,810-base pair mitochondrial genome. Together with the first mitochondrial genome for the brown bear western lineage, this study provides a statistically secured molecular phylogeny assessing the cave bear as a sister taxon to the brown bear and polar bear clade, with a divergence inferred to 1.6 million years ago. With the first mitochondrial genome for a Pleistocene carnivore to be delivered, our study establishes the Chauvet-Pont d'Arc Cave as a new reservoir for Paleogenetic studies. These molecular data enable establishing the chronology of bear speciation, and provide a helpful resource to rescue for genetic analysis archeological samples initially diagnosed as devoid of amplifiable DNA. PMID:18955696

Development and evaluation of a microdevice for amino acid biomarker detection and analysis on Mars

PubMed Central

Skelley, Alison M.; Scherer, James R.; Aubrey, Andrew D.; Grover, William H.; Ivester, Robin H. C.; Ehrenfreund, Pascale; Grunthaner, Frank J.; Bada, Jeffrey L.; Mathies, Richard A.

2005-01-01

The Mars Organic Analyzer (MOA), a microfabricated capillary electrophoresis (CE) instrument for sensitive amino acid biomarker analysis, has been developed and evaluated. The microdevice consists of a four-wafer sandwich combining glass CE separation channels, microfabricated pneumatic membrane valves and pumps, and a nanoliter fluidic network. The portable MOA instrument integrates high voltage CE power supplies, pneumatic controls, and fluorescence detection optics necessary for field operation. The amino acid concentration sensitivities range from micromolar to 0.1 nM, corresponding to part-per-trillion sensitivity. The MOA was first used in the lab to analyze soil extracts from the Atacama Desert, Chile, detecting amino acids ranging from 10–600 parts per billion. Field tests of the MOA in the Panoche Valley, CA, successfully detected amino acids at 70 parts per trillion to 100 parts per billion in jarosite, a sulfate-rich mineral associated with liquid water that was recently detected on Mars. These results demonstrate the feasibility of using the MOA to perform sensitive in situ amino acid biomarker analysis on soil samples representative of a Mars-like environment. PMID:15657130

Development and evaluation of a microdevice for amino acid biomarker detection and analysis on Mars.

PubMed

Skelley, Alison M; Scherer, James R; Aubrey, Andrew D; Grover, William H; Ivester, Robin H C; Ehrenfreund, Pascale; Grunthaner, Frank J; Bada, Jeffrey L; Mathies, Richard A

2005-01-25

The Mars Organic Analyzer (MOA), a microfabricated capillary electrophoresis (CE) instrument for sensitive amino acid biomarker analysis, has been developed and evaluated. The microdevice consists of a four-wafer sandwich combining glass CE separation channels, microfabricated pneumatic membrane valves and pumps, and a nanoliter fluidic network. The portable MOA instrument integrates high voltage CE power supplies, pneumatic controls, and fluorescence detection optics necessary for field operation. The amino acid concentration sensitivities range from micromolar to 0.1 nM, corresponding to part-per-trillion sensitivity. The MOA was first used in the lab to analyze soil extracts from the Atacama Desert, Chile, detecting amino acids ranging from 10-600 parts per billion. Field tests of the MOA in the Panoche Valley, CA, successfully detected amino acids at 70 parts per trillion to 100 parts per billion in jarosite, a sulfate-rich mineral associated with liquid water that was recently detected on Mars. These results demonstrate the feasibility of using the MOA to perform sensitive in situ amino acid biomarker analysis on soil samples representative of a Mars-like environment.

Siting, design and operational controls for snow disposal sites.

PubMed

Wheaton, S R; Rice, W J

2003-01-01

The Municipality of Anchorage (MOA), at 61 degrees north latitude, ploughs and hauls snow from urban streets throughout the winter, incorporating grit and chloride applied to street surfaces for traffic safety. Hauled snow is stored at snow disposal facilities, where it melts at ambient spring temperatures. MOA studies performed from 1998 through 2001 show that disposal site melt processes can be manipulated, through site design and operation practices, to control chloride and turbidity in meltwater. An experimental passive "V-swale" pad configuration tested by MOA investigators reduced site meltwater turbidity by an order of magnitude (to about 50 NTU from the 500 NTU typical of more conventional planar pad geometry). The MOA has developed new siting, design and operational criteria for snow disposal facilities to conform to the tested V-swale pad configuration.

Military Governorship as a Solution to the Insurgency Problem in Southern Philippines

DTIC Science & Technology

2012-03-01

Governor Al Rasheed Sakalahul would go on further in quipping that “only goats report to the Municipal Hall” in Basilan.67 To curb this problem, the...comprehensive discussion of the MOA-AD see Fr. Eliseo Mercado OMI, “MOA-AD: Quo Vadis,” Autonomy and Peace Review 4, no. 3 (2008): 9 – 20, accessed...documents/ADRRN_ChallengesTo HumanSecurityInComplexSituations_TheCaseOfConflictInTheSouthernPhilippin es.pdf Mercado OMI, Fr. Eliseo. “MOA-AD: Quo

33 CFR 337.4 - Memoranda of Agreement (MOA).

Code of Federal Regulations, 2010 CFR

2010-07-01

... eliminate administrative duplication, when such duplication does not contribute to the overall decision-making process. MOAs for purposes of this regulation will not be used to implement provisions not related...

Ratite oils promote keratinocyte cell growth and inhibit leukocyte activation.

PubMed

Bennett, Darin C; Leung, Gigi; Wang, Eddy; Ma, Sam; Lo, Blanche K K; McElwee, Kevin J; Cheng, Kimberly M

2015-09-01

Traditionally, native Australian aborigines have used emu oil for the treatment of inflammation and to accelerate wound healing. Studies on mice suggest that topically applied emu oil may have anti-inflammatory properties and may promote wound healing. We investigated the effects of ratite oils (6 emu, 3 ostrich, 1 rhea) on immortalized human keratinocytes (HaCaT cells) in vitro by culturing the cells in media with oil concentrations of 0%, 0.5%, and 1.0%. Peking duck, tea tree, and olive oils were used as comparative controls. The same oils at 0.5% concentration were evaluated for their influence on peripheral blood mononuclear cell (PBMC) survival over 48 hr and their ability to inhibit IFNγ production in PBMCs activated by phytohemagglutinin (PHA) in ELISpot assays. Compared to no oil control, significantly shorter population doubling time durations were observed for HaCaT cells cultured in emu oil (1.51×faster), ostrich oil (1.46×faster), and rhea oil (1.64×faster). Tea tree oil demonstrated significant antiproliferative activity and olive oil significantly prolonged (1.35×slower) cell population doubling time. In contrast, almost all oils, particularly tea tree oil, significantly reduced PBMC viability. Different oils had different levels of inhibitory effect on IFNγ production with individual emu, ostrich, rhea, and duck oil samples conferring full inhibition. This preliminary investigation suggests that emu oil might promote wound healing by accelerating the growth rate of keratinocytes. Combined with anti-inflammatory properties, ratite oil may serve as a useful component in bandages and ointments for the treatment of wounds and inflammatory skin conditions. © 2015 Poultry Science Association Inc.

Natural Compounds as Next-Generation Herbicides

PubMed Central

Dayan, Franck E.; Duke, Stephen O.

2014-01-01

Herbicides with new modes of action (MOAs) are badly needed due to the rapidly evolving resistance to commercial herbicides, but a new MOA has not been introduced in over 20 years. The greatest pest management challenge for organic agriculture is the lack of effective natural product herbicides. The structural diversity and evolved biological activity of natural phytotoxins offer opportunities for the development of both directly used natural compounds and synthetic herbicides with new target sites based on the structures of natural phytotoxins. Natural phytotoxins are also a source for the discovery of new herbicide target sites that can serve as the focus of traditional herbicide discovery efforts. There are many examples of strong natural phytotoxins with MOAs other than those used by commercial herbicides, which indicates that there are molecular targets of herbicides that can be added to the current repertoire of commercial herbicide MOAs. PMID:24784133

High-internal-phase emulsions stabilized by metal-organic frameworks and derivation of ultralight metal-organic aerogels

PubMed Central

Zhang, Bingxing; Zhang, Jianling; Liu, Chengcheng; Peng, Li; Sang, Xinxin; Han, Buxing; Ma, Xue; Luo, Tian; Tan, Xiuniang; Yang, Guanying

2016-01-01

To design high-internal-phase emulsion (HIPE) systems is of great interest from the viewpoints of both fundamental researches and practical applications. Here we demonstrate for the first time the utilization of metal-organic framework (MOF) for HIPE formation. By stirring the mixture of water, oil and MOF at room temperature, the HIPE stabilized by the assembly of MOF nanocrystals at oil-water interface could be formed. The MOF-stabilized HIPE provides a novel route to produce highly porous metal-organic aerogel (MOA) monolith. After removing the liquids from the MOF-stabilized HIPE, the ultralight MOA with density as low as 0.01 g·cm−3 was obtained. The HIPE approach for MOA formation has unique advantages and is versatile in producing different kinds of ultralight MOAs with tunable porosities and structures. PMID:26892258

Natural compounds as next-generation herbicides.

PubMed

Dayan, Franck E; Duke, Stephen O

2014-11-01

Herbicides with new modes of action (MOAs) are badly needed due to the rapidly evolving resistance to commercial herbicides, but a new MOA has not been introduced in over 20 years. The greatest pest management challenge for organic agriculture is the lack of effective natural product herbicides. The structural diversity and evolved biological activity of natural phytotoxins offer opportunities for the development of both directly used natural compounds and synthetic herbicides with new target sites based on the structures of natural phytotoxins. Natural phytotoxins are also a source for the discovery of new herbicide target sites that can serve as the focus of traditional herbicide discovery efforts. There are many examples of strong natural phytotoxins with MOAs other than those used by commercial herbicides, which indicates that there are molecular targets of herbicides that can be added to the current repertoire of commercial herbicide MOAs. © 2014 American Society of Plant Biologists. All Rights Reserved.

Hypothesis-based weight-of-evidence evaluation and risk assessment for naphthalene carcinogenesis

PubMed Central

Bailey, Lisa A.; Nascarella, Marc A.; Kerper, Laura E.; Rhomberg, Lorenz R.

2016-01-01

Inhalation of naphthalene causes olfactory epithelial nasal tumors in rats (but not in mice) and benign lung adenomas in mice (but not in rats). The limited available human data have not identified an association between naphthalene exposure and increased respiratory cancer risk. Assessing naphthalene's carcinogenicity in humans, therefore, depends entirely on experimental evidence from rodents. We evaluated the respiratory carcinogenicity of naphthalene in rodents, and its potential relevance to humans, using our Hypothesis-Based Weight-of-Evidence (HBWoE) approach. We systematically and comparatively reviewed data relevant to key elements in the hypothesized modes of action (MoA) to determine which is best supported by the available data, allowing all of the data from each realm of investigation to inform interpretation of one another. Our analysis supports a mechanism that involves initial metabolism of naphthalene to the epoxide, followed by GSH depletion, cytotoxicity, chronic inflammation, regenerative hyperplasia, and tumor formation, with possible weak genotoxicity from downstream metabolites occurring only at high cytotoxic doses, strongly supporting a non-mutagenic threshold MoA in the rat nose. We also conducted a dose–response analysis, based on the likely MoA, which suggests that the rat nasal MoA is not relevant in human respiratory tissues at typical environmental exposures. Our analysis illustrates how a thorough WoE evaluation can be used to support a MoA, even when a mechanism of action cannot be fully elucidated. A non-mutagenic threshold MoA for naphthalene-induced rat nasal tumors should be considered as a basis to determine human relevance and to guide regulatory and risk-management decisions. PMID:26202831

Chemogenomics approaches to rationalizing the mode-of-action of traditional Chinese and Ayurvedic medicines.

PubMed

Mohd Fauzi, Fazlin; Koutsoukas, Alexios; Lowe, Robert; Joshi, Kalpana; Fan, Tai-Ping; Glen, Robert C; Bender, Andreas

2013-03-25

Traditional Chinese medicine (TCM) and Ayurveda have been used in humans for thousands of years. While the link to a particular indication has been established in man, the mode-of-action (MOA) of the formulations often remains unknown. In this study, we aim to understand the MOA of formulations used in traditional medicine using an in silico target prediction algorithm, which aims to predict protein targets (and hence MOAs), given the chemical structure of a compound. Following this approach we were able to establish several links between suggested MOAs and experimental evidence. In particular, compounds from the 'tonifying and replenishing medicinal' class from TCM exhibit a hypoglycemic effect which can be related to activity of the ingredients against the Sodium-Glucose Transporters (SGLT) 1 and 2 as well as Protein Tyrosine Phosphatase (PTP). Similar results were obtained for Ayurvedic anticancer drugs. Here, both primary anticancer targets (those directly involved in cancer pathogenesis) such as steroid-5-alpha-reductase 1 and 2 were predicted as well as targets which act synergistically with the primary target, such as the efflux pump P-glycoprotein (P-gp). In addition, we were able to elucidate some targets which may point us to novel MOAs as well as explain side effects. Most notably, GPBAR1, which was predicted as a target for both 'tonifying and replenishing medicinal' and anticancer classes, suggests an influence of the compounds on metabolism. Understanding the MOA of these compounds is beneficial as it provides a resource for NMEs with possibly higher efficacy in the clinic than those identified by single-target biochemical assays.

Identification of transcriptional networks involved in peroxisome proliferator chemical-induced hepatocyte proliferation

EPA Science Inventory

Peroxisome proliferator chemical (PPC) exposure leads to increases in rodent liver tumors through a non-genotoxic mode of action (MOA). The PPC MOA includes increased oxidative stress, hepatocyte proliferation and decreased apoptosis. We investigated the putative genetic regulato...

WFIRST: Searching for Microlens Planets in Very Wide Orbits and the MOA Microlensing Data Release

NASA Astrophysics Data System (ADS)

Hirao, Yuki; Bennett, David; Sumi, Takahiro; MOA Collaboration

2018-01-01

Gravitational microlensing is an unique technique to detect exoplanets down to low mass planets beyond the snow line because it is sensitive to planets orbiting near the Einstein ring radius of a few AU away from its host star, which is complementary to the other methods. Detecting such planets are important for understanding the formation of our solar system because gas giants and ice giants planets are believed to be formed beyond the snow line, where the protoplanetary disk is cold enough for ice to condense, in the core accretion theory. Microlensing Observations in Astrophysics (MOA) group has conducted high cadence survey observations towards the Galactic bulge to detect exoplanets since 2006 at Mt.John University Observatory in NZ using MOA-II 1.8 meter telescope equipped with a very wide field-of-view MOA-cam3 CCD camera. MOA has alerted about 600 microlensing events every year and detected dozens of exoplanets in wide orbits. Future space telescope, WFIRST will conduct survey observations towards the Galactic bulge and is expected to detect thousands of planets in wide orbit via microlensing to complete the census of exoplanets begun by Kepler Space telescope which found planets in close orbits via transit method. To contribute to the WFIRST and make the microlensing community larger, MOA will open its data from 2006 to 2014 to the public. Through the off-line analysis, we have found some short binary events which were not detected in the real time analysis. Short-timescale microlensing events are important because they are candidates of free-floating or wide-separation planets. The poster will present the data release and some results of the analysis of short-timescale binary events.

Horizontal acquisition of a hypoxia-responsive molybdenum cofactor biosynthesis pathway contributed to Mycobacterium tuberculosis pathoadaptation.

PubMed

Levillain, Florence; Poquet, Yannick; Mallet, Ludovic; Mazères, Serge; Marceau, Michael; Brosch, Roland; Bange, Franz-Christoph; Supply, Philip; Magalon, Axel; Neyrolles, Olivier

2017-11-01

The unique ability of the tuberculosis (TB) bacillus, Mycobacterium tuberculosis, to persist for long periods of time in lung hypoxic lesions chiefly contributes to the global burden of latent TB. We and others previously reported that the M. tuberculosis ancestor underwent massive episodes of horizontal gene transfer (HGT), mostly from environmental species. Here, we sought to explore whether such ancient HGT played a part in M. tuberculosis evolution towards pathogenicity. We were interested by a HGT-acquired M. tuberculosis-specific gene set, namely moaA1-D1, which is involved in the biosynthesis of the molybdenum cofactor. Horizontal acquisition of this gene set was striking because homologues of these moa genes are present all across the Mycobacterium genus, including in M. tuberculosis. Here, we discovered that, unlike their paralogues, the moaA1-D1 genes are strongly induced under hypoxia. In vitro, a M. tuberculosis moaA1-D1-null mutant has an impaired ability to respire nitrate, to enter dormancy and to survive in oxygen-limiting conditions. Conversely, heterologous expression of moaA1-D1 in the phylogenetically closest non-TB mycobacterium, Mycobacterium kansasii, which lacks these genes, improves its capacity to respire nitrate and grants it with a marked ability to survive oxygen depletion. In vivo, the M. tuberculosis moaA1-D1-null mutant shows impaired survival in hypoxic granulomas in C3HeB/FeJ mice, but not in normoxic lesions in C57BL/6 animals. Collectively, our results identify a novel pathway required for M. tuberculosis resistance to host-imposed stress, namely hypoxia, and provide evidence that ancient HGT bolstered M. tuberculosis evolution from an environmental species towards a pervasive human-adapted pathogen.

9 CFR 93.105 - Inspection at the port of entry.

Code of Federal Regulations, 2010 CFR

2010-01-01

... IMPORTATION OF CERTAIN ANIMALS, BIRDS, FISH, AND POULTRY, AND CERTAIN ANIMAL, BIRD, AND POULTRY PRODUCTS; REQUIREMENTS FOR MEANS OF CONVEYANCE AND SHIPPING CONTAINERS Birds § 93.105 Inspection at the port of entry. (a) All commercial birds, zoological birds, and research birds, including hatching eggs of ratites, but...

Ochratoxin a and mitotic disruption: mode of action analysis of renal tumor formation by ochratoxin A.

PubMed

Mally, Angela

2012-06-01

The mycotoxin and food contaminant ochratoxin A (OTA) is a potent renal carcinogen in rodents, but its mode of action (MoA) is still poorly defined. In 2006, the European Food Safety Authority concluded that there is a "lack of evidence for the existence of OTA-DNA adducts" and thus insufficient evidence to establish DNA reactivity as a MoA for tumor formation by OTA. In reviewing the available database on OTA toxicity, a MoA for renal carcinogenicity of OTA is developed that involves a combination of genetic instability and increased proliferative drive as consequences of OTA-mediated disruption of mitosis, whereby the organ- and site-specificity of tumor formation by OTA is determined by selective renal uptake of OTA into the proximal tubule epithelium. The proposed MoA is critically assessed with respect to concordance of dose-response of the suggested key events and tumor formation, their temporal association, consistency, and biological plausibility. Uncertainties, data gaps and needs for further research are highlighted.

Mode of Action Profiles for Pesticide Compounds with Rodent Liver Tumor Outcomes

EPA Science Inventory

Mode of action (MOA) provides a central framework for assessing human relevance of adverse health outcomes observed in nonclinical safety studies. The goal of this study was to characterize MOA profiles for known rodent liver tumorigens identified from a database of pesticides as...

The growing need for biochemical bioherbicides

USDA-ARS?s Scientific Manuscript database

The volume of herbicide use outpaces that of other pesticides. Evolution of resistance to the currently used herbicides has greatly increased the need for new modes of action (MOAs). More than 20 years have passed since the last new herbicide MOA was introduced. Natural products offer a source of...

U.S. EPA framework for determining mutagenic mode of action for carcinogens

EPA Science Inventory

U.S. EPA's Guidelines for Carcinogen Risk Assessment (Cancer Guidelines) specify that information on a chemical's mode of action (MOA) is key to the risk assessment process. MOA determines conditions under which a chemical is considered to be carcinogenic, appropriate low dose ex...

A Critical Review of Mode of Action (MOA) Assignment Classifications for Ecotoxicology

EPA Science Inventory

There are various structure-based classification schemes to categorize chemicals based on mode of action (MOA) which have been applied for both eco and human health toxicology. With increasing calls to assess thousands of chemicals, some of which have little available informatio...

Multichannel Mars Organic Analyzer (McMOA): Microfluidic Networks for the Automated In Situ Microchip Electrophoretic Analysis of Organic Biomarkers on Mars

NASA Astrophysics Data System (ADS)

Chiesl, T. N.; Benhabib, M.; Stockton, A. M.; Mathies, R. A.

2010-04-01

We present the Multichannel Mars Organic Analyzer (McMOA) for the analysis of Amino Acids, PAHs, and Oxidized Carbon. Microfluidic architecures integrating automated metering, mixing, on chip reactions, and serial dilutions are also discussed.

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

PubMed Central

Proctor, Deborah M.; Suh, Mina; Haws, Laurie C.; Kirman, Christopher R.; Harris, Mark A.

2013-01-01

Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors. PMID:23445218

Comparative analysis of pharmaceuticals versus industrial chemicals acute aquatic toxicity classification according to the United Nations classification system for chemicals. Assessment of the (Q)SAR predictability of pharmaceuticals acute aquatic toxicity and their predominant acute toxic mode-of-action.

PubMed

Sanderson, Hans; Thomsen, Marianne

2009-06-01

Pharmaceuticals have been reported to be ubiquitously present in surface waters prompting concerns of effects of these bioactive substances. Meanwhile, there is a general scarcity of publicly available ecotoxicological data concerning pharmaceuticals. The aim of this paper was to compile a comprehensive database based on OECD's standardized measured ecotoxicological data and to evaluate if there is generally cause of greater concern with regards to pharmaceutical aquatic toxicological profiles relative to industrial chemicals. Comparisons were based upon aquatic ecotoxicity classification under the United Nations Global Harmonized System for classification and labeling of chemicals (GHS). Moreover, we statistically explored whether the predominant mode-of-action (MOA) for pharmaceuticals is narcosis. We found 275 pharmaceuticals with 569 acute aquatic effect data; 23 pharmaceuticals had chronic data. Pharmaceuticals were found to be more frequent than industrial chemicals in GHS category III. Acute toxicity was predictable (>92%) using a generic (Q)SAR ((Quantitative) Structure Activity Relationship) suggesting a narcotic MOA. Analysis of model prediction error suggests that 68% of the pharmaceuticals have a non-specific MOA. Additionally, the acute-to-chronic ratio (ACR) for 70% of the analyzed pharmaceuticals was below 25 further suggesting a non-specific MOA. Sub-lethal receptor-mediated effects may however have a more specific MOA.

MOA Data Reveal a New Mass, Distance, and Relative Proper Motion for Planetary System OGLE-2015-BLG-0954L

NASA Astrophysics Data System (ADS)

Bennett, D. P.; Bond, I. A.; Abe, F.; Asakura, Y.; Barry, R.; Bhattacharya, A.; Donachie, M.; Evans, P.; Fukui, A.; Hirao, Y.; Itow, Y.; Koshimoto, N.; Li, M. C. A.; Ling, C. H.; Masuda, K.; Matsubara, Y.; Muraki, Y.; Nagakane, M.; Ohnishi, K.; Ranc, C.; Rattenbury, N. J.; Saito, To.; Sharan, A.; Sullivan, D. J.; Sumi, T.; Suzuki, D.; Tristram, P. J.; Yamada, T.; Yamada, T.; Yonehara, A.; MOA Collaboration

2017-08-01

We present the MOA Collaboration light-curve data for the planetary microlensing event OGLE-2015-BLG-0954, which was previously announced in a paper by the KMTNet and OGLE Collaborations. The MOA data cover the caustic exit, which was not covered by the KMTNet or Optical Gravitational Lensing Experiment (OGLE) data, and they provide a more reliable measurement of the finite source effect. The MOA data also provide a new source color measurement that reveals a lens-source relative proper motion of μ rel = 11.8 ± 0.8 mas yr-1, which compares to the value of μ rel = 18.4 ± 1.7 mas yr-1 reported in the KMTNet-OGLE paper. This new MOA value for μ rel has an a priori probability that is a factor of ≳100 times larger than the previous value, and it does not require a lens system distance of D L < 1 kpc. Based on the corrected source color, we find that the lens system consists of a planet of mass {3.4}-1.6+3.7 {M}{Jup} orbiting a {0.30}-0.14+0.34 {M}⊙ star at an orbital separation of {2.1}-1.0+2.2 {au} and a distance of {1.2}-0.5+1.1 {kpc}.

Mode of Action (MOA) Assignment Classifications for Ecotoxicology: Evaluation of Available Methods

EPA Science Inventory

There are various structure-based classification schemes to categorize chemicals based on mode of action (MOA) which have been applied for both eco and human toxicology. With increasing calls to assess 1000s of chemicals, some of which have little available information other tha...

24 CFR 902.75 - Troubled performers.

Code of Federal Regulations, 2012 CFR

2012-04-01

...) at HUD, for remedial action, oversight, and monitoring. The actions to be taken by HUD and the PHA... troubled performer, HUD will initiate activities to negotiate and develop an MOA. An MOA is required for a... the resolution of outstanding HUD monitoring findings; (5) The PHA's commitment to take all actions...

24 CFR 902.75 - Troubled performers.

Code of Federal Regulations, 2014 CFR

2014-04-01

...) at HUD, for remedial action, oversight, and monitoring. The actions to be taken by HUD and the PHA... troubled performer, HUD will initiate activities to negotiate and develop an MOA. An MOA is required for a... the resolution of outstanding HUD monitoring findings; (5) The PHA's commitment to take all actions...

24 CFR 902.75 - Troubled performers.

Code of Federal Regulations, 2013 CFR

2013-04-01

...) at HUD, for remedial action, oversight, and monitoring. The actions to be taken by HUD and the PHA... troubled performer, HUD will initiate activities to negotiate and develop an MOA. An MOA is required for a... the resolution of outstanding HUD monitoring findings; (5) The PHA's commitment to take all actions...

24 CFR 902.75 - Troubled performers.

Code of Federal Regulations, 2011 CFR

2011-04-01

...) at HUD, for remedial action, oversight, and monitoring. The actions to be taken by HUD and the PHA... troubled performer, HUD will initiate activities to negotiate and develop an MOA. An MOA is required for a... the resolution of outstanding HUD monitoring findings; (5) The PHA's commitment to take all actions...

Mode(s) of action of arsenic-induced tumors and toxicity.

EPA Science Inventory

Although arsenic has long been known for its toxicity and carcinogenicity, it is unknown exactly how these adverse health effects ocurr. Three of the biggest unresolved issues in arsenic exposures and adverse health effects are (a) what is (are) the mode of action (MOA)(s) of ar...

A genetic approach to elucidate the genotoxic pathway of monomethylarsonousacid (MMAIII) suggests a key role for catalase

EPA Science Inventory

Arsenic-contaminated drinking water causes cancer, neuropathy, respiratory effects, diabetes, and cardiovascular disease. Its exact mode of action (MOA) is not fully understood. Oxidative stress has been proposed as a key event in the toxic MOA of arsenic. Our studies are centere...

Catalase can protect cells against the genotoxic effects of monomethylarsonous acid

EPA Science Inventory

Although it is widely known that arsenic-contaminated drinking water causes cancer and other health effects, its exact mode of action (MOA) is not fully understood. Induction of oxidative stress has been proposed as a key event in the MOA of arsenic. Our studies are centered on i...

Use of Toxicogenomic Data at the US EPA to Inform the Cancer Asessment of the Fungicide Propiconazole

EPA Science Inventory

The Office of Pesticide Programs’ (OPP) routinely utilizes mode of action (MOA) data when available for pesticide cancer risk assessment. A MOA analysis incorporates data from required toxicology studies and supplemental mechanistic data. These data are evaluated to identify a ...

Genetically altered mice for evaluation of mode-of-action (MOA)

EPA Science Inventory

Genetically altered mice for evaluation of mode-of-action (MOA). Barbara D. Abbott, Cynthia J. Wolf, Kaberi P. Das, Christopher S. Lau. (Presented by B. Abbott). This presentation provides an example of the use of genetically modified mice to determine the mode-of-action of r...

Biogeochemistry of mineral-organic associations across a long-term mineralogical soil gradient (0.3-4100 kyr), Hawaiian Islands

NASA Astrophysics Data System (ADS)

Mikutta, Robert; Schaumann, Gabriele E.; Gildemeister, Daniela; Bonneville, Steeve; Kramer, Marc G.; Chorover, Jon; Chadwick, Oliver A.; Guggenberger, Georg

2009-04-01

Organic matter (OM) in mineral-organic associations (MOAs) represents a large fraction of carbon in terrestrial ecosystems which is considered stable against biodegradation. To assess the role of MOAs in carbon cycling, there is a need to better understand (i) the time-dependent biogeochemical evolution of MOAs in soil, (ii) the effect of the mineral composition on the physico-chemical properties of attached OM, and (iii) the resulting consequences for the stabilization of OM. We studied the development of MOAs across a mineralogical soil gradient (0.3-4100 kyr) at the Hawaiian Islands that derived from basaltic tephra under comparable climatic and hydrological regimes. Mineral-organic associations were characterized using biomarker analyses of OM with chemolytic methods (lignin phenols, non-cellulosic carbohydrates) and wet chemical extractions, surface area/porosity measurements (N 2 at 77 K and CO 2 at 273 K), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), and differential scanning calorimetry (DSC). The results show that in the initial weathering stage (0.3 kyr), MOAs are mainly composed of primary, low-surface area minerals (olivine, pyroxene, feldspar) with small amounts of attached OM and lignin phenols but a large contribution of microbial-derived carbohydrates. As high-surface area, poorly crystalline (PC) minerals increase in abundance during the second weathering stage (20-400 kyr), the content of mineral-associated OM increased sharply, up to 290 mg C/g MOA, with lignin phenols being favored over carbohydrates in the association with minerals. In the third and final weathering stage (1400-4100 kyr), metastable PC phases transformed into well crystalline secondary Fe and Al (hydr)oxides and kaolin minerals that were associated with less OM overall, and depleted in both lignin and carbohydrate as a fraction of total OM. XPS, the N 2 pore volume data and OM-mineral volumetric ratios suggest that, in contrast to the endmember sites where OM accumulated at the surfaces of larger mineral grains, topsoil MOAs of the 20-400-kyr sites are composed of a homogeneous admixture of small-sized PC minerals and OM, which originated from both adsorption and precipitation processes. The chemical composition of OM in surface-horizon MOAs, however, was largely controlled by the uniform source vegetation irrespective of the substrate age whereas in subsoil horizons, aromatic and carboxylic C correlated positively with oxalate-extractable Al and Si and CuCl 2-extractable Al concentrations representing PC aluminosilicates and Al-organic complexes ( r2 > 0.85). Additionally, XPS depth profiles suggest a zonal structure of sorbed OM with aromatic carbons being enriched in the proximity of mineral surfaces and amide carbons (peptides/proteins) being located in outer regions of MOAs. Albeit the mineralogical and compositional changes of OM, the rigidity of mineral-associated OM as analyzed by DSC changed little over time. A significantly reduced side chain mobility of sorbed OM was, however, observed in subsoil MOAs, which likely arose from stronger mineral-organic bindings. In conclusion, our study shows that the properties of soil MOAs change substantially over time with different mineral assemblages favoring the association of different types of OM, which is further accentuated by a vertical gradient of OM composition on mineral surfaces. Factors supporting the stabilization of sorbed OM were (i) the surface area and reactivity of minerals (primary or secondary crystalline minerals versus PC secondary minerals), (ii) the association of OM with micropores of PC minerals (via 'sterically' enhanced adsorption), (iii) the effective embedding of OM in 'well mixed' arrays with PC minerals and monomeric/polymeric metal species, (iv) the inherent stability of acidic aromatic OM components, and (iv) an impaired segmental mobility of sorbed OM, which might increase its stability against desorption and microbial utilization.

An eight-year survey of the intestinal parasites of carnivores, hoofed mammals, primates, ratites and reptiles in the Ljubljana zoo in Slovenia.

PubMed

Kvapil, Pavel; Kastelic, Marjan; Dovc, Alenka; Bartova, Eva; Cizek, Petr; Lima, Natacha; Strus, Spela

2017-04-21

Problems with parasitic infections and their interspecies transmissions are common in zoological gardens and could pose serious health damage to captive animals. This study presents results of eight-year monitoring of intestinal parasites in animals from Zoo Ljubljana, Slovenia. A total of 741 faecal samples from 40 animal species were collected two to four times per year and examined microscopically. Intestinal parasites were detected in 45% of samples, with detection of helminths (Cestoda, Nematoda - Ascaridida, Enoplida, Strongylida, Oxyurida, Rhabditida and Trichurida) and protists (Apicomplexa and Ciliophora) in 25% and 13% of samples, respectively; mixed infection was found in 7% of samples. The mostly infected were ungulates (61%), followed by reptiles (44%), ratites (29%), primates (22%) and carnivores (7%). During the observation period, the number of infected animal species increased from 8 to 25. This is the first long-term monitoring study of intestinal parasites in zoo animals from Slovenia. Routine monitoring of parasitic infection and regular deworming and hygienic measures are necessary to prevent gastrointestinal infections in captive animals.

VizieR Online Data Catalog: Frequency of snowline-region planets (Shvartzvald+, 2016)

NASA Astrophysics Data System (ADS)

Shvartzvald, Y.; Maoz, D.; Udalski, A.; Sumi, T.; Friedmann, M.; Kaspi, S.; Poleski, R.; Szymanski, M. K.; Skowron, J.; Kozlowski, S.; Wyrzykowski, L.; Mroz, P.; Pietrukowicz, P.; Pietrzynski, G.; Soszynski, I.; Ulaczyk, K.; Abe, F.; Barry, R. K.; Bennett, D. P.; Bhattacharya, A.; Bond, I. A.; Freeman, M.; Inayama, K.; Itow, Y.; Koshimoto, N.; Ling, C. H.; Masuda, K.; Fukui, A.; Matsubara, Y.; Muraki, Y.; Ohnishi, K.; Rattenbury, N. J.; Saito, T.; Sullivan, D. J.; Suzuki, D.; Tristram, P. J.; Wakiyama, Y.; Yonehara, A.

2017-06-01

Our genII survey network is a collaboration between three groups: OGLE, MOA, and Wise. The OGLE and MOA groups regularly monitor a large region of the Galactic bulge, and routinely identify and monitor microlensing events. The Wise group monitors a field of 8 deg2, within the observational footprints of both OGLE and MOA, having the highest event rates based on previous years' observations (see Shvartzvald & Maoz, 2012MNRAS.419.3631S). The sample of microlensing events analysed here consists of 224 events from the 2011-2014 bulge seasons, observed by all three groups, and with each group having data near the peak of the event. (1 data file).

State of the art knowledge in adrenocortical and behavioral responses to environmental challenges in a threatened South American ratite: Implications to in situ and ex-situ conservation.

PubMed

Luis, Navarro Joaquín; Lèche, Alvina; Costa, Natalia S Della; Cortez, Marilina Vera; Marin, Raúl H; Martella, Mónica B

2018-04-12

The Greater Rhea (Rhea americana) is an endemic ratite to South America, whose wild populations have undergone a remarkable decrease due to habitat degradation and fragmentation by the expansion of the agricultural frontier, poaching and predation by dogs. Anthropogenic perturbations in wild environments, as well as the management in captivity, can generate different stress responses in this species, thus, the monitoring of adrenocortical and behavioral activities are considered primary assessment tools with both conservation and welfare implications. In this review we analyze and integrate the different measurements of glucocorticoids (in plasma, feces, and yolk) carried out in different captive and wild populations, taking into account the diverse predictable and unpredictable conditions to which the Greater Rhea responds in each of those environments. In addition, the translocation of this bird is presented as an application of stress physiology in field ecology for conservation purposes, in which we evaluated how this species responds when it is released into a novel environment. Our results indicate that this ratite has a striking high sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis compared to that of other bird species and shows a wide variety of adrenocortical responses depending on the environment in which it lives. This suggests that its HPA axis has a phenotypic plasticity that enables the rhea to cope with the environmental challenges. In this sense, we propose that one of the routes of this plasticity could be mediated by the maternal transfer of steroid hormones to the egg. Finally, we discuss the importance of integrating the monitoring of the adrenocortical response along with the environmental variables that define the life history of the species, in management and conservation programs ex-situ and in situ. Copyright © 2018. Published by Elsevier Inc.

75 FR 73059 - Record of Decision and Floodplain Statement of Findings for the Cushman Hydroelectric Project...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-29

... license to include inter alia conditions for fish passage facilities and authorization to construct the... originally opposed Tacoma's Cultural Resource Summary Report, and cultural resource protection became a... in the MOA. The MOA includes a Treatment Plan that Tacoma must follow to protect cultural resources...

A genetic approach to elucidate the genotoxic pathway of monomethylarsonous acid suggests a key role for catalase

EPA Science Inventory

Although it is widely known that arsenic-contaminated drinking water causes many diseases, arsenic's exact mode of action (MOA) is not fully understood. Induction of oxidative stress has been proposed as an important key event in the toxic MOA of arsenic. Our studies are centered...

"Mode of Acquisition" of Word Meanings: The Viability of a Theoretical Construct.

ERIC Educational Resources Information Center

Wauters, Loes N.; Tellings, Agnes E. J. M.; Van Bon, Wim H. J.; Van Haaften, A. Wouter

2003-01-01

Examines the reliability and validity of the construct, "mode of acquisition" (MOA). The MOA of a word denotes the way in which the word's meaning is learned. Subjects in one study were volunteers from third year special education courses and in a second study, educational professionals. (Author/VWL)

Exploring the molecular mechanisms of Traditional Chinese Medicine components using gene expression signatures and connectivity map.

PubMed

Yoo, Minjae; Shin, Jimin; Kim, Hyunmin; Kim, Jihye; Kang, Jaewoo; Tan, Aik Choon

2018-04-04

Traditional Chinese Medicine (TCM) has been practiced over thousands of years in China and other Asian countries for treating various symptoms and diseases. However, the underlying molecular mechanisms of TCM are poorly understood, partly due to the "multi-component, multi-target" nature of TCM. To uncover the molecular mechanisms of TCM, we perform comprehensive gene expression analysis using connectivity map. We interrogated gene expression signatures obtained 102 TCM components using the next generation Connectivity Map (CMap) resource. We performed systematic data mining and analysis on the mechanism of action (MoA) of these TCM components based on the CMap results. We clustered the 102 TCM components into four groups based on their MoAs using next generation CMap resource. We performed gene set enrichment analysis on these components to provide additional supports for explaining these molecular mechanisms. We also provided literature evidence to validate the MoAs identified through this bioinformatics analysis. Finally, we developed the Traditional Chinese Medicine Drug Repurposing Hub (TCM Hub) - a connectivity map resource to facilitate the elucidation of TCM MoA for drug repurposing research. TCMHub is freely available in http://tanlab.ucdenver.edu/TCMHub. Molecular mechanisms of TCM could be uncovered by using gene expression signatures and connectivity map. Through this analysis, we identified many of the TCM components possess diverse MoAs, this may explain the applications of TCM in treating various symptoms and diseases. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Spatiotemporal differentiation in auditory and motor regions during auditory phoneme discrimination.

PubMed

Aerts, Annelies; Strobbe, Gregor; van Mierlo, Pieter; Hartsuiker, Robert J; Corthals, Paul; Santens, Patrick; De Letter, Miet

2017-06-01

Auditory phoneme discrimination (APD) is supported by both auditory and motor regions through a sensorimotor interface embedded in a fronto-temporo-parietal cortical network. However, the specific spatiotemporal organization of this network during APD with respect to different types of phonemic contrasts is still unclear. Here, we use source reconstruction, applied to event-related potentials in a group of 47 participants, to uncover a potential spatiotemporal differentiation in these brain regions during a passive and active APD task with respect to place of articulation (PoA), voicing and manner of articulation (MoA). Results demonstrate that in an early stage (50-110 ms), auditory, motor and sensorimotor regions elicit more activation during the passive and active APD task with MoA and active APD task with voicing compared to PoA. In a later stage (130-175 ms), the same auditory and motor regions elicit more activation during the APD task with PoA compared to MoA and voicing, yet only in the active condition, implying important timing differences. Degree of attention influences a frontal network during the APD task with PoA, whereas auditory regions are more affected during the APD task with MoA and voicing. Based on these findings, it can be carefully suggested that APD is supported by the integration of early activation of auditory-acoustic properties in superior temporal regions, more perpetuated for MoA and voicing, and later auditory-to-motor integration in sensorimotor areas, more perpetuated for PoA.

Assessment of the mode of action underlying development of forestomach tumors in rodents following oral exposure to ethyl acrylate and relevance to humans.

PubMed

Thompson, Chad M; Suh, Mina; Chappell, Grace; Borghoff, Susan; Ellis-Hutchings, Robert; Wiench, Karin; Finch, Lavorgie; Proctor, Deborah M

2018-05-05

Chronic repeated gavage dosing of high concentrations of ethyl acrylate (EA) causes forestomach tumors in rats and mice. For two decades, there has been general consensus that these tumors are unique to rodents because of: i) lack of carcinogenicity in other organs, ii) specificity to the forestomach (an organ unique to rodents which humans do not possess), iii) lack of carcinogenicity by other routes of exposure, and iv) obvious site of contact toxicity at carcinogenic doses. In 1986, EA was classified as possibly carcinogenic to humans by the International Agency for Research on Cancer (IARC). However, by applying a MOA analyses and human relevance framework assessment, the weight-of-evidence supports a cytotoxic MOA with the following key events: i) bolus delivery of EA to forestomach lumen and subsequent absorption, ii) cytotoxicity likely due to saturation of enzymatic detoxification, iii) chronic regenerative hyperplasia, and iv) spontaneous mutation due to increased cell replication and cell population. Clonal expansion of initiated cells thus results in late onset tumorigenesis. The key events in this 'wound and healing' MOA provide high confidence in the MOA as assessed by evolved Bradford-Hill Criteria. The weight-of-evidence supported by the proposed MOA, combined with a unique tissue that does not exist in humans, indicates that EA is highly unlikely to pose a human cancer hazard. Copyright © 2018. Published by Elsevier Inc.

Insecticidal Suppression of Asian Citrus Psyllid Diaphorina citri (Hemiptera: Liviidae) Vector of Huanglongbing Pathogens

PubMed Central

Qureshi, Jawwad A.; Kostyk, Barry C.; Stansly, Philip A.

2014-01-01

Diaphorina citri vectors pathogens that cause ‘huanglongbing’ or citrus greening disease which poses a serious threat to citrus production worldwide. Vector suppression is critical to reduce disease spread. Efficacy is a main concern when choosing an insecticide. Insecticidal treatments of 49 products or 44 active ingredients (a.i) labeled or experimental were field tested between 2005–2013 as foliar sprays (250 treatments, 39 a.i) or soil applications (47 treatments, 9 a.i) to control D. citri in citrus. A combined effect of nymphal and adult suppression in response to sprays of 23 insecticides representing 9 modes of action (MoA) groups and 3 unknown MoA provided more than 90% reduction of adult D. citri over 24–68 days. Observable effects on nymphs were generally of shorter duration due to rapid maturation of flush. However, reduction of 76–100% nymphs or adults over 99–296 days was seen on young trees receiving drenches of the neonicotinoids imidacloprid, thiamethoxam or clothianidin (MoA 4A) and a novel anthranilic diamide, cyantraniliprole (MoA 28). Effective products identified for foliar sprays to control D. citri provide sufficient MoA groups for rotation to delay evolution of insecticide resistance by D. citri and other pests. However, cyantraniliprole is now the only available alternative for rotation with neonicotinoids in soil application to young trees. Sprays of up to eight of the most effective insecticides could be rotated over a year without repetition of any MoA and little or no recourse to neonicotinoids or cyantraniliprole, so important for protection of young trees. Other considerations effecting decisions of what and when to spray include prevalence of huanglongbing, pest pressure, pre-harvest intervals, overall budget, equipment availability, and conservation of beneficial arthropods. Examples of spray programs utilizing broad-spectrum and relatively selective insecticides are provided to improve vector management and may vary depending on individual or regional assessment of all factors. PMID:25437858

Insecticidal suppression of Asian citrus psyllid Diaphorina citri (Hemiptera: Liviidae) vector of huanglongbing pathogens.

PubMed

Qureshi, Jawwad A; Kostyk, Barry C; Stansly, Philip A

2014-01-01

Diaphorina citri vectors pathogens that cause 'huanglongbing' or citrus greening disease which poses a serious threat to citrus production worldwide. Vector suppression is critical to reduce disease spread. Efficacy is a main concern when choosing an insecticide. Insecticidal treatments of 49 products or 44 active ingredients (a.i) labeled or experimental were field tested between 2005-2013 as foliar sprays (250 treatments, 39 a.i) or soil applications (47 treatments, 9 a.i) to control D. citri in citrus. A combined effect of nymphal and adult suppression in response to sprays of 23 insecticides representing 9 modes of action (MoA) groups and 3 unknown MoA provided more than 90% reduction of adult D. citri over 24-68 days. Observable effects on nymphs were generally of shorter duration due to rapid maturation of flush. However, reduction of 76-100% nymphs or adults over 99-296 days was seen on young trees receiving drenches of the neonicotinoids imidacloprid, thiamethoxam or clothianidin (MoA 4A) and a novel anthranilic diamide, cyantraniliprole (MoA 28). Effective products identified for foliar sprays to control D. citri provide sufficient MoA groups for rotation to delay evolution of insecticide resistance by D. citri and other pests. However, cyantraniliprole is now the only available alternative for rotation with neonicotinoids in soil application to young trees. Sprays of up to eight of the most effective insecticides could be rotated over a year without repetition of any MoA and little or no recourse to neonicotinoids or cyantraniliprole, so important for protection of young trees. Other considerations effecting decisions of what and when to spray include prevalence of huanglongbing, pest pressure, pre-harvest intervals, overall budget, equipment availability, and conservation of beneficial arthropods. Examples of spray programs utilizing broad-spectrum and relatively selective insecticides are provided to improve vector management and may vary depending on individual or regional assessment of all factors.

From the Cover: Fenretinide, Troglitazone, and Elmiron Add to Weight of Evidence Support for Hemangiosarcoma Mode-of-Action From Studies in Mice.

PubMed

Cook, Jon C; Obert, Leslie A; Koza-Taylor, Petra; Coskran, Timothy M; Opsahl, Alan C; Ziemek, Daniel; Roy, Marc; Qian, Jessie; Lawton, Michael P; Criswell, Kay A

2018-01-01

Pharmaceuticals and chemicals produce hemangiosarcomas (HS) in mice, often by nongenotoxic, proliferative mechanisms. A mode-of-action (MOA) for hemangiosarcoma was proposed based on information presented at an international workshop (Cohen et al., Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance. Toxicol. Sci. 111, 4-18.). Five key elements of the MOA were articulated and included hypoxia, macrophage activation, increased angiogenic growth factors, dysregulated angiogenesis/erythropoiesis, and endothial cell proliferation. The goal of the current study was to add to the weight-of-evidence for the proposed MOA by assessing these key elements with 3 different compounds of varying potency for HS induction: fenretinide (high), troglitazone (intermediate), and elmiron (low). Multiple endpoints, including hypoxia (hyproxyprobe, transcriptomics), endothelial cell (EC) proliferation, and clinical and anatomic pathology, were assessed after 2, 4, and 13-weeks of treatment in B6C3F1 mice. All 3 compounds demonstrated strong evidence for dysregulated erythropoiesis (decrease in RBC and a failure to increase reticulocytes) and macrophage activation (4- to 11-fold increases); this pattern of hematological changes in mice might serve as an early biomarker to evaluate EC proliferation in suspected target organs for potential HS formation. Fenretinide demonstrated all 5 key elements, while troglitazone demonstrated 4 and elmiron demonstrated 3. Transcriptomics provided support for the 5 elements of the MOA, but was not any more sensitive than hypoxyprobe immunohistochemistry for detecting hypoxia. The overall transcriptional evidence for the key elements of the proposed MOA was also consistent with the potency of HS induction. These data, coupled with the previous work with 2-butoxyethanol and pregablin, increase the weight-of-evidence for the proposed MOA for HS formation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Outcomes of tumor necrosis factor inhibitor cycling versus switching to a disease-modifying anti-rheumatic drug with a new mechanism of action among patients with rheumatoid arthritis.

PubMed

Chastek, Benjamin; Becker, Laura K; Chen, Chieh-I; Mahajan, Puneet; Curtis, Jeffrey R

2017-05-01

To examine treatment patterns, treatment effectiveness, and treatment costs for 1 year after patients with rheumatoid arthritis switched from a tumor necrosis factor inhibitor (TNFi) (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab), either cycling to another TNFi ("TNFi cyclers") or switching to a new mechanism of action (abatacept, tocilizumab, or tofacitinib) ("new MOA switchers"). This retrospective cohort study used administrative claims data for a national insurer. Treatment persistence (without switching again, restarting, or discontinuing), treatment effectiveness (defined below), and costs were assessed for the 12-month post-switch period. Patients were "effectively treated" if they satisfied all six criteria for a treatment effectiveness algorithm (high adherence, no dose increase, no new conventional synthetic disease-modifying anti-rheumatic drug, no subsequent switch in therapy, no new/increased oral glucocorticoids, and <2 glucocorticoid injections). Multivariable logistic models were used to adjust for baseline factors. The database included 581 new MOA switchers and 935 TNFi cyclers. New MOA switchers were 39% more likely than TNFi cyclers to persist after the switch (odds ratio [OR] = 1.39; 95% confidence interval [CI] = 1.12-1.74; p = .003) and 36% less likely to switch therapy again (OR = 0.64; 95% CI = 0.51-0.81; p < .001). New MOA switchers were 43% more likely than TNFi cyclers to be effectively treated (OR = 1.43; 95% CI = 1.11-1.85; p = .006). New MOA switchers had 16% lower drug costs than TNFi cyclers (cost ratio = 0.84; 95% CI = 0.79-0.88; p < .001) and 11% lower total costs of rheumatoid arthritis-related medical care (cost ratio = 0.89; 95% CI = 0.84-0.94; p < .001). Claims payments may not reflect rebates or other cost offsets. Medical and pharmacy claims do not include clinical end-points or reasons that lead to new MOA switching vs TNFi cycling. These results support switching to a new MOA after a patient fails treatment with a TNFi, which is consistent with recent guidelines for the pharmacologic management of established rheumatoid arthritis.

INVESTIGATIONS INTO THE MODE OF ACTION (MOA) OF ARSENIC USING THE SINGLE CELL GEL (SCG) ASSAY AND CYTOGENETICS

EPA Science Inventory

Arsenic is a globally important pollutant found in the air, food, and in many water systems causing significant human exposure and in some cases illness. While there is no doubt that arsenic is a human carcinogen, there is no consensus on its carcinogenic MOA. Numerous hypotheses...

A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors-abstract

EPA Science Inventory

The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity but MoA classification in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity mode of action using a recently published dataset contain...

Catalase Has a Key Role in Protecting Cells from the Genotoxic Effects of Monomethylarsonous Acid, a Highly Active Metabolite of Arsenic

EPA Science Inventory

ABSTRACT Although it is widely known that arsenic-contaminated drinking water causes many diseases, arsenic’s exact mode of action (MOA) is not fully understood. Induction of oxidative stress has been proposed as an important key event in the toxic MOA of arsenic. The author's...

DOSE RESPONSE FROM HIGH THROUGHPUT GENE EXPRESSION STUDIES AND THE INFLUENCE OF TIME AND CELL LINE ON INFERRED MODE OF ACTION BY ONTOLOGIC ENRICHMENT (SOT)

EPA Science Inventory

Gene expression with ontologic enrichment and connectivity mapping tools is widely used to infer modes of action (MOA) for therapeutic drugs. Despite progress in high-throughput (HT) genomic systems, strategies suitable to identify industrial chemical MOA are needed. The L1000 is...

Cross-species chemogenomic profiling reveals evolutionarily conserved drug mode of action

PubMed Central

Kapitzky, Laura; Beltrao, Pedro; Berens, Theresa J; Gassner, Nadine; Zhou, Chunshui; Wüster, Arthur; Wu, Julie; Babu, M Madan; Elledge, Stephen J; Toczyski, David; Lokey, R Scott; Krogan, Nevan J

2010-01-01

We present a cross-species chemogenomic screening platform using libraries of haploid deletion mutants from two yeast species, Saccharomyces cerevisiae and Schizosaccharomyces pombe. We screened a set of compounds of known and unknown mode of action (MoA) and derived quantitative drug scores (or D-scores), identifying mutants that are either sensitive or resistant to particular compounds. We found that compound–functional module relationships are more conserved than individual compound–gene interactions between these two species. Furthermore, we observed that combining data from both species allows for more accurate prediction of MoA. Finally, using this platform, we identified a novel small molecule that acts as a DNA damaging agent and demonstrate that its MoA is conserved in human cells. PMID:21179023

OGLE 2003-BLG-235/MOA 2003-BLG-53: A Planetary Microlensing Event

NASA Astrophysics Data System (ADS)

Bond, I. A.; Udalski, A.; Jaroszyński, M.; Rattenbury, N. J.; Paczyński, B.; Soszyński, I.; Wyrzykowski, L.; Szymański, M. K.; Kubiak, M.; Szewczyk, O.; Żebruń, K.; Pietrzyński, G.; Abe, F.; Bennett, D. P.; Eguchi, S.; Furuta, Y.; Hearnshaw, J. B.; Kamiya, K.; Kilmartin, P. M.; Kurata, Y.; Masuda, K.; Matsubara, Y.; Muraki, Y.; Noda, S.; Okajima, K.; Sako, T.; Sekiguchi, T.; Sullivan, D. J.; Sumi, T.; Tristram, P. J.; Yanagisawa, T.; Yock, P. C. M.; OGLE Collaboration

2004-05-01

We present observations of the unusual microlensing event OGLE 2003-BLG-235/MOA 2003-BLG-53. In this event, a short-duration (~7 days) low-amplitude deviation in the light curve due to a single-lens profile was observed in both the MOA (Microlensing Observations in Astrophysics) and OGLE (Optical Gravitational Lensing Experiment) survey observations. We find that the observed features of the light curve can only be reproduced using a binary microlensing model with an extreme (planetary) mass ratio of 0.0039+11-07 for the lensing system. If the lens system comprises a main-sequence primary, we infer that the secondary is a planet of about 1.5 Jupiter masses with an orbital radius of ~3 AU.

9 CFR 381.72 - Segregation of suspects on ante mortem inspection.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Segregation of suspects on ante mortem inspection. 381.72 Section 381.72 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT... Inspection § 381.72 Segregation of suspects on ante mortem inspection. (a) All birds, except ratites, that on...

9 CFR 381.72 - Segregation of suspects on ante mortem inspection.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Segregation of suspects on ante mortem inspection. 381.72 Section 381.72 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT... Inspection § 381.72 Segregation of suspects on ante mortem inspection. (a) All birds, except ratites, that on...

A Microplate Growth Inhibition Assay for Screening Bacteriocins against Listeria monocytogenes to Differentiate Their Mode-of-Action.

PubMed

Vijayakumar, Paul Priyesh; Muriana, Peter M

2015-06-11

Lactic acid bacteria (LAB) have historically been used in food fermentations to preserve foods and are generally-recognized-as-safe (GRAS) by the FDA for use as food ingredients. In addition to lactic acid; some strains also produce bacteriocins that have been proposed for use as food preservatives. In this study we examined the inhibition of Listeria monocytogenes 39-2 by neutralized and non-neutralized bacteriocin preparations (Bac+ preps) produced by Lactobacillus curvatus FS47; Lb. curvatus Beef3; Pediococcus acidilactici Bac3; Lactococcus lactis FLS1; Enterococcus faecium FS56-1; and Enterococcus thailandicus FS92. Activity differences between non-neutralized and neutralized Bac+ preps in agar spot assays could not readily be attributed to acid because a bacteriocin-negative control strain was not inhibitory to Listeria in these assays. When neutralized and non-neutralized Bac+ preps were used in microplate growth inhibition assays against L. monocytogenes 39-2 we observed some differences attributed to acid inhibition. A microplate growth inhibition assay was used to compare inhibitory reactions of wild-type and bacteriocin-resistant variants of L. monocytogenes to differentiate bacteriocins with different modes-of-action (MOA) whereby curvaticins FS47 and Beef3, and pediocin Bac3 were categorized to be in MOA1; enterocins FS92 and FS56-1 in MOA2; and lacticin FLS1 in MOA3. The microplate bacteriocin MOA assay establishes a platform to evaluate the best combination of bacteriocin preparations for use in food applications as biopreservatives against L. monocytogenes.

Mechanism of altruism approach to blood donor recruitment and retention: a review and future directions.

PubMed

Ferguson, E

2015-08-01

Why do people donate blood? Altruism is the common answer. However, altruism is a complex construct and to answer this question requires a systematic analysis of the insights from the biology, economics and psychology of altruism. I term this the mechanism of altruism (MOA) approach and apply it here for understanding blood donor motivation. The answer also has enormous implications for the type of interventions we choose to adopt as a society. A MOA approach so far shows that blood donors are a mixture of (i) warm-glow givers (donation is emotionally rewarding) and (ii) reluctant altruists (cooperate rather than defect when free-riding is high). Donors also show 'saintly sinning' with the extra 'moral currency' form blood donation allowing them to be less generous in other contexts. The MOA approach suggests why financial incentives, in terms of gifts/lottery tickets, are effective and suggests a number of novel interventions for donor recruitment: 'voluntary reciprocal altruism' and 'charitable incentivisation'. The MOA approach also highlights the need for an intervention developed specifically for recipients to allow them to show their gratitude to donors and for society to celebrate blood donation. It is suggests a 'Monument to Blood Donors' will achieve this. The approach suggests a number of novel research questions into (i) donor self-selection effects, (ii) conditional cooperation and (iii) construct overlap with Theory of Planned Behaviour (e.g. affective attitudes and warm-glow). The MOA offers a powerful way to understand blood donor motivations around altruism and develop theoretically driven interventions. © 2015 British Blood Transfusion Society.

Use of genomic data in risk assessment case study: I. Evaluation of the dibutyl phthalate male reproductive development toxicity data set

DOE Office of Scientific and Technical Information (OSTI.GOV)

Makris, Susan L., E-mail: makris.susan@epa.gov; Euling, Susan Y.; Gray, L. Earl

2013-09-15

A case study was conducted, using dibutyl phthalate (DBP), to explore an approach to using toxicogenomic data in risk assessment. The toxicity and toxicogenomic data sets relative to DBP-related male reproductive developmental outcomes were considered conjointly to derive information about mode and mechanism of action. In this manuscript, we describe the case study evaluation of the toxicological database for DBP, focusing on identifying the full spectrum of male reproductive developmental effects. The data were assessed to 1) evaluate low dose and low incidence findings and 2) identify male reproductive toxicity endpoints without well-established modes of action (MOAs). These efforts ledmore » to the characterization of data gaps and research needs for the toxicity and toxicogenomic studies in a risk assessment context. Further, the identification of endpoints with unexplained MOAs in the toxicity data set was useful in the subsequent evaluation of the mechanistic information that the toxicogenomic data set evaluation could provide. The extensive analysis of the toxicology data set within the MOA context provided a resource of information for DBP in attempts to hypothesize MOAs (for endpoints without a well-established MOA) and to phenotypically anchor toxicogenomic and other mechanistic data both to toxicity endpoints and to available toxicogenomic data. This case study serves as an example of the steps that can be taken to develop a toxicological data source for a risk assessment, both in general and especially for risk assessments that include toxicogenomic data.« less

Integrating toxicogenomics into human health risk assessment: lessons learned from the benzo[a]pyrene case study.

PubMed

Chepelev, Nikolai L; Moffat, Ivy D; Labib, Sarah; Bourdon-Lacombe, Julie; Kuo, Byron; Buick, Julie K; Lemieux, France; Malik, Amal I; Halappanavar, Sabina; Williams, Andrew; Yauk, Carole L

2015-01-01

The use of short-term toxicogenomic tests to predict cancer (or other health effects) offers considerable advantages relative to traditional toxicity testing methods. The advantages include increased throughput, increased mechanistic data, and significantly reduced costs. However, precisely how toxicogenomics data can be used to support human health risk assessment (RA) is unclear. In a companion paper ( Moffat et al. 2014 ), we present a case study evaluating the utility of toxicogenomics in the RA of benzo[a]pyrene (BaP), a known human carcinogen. The case study is meant as a proof-of-principle exercise using a well-established mode of action (MOA) that impacts multiple tissues, which should provide a best case example. We found that toxicogenomics provided rich mechanistic data applicable to hazard identification, dose-response analysis, and quantitative RA of BaP. Based on this work, here we share some useful lessons for both research and RA, and outline our perspective on how toxicogenomics can benefit RA in the short- and long-term. Specifically, we focus on (1) obtaining biologically relevant data that are readily suitable for establishing an MOA for toxicants, (2) examining the human relevance of an MOA from animal testing, and (3) proposing appropriate quantitative values for RA. We describe our envisioned strategy on how toxicogenomics can become a tool in RA, especially when anchored to other short-term toxicity tests (apical endpoints) to increase confidence in the proposed MOA, and emphasize the need for additional studies on other MOAs to define the best practices in the application of toxicogenomics in RA.

A Microplate Growth Inhibition Assay for Screening Bacteriocins against Listeria monocytogenes to Differentiate Their Mode-of-Action

PubMed Central

Vijayakumar, Paul Priyesh; Muriana, Peter M.

2015-01-01

Lactic acid bacteria (LAB) have historically been used in food fermentations to preserve foods and are generally-recognized-as-safe (GRAS) by the FDA for use as food ingredients. In addition to lactic acid; some strains also produce bacteriocins that have been proposed for use as food preservatives. In this study we examined the inhibition of Listeria monocytogenes 39-2 by neutralized and non-neutralized bacteriocin preparations (Bac+ preps) produced by Lactobacillus curvatus FS47; Lb. curvatus Beef3; Pediococcus acidilactici Bac3; Lactococcus lactis FLS1; Enterococcus faecium FS56-1; and Enterococcus thailandicus FS92. Activity differences between non-neutralized and neutralized Bac+ preps in agar spot assays could not readily be attributed to acid because a bacteriocin-negative control strain was not inhibitory to Listeria in these assays. When neutralized and non-neutralized Bac+ preps were used in microplate growth inhibition assays against L. monocytogenes 39-2 we observed some differences attributed to acid inhibition. A microplate growth inhibition assay was used to compare inhibitory reactions of wild-type and bacteriocin-resistant variants of L. monocytogenes to differentiate bacteriocins with different modes-of-action (MOA) whereby curvaticins FS47 and Beef3, and pediocin Bac3 were categorized to be in MOA1; enterocins FS92 and FS56-1 in MOA2; and lacticin FLS1 in MOA3. The microplate bacteriocin MOA assay establishes a platform to evaluate the best combination of bacteriocin preparations for use in food applications as biopreservatives against L. monocytogenes. PMID:26111195

Memorandum of Agreement (MOA) Between the Director of Military Support and the United State Coast Guard for Aerial Application of Dispersants During Oil Spill Cleanup and Recovery Operations

DOT National Transportation Integrated Search

1995-01-01

Prepared ca. 1995. The purposes of this MOA are: A.) To specify the procedures by which the United States Coast Guard can request and the United States Air Force Reserve will provide aircraft, equipment and personnel for the application of oil disper...

78 FR 37103 - Amendment of VOR Federal Airways V-55 and V-169 in Eastern North Dakota

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-20

... by removing reference to special use airspace (SUA) exclusionary language no longer needed. DATES... level (MSL) to 10,000 feet MSL and the Devils Lake West MOA existed from 4,000 feet MSL to 10,000 feet... not including, flight level (FL) 180. Within the proposed Devils Lake East MOA, V-55 would be...

Exploring the Mode of Action of Bioactive Compounds by Microfluidic Transcriptional Profiling in Mycobacteria

PubMed Central

Lim, Vivian; Naim, Ahmad Nazri Mohamed; Bifani, Pablo; Boshoff, Helena I. M.; Sambandamurthy, Vasan K.; Dick, Thomas; Hibberd, Martin L.; Schreiber, Mark; Rao, Srinivasa P. S.

2013-01-01

Most candidate anti-bacterials are identified on the basis of their whole cell anti-bacterial activity. A critical bottleneck in the early discovery of novel anti-bacterials is tracking the structure activity relationship (SAR) of the novel compounds synthesized during the hit to lead and lead optimization stage. It is often very difficult for medicinal chemists to visualize if the novel compounds synthesized for understanding SAR of a particular scaffold have similar molecular mechanism of action (MoA) as that of the initial hit. The elucidation of the molecular MoA of bioactive inhibitors is critical. Here, a new strategy and routine assay for MoA de-convolution, using a microfluidic platform for transcriptional profiling of bacterial response to inhibitors with whole cell activity has been presented. First a reference transcriptome compendium of Mycobacterial response to various clinical and investigational drugs was built. Using feature reduction, it was demonstrated that subsets of biomarker genes representative of the whole genome are sufficient for MoA classification and deconvolution in a medium-throughput microfluidic format ultimately leading to a cost effective and rapid tool for routine antibacterial drug-discovery programs. PMID:23935951

Observation of open-orbit Fermi surface topology in the extremely large magnetoresistance semimetal MoAs2

NASA Astrophysics Data System (ADS)

Lou, R.; Xu, Y. F.; Zhao, L.-X.; Han, Z.-Q.; Guo, P.-J.; Li, M.; Wang, J.-C.; Fu, B.-B.; Liu, Z.-H.; Huang, Y.-B.; Richard, P.; Qian, T.; Liu, K.; Chen, G.-F.; Weng, H. M.; Ding, H.; Wang, S.-C.

2017-12-01

While recent advances in band theory and sample growth have expanded the series of extremely large magnetoresistance (XMR) semimetals in transition-metal dipnictides T m P n2 (T m =Ta , Nb; P n =P , As, Sb), the experimental study on their electronic structure and the origin of XMR is still absent. Here, using angle-resolved photoemission spectroscopy combined with first-principles calculations and magnetotransport measurements, we performed a comprehensive investigation on MoAs2, which is isostructural to the T m P n2 family and also exhibits quadratic XMR. We resolve a clear band structure well agreeing with the predictions. Intriguingly, the unambiguously observed Fermi surfaces (FSs) are dominated by an open-orbit topology extending along both the [100] and [001] directions in the three-dimensional Brillouin zone. We further reveal the trivial topological nature of MoAs2 by bulk parity analysis. Based on these results, we examine the proposed XMR mechanisms in other semimetals, and conclusively ascribe the origin of quadratic XMR in MoAs2 to the carriers motion on the FSs with dominant open-orbit topology, innovating in the understanding of quadratic XMR in semimetals.

Implementing Marine Organic Aerosols Into the GEOS-Chem Model

NASA Technical Reports Server (NTRS)

Johnson, Matthew S.

2015-01-01

Marine-sourced organic aerosols (MOA) have been shown to play an important role in tropospheric chemistry by impacting surface mass, cloud condensation nuclei, and ice nuclei concentrations over remote marine and coastal regions. In this work, an online marine primary organic aerosol emission parameterization, designed to be used for both global and regional models, was implemented into the GEOS-Chem model. The implemented emission scheme improved the large under-prediction of organic aerosol concentrations in clean marine regions (normalized mean bias decreases from -79% when using the default settings to -12% when marine organic aerosols are added). Model predictions were also in good agreement (correlation coefficient of 0.62 and normalized mean bias of -36%) with hourly surface concentrations of MOA observed during the summertime at an inland site near Paris, France. Our study shows that MOA have weaker coastal-to-inland concentration gradients than sea-salt aerosols, leading to several inland European cities having > 10% of their surface submicron organic aerosol mass concentration with a marine source. The addition of MOA tracers to GEOS-Chem enabled us to identify the regions with large contributions of freshly-emitted or aged aerosol having distinct physicochemical properties, potentially indicating optimal locations for future field studies.

Probing the Fermi surface and magnetotransport properties of MoAs2

NASA Astrophysics Data System (ADS)

Singha, Ratnadwip; Pariari, Arnab; Gupta, Gaurav Kumar; Das, Tanmoy; Mandal, Prabhat

2018-04-01

Transition-metal dipnictides (TMDs) have recently been identified as possible candidates to host a topology-protected electronic band structure. These materials belong to an isostructural family and show several exotic transport properties. Especially, the large values of magnetoresistance (MR) and carrier mobility have drawn significant attention from the perspective of technological applications. In this paper, we investigate the magnetotransport and Fermi surface properties of single-crystalline MoAs2, another member of this group of compounds. A field-induced resistivity plateau and a large MR have been observed, which are comparable to those in several topological systems. Interestingly, in contrast to other isostructural materials, the carrier density in MoAs2 is quite high and shows single-band-dominated transport. The Fermi pockets, which have been identified from the quantum oscillation, are the largest among the members of this group and have significant anisotropy with crystallographic direction. Our first-principles calculations reveal a substantial difference between the band structures of MoAs2 and that of other TMDs. The calculated Fermi surface consists of one electron pocket and another "open-orbit" hole pocket, which has not been observed in TMDs so far.

Maternal personality profile of children affected by migraine

PubMed Central

Esposito, Maria; Roccella, Michele; Gallai, Beatrice; Parisi, Lucia; Lavano, Serena Marianna; Marotta, Rosa; Carotenuto, Marco

2013-01-01

Background Empirical evidence of the important role of the family in primary pediatric headache has grown significantly in the last few years, although the interconnections between the dysfunctional process and the family interaction are still unclear. Even though the role of parenting in childhood migraine is well known, no studies about the personality of parents of migraine children have been conducted. The aim of the present study was to assess, using an objective measure, the personality profile of mothers of children affected by migraine without aura (MoA). Materials and methods A total of 269 mothers of MoA children (153 male, 116 female, aged between 6 and 12 years; mean 8.93 ± 3.57 years) were compared with the findings obtained from a sample of mothers of 587 healthy children (316 male, 271 female, mean age 8.74 ± 3.57 years) randomly selected from schools in the Campania, Umbria, Calabria, and Sicily regions. Each mother filled out the Minnesota Multiphasic Personality Inventory – second edition (MMPI-2), widely used to diagnose personality and psychological disorders. The t-test was used to compare age and MMPI-2 clinical basic and content scales between mothers of MoA and typical developing children, and Pearson’s correlation test was used to evaluate the relation between MMPI-2 scores of mothers of MoA children and frequency, intensity, and duration of migraine attacks of their children. Results Mothers of MoA children showed significantly higher scores in the paranoia and social introversion clinical basic subscales, and in the anxiety, obsessiveness, depression, health concerns, bizarre mentation, cynicism, type A, low self-esteem, work interference, and negative treatment indicator clinical content subscales (P < 0.001 for all variables). Moreover, Pearson’s correlation analysis showed a significant relationship between MoA frequency of children and anxiety (r = 0.4903, P = 0.024) and low self-esteem (r = 0.5130, P = 0.017), while the MoA duration of children was related with hypochondriasis (r = 0.6155, P = 0.003), hysteria (r = 0.6235, P = 0.003), paranoia (r = 0.5102, P = 0.018), psychasthenia (r = 0.4806, P = 0.027), schizophrenia (r = 0.4350, P = 0.049), anxiety (r = 0.4332, P = 0.050), and health concerns (r = 0.7039, P < 0.001) MMPI-2 scores of their mothers. Conclusion This could be considered a preliminary study that indicates the potential value of maternal personality assessment for better comprehension and clinical management of children affected by migraine, though further studies on the other primary headaches are necessary. PMID:24049447

Correlating chemical sensitivity and basal gene expression reveals mechanism of action | Office of Cancer Genomics

Cancer.gov

Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown.

NASA EPA MOA Signing

NASA Image and Video Library

2010-04-25

NASA Administrator Charles Bolden, left, and U.S. Environmental Protection Agency (EPA) Administrator Lisa P. Jackson, right, sign a Memorandum of Agreement (MOA) to promote collaboration between the two agencies for cooperation in environmental and Earth sciences and environmental management applications as students from the Howard University Middle School of Mathematics and Science look on, Monday, April 26, 2010, at the school in Washington. Photo Credit: (NASA/Paul E. Alers)

NASA EPA MOA Signing

NASA Image and Video Library

2010-04-25

NASA Administrator Charles Bolden, foreground, speaks with Howard University students after he and and U.S. Environmental Protection Agency (EPA) Administrator Lisa P. Jackson, right, signed a Memorandum of Agreement (MOA) to promote collaboration between the two agencies for cooperation in environmental and Earth sciences and environmental management applications at the Howard University Middle School of Mathematics and Science, Monday, April 26, 2010, in Washington. Photo Credit: (NASA/Paul E. Alers)

Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bogen, K T

2007-01-30

As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate ''linear'' (genotoxic) vs. ''nonlinear'' (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to lowmore » levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach--similar to that used in reference dose procedures for classic toxicity endpoints--can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a ''nonlinear'' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2- and 1,4-naphthoquinone. Resulting bounds each provided the basis for a corresponding ''uncertainty'' factor <1 appropriate to apply to estimates of naphthalene risk obtained by linear extrapolation under a default genotoxic MOA assumption. This procedure is proposed as scientifically credible method to address MOA uncertainty for DMOA carcinogens.« less

Toxicogenomics and cancer risk assessment: a framework for key event analysis and dose-response assessment for nongenotoxic carcinogens.

PubMed

Bercu, Joel P; Jolly, Robert A; Flagella, Kelly M; Baker, Thomas K; Romero, Pedro; Stevens, James L

2010-12-01

In order to determine a threshold for nongenotoxic carcinogens, the traditional risk assessment approach has been to identify a mode of action (MOA) with a nonlinear dose-response. The dose-response for one or more key event(s) linked to the MOA for carcinogenicity allows a point of departure (POD) to be selected from the most sensitive effect dose or no-effect dose. However, this can be challenging because multiple MOAs and key events may exist for carcinogenicity and oftentimes extensive research is required to elucidate the MOA. In the present study, a microarray analysis was conducted to determine if a POD could be identified following short-term oral rat exposure with two nongenotoxic rodent carcinogens, fenofibrate and methapyrilene, using a benchmark dose analysis of genes aggregated in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) biological processes, which likely encompass key event(s) for carcinogenicity. The gene expression response for fenofibrate given to rats for 2days was consistent with its MOA and known key events linked to PPARα activation. The temporal response from daily dosing with methapyrilene demonstrated biological complexity with waves of pathways/biological processes occurring over 1, 3, and 7days; nonetheless, the benchmark dose values were consistent over time. When comparing the dose-response of toxicogenomic data to tumorigenesis or precursor events, the toxicogenomics POD was slightly below any effect level. Our results suggest that toxicogenomic analysis using short-term studies can be used to identify a threshold for nongenotoxic carcinogens based on evaluation of potential key event(s) which then can be used within a risk assessment framework. Copyright © 2010 Elsevier Inc. All rights reserved.

Endocrine disrupting chemicals in fish: developing exposure indicators and predictive models of effects based on mechanism of action.

PubMed

Ankley, Gerald T; Bencic, David C; Breen, Michael S; Collette, Timothy W; Conolly, Rory B; Denslow, Nancy D; Edwards, Stephen W; Ekman, Drew R; Garcia-Reyero, Natalia; Jensen, Kathleen M; Lazorchak, James M; Martinović, Dalma; Miller, David H; Perkins, Edward J; Orlando, Edward F; Villeneuve, Daniel L; Wang, Rong-Lin; Watanabe, Karen H

2009-05-05

Knowledge of possible toxic mechanisms (or modes) of action (MOA) of chemicals can provide valuable insights as to appropriate methods for assessing exposure and effects, thereby reducing uncertainties related to extrapolation across species, endpoints and chemical structure. However, MOA-based testing seldom has been used for assessing the ecological risk of chemicals. This is in part because past regulatory mandates have focused more on adverse effects of chemicals (reductions in survival, growth or reproduction) than the pathways through which these effects are elicited. A recent departure from this involves endocrine-disrupting chemicals (EDCs), where there is a need to understand both MOA and adverse outcomes. To achieve this understanding, advances in predictive approaches are required whereby mechanistic changes caused by chemicals at the molecular level can be translated into apical responses meaningful to ecological risk assessment. In this paper we provide an overview and illustrative results from a large, integrated project that assesses the effects of EDCs on two small fish models, the fathead minnow (Pimephales promelas) and zebrafish (Danio rerio). For this work a systems-based approach is being used to delineate toxicity pathways for 12 model EDCs with different known or hypothesized toxic MOA. The studies employ a combination of state-of-the-art genomic (transcriptomic, proteomic, metabolomic), bioinformatic and modeling approaches, in conjunction with whole animal testing, to develop response linkages across biological levels of organization. This understanding forms the basis for predictive approaches for species, endpoint and chemical extrapolation. Although our project is focused specifically on EDCs in fish, we believe that the basic conceptual approach has utility for systematically assessing exposure and effects of chemicals with other MOA across a variety of biological systems.

Proposed Mode of Action for Acrolein Respiratory Toxicity Associated with Inhaled Tobacco Smoke.

PubMed

Yeager, R Philip; Kushman, Mary; Chemerynski, Susan; Weil, Roxana; Fu, Xin; White, Marcella; Callahan-Lyon, Priscilla; Rosenfeldt, Hans

2016-06-01

This article presents a mode of action (MOA) analysis that identifies key mechanisms in the respiratory toxicity of inhaled acrolein and proposes key acrolein-related toxic events resulting from the inhalation of tobacco smoke. Smoking causes chronic obstructive pulmonary disorder (COPD) and acrolein has been previously linked to the majority of smoking-induced noncancer respiratory toxicity. In contrast to previous MOA analyses for acrolein, this MOA focuses on the toxicity of acrolein in the lower respiratory system, reflecting the exposure that smokers experience upon tobacco smoke inhalation. The key mechanisms of acrolein toxicity identified in this proposed MOA include (1) acrolein chemical reactivity with proteins and other macromolecules of cells lining the respiratory tract, (2) cellular oxidative stress, including compromise of the important anti-oxidant glutathione, (3) chronic inflammation, (4) necrotic cell death leading to a feedback loop where necrosis-induced inflammation leads to more necrosis and oxidative damage and vice versa, (5) tissue remodeling and destruction, and (6) loss of lung elasticity and enlarged lung airspaces. From these mechanisms, the proposed MOA analysis identifies the key cellular processes in acrolein respiratory toxicity that consistently occur with the development of COPD: inflammation and necrosis in the middle and lower regions of the respiratory tract. Moreover, the acrolein exposures that occur as a result of smoking are well above exposures that induce both inflammation and necrosis in laboratory animals, highlighting the importance of the role of acrolein in smoking-related respiratory disease. Published by Oxford University Press on behalf of the Society of Toxicology 2016. This work is written by US Government employees and is in the public domain in the US.

Discriminating modes of toxic action in mice using toxicity in BALB/c mouse fibroblast (3T3) cells.

PubMed

Huang, Tao; Yan, Lichen; Zheng, Shanshan; Wang, Yue; Wang, Xiaohong; Fan, Lingyun; Li, Chao; Zhao, Yuanhui; Martyniuk, Christopher J

2017-12-01

The objective of this study was to determine whether toxicity in mouse fibroblast cells (3T3 cells) could predict toxicity in mice. Synthesized data on toxicity was subjected to regression analysis and it was observed that relationship of toxicities between mice and 3T3 cells was not strong (R 2  = 0.41). Inclusion of molecular descriptors (e.g. ionization, pKa) improved the regression to R 2  = 0.56, indicating that this relationship is influenced by kinetic processes of chemicals or specific toxic mechanisms associated to the compounds. However, to determine if we were able to discriminate modes of action (MOAs) in mice using the toxicities generated from 3T3 cells, compounds were first classified into "baseline" and "reactive" guided by the toxic ratio (TR) for each compound in mice. Sequence, binomial and recursive partitioning analyses provided strong predictions of MOAs in mice based upon toxicities in 3T3 cells. The correct classification of MOAs based on these methods was 86%. Nearly all the baseline compounds predicted from toxicities in 3T3 cells were identified as baseline compounds from the TR in mice. The incorrect assignment of MOAs for some compounds is hypothesized to be due to experimental uncertainty that exists in toxicity assays for both mice and 3T3 cells. Conversely, lack of assignment can also arise because some reactive compounds have MOAs that are different in mice compared to 3T3 cells. The methods developed here are novel and contribute to efforts to reduce animal numbers in toxicity tests that are used to evaluate risks associated with organic pollutants in the environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

NASA EPA MOA Signing

NASA Image and Video Library

2010-04-25

NASA Administrator Charles Bolden, left, and U.S. Environmental Protection Agency (EPA) Administrator Lisa P. Jackson, right, answer questions from students and faculty from the Howard University Middle School of Mathematics and Science after signing a Memorandum of Agreement (MOA) to promote collaboration between the two agencies for cooperation in environmental and Earth sciences and environmental management applications, Monday, April 26, 2010, at the school in Washington. Photo Credit: (NASA/Paul E. Alers)

Live-cell Imaging of Fungal Cells to Investigate Modes of Entry and Subcellular Localization of Antifungal Plant Defensins.

PubMed

Islam, Kazi T; Shah, Dilip M; El-Mounadi, Kaoutar

2017-12-24

Small cysteine-rich defensins are one of the largest groups of host defense peptides present in all plants. Many plant defensins exhibit potent in vitro antifungal activity against a broad-spectrum of fungal pathogens and therefore have the potential to be used as antifungal agents in transgenic crops. In order to harness the full potential of plant defensins for diseases control, it is crucial to elucidate their mechanisms of action (MOA). With the advent of advanced microscopy techniques, live-cell imaging has become a powerful tool for understanding the dynamics of the antifungal MOA of plant defensins. Here, a confocal microscopy based live-cell imaging method is described using two fluorescently labeled plant defensins (MtDef4 and MtDef5) in combination with vital fluorescent dyes. This technique enables real-time visualization and analysis of the dynamic events of MtDef4 and MtDef5 internalization into fungal cells. Importantly, this assay generates a wealth of information including internalization kinetics, mode of entry and subcellular localization of these peptides. Along with other cell biological tools, these methods have provided critical insights into the dynamics and complexity of the MOA of these peptides. These tools can also be used to compare the MOA of these peptides against different fungi.

Implementing marine organic aerosols into the GEOS-Chem model

DOE PAGES

Gantt, B.; Johnson, M. S.; Crippa, M.; ...

2015-03-17

Marine-sourced organic aerosols (MOAs) have been shown to play an important role in tropospheric chemistry by impacting surface mass, cloud condensation nuclei, and ice nuclei concentrations over remote marine and coastal regions. In this work, an online marine primary organic aerosol emission parameterization, designed to be used for both global and regional models, was implemented into the GEOS-Chem (Global Earth Observing System Chemistry) model. The implemented emission scheme improved the large underprediction of organic aerosol concentrations in clean marine regions (normalized mean bias decreases from -79% when using the default settings to -12% when marine organic aerosols are added). Modelmore » predictions were also in good agreement (correlation coefficient of 0.62 and normalized mean bias of -36%) with hourly surface concentrations of MOAs observed during the summertime at an inland site near Paris, France. Our study shows that MOAs have weaker coastal-to-inland concentration gradients than sea-salt aerosols, leading to several inland European cities having >10% of their surface submicron organic aerosol mass concentration with a marine source. The addition of MOA tracers to GEOS-Chem enabled us to identify the regions with large contributions of freshly emitted or aged aerosol having distinct physicochemical properties, potentially indicating optimal locations for future field studies.« less

Dose-response approaches for nuclear receptor-mediated ...

EPA Pesticide Factsheets

A public workshop, organized by a Steering Committee of scientists from government, industry, universities, and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose-response implications of toxicant modes of action (MOA) mediated by nuclear receptors. The dominant paradigm in human health risk assessment has been linear extrapolation without a threshold for cancer, and estimation of sub-threshold doses for non-cancer and (in appropriate cases) cancer endpoints. However, recent publications question the application of dose-response modeling approaches with a threshold. The growing body of molecular toxicology information and computational toxicology tools has allowed for exploration of the presence or absence of subthreshold doses for a number of receptor-mediated MOPs. The workshop explored the development of dose-response approaches for nuclear receptor-mediated liver cancer, within a MOA Human Relevance framework (HRF). Case studies addressed activation of the AHR; the CAR/PXR, and the PPARa. This paper describes the workshop process, key issues discussed, and conclusions. The value of an interactive workshop approach to apply current MOA/HRF frameworks was demonstrated. The results may help direct research on the MOA and dose-response of receptor-based toxicity, since there are commonalities for many receptors in the basic pathways involved for late steps in the

Capillary Electrophoresis Analysis of Organic Amines and Amino Acids in Saline and Acidic Samples Using the Mars Organic Analyzer

NASA Astrophysics Data System (ADS)

Stockton, Amanda M.; Chiesl, Thomas N.; Lowenstein, Tim K.; Amashukeli, Xenia; Grunthaner, Frank; Mathies, Richard A.

2009-11-01

The Mars Organic Analyzer (MOA) has enabled the sensitive detection of amino acid and amine biomarkers in laboratory standards and in a variety of field sample tests. However, the MOA is challenged when samples are extremely acidic and saline or contain polyvalent cations. Here, we have optimized the MOA analysis, sample labeling, and sample dilution buffers to handle such challenging samples more robustly. Higher ionic strength buffer systems with pKa values near pH 9 were developed to provide better buffering capacity and salt tolerance. The addition of ethylaminediaminetetraacetic acid (EDTA) ameliorates the negative effects of multivalent cations. The optimized protocol utilizes a 75 mM borate buffer (pH 9.5) for Pacific Blue labeling of amines and amino acids. After labeling, 50 mM (final concentration) EDTA is added to samples containing divalent cations to ameliorate their effects. This optimized protocol was used to successfully analyze amino acids in a saturated brine sample from Saline Valley, California, and a subcritical water extract of a highly acidic sample from the Río Tinto, Spain. This work expands the analytical capabilities of the MOA and increases its sensitivity and robustness for samples from extraterrestrial environments that may exhibit pH and salt extremes as well as metal ions.

Capillary electrophoresis analysis of organic amines and amino acids in saline and acidic samples using the Mars organic analyzer.

PubMed

Stockton, Amanda M; Chiesl, Thomas N; Lowenstein, Tim K; Amashukeli, Xenia; Grunthaner, Frank; Mathies, Richard A

2009-11-01

The Mars Organic Analyzer (MOA) has enabled the sensitive detection of amino acid and amine biomarkers in laboratory standards and in a variety of field sample tests. However, the MOA is challenged when samples are extremely acidic and saline or contain polyvalent cations. Here, we have optimized the MOA analysis, sample labeling, and sample dilution buffers to handle such challenging samples more robustly. Higher ionic strength buffer systems with pK(a) values near pH 9 were developed to provide better buffering capacity and salt tolerance. The addition of ethylaminediaminetetraacetic acid (EDTA) ameliorates the negative effects of multivalent cations. The optimized protocol utilizes a 75 mM borate buffer (pH 9.5) for Pacific Blue labeling of amines and amino acids. After labeling, 50 mM (final concentration) EDTA is added to samples containing divalent cations to ameliorate their effects. This optimized protocol was used to successfully analyze amino acids in a saturated brine sample from Saline Valley, California, and a subcritical water extract of a highly acidic sample from the Río Tinto, Spain. This work expands the analytical capabilities of the MOA and increases its sensitivity and robustness for samples from extraterrestrial environments that may exhibit pH and salt extremes as well as metal ions.

Arrester Resistive Current Measuring System Based on Heterogeneous Network

NASA Astrophysics Data System (ADS)

Zhang, Yun Hua; Li, Zai Lin; Yuan, Feng; Hou Pan, Feng; Guo, Zhan Nan; Han, Yue

2018-03-01

Metal Oxide Arrester (MOA) suffers from aging and poor insulation due to long-term impulse voltage and environmental impact, and the value and variation tendency of resistive current can reflect the health conditions of MOA. The common wired MOA detection need to use long cables, which is complicated to operate, and that wireless measurement methods are facing the problems of poor data synchronization and instability. Therefore a novel synchronous measurement system of arrester current resistive based on heterogeneous network is proposed, which simplifies the calculation process and improves synchronization, accuracy and stability and of the measuring system. This system combines LoRa wireless network, high speed wireless personal area network and the process layer communication, and realizes the detection of arrester working condition. Field test data shows that the system has the characteristics of high accuracy, strong anti-interference ability and good synchronization, which plays an important role in ensuring the stable operation of the power grid.

Final Environmental Assessment for the Defensive Training Initiative, Cannon Air Force Base, New Mexico

DTIC Science & Technology

2001-09-01

100 miles southwest of Melrose AFR near Ruidoso , New Mexico. The Jicarilla Apache Reservation is 195 miles northwest of the range. The Comanche Tribe...of the MOAs near Ruidoso , New Mexico. The Jicarilla Apache Reservation is about 150 miles northwest of the MOAs; and the Comanche Reservation is in...and Comanche. The Mescalero Apache Reservation is located approximately 25 miles south of VRs-100/125 near Ruidoso , New Mexico. The Jicarilla

Whole-Organism Transcriptomic Analysis Provides Mechanistic Insight into the Acute Toxicity of Emamectin Benzoate in Daphnia magna.

PubMed

Song, You; Rundberget, Jan Thomas; Evenseth, Linn Mari; Xie, Li; Gomes, Tânia; Høgåsen, Tore; Iguchi, Taisen; Tollefsen, Knut Erik

2016-11-01

Emamectin benzoate (EMB) is an antisea lice chemical widely used in the aquaculture that may also unintentionally affect nontarget crustaceans in the environment. Although the adverse effects of this compound are well documented in various species, the full modes of action (MoAs) are still not well characterized. The current study was therefore conducted to characterize the MoAs of EMB and link perturbations of key toxicological pathways to adverse effects in the model freshwater crustacean Daphnia magna. Effects on molting and survival were determined after 48 h exposure to EMB, whereas global transcriptional changes and the ecdysone receptor (EcR) binding potency was determined to characterize the MoA. The results showed that the molting frequency and survival of D. magna decreased in a concentration-dependent manner, and the observed changes could not be attributed to direct interactions with the EcR. Major MoAs such as activation of glutamate-gated chloride channels and gamma-aminobutyric acid signaling, disruption of neuroendocrine regulation of molting, perturbation of energy homeostasis, suppression of DNA repair and induction of programmed cell death were observed by transcriptional analysis and successfully linked to the adverse effects. This study has demonstrated that acute exposure to intermediate and high pM levels of EMB may pose hazards to nontarget crustaceans in the aquatic environment.

Rapid Inhibition Profiling in Bacillus subtilis to Identify the Mechanism of Action of New Antimicrobials.

PubMed

Lamsa, Anne; Lopez-Garrido, Javier; Quach, Diana; Riley, Eammon P; Pogliano, Joe; Pogliano, Kit

2016-08-19

Increasing antimicrobial resistance has become a major public health crisis. New antimicrobials with novel mechanisms of action (MOA) are desperately needed. We previously developed a method, bacterial cytological profiling (BCP), which utilizes fluorescence microscopy to rapidly identify the MOA of antimicrobial compounds. BCP is based upon our discovery that cells treated with antibiotics affecting different metabolic pathways generate different cytological signatures, providing quantitative information that can be used to determine a compound's MOA. Here, we describe a system, rapid inhibition profiling (RIP), for creating cytological profiles of new antibiotic targets for which there are currently no chemical inhibitors. RIP consists of the fast, inducible degradation of a target protein followed by BCP. We demonstrate that degrading essential proteins in the major metabolic pathways for DNA replication, transcription, fatty acid biosynthesis, and peptidoglycan biogenesis in Bacillus subtilis rapidly produces cytological profiles closely matching that of antimicrobials targeting the same pathways. Additionally, RIP and antibiotics targeting different steps in fatty acid biosynthesis can be differentiated from each other. We utilize RIP and BCP to show that the antibacterial MOA of four nonsteroidal anti-inflammatory antibiotics differs from that proposed based on in vitro data. RIP is a versatile method that will extend our knowledge of phenotypes associated with inactivating essential bacterial enzymes and thereby allow for screening for molecules that inhibit novel essential targets.

Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment.

PubMed

Bradley, Ann E; Shoenfelt, Joanna L; Durda, Judi L

2016-04-01

Alpha-hexachlorocyclohexane (alpha-HCH) is one of eight structural isomers that have been used worldwide as insecticides. Although no longer produced or used agriculturally in the United States, exposure to HCH isomers is of continuing concern due to legacy usage and persistence in the environment. The U.S. Environmental Protection Agency (EPA) classifies alpha-HCH as a probable human carcinogen and provides a slope factor of 6.3 (mg/kg-day)(-1) for the compound, based on hepatic nodules and hepatocellular carcinomas observed in male mice and derived using a default linear approach for modeling carcinogens. EPA's evaluation, last updated in 1993, does not consider more recently available guidance that allows for the incorporation of mode of action (MOA) for determining a compound's dose-response. Contrary to the linear approach assumed by EPA, the available data indicate that alpha-HCH exhibits carcinogenicity via an MOA that yields a nonlinear, threshold dose-response. In our analysis, we conducted an MOA evaluation and dose-response analysis for alpha-HCH-induced liver carcinogenesis. We concluded that alpha-HCH causes liver tumors in rats and mice through an MOA involving increased promotion of cell growth, or mitogenesis. Based on these findings, we developed a threshold, cancer-based, reference dose (RfD) for alpha-HCH. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Inhibition of Listeria monocytogenes on Ready-to-Eat Meats Using Bacteriocin Mixtures Based on Mode-of-Action

PubMed Central

Vijayakumar, Paul Priyesh; Muriana, Peter M.

2017-01-01

Bacteriocin-producing (Bac+) lactic acid bacteria (LAB) comprising selected strains of Lactobacillus curvatus, Lactococcus lactis, Pediococcus acidilactici, and Enterococcus faecium and thailandicus were examined for inhibition of Listeria monocytogenes during hotdog challenge studies. The Bac+ strains, or their cell-free supernatants (CFS), were grouped according to mode-of-action (MOA) as determined from prior studies. Making a mixture of as many MOAs as possible is a practical way to obtain a potent natural antimicrobial mixture to address L. monocytogenes contamination of RTE meat products (i.e., hotdogs). The heat resistance of the bacteriocins allowed the use of pasteurization to eliminate residual producer cells for use as post-process surface application or their inclusion into hotdog meat emulsion during cooking. The use of Bac+ LAB comprising 3× MOAs directly as co-inoculants on hotdogs was not effective at inhibiting L. monocytogenes. However, the use of multiple MOA Bac+ CFS mixtures in a variety of trials demonstrated the effectiveness of this approach by showing a >2-log decrease of L. monocytogenes in treatment samples and 6–7 log difference vs. controls. These data suggest that surface application of multiple mode-of-action bacteriocin mixtures can provide for an Alternative 2, and possibly Alternative 1, process category as specified by USDA-FSIS for control of L. monocytogenes on RTE meat products. PMID:28335414

Inhibition of Listeria monocytogenes on Ready-to-Eat Meats Using Bacteriocin Mixtures Based on Mode-of-Action.

PubMed

Vijayakumar, Paul Priyesh; Muriana, Peter M

2017-03-14

Bacteriocin-producing (Bac⁺) lactic acid bacteria (LAB) comprising selected strains of Lactobacillus curvatus , Lactococcus lactis , Pediococcus acidilactici , and Enterococcus faecium and thailandicus were examined for inhibition of Listeria monocytogenes during hotdog challenge studies. The Bac⁺ strains, or their cell-free supernatants (CFS), were grouped according to mode-of-action (MOA) as determined from prior studies. Making a mixture of as many MOAs as possible is a practical way to obtain a potent natural antimicrobial mixture to address L. monocytogenes contamination of RTE meat products (i.e., hotdogs). The heat resistance of the bacteriocins allowed the use of pasteurization to eliminate residual producer cells for use as post-process surface application or their inclusion into hotdog meat emulsion during cooking. The use of Bac⁺ LAB comprising 3× MOAs directly as co-inoculants on hotdogs was not effective at inhibiting L. monocytogenes. However, the use of multiple MOA Bac⁺ CFS mixtures in a variety of trials demonstrated the effectiveness of this approach by showing a >2-log decrease of L. monocytogenes in treatment samples and 6-7 log difference vs. These data suggest that surface application of multiple mode-of-action bacteriocin mixtures can provide for an Alternative 2, and possibly Alternative 1, process category as specified by USDA-FSIS for control of L. monocytogenes on RTE meat products.

Effectiveness and safety of Nintendo Wii Fit Plus™ training in children with migraine without aura: a preliminary study

PubMed Central

Esposito, Maria; Ruberto, Maria; Gimigliano, Francesca; Marotta, Rosa; Gallai, Beatrice; Parisi, Lucia; Lavano, Serena Marianna; Roccella, Michele; Carotenuto, Marco

2013-01-01

Background Migraine without aura (MoA) is a painful syndrome, particularly in childhood; it is often accompanied by severe impairments, including emotional dysfunction, absenteeism from school, and poor academic performance, as well as issues relating to poor cognitive function, sleep habits, and motor coordination. Materials and methods The study population consisted of 71 patients affected by MoA (32 females, 39 males) (mean age: 9.13±1.94 years); the control group consisted of 93 normally developing children (44 females, 49 males) (mean age: 8.97±2.03 years) recruited in the Campania school region. The entire population underwent a clinical evaluation to assess total intelligence quotient level, visual-motor integration (VMI) skills, and motor coordination performance, the later using the Movement Assessment Battery for Children (M-ABC). Children underwent training using the Wii-balance board and Nintendo Wii Fit Plus™ software (Nintendo Co, Ltd, Kyoto, Japan); training lasted for 12 weeks and consisted of three 30-minute sessions per week at their home. Results The two starting populations (MoA and controls) were not significantly different for age (P=0.899) and sex (P=0.611). M-ABC and VMI performances at baseline (T0) were significantly different in dexterity, balance, and total score for M-ABC (P<0.001) and visual (P=0.003) and motor (P<0.001) tasks for VMI. After 3 months of Wii training (T1), MoA children showed a significant improvement in M-ABC global performance (P<0.001), M-ABC dexterity (P<0.001), M-ABC balance (P<0.001), and VMI motor task (P<0.001). Conclusion Our study reported the positive effects of the Nintendo Wii Fit Plus™ system as a rehabilitative device for the visuomotor and balance skills impairments among children affected by MoA, even if further research and longer follow-up are needed. PMID:24453490

Effectiveness and safety of Nintendo Wii Fit Plus™ training in children with migraine without aura: a preliminary study.

PubMed

Esposito, Maria; Ruberto, Maria; Gimigliano, Francesca; Marotta, Rosa; Gallai, Beatrice; Parisi, Lucia; Lavano, Serena Marianna; Roccella, Michele; Carotenuto, Marco

2013-01-01

Migraine without aura (MoA) is a painful syndrome, particularly in childhood; it is often accompanied by severe impairments, including emotional dysfunction, absenteeism from school, and poor academic performance, as well as issues relating to poor cognitive function, sleep habits, and motor coordination. The study population consisted of 71 patients affected by MoA (32 females, 39 males) (mean age: 9.13±1.94 years); the control group consisted of 93 normally developing children (44 females, 49 males) (mean age: 8.97±2.03 years) recruited in the Campania school region. The entire population underwent a clinical evaluation to assess total intelligence quotient level, visual-motor integration (VMI) skills, and motor coordination performance, the later using the Movement Assessment Battery for Children (M-ABC). Children underwent training using the Wii-balance board and Nintendo Wii Fit Plus™ software (Nintendo Co, Ltd, Kyoto, Japan); training lasted for 12 weeks and consisted of three 30-minute sessions per week at their home. The two starting populations (MoA and controls) were not significantly different for age (P=0.899) and sex (P=0.611). M-ABC and VMI performances at baseline (T0) were significantly different in dexterity, balance, and total score for M-ABC (P<0.001) and visual (P=0.003) and motor (P<0.001) tasks for VMI. After 3 months of Wii training (T1), MoA children showed a significant improvement in M-ABC global performance (P<0.001), M-ABC dexterity (P<0.001), M-ABC balance (P<0.001), and VMI motor task (P<0.001). Our study reported the positive effects of the Nintendo Wii Fit Plus™ system as a rehabilitative device for the visuomotor and balance skills impairments among children affected by MoA, even if further research and longer follow-up are needed.

Comparison of in vivo genotoxic and carcinogenic potency to augment mode of action analysis: Case study with hexavalent chromium.

PubMed

Thompson, Chad M; Bichteler, Anne; Rager, Julia E; Suh, Mina; Proctor, Deborah M; Haws, Laurie C; Harris, Mark A

2016-04-01

Recent analyses-highlighted by the International Workshops on Genotoxicity Testing Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment-have identified a correlation between (log) estimates of a carcinogen's in vivo genotoxic potency and in vivo carcinogenic potency in typical laboratory animal models, even when the underlying data have not been matched for tissue, species, or strain. Such a correlation could have important implications for risk assessment, including informing the mode of action (MOA) of specific carcinogens. When in vivo genotoxic potency is weak relative to carcinogenic potency, MOAs other than genotoxicity (e.g., endocrine disruption or regenerative hyperplasia) may be operational. Herein, we review recent in vivo genotoxicity and carcinogenicity data for hexavalent chromium (Cr(VI)), following oral ingestion, in relevant tissues and species in the context of the aforementioned correlation. Potency estimates were generated using benchmark doses, or no-observable-adverse-effect-levels when data were not amenable to dose-response modeling. While the ratio between log values for carcinogenic and genotoxic potency was ≥1 for many compounds, the ratios for several Cr(VI) datasets (including in target tissue) were less than unity. In fact, the ratios for Cr(VI) clustered closely with ratios for chloroform and diethanolamine, two chemicals posited to have non-genotoxic MOAs. These findings suggest that genotoxicity may not play a major role in the cancers observed in rodents following exposure to high concentrations of Cr(VI) in drinking water-a finding consistent with recent MOA and adverse outcome pathway (AOP) analyses concerning Cr(VI). This semi-quantitative analysis, therefore, may be useful to augment traditional MOA and AOP analyses. More case examples will be needed to further explore the general applicability and validity of this approach for human health risk assessment. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Realistic Bomber Training Initiative Supplemental Environmental Impact Statement

DTIC Science & Technology

2007-03-01

mph at the surface and 27 mph at 22 feet AGL; e ) A pull-up maneuver by the B-1B, which may be executed once or twice per sortie- operation, can...avoid resources, where feasible. ( e ) Developing and implementing site-specifi.c mitigation measures, if required. (3) The Air Force will avoid or...form a complete MOA, the LancerMOA. (2) Concerns were expressed about the structw~ e of the proposed MTR, IR 178. The Air Force reduced noise

Attracted by a magnet: Exploration behaviour of rodents in the presence of magnetic objects.

PubMed

Malewski, Sandra; Malkemper, E Pascal; Sedláček, František; Šumbera, Radim; Caspar, Kai R; Burda, Hynek; Begall, Sabine

2018-06-01

Magnetosensitivity is widespread among animals with rodents being the most intensively studied mammalian group. The available behavioural assays for magnetoreception are time-consuming, which impedes screens for treatment effects that could characterize the enigmatic magnetoreceptors. Here, we present a fast and simple approach to test if an animal responds to magnetic stimuli: the magnetic object assay (MOA). The MOA focuses on investigating an animal's spontaneous exploration behaviour in the presence of a bar magnet compared to a demagnetised control. We present consistently longer exploration of the magnet in three different rodent species: Ansell's mole-rat (Fukomys anselli), C57BL/6J laboratory mouse, and naked mole-rat (Heterocephalus glaber). For the naked mole-rat this is the first report that this species reacts on magnetic stimuli. We conclude that the MOA holds the potential to screen if an animal responds to magnetic stimuli, indicating the possession of a magnetic sense. Copyright © 2018 Elsevier B.V. All rights reserved.

Development of a data-processing method based on Bayesian k-means clustering to discriminate aneugens and clastogens in a high-content micronucleus assay.

PubMed

Huang, Z H; Li, N; Rao, K F; Liu, C T; Huang, Y; Ma, M; Wang, Z J

2018-03-01

Genotoxicants can be identified as aneugens and clastogens through a micronucleus (MN) assay. The current high-content screening-based MN assays usually discriminate an aneugen from a clastogen based on only one parameter, such as the MN size, intensity, or morphology, which yields low accuracies (70-84%) because each of these parameters may contribute to the results. Therefore, the development of an algorithm that can synthesize high-dimensionality data to attain comparative results is important. To improve the automation and accuracy of detection using the current parameter-based mode of action (MoA), the MN MoA signatures of 20 chemicals were systematically recruited in this study to develop an algorithm. The results of the algorithm showed very good agreement (93.58%) between the prediction and reality, indicating that the proposed algorithm is a validated analytical platform for the rapid and objective acquisition of genotoxic MoA messages.

Evolved pesticide tolerance in amphibians: Predicting mechanisms based on pesticide novelty and mode of action.

PubMed

Hua, Jessica; Jones, Devin K; Mattes, Brian M; Cothran, Rickey D; Relyea, Rick A; Hoverman, Jason T

2015-11-01

We examined 10 wood frog populations distributed along an agricultural gradient for their tolerance to six pesticides (carbaryl, malathion, cypermethrin, permethrin, imidacloprid, and thiamethoxam) that differed in date of first registration (pesticide novelty) and mode-of-action (MOA). Our goals were to assess whether: 1) tolerance was correlated with distance to agriculture for each pesticide, 2) pesticide novelty predicted the likelihood of evolved tolerance, and 3) populations display cross-tolerance between pesticides that share and differ in MOA. Wood frog populations located close to agriculture were more tolerant to carbaryl and malathion than populations far from agriculture. Moreover, the strength of the relationship between distance to agriculture and tolerance was stronger for older pesticides compared to newer pesticides. Finally, we found evidence for cross-tolerance between carbaryl and malathion (two pesticides that share MOA). This study provides one of the most comprehensive approaches for understanding patterns of evolved tolerance in non-pest species. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Exoplanet Mass-Ratio Function From the MOA-II Survey: Discovery of a Break and Likely Peak at a Neptune Mass

NASA Technical Reports Server (NTRS)

Suzuki, D.; Bennett, D. P.; Sumi, T.; Bond, I. A.; Rogers, L. A.; Abe, F.; Asakura, Y.; Bhattacharya, A.; Donachie, M.; Freeman, M.;

Adverse Outcome Pathway (AOP) for a Mutagenic Mode of ...

EPA Pesticide Factsheets

AOPs provide a framework to describe a sequence of measureable key events (KEs), beginning with a molecular initiating event (MIE), followed by a series of identified KEs linked to one another by KE Relationships (KERs), all anchored by a specific adverse outcome (AO). Each KE/KER is supported by data and evaluated against criteria to assess biological plausibility, weight/strength of evidence, specificity, and confidence. AOPs offer an approach to using toxicological data and predictive modeling to actualize use of mode-of-action (MOA) for such purposes as read-across, integrated approaches to testing & assessment, and risk assessment. Different applications will depend partly on the scientific confidence underpinning each KE/KER and the overall AOP. An OECD program encourages development of AOPs, with a wiki that allows for public review & comment to foster collaborations and broaden understanding & application of AOPs. Developing an AOP for a mutagenic MOA for cancer as a case study in the OECD program lays a path towards determination of such an MOA and its use in chemical assessment programs. Aflatoxin B1 (AFB1), with ubiquitous exposure and a rich database, was selected for this case study. AFB1 has been determined to induce HCC via a DNA-reactive MOA in many species, including humans. The sequential KEs identified for AFB1 are as follows: pre-MIE: Hepatic metabolic activation; MIE: Formation of a pro-mutagenic DNA adduct (N7-AFB1-guanine or AFB1-FAPy); KE

CACODYLIC ACID (DMAV): METABOLISM AND ...

EPA Pesticide Factsheets

The cacodylic acid (DMAV) issue paper discusses the metabolism and pharmacokinetics of the various arsenical chemicals; evaluates the appropriate dataset to quantify the potential cancer risk to the organic arsenical herbicides; provides an evaluation of the mode of carcinogenic action (MOA) for DMAV including a consideration of the key events for bladder tumor formation in rats, other potential modes of action; and also considers the human relevance of the proposed animal MOA. As part of tolerance reassessment under the Food Quality Protection Act for the August 3, 2006 deadline, the hazard of cacodylic acid is being reassessed.

The first eclipsing binary catalogue from the MOA-II data base

NASA Astrophysics Data System (ADS)

Li, M. C. A.; Rattenbury, N. J.; Bond, I. A.; Sumi, T.; Bennett, D. P.; Koshimoto, N.; Abe, F.; Asakura, Y.; Barry, R.; Bhattacharya, A.; Donachie, M.; Evans, P.; Freeman, M.; Fukui, A.; Hirao, Y.; Itow, Y.; Ling, C. H.; Masuda, K.; Matsubara, Y.; Muraki, Y.; Nagakane, M.; Ohnishi, K.; Saito, To.; Sharan, A.; Sullivan, D. J.; Suzuki, D.; Tristram, P. J.; Yonehara, A.

2017-09-01

We present the first catalogue of eclipsing binaries in two MOA (Microlensing Observations in Astrophysics) fields towards the Galactic bulge, in which over 8000 candidates, mostly contact and semidetached binaries of periods <1 d, were identified. In this paper, the light curves of a small number of interesting candidates, including eccentric binaries, binaries with noteworthy phase modulations and eclipsing RS Canum Venaticorum type stars, are shown as examples. In addition, we identified three triple object candidates by detecting the light-travel-time effect in their eclipse time variation curves.

NESHAP Annual Report for CY 2015 Sandia National Laboratories Tonopah Test Range

DOE Office of Scientific and Technical Information (OSTI.GOV)

Evelo, Stacie

2016-05-01

This National Emission Standards for Hazardous Air Pollutants (NESHAP) Annual Report has been prepared in a format to comply with the reporting requirements of 40 CFR 61.94 and the April 5, 1995 Memorandum of Agreement (MOA) between the Department of Energy (DOE) and the Environmental Protection Agency (EPA). According to the EPA approved NESHAP Monitoring Plan for the Tonopah Test Range (TTR), 40 CFR 61, subpart H, and the MOA, no additional monitoring or measurements are required at TTR in order to demonstrate compliance with the NESHAP regulation.

Seasonal Changes in Plasma Levels of Sex Hormones in the Greater Rhea (Rhea americana), a South American Ratite with a Complex Mating System

PubMed Central

Valdez, Diego J.; Vera Cortez, Marilina; Della Costa, Natalia S.; Lèche, Alvina; Hansen, Cristian; Navarro, Joaquín L.; Martella, Mónica B.

2014-01-01

Seasonal rhythm in sex hormones has been extensively studied in birds, as well as its relationship with the type of mating system. The Greater Rhea (Rhea americana), a South American ratite species, reproduces seasonally and has a complex mating system: female-defense polygyny and sequential polyandry. The present study aimed at analyzing the endocrine basis of reproduction in this species and its relationship with its mating system. We used HPLC and electrochemiluminescence techniques to identify and measure plasma testosterone and estradiol levels. Annual oscillations in sex hormones, testosterone and estradiol, in adult males and females were observed. Lower levels of these hormones were exhibited during the non reproductive season (February to July), whereas their maximum values were reached in September for males and November-December for females. These fluctuations reflect the seasonal changes in gonadal function. By contrast, no significant sex hormones oscillations were observed in juvenile males and females (negative control of seasonal changes). Greater rheas maintain high testosterone and estradiol levels throughout the reproductive period. The high testosterone levels during incubation and chick rearing did not inhibit parental behavior in males, which appears not to conform to the “Challenge Hypothesis”. In females, the high estradiol levels throughout the reproductive season would be needed to sustain their long egg-laying period. PMID:24837464

Comparative effects of in ovo versus subcutaneous administration of the Marek's disease vaccine and pre-placement holding time on the post-hatch performance of Ross 708 broilers1,2,3.

PubMed

Peebles, E D; Barbosa, T M; Cummings, T S; Dickson, J; Womack, S K; Gerard, P D

2017-05-01

Effects of 2 types of methods of administration (moa; in ovo or s.c.) of the Marek's disease (MD) vaccine and 4 and 18 h pre-placement holding times (pht) on the performance of male broilers through 48 d of age were investigated. Ross 708 broiler hatching eggs (3,900) were either in ovo-vaccinated at 18 d of incubation or chicks from eggs that were not in ovo-injected were vaccinated s.c. at hatch, and chicks from each moa group were held for one of the 2 pht. In ovo injections (50 μL) were delivered by a commercial multi-egg injector and s.c. injections (0.2 mL) were delivered by an automatic pneumatic s.c. injector. Sixteen birds were assigned to each of 15 replicate floor pens belonging to each of the 4 moa and pht combination groups. Mortality and BW gain were determined at weekly intervals, and feed consumption and conversion were determined in the zero to 14, 14 to 28, 28 to 42, and 42 to 48 d age intervals. No interactive effects between moa and pht were observed for any variable, and mortality was not significantly affected by moa or pht. The 14 to 28 d feed consumption and 14 to 21 d BW gain of s.c.-vaccinated birds were lower than that of in ovo-vaccinated birds, and the increase in pht from 4 to 18 h decreased feed consumption through 28 d post hatch and BW gain through 35 d post hatch. Overall, the performances of male Ross 708 broilers through 48 d of age in response to in ovo and s.c. injections of the MD vaccine were comparable, and delays in hatchling placement should be less that 18 h in duration. Furthermore, despite the decrease in BW gain through 35 d associated with the reduction in feed consumption through 28 d in response to the 14 h increase in pht, in ovo injection did not exacerbate the effect of the increase in pht. © 2016 Poultry Science Association Inc.

Mode of action associated with development of hemangiosarcoma in mice given pregabalin and assessment of human relevance.

PubMed

Criswell, Kay A; Cook, Jon C; Wojcinski, Zbigniew; Pegg, David; Herman, James; Wesche, David; Giddings, John; Brady, Joseph T; Anderson, Timothy

2012-07-01

Pregabalin increased the incidence of hemangiosarcomas in carcinogenicity studies of 2-year mice but was not tumorigenic in rats. Serum bicarbonate increased within 24 h of pregabalin administration in mice and rats. Rats compensated appropriately, but mice developed metabolic alkalosis and increased blood pH. Local tissue hypoxia and increased endothelial cell proliferation were also confirmed in mice alone. The combination of hypoxia and sustained increases in endothelial cell proliferation, angiogenic growth factors, dysregulated erythropoiesis, and macrophage activation is proposed as the key event in the mode of action (MOA) for hemangiosarcoma formation. Hemangiosarcomas occur spontaneously in untreated control mice but occur only rarely in humans. The International Programme on Chemical Safety and International Life Sciences Institute developed a Human Relevance Framework (HRF) analysis whereby presence or absence of key events can be used to assess human relevance. The HRF combines the MOA with an assessment of biologic plausibility in humans to assess human relevance. This manuscript compares the proposed MOA with Hill criteria, a component of the HRF, for strength, consistency, specificity, temporality, and dose response, with an assessment of key biomarkers in humans, species differences in response to disease conditions, and spontaneous incidence of hemangiosarcoma to evaluate human relevance. Lack of key biomarker events in the MOA in rats, monkeys, and humans supports a species-specific process and demonstrates that the tumor findings in mice are not relevant to humans at the clinical dose of pregabalin. Based on this collective dataset, clinical use of pregabalin would not pose an increased risk for hemangiosarcoma to humans.

Integrative rodent models for assessing male reproductive toxicity of environmental endocrine active substances

PubMed Central

Auger, Jacques; Eustache, Florence; Rouiller-Fabre, Virginie; Canivenc-Lavier, Marie Chantal; Livera, Gabriel

2014-01-01

In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance (EAS) exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action (MOA) of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool (together with the epidemiological approach) for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction. PMID:24369134

Key Issues in the Modes of Action and Effects of Trichloroethylene Metabolites for Liver and Kidney Tumorigenesis

PubMed Central

Caldwell, Jane C.; Keshava, Nagalakshmi

2006-01-01

Trichloroethylene (TCE) exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies. The U.S. Environmental Protection Agency 2001 draft TCE risk assessment concluded that it is difficult to determine which TCE metabolites may be responsible for these effects, the key events involved in their modes of action (MOAs), and the relevance of these MOAs to humans. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we present a review of recently published scientific literature examining the effects of TCE metabolites in the context of the preceding questions. Studies of the TCE metabolites dichloroacetic acid (DCA), trichloroacetic acid (TCA), and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans. Studies of S-(1,2-dichlorovinyl)-l-cysteine have revealed a number of different possible cell signaling effects that may be related to kidney tumorigenesis at lower concentrations than those leading to cytotoxicity. Recent studies of trichloroethanol exploring an alternative hypothesis for kidney tumorigenesis have failed to establish the formation of formate as a key event for TCE-induced kidney tumors. Overall, although MOAs and key events for TCE-induced liver and kidney tumors have yet to be definitively established, these results support the likelihood that toxicity is due to multiple metabolites through several MOAs, none of which appear to be irrelevant to humans. PMID:16966105

Effect of branched-chain fatty acids, 3-methylindole and 4-methylphenol on consumer sensory scores of grilled lamb meat.

PubMed

Watkins, P J; Kearney, G; Rose, G; Allen, D; Ball, A J; Pethick, D W; Warner, R D

2014-02-01

Tenderness, flavour, overall liking and odour are important components of sheepmeat eating quality. Consumer assessment of these attributes has been made for carcasses from the Information Nucleus Flock (INF) of the Cooperative Research Centre for Sheep Industry Innovation. The concentrations of three branched chain fatty acids, 4-methyloctanoic (MOA), 4-ethyloctanoic (EOA) and 4-methylnonanoic acids (compounds related to 'mutton flavour' in cooked sheepmeat) and 3-methylindole and 4-methylphenol (compounds related to 'pastoral' flavour) were determined for 178 fat samples taken from INF carcasses. Statistical modelling revealed that both MOA and EOA impacted on the 'Like Smell' consumer sensory score of the cooked meat product (P<0.05), with increasing concentration causing lower consumer acceptance of the product. None of the compounds though had an effect on the liking of flavour. Obviously, reducing the effect of MOA and EOA on the odour of grilled lamb will improve consumer acceptance of the cooked product but other factors affecting the eating quality also need to be considered. Copyright © 2012 The Authors. Published by Elsevier Ltd.. All rights reserved.

Ratite eggshells from lanzarote, canary islands.

PubMed

Franz Sauer, E G; Rothe, P

1972-04-07

Struthious and aepyornithoid eggshells from Tertiary calcareous sediments on Lanzarote prove the presence, until about 12 million years ago, of large flightless birds. The calcarenite horizon is recognized as an old land surface. Mesozoic sedimentary rocks in the basement of the volcanic islands of Lanzarote and neighboring Fuerteventura indicate that at least part of the Canary Archipelago is underlain by continental crust. Separation of the eastern Canaries from Africa raight have been by rifting, and a land connection might still have existed in the lower Pliocene.

Investigation on modes of toxic action to rats based on aliphatic and aromatic compounds and comparison with fish toxicity based on exposure routes.

PubMed

He, Jia; Li, Jin J; Wen, Yang; Tai, Hong W; Yu, Yang; Qin, Wei C; Su, Li M; Zhao, Yuan H

2015-06-01

The modes of toxic action (MOAs) play an important role in the assessment of the ecotoxicity of organic pollutants. However, few studies have been reported on the MOAs in rat toxicity. In this paper, the toxic contributions of functional groups in 1255 aromatic compounds were calculated from regression and were then compared with the toxic contributions in aliphatic compounds. The results show that some functional groups have same toxic contributions both in aromatic and aliphatic compounds, but some have not. To investigate the MOAs in rat toxicity, the distribution of toxic ratio (TR) was examined for well-known baseline and less inert compounds and thresholds of log TR=0.3 and 0.5 were used to classify baseline, less inert and reactive compounds. The results showed that some compounds identified as baseline compounds in fish toxicity were also classified as baseline compounds in rat toxicity. Except for phenols and anilines which were identified as less inert compounds in fish toxicity, aromatic compounds with functional groups such as ether, nitrile, nitrophenol, isocyanatoe and chloro were identified as less inert chemicals in rat toxicity. Reactive compounds identified in fish toxicity exhibit greater toxicity to rats. These compounds can undergo nucleophilic substitution, acylation and Schiff base formation with biological macromolecules. The critical body residues (CBRs) calculated from absorption and bioconcentration show that log 1/CBRs in rat toxicity are not equal to that in fish for some compounds. It suggests that the exposure route can affect the identification of MOAs between these two species for these compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

MOA-2008-BLG-379Lb: A massive planet from a high magnification event with a faint source

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suzuki, D.; Sumi, T.; Fukagawa, M.

2014-01-10

We report on the analysis of the high microlensing event MOA-2008-BLG-379, which has a strong microlensing anomaly at its peak due to a massive planet with a mass ratio of q = 6.9 × 10{sup –3}. Because the faint source star crosses the large resonant caustic, the planetary signal dominates the light curve. This is unusual for planetary microlensing events, and as a result, the planetary nature of this light curve was not immediately noticed. The planetary nature of the event was found when the Microlensing Observations in Astrophysics (MOA) Collaboration conducted a systematic study of binary microlensing events previouslymore » identified by the MOA alert system. We have conducted a Bayesian analysis based on a standard Galactic model to estimate the physical parameters of the lens system. This yields a host star mass of M{sub L}=3.3{sub −1.2}{sup +1.7} M{sub ⊙} orbited by a planet of mass m{sub P}=0.56{sub −0.27}{sup +0.24} M{sub Jup} at an orbital separation of a=3.3{sub −1.2}{sup +1.3} AU at a distance of D{sub L}=4.1{sub −1.9}{sup +1.7} kpc. The faint source magnitude of I {sub S} = 21.30 and relatively high lens-source relative proper motion of μ{sub rel} = 7.6 ± 1.6 mas yr{sup –1} imply that high angular resolution adaptive optics or Hubble Space Telescope observations are likely to be able to detect the source star, which would determine the masses and distance of the planet and its host star.« less

Enhanced pain expectation in migraine: EEG-based evidence for impaired prefrontal function.

PubMed

Lev, Rina; Granovsky, Yelena; Yarnitsky, David

2013-01-01

Dysexcitability characterizes the interictal migraineous brain. The main central expressions of this dysexcitability are decreased habituation and enhanced anticipation and attention to pain and other external sensory stimuli. This study evaluates the effects of anticipation on pain modulation and their neural correlates in migraine. In 39 migraineurs (20 migraine with aura [MWA] and 19 migraine without aura [MOA]) and 22 healthy controls, cortical responses to 2 successive trains of noxious contact-heat stimuli, presented in either predicted or unpredicted manner, were analyzed using standardized low-resolution electromagnetic tomography key. A lack of habituation to repeated predicted pain was associated with significantly increased pain-evoked potential amplitudes in MWAs (increase of 3.9 μV) and unchanged ones in MOAs (1.1 μV) but not in controls (decrease of 5 μV). Repeated unpredicted pain resulted in enhanced pain-evoked potential amplitudes in both MWA and MOA groups (increase of 5.5 μV and 4.4 μV, respectively) compared with controls (decrease of 0.2 μV). Source localization revealed reduced activations in the anterior-medial prefrontal cortices and subsequent increased somatosensory activity in migraineurs (P < .05). The prefrontal-somatosensory dysfunction positively correlated with lifetime headache duration (P < .05) and concern of upcoming migraine attacks (P < .05) in MWAs, and with frequency of migraine attacks in MOAs (P < .05). Our findings of impaired modulation of anticipated pain in migraine suggest a heightened state of anticipatory readiness combined with ineffective recruitment of prefrontal inhibitory pathways during experience of pain; the latter might account for the former, at least partially. In line, less efficient inhibitory capability is a plausible mechanistic explanation for patients' high concern about their upcoming migraine attacks. © 2012 American Headache Society.

Update: Mode of action (MOA) for liver tumors induced by oral exposure to 1,4-dioxane.

PubMed

Dourson, Michael L; Higginbotham, Jeri; Crum, Jeff; Burleigh-Flayer, Heather; Nance, Patricia; Forsberg, Norman D; Lafranconi, Mark; Reichard, John

2017-08-01

Previous work has shown that the weight of evidence supports the hypothesis that 1,4-dioxane causes liver tumors in rodents through cytotoxicity and subsequent regenerative hyperplasia. Questions regarding a lack of concordant findings for this mode of action (MOA) in mice have not been resolved, however. In the current work, a reanalysis of data from two chronic mouse cancer bioassays on 1,4-dioxane, one 13-week mouse study, seven rat cancer bioassays, coupled with other data such as 1,4-dioxane's negative mutagenicity, its lack of up-regulated DNA repair, and the appearance of liver tumors with a high background incidence, support the conclusion that rodent liver tumors, including those in mice, are evoked by a regenerative hyperplasia MOA. The initiating event for this MOA is metabolic saturation of 1,4-dioxane. Above metabolic saturation, higher doses of the parent compound cause an ever increasing toxicity in the rodent liver as evidenced by higher blood levels of enzymes indicative of liver cell damage and associated histopathology that occurs in a dose and time related manner. Importantly, alternative modes of action can be excluded. The observed liver toxicity has a threshold in the dose scale at or below levels that saturate metabolism, and generally in the range of 9.6-42 mg/kg-day for rats and 57 to 66 mg/kg-day for mice. It follows that threshold approaches to the assessment of this chemical's toxicity are supported by the non-mutagenic, metabolic saturation kinetics, and cytotoxicity-generated regenerative repair information available for 1,4-dioxane promoted rodent liver tumors. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors. II: Additional Mechanistic Studies.

PubMed

Strupp, Christian; Bomann, Werner; Cohen, Samuel M; Weber, Klaus

2016-12-01

Fluensulfone is a nematicide for agricultural use. Chronic dietary exposure led to bronchiolo-alveolar hyperplasia and bronchiolo-alveolar adenomas in CD-1 mice but not in rats. Genotoxicity could be excluded as a mode of action (MOA). An earlier publication (Strupp, C., Banas, D. A., Cohen, S. M., Gordon, E. B., Jaeger, M., and Weber, K. (2012). Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors: analysis of their human relevance using the IPCS framework. Toxicol. Sci. 128, 284-294.) reported MOA studies identifying the following key events: increased metabolism of fluensulfone by CYP2f2 in mouse lung Club cells, followed by local proliferation, finally leading to adenoma formation. Human lung microsomes were found not to metabolize fluensulfone. The Joint FAO/WHO Meeting on Pesticide Residues has reviewed the previous data and concluded that the MOA is plausible however some areas of uncertainty were identified. This publication provides additional data to address these. New cell proliferation studies in mice showed that the MOA is functionally independent of sex. A threshold of cell proliferation in Club cells correlating with the dose response for adenoma formation was shown. CYP2f2 knockout mice did not react to fluensulfone exposure with cell proliferation like wild-type mice, confirming the key role of this enzyme. The collective data for fluensulfone were evaluated according to the International Programme on Chemical Safety (IPCS) Mode of Action Framework which leads to the conclusion that the mouse-specific lung tumors after fluensulfone are not relevant to humans. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A novel mode-of-action mediated by the fetal muscle nicotinic acetylcholine receptor resulting in developmental toxicity in rats.

PubMed

Rasoulpour, Reza J; Ellis-Hutchings, Robert G; Terry, Claire; Millar, Neil S; Zablotny, Carol L; Gibb, Alasdair; Marshall, Valerie; Collins, Toby; Carney, Edward W; Billington, Richard

2012-06-01

Sulfoxaflor (X11422208), a novel agricultural molecule, induced fetal effects (forelimb flexure, hindlimb rotation, and bent clavicle) and neonatal death in rats at high doses (≥ 400 ppm in diet); however, no such effects occurred in rabbit dietary studies despite achieving similar maternal and fetal plasma exposure levels. Mode-of-action (MoA) studies were conducted to test the hypothesis that the effects in rats had a single MoA induced by sulfoxaflor agonism on the fetal rat muscle nicotinic acetylcholine receptor (nAChR). The studies included cross-fostering and critical windows of exposure studies in rats, fetal ((α1)(2)β1γδ) and adult ((α1)(2)β1δε) rat and human muscle nAChR in vitro agonism experiments, and neonatal rat phrenic nerve-hemidiaphragm contracture studies. The weight of evidence from these studies supported a novel MoA where sulfoxaflor is an agonist to the fetal, but not adult, rat muscle nAChR and that prolonged agonism on this receptor in fetal/neonatal rats causes sustained striated muscle contracture resulting in concomitant reduction in muscle responsiveness to physiological nerve stimulation. Fetal effects were inducible with as little as 1 day of exposure at the end of gestation, but were rapidly reversible after birth, consistent with a pharmacological MoA. With respect to human relevance, sulfoxaflor was shown to have no agonism on human fetal or adult muscle nAChRs. Taken together, the data support the hypothesis that the developmental effects of sulfoxaflor in rats are mediated via sustained agonism on the fetal muscle nAChR during late fetal development and are considered not relevant to humans.

Risk Balance: A Key Tool for Mission Operations Assurance

NASA Technical Reports Server (NTRS)

Bryant, Larry W.; Faris, Grant B.

2011-01-01

The Mission Operations Assurance (MOA) discipline actively participates as a project member to achieve their common objective of full mission success while also providing an independent risk assessment to the Project Manager and Office of Safety and Mission Success staff. The cornerstone element of MOA is the independent assessment of the risks the project faces in executing its mission. Especially as the project approaches critical mission events, it becomes imperative to clearly identify and assess the risks the project faces. Quite often there are competing options for the project to select from in deciding how to execute the event. An example includes choices between proven but aging hardware components and unused but unproven components. Timing of the event with respect to visual or telecommunications visibility can be a consideration in the case of Earth reentry or hazardous maneuver events. It is in such situations that MOA is called upon for a risk balance assessment or risk trade study to support their recommendation to the Project Manager for a specific option to select. In the following paragraphs we consider two such assessments, one for the Stardust capsule Earth return and the other for the choice of telecommunications system configuration for the EPOXI flyby of the comet Hartley 2. We discuss the development of the trade space for each project's scenario and characterize the risks of each possible option. The risk characterization we consider includes a determination of the severity or consequence of each risk if realized and the likelihood of its occurrence. We then examine the assessment process to arrive at a MOA recommendation. Finally we review each flight project's decision process and the outcome of their decisions.

High Throughput Transcriptomics @ USEPA (Toxicology ...

EPA Pesticide Factsheets

The ideal chemical testing approach will provide complete coverage of all relevant toxicological responses. It should be sensitive and specific It should identify the mechanism/mode-of-action (with dose-dependence). It should identify responses relevant to the species of interest. Responses should ideally be translated into tissue-, organ-, and organism-level effects. It must be economical and scalable. Using a High Throughput Transcriptomics platform within US EPA provides broader coverage of biological activity space and toxicological MOAs and helps fill the toxicological data gap. Slide presentation at the 2016 ToxForum on using High Throughput Transcriptomics at US EPA for broader coverage biological activity space and toxicological MOAs.

Sensitive Amino Acid Composition and Chirality Analysis with the Mars Organic Analyzer (MOA)

NASA Technical Reports Server (NTRS)

Skelley, Alison M.; Scherer, James R.; Aubrey, Andrew D.; Grover, William H.; Ivester, Robin H. C.; Ehrenfreund, Pascale; Grunthaner, Frank J.; Bada, Jeffrey L.; Mathies, Richard A.

2005-01-01

Detection of life on Mars requires definition of a suitable biomarker and development of sensitive yet compact instrumentation capable of performing in situ analyses. Our studies are focused on amino acid analysis because amino acids are more resistant to decomposition than other biomolecules, and because amino acid chirality is a well-defined biomarker. Amino acid composition and chirality analysis has been previously demonstrated in the lab using microfabricated capillary electrophoresis (CE) chips. To analyze amino acids in the field, we have developed the Mars Organic Analyzer (MOA), a portable analysis system that consists of a compact instrument and a novel multi-layer CE microchip.

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colman, Joan; Rice, Glenn E., E-mail: rice.glenn@epa.gov; Wright, J. Michael

Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures. As a first step in a mixtures risk assessment for DBP developmentalmore » effects, this paper identifies developmentally toxic DBPs and examines data relevant to the mode of action (MOA) for DBP developmental toxicity. We identified 24 developmentally toxic DBPs and four adverse developmental outcomes associated with human DBP exposures: spontaneous abortion, cardiovascular defects, neural tube defects, and low birth weight infancy. A plausible MOA, involving hormonal disruption of pregnancy, is delineated for spontaneous abortion, which some epidemiologic studies associate with total trihalomethane and bromodichloromethane exposures. The DBP data for the other three outcomes were inadequate to define key MOA steps.« less

A novel method for determination and quantification of 4-methyloctanoic and 4-methylnonanoic acids in mutton by hollow fiber supported liquid membrane extraction coupled with gas chromatography.

PubMed

Chen, Haigui; Wang, Yunfan; Jiang, Houyang; Zhao, Guohua

2012-12-01

4-Methyloctanoic acid (MOA) and 4-methylnonanoic acid (MNA) are the main compounds responsible for "sweaty" odor of mutton. A novel method for their determination has been developed and validated. Hollow fiber supported liquid membrane (HF-SLM) was applied to selectively extract MOA and MNA prior to gas chromatography (GC) analysis. For HF-SLM, the donor outside the fiber was the acidified supernatant (pH 4) from aqueous mutton slurry. Liquid membrane was 5% tri-n-octylphoshphine oxide in di-n-hexyl ether and 0.3M NaOH aqueous solution filled in the lumen of the fiber was used as the acceptor. The extraction last for 4h. After acidification with HCl, the acceptor was directly analyzed by GC. Importantly, HF-SLM provided high enrichment factors for MOA (133) and MNA (116). The method developed had low detection limits of 0.0007-0.0015 mg/kg, good linearity (R²>0.9956), reasonable recovery (88.54-122.13%), satisfactory intra-assay (7.83-9.73%) and inter-assay (15.68-16.14%) precision. Copyright © 2012 Elsevier Ltd. All rights reserved.

Managing the evolution of herbicide resistance.

PubMed

Evans, Jeffrey A; Tranel, Patrick J; Hager, Aaron G; Schutte, Brian; Wu, Chenxi; Chatham, Laura A; Davis, Adam S

2016-01-01

Understanding and managing the evolutionary responses of pests and pathogens to control efforts is essential to human health and survival. Herbicide-resistant (HR) weeds undermine agricultural sustainability, productivity and profitability, yet the epidemiology of resistance evolution - particularly at landscape scales - is poorly understood. We studied glyphosate resistance in a major agricultural weed, Amaranthus tuberculatus (common waterhemp), using landscape, weed and management data from 105 central Illinois grain farms, including over 500 site-years of herbicide application records. Glyphosate-resistant (GR) A. tuberculatus occurrence was greatest in fields with frequent glyphosate applications, high annual rates of herbicide mechanism of action (MOA) turnover and few MOAs field(-1) year(-1) . Combining herbicide MOAs at the time of application by herbicide mixing reduced the likelihood of GR A. tuberculatus. These findings illustrate the importance of examining large-scale evolutionary processes at relevant spatial scales. Although measures such as herbicide mixing may delay GR or other HR weed traits, they are unlikely to prevent them. Long-term weed management will require truly diversified management practices that minimize selection for herbicide resistance traits. © 2015 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Application of the Mars Organic Analyzer to nucleobase and amine biomarker detection.

PubMed

Skelley, Alison M; Cleaves, H James; Jayarajah, Christine N; Bada, Jeffrey L; Mathies, Richard A

2006-12-01

The Mars Organic Analyzer (MOA), a portable microfabricated capillary electrophoresis instrument being developed for planetary exploration, is used to analyze a wide variety of fluorescamine-labeled amine-containing biomarker compounds, including amino acids, mono and diaminoalkanes, amino sugars, nucleobases, and nucleobase degradation products. The nucleobases cytosine and adenine, which contain an exocyclic primary amine, were effectively labeled, separated, and detected at concentrations <500 nM. To test the general applicability of the MOA for biomarker detection, amino acids and mono- and diamines were extracted from bacterial cells using both hydrolysis and sublimation followed by analysis. The extrapolated limit of detection provided by the valine biomarker was approximately 4 x 10(3) cells per sample. Products of an NH(4)CN polymerization that simulate a prebiotic synthesis were also successfully isolated via sublimation and analyzed. Adenine and alanine/serine were detected with no additional sample cleanup at 120 +/- 13 microM and 4.1 +/- 1 microM, respectively, corresponding to a reaction yield of 0.04% and 0.0003%, respectively. This study demonstrates that the MOA provides sensitive detection and analysis of low levels of a wide variety of amine-containing organic compounds from both biological and abiotic sources.

Effects of Omega-3 in the treatment of violent schizophrenia patients.

PubMed

Qiao, Yi; Mei, Yi; Han, Huiqin; Liu, FengJu; Yang, Xiao Min; Shao, Yang; Xie, Bin; Long, Bin

2018-05-01

This study was designed to explore the relationship in between the daily consumption of fish oil (360mg DHA+540mg EPA), and reduction of symptoms and violent behavior among patients with schizophrenia. Fifty inpatients meeting ICD-10 criteria for schizophrenia and scoring more than four of Modified Overt Aggression Scale (MOAS) with antipsychotics treatment were randomly assigned to receive either fish oil (N=28) or a placebo (N=22) in a twelve week, double-blind supplementation trial. Assessments were performed at baseline and at weeks 4, 8 and 12. The PANSS and CGI scores decreased at the week of 4, 8 and 12, but no differences were found between the two groups. MOAS scores declined significantly at weeks 4, 8 and 12. At week 12, MOAS scores of the fish oil group declined significantly than the placebo group (t=-2.40, P<0.05). violent schizophrenia patients treated with fish oil (360mg DHA+540mg EPA) demonstrated a decrease in violence, but improvement in positive and negative symptoms was no greater than patients treated with the placebo after twelve weeks. Copyright © 2017. Published by Elsevier B.V.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bogen, K T

A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr approach recommended by the USEPA Guidelines for Cancer Risk Assessment to oach address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained usingmore » separate 'linear' (genotoxic) vs. 'nonlinear' (nongenotoxic) approaches to low low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient t to parameterize a biologically based model that reliably o extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach - similar to that used in reference dose procedures for classic toxicity endpoints - can address MOA uncertainty in a way that avoids explicit modeling of low low-dose risk as a function of administere administered or internal dose. Even when a 'nonlinear' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was i illustrated llustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based p pharmacokinetic and 2 harmacokinetic 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat rat-tumor tumor-type specific DMOA DMOA-related uncertainty were obtained using a 2-stage model adapted to reflec reflect the empirical link between genotoxic and cytotoxic effects of t the most potent identified genotoxic naphthalene metabolites, 1,2 1,2- and 1,4 1,4-naphthoquinone. Bound Bound-specific 'adjustment' factors were then used to reduce naphthalene risk estimated by linear ex extrapolation (under the default genotoxic MOA assumption), to account for the DMOA trapolation exhibited by this compound.« less

An appraisal of Indonesia's immense peat carbon stock using national peatland maps: uncertainties and potential losses from conversion.

PubMed

Warren, Matthew; Hergoualc'h, Kristell; Kauffman, J Boone; Murdiyarso, Daniel; Kolka, Randall

2017-12-01

A large proportion of the world's tropical peatlands occur in Indonesia where rapid conversion and associated losses of carbon, biodiversity and ecosystem services have brought peatland management to the forefront of Indonesia's climate mitigation efforts. We evaluated peat volume from two commonly referenced maps of peat distribution and depth published by Wetlands International (WI) and the Indonesian Ministry of Agriculture (MoA), and used regionally specific values of carbon density to calculate carbon stocks. Peatland extent and volume published in the MoA maps are lower than those in the WI maps, resulting in lower estimates of carbon storage. We estimate Indonesia's total peat carbon store to be within 13.6 GtC (the low MoA map estimate) and 40.5 GtC (the high WI map estimate) with a best estimate of 28.1 GtC: the midpoint of medium carbon stock estimates derived from WI (30.8 GtC) and MoA (25.3 GtC) maps. This estimate is about half of previous assessments which used an assumed average value of peat thickness for all Indonesian peatlands, and revises the current global tropical peat carbon pool to 75 GtC. Yet, these results do not diminish the significance of Indonesia's peatlands, which store an estimated 30% more carbon than the biomass of all Indonesian forests. The largest discrepancy between maps is for the Papua province, which accounts for 62-71% of the overall differences in peat area, volume and carbon storage. According to the MoA map, 80% of Indonesian peatlands are <300 cm thick and thus vulnerable to conversion outside of protected areas according to environmental regulations. The carbon contained in these shallower peatlands is conservatively estimated to be 10.6 GtC, equivalent to 42% of Indonesia's total peat carbon and about 12 years of global emissions from land use change at current rates. Considering the high uncertainties in peatland extent, volume and carbon storage revealed in this assessment of current maps, a systematic revision of Indonesia's peat maps to produce a single geospatial reference that is universally accepted would improve national peat carbon storage estimates and greatly benefit carbon cycle research, land use management and spatial planning.

77 FR 4407 - Modernization of Poultry Slaughter Inspection

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-27

...The Food Safety and Inspection Service (FSIS) is proposing a new inspection system for young chicken and turkey slaughter establishments that would replace the current Streamlined Inspection System (SIS), the New Line Speed Inspection System (NELS), and the New Turkey Inspection System (NTIS). The Agency is also proposing several changes that would affect all establishments that slaughter poultry other than ratites, regardless of the inspection system under which they operate. This proposed rule is a result of the Agency's 2011 regulatory review efforts conducted under Executive Order 13563 on Improving Regulation and Regulatory Review.

Toxicity of 13 different antibiotics towards freshwater green algae Pseudokirchneriella subcapitata and their modes of action.

PubMed

Fu, Ling; Huang, Tao; Wang, Shuo; Wang, Xiaohong; Su, Limin; Li, Chao; Zhao, Yuanhui

2017-02-01

Although modes of action (MOAs) play a key role in the understanding of the toxic mechanism of chemicals, the MOAs have not been investigated for antibiotics to green algae. This paper is to discriminate excess toxicity from baseline level and investigate the MOAs of 13 different antibiotics to algae by using the determined toxicity values. Comparison of the toxicities shows that the inhibitors of protein synthesis to bacteria, such as azithromycin, doxycycline, florfenicol and oxytetracycline, exhibit significantly toxic effects to algae. On the other hand, the cell wall synthesis inhibitors, such as cefotaxime and amoxicillin, show relatively low toxic effects to the algae. The concentrations determined by HPLC indicate that quinocetone and amoxicillin can be easily photodegraded or hydrolyzed during the toxic tests. The toxic effects of quinocetone and amoxicillin to the algae are attributed to not only their parent compounds, but also their metabolites. Investigation on the mode of action shows that, except rifampicin, all the tested antibiotics exhibit excess toxicity to Pseudokirchneriella subcapitata (P. subcapitata). These antibiotics can be identified as reactive modes of action to the algae. They act as electrophilic mechanism of action to P. subcapitata. These results are valuable for the understanding of the toxic mechanism to algae. Copyright © 2016 Elsevier Ltd. All rights reserved.

Adverse Outcome Pathways – Organizing Toxicological ...

EPA Pesticide Factsheets

The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High throughput screening (HTS) commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a natural framework for connecting high throughput toxicity testing (HTT) results to potential impacts on humans and wildlife populations. An AOP consists of two main components that describe the biological mechanisms driving toxicity. Key events represent biological processes essential for causing the adverse outcome that are also measurable experimentally. Key event relationships capture the biological processes connecting the key events. Evidence documented for each KER based on measurements of the KEs can provide the confidence needed for extrapolating HTT from early key events to overt toxicity represented by later key events based on the AOP. The IPCS mode of action (MOA) framework incorporates information required for making a chemical-specific toxicity determination. Given the close relationship between the AOP and MOA frameworks, it is possible to assemble an MOA by incorporating HTT results, chemical properties including absorption, distribution, metabolism, and excretion (ADME), and an AOP describing the biological basis of toxicity thereby streamlining the process. While current applications focus on the assessment of risk for environmental chemicals,

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli.

PubMed Central

Taverna, P; Sedgwick, B

1996-01-01

Escherichia coli ada ogt mutants, which are totally deficient in O6-methylguanine-DNA methyltransferases, have an increased spontaneous mutation rate. This phenotype is particularly evident in starving cells and suggests the generation of an endogenous DNA alkylating agent under this growth condition. We have found that in wild-type cells, the level of the inducible Ada protein is 20-fold higher in stationary-phase and starving cells than in rapidly growing cells, thus enhancing the defense of these cells against DNA damage. The increased level of Ada in stationary cells is dependent on RpoS, a stationary-phase-specific sigma subunit of RNA polymerase. We have also identified a potential source of the mutagenic agent. Nitrosation of amides and related compounds can generate directly acting methylating agents and can be catalyzed by bacteria] enzymes. E. coli moa mutants, which are defective in the synthesis of a molybdopterin cofactor required by several reductases, are deficient in nitrosation activity. It is reported here that a moa mutant shows reduced generation of a mutagenic methylating agent from methylamine (or methylurea) and nitrite added to agar plates. Moreover, a moa mutation eliminates much of the spontaneous mutagenesis in ada ogt mutants. These observations indicate that the major endogenous mutagen is not S-adenosylmethionine but arises by bacterially catalyzed nitrosation. PMID:8752326

Dose and temporal evaluation of ethylene oxide-induced mutagenicity in the lungs of male big blue mice following inhalation exposure to carcinogenic concentrations.

PubMed

Manjanatha, Mugimane G; Shelton, Sharon D; Chen, Ying; Parsons, Barbara L; Myers, Meagan B; McKim, Karen L; Gollapudi, B Bhaskar; Moore, Nigel P; Haber, Lynne T; Allen, Bruce; Moore, Martha M

2017-04-01

Ethylene oxide (EO) is a direct acting alkylating agent; in vitro and in vivo studies indicate that it is both a mutagen and a carcinogen. However, it remains unclear whether the mode of action (MOA) for cancer for EO is a mutagenic MOA, specifically via point mutation. To investigate the MOA for EO-induced mouse lung tumors, male Big Blue (BB) B6C3F1 mice (10/group) were exposed to EO by inhalation, 6 hr/day, 5 days/week for 4 (0, 10, 50, 100, or 200 ppm EO), 8, or 12 weeks (0, 100, or 200 ppm EO). Lung DNA samples were analyzed for cII mutant frequency (MF) at 4, 8 and 12 weeks of exposure; the mutation spectrum was analyzed for mutants from control and 200 ppm EO treatments. Although EO-induced cII MFs were 1.5- to 2.7-fold higher than the concurrent controls at 4 weeks, statistically significant increases in the cII MF were found only after 8 and 12 weeks of exposure and only at 200 ppm EO (P ≤ 0.05), which is twice the highest concentration used in the cancer bioassay. Consistent with the positive response, DNA sequencing of cII mutants showed a significant shift in the mutational spectra between control and 200 ppm EO following 8 and 12 week exposures (P ≤ 0.035), but not at 4 weeks. Thus, EO mutagenic activity in vivo was relatively weak and required higher than tumorigenic concentrations and longer than 4 weeks exposure durations. These data do not follow the classical patterns for a MOA mediated by point mutations. Environ. Mol. Mutagen. 58:122-134, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

MOA: Magnetic Field Oscillating Amplified Thruster and its Application for Nuclear Electric and Thermal Propulsion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frischauf, Norbert; Hettmer, Manfred; Grassauer, Andreas

More than 60 years after the later Nobel laureate Hannes Alfven had published a letter stating that oscillating magnetic fields can accelerate ionised matter via magneto-hydrodynamic interactions in a wave like fashion, the technical implementation of Alfven waves for propulsive purposes has been proposed, patented and examined for the first time by a group of inventors. The name of the concept, utilising Alfven waves to accelerate ionised matter for propulsive purposes, is MOA - Magnetic field Oscillating Amplified thruster. Alfven waves are generated by making use of two coils, one being permanently powered and serving also as magnetic nozzle, themore » other one being switched on and off in a cyclic way, deforming the field lines of the overall system. It is this deformation that generates Alfven waves, which are in the next step used to transport and compress the propulsive medium, in theory leading to a propulsion system with a much higher performance than any other electric propulsion system. Based on computer simulations, which were conducted to get a first estimate on the performance of the system, MOA is a highly flexible propulsion system, whose performance parameters might easily be adapted, by changing the mass flow and/or the power level. As such the system is capable to deliver a maximum specific impulse of 13116 s (12.87 mN) at a power level of 11.16 kW, using Xe as propellant, but can also be attuned to provide a thrust of 236.5 mN (2411 s) at 6.15 kW of power. While space propulsion is expected to be the prime application for MOA and is supported by numerous applications such as Solar and/or Nuclear Electric Propulsion or even as an 'afterburner system' for Nuclear Thermal Propulsion, other terrestrial applications can be thought of as well, making the system highly suited for a common space-terrestrial application research and utilisation strategy. (authors)« less

Contribution of new technologies to characterization and prediction of adverse effects.

PubMed

Rouquié, David; Heneweer, Marjoke; Botham, Jane; Ketelslegers, Hans; Markell, Lauren; Pfister, Thomas; Steiling, Winfried; Strauss, Volker; Hennes, Christa

2015-02-01

Identification of the potential hazards of chemicals has traditionally relied on studies in laboratory animals where changes in clinical pathology and histopathology compared to untreated controls defined an adverse effect. In the past decades, increased consistency in the definition of adversity with chemically-induced effects in laboratory animals, as well as in the assessment of human relevance has been reached. More recently, a paradigm shift in toxicity testing has been proposed, mainly driven by concerns over animal welfare but also thanks to the development of new methods. Currently, in vitro approaches, toxicogenomic technologies and computational tools, are available to provide mechanistic insight in toxicological Mode of Action (MOA) of the adverse effects observed in laboratory animals. The vision described as Tox21c (Toxicity Testing in the 21st century) aims at predicting in vivo toxicity using a bottom-up-approach, starting with understanding of MOA based on in vitro data to ultimately predict adverse effects in humans. At present, a practical application of the Tox21c vision is still far away. While moving towards toxicity prediction based on in vitro data, a stepwise reduction of in vivo testing is foreseen by combining in vitro with in vivo tests. Furthermore, newly developed methods will also be increasingly applied, in conjunction with established methods in order to gain trust in these new methods. This confidence is based on a critical scientific prerequisite: the establishment of a causal link between data obtained with new technologies and adverse effects manifested in repeated-dose in vivo toxicity studies. It is proposed to apply the principles described in the WHO/IPCS framework of MOA to obtain this link. Finally, an international database of known MOAs obtained in laboratory animals using data-rich chemicals will facilitate regulatory acceptance and could further help in the validation of the toxicity pathway and adverse outcome pathway concepts.

A frozen super-Earth orbiting a star at the bottom of the main sequence

NASA Astrophysics Data System (ADS)

Kubas, D.; Beaulieu, J. P.; Bennett, D. P.; Cassan, A.; Cole, A.; Lunine, J.; Marquette, J. B.; Dong, S.; Gould, A.; Sumi, T.; Batista, V.; Fouqué, P.; Brillant, S.; Dieters, S.; Coutures, C.; Greenhill, J.; Bond, I.; Nagayama, T.; Udalski, A.; Pompei, E.; Nürnberger, D. E. A.; Le Bouquin, J. B.

2012-04-01

Context. Microlensing is a unique method to probe low mass exoplanets beyond the snow line. However, the scientific potential of the new microlensing planet discovery is often unfulfilled due to lack of knowledge of the properties of the lens and source stars. The discovery light curve of the super Earth MOA-2007-BLG-192Lb suffers from significant degeneracies that limit what can be inferred about its physical properties. Aims: High resolution adaptive optics images allow us to solve this problem by resolving the microlensing target from all unrelated background stars, yielding the unique determination of magnified source and lens fluxes. This estimation permits the solution of our microlens model for the mass of the planet and its host and their physical projected separation. Methods: We observed the microlensing event MOA-2007-BLG-192 at high angular resolution in JHKs with the NACO adaptive optics system on the VLT while the object was still amplified by a factor 1.23 and then at baseline 18 months later. We analyzed and calibrated the NACO photometry in the standard 2MASS system in order to accurately constrain the source and the lens star fluxes. Results: We detect light from the host star of MOA-2007-BLG-192Lb, which significantly reduces the uncertainties in its characteristics as compared to earlier analyses. We find that MOA-2007-BLG-192L is most likely a very low mass late type M-dwarf (0.084-0.012+0.015 M⊙) at a distance of 660-70+100 pc orbited by a 3.2-1.8+5.2 M⊕ super-Earth at 0.66-0.22+0.51 AU. We then discuss the properties of this cold planetary system. Based on observations under ESO Prog.IDs: 279.C-5044(A) and 383-C.0495(A).

A fiber-based implantable multi-optrode array with contiguous optical and electrical sites

NASA Astrophysics Data System (ADS)

Chen, Sanyuan; Pei, Weihua; Gui, Qiang; Chen, Yuanfang; Zhao, Shanshan; Wang, Huan; Chen, Hongda

2013-08-01

Objective. Although various kinds of optrodes are designed to deliver light and sense electrophysiological responses, few have a tightly closed optical delivering site or electrical recording site. The large space between them often blurs the stimulation location and light intensity threshold. Approach. Based on an optical fiber, we develop an optrode structure which has a coniform tip where the light exit point and gold-based electrode site are located. The optrode is fabricated by integrating a metal membrane electrode on the outside of a tapered fiber. Half of the cone-shape tip is covered by a layer of gold membrane to form the electrode. A commercial fiber connector, mechanical transfer (MT) module, is chosen to assemble the multi-optrode array (MOA). The MT connector acts as both the holder of the optrode array and an aligning part to connect the MOA with the light source. Main results. We fabricated a pluggable MOA weighing only 0.2 g. The scanning electron microscope images showed a tight cover of the metal layer on the optrode tip with an exposure area of 1500 µm2. The electrochemical impedance of the optrode at 1 kHz was 100 kΩ on average and the light emission intensity reached 13 mW. The optical modulating and electrophysiological recording ability of the MOA was validated by monitoring the response of cells in a ChR2-expressing mouse's cerebral cortex. Neurons that maintained high cluster quality (signal-to-noise ratio = 5:1) and coherence in response to trains of 20 Hz stimulation were monitored. Significance. The optrode array reduces the distance between the optical stimulating sites and electrophysiological sites dramatically and can supply multiple channels to guide different lights simultaneously. This optrode with its novel structure may lead to a different kind of optical neural control prosthetic device, opening up a new option for neural modulation in the brain.

Comparison of Toxicities to Vibrio fischeri and Fish Based on Discrimination of Excess Toxicity from Baseline Level

PubMed Central

Wang, Xiao H.; Yu, Yang; Huang, Tao; Qin, Wei C.; Su, Li M.; Zhao, Yuan H.

2016-01-01

Investigations on the relationship of toxicities between species play an important role in the understanding of toxic mechanisms to environmental organisms. In this paper, the toxicity data of 949 chemicals to fish and 1470 chemicals to V. fischeri were used to investigate the modes of action (MOAs) between species. The results show that although there is a positive interspecies correlation, the relationship is poor. Analysis on the excess toxicity calculated from toxic ratios (TR) shows that many chemicals have close toxicities and share the same MOAs between the two species. Linear relationships between the toxicities and octanol/water partition coefficient (log KOW) for baseline and less inert compounds indicate that the internal critical concentrations (CBRs) approach a constant both to fish and V. fischeri for neutral hydrophobic compounds. These compounds share the same toxic mechanisms and bio-uptake processes between species. On the other hand, some hydrophilic compounds exhibit different toxic effects with greatly different log TR values between V. fischeri and fish species. These hydrophilic compounds were identified as reactive MOAs to V. fischeri, but not to fish. The interspecies correlation is improved by adding a hydrophobic descriptor into the correlation equation. This indicates that the differences in the toxic ratios between fish and V. fischeri for these hydrophilic compounds can be partly attributed to the differences of bioconcentration between the two species, rather than the differences of reactivity with the target macromolecules. These hydrophilic compounds may more easily pass through the cell membrane of V. fischeri than the gill and skin of fish, react with the target macromolecules and exhibit excess toxicity. The compounds with log KOW > 7 exhibiting very low toxicity (log TR < –1) to both species indicate that the bioconcentration potential of a chemical plays a very important role in the identification of excess toxicity and MOAs. PMID:26901437

Temperature response of permafrost soil carbon is attenuated by mineral protection.

PubMed

Gentsch, Norman; Wild, Birgit; Mikutta, Robert; Čapek, Petr; Diáková, Katka; Schrumpf, Marion; Turner, Stephanie; Minnich, Cynthia; Schaarschmidt, Frank; Shibistova, Olga; Schnecker, Jörg; Urich, Tim; Gittel, Antje; Šantrůčková, Hana; Bárta, Jiři; Lashchinskiy, Nikolay; Fuß, Roland; Richter, Andreas; Guggenberger, Georg

2018-05-18

Climate change in Arctic ecosystems fosters permafrost thaw and makes massive amounts of ancient soil organic carbon (OC) available to microbial breakdown. However, fractions of the organic matter (OM) may be protected from rapid decomposition by their association with minerals. Little is known about the effects of mineral-organic associations (MOA) on the microbial accessibility of OM in permafrost soils and it is not clear which factors control its temperature sensitivity. In order to investigate if and how permafrost soil OC turnover is affected by mineral controls, the heavy fraction (HF) representing mostly MOA was obtained by density fractionation from 27 permafrost soil profiles of the Siberian Arctic. In parallel laboratory incubations, the unfractionated soils (bulk) and their HF were comparatively incubated for 175 days at 5 and 15°C. The HF was equivalent to 70 ± 9% of the bulk CO 2 respiration as compared to a share of 63 ± 1% of bulk OC that was stored in the HF. Significant reduction of OC mineralization was found in all treatments with increasing OC content of the HF (HF-OC), clay-size minerals and Fe or Al oxyhydroxides. Temperature sensitivity (Q10) decreased with increasing soil depth from 2.4 to 1.4 in the bulk soil and from 2.9 to 1.5 in the HF. A concurrent increase in the metal-to-HF-OC ratios with soil depth suggests a stronger bonding of OM to minerals in the subsoil. There, the younger 14 C signature in CO 2 than that of the OC indicates a preferential decomposition of the more recent OM and the existence of a MOA fraction with limited access of OM to decomposers. These results indicate strong mineral controls on the decomposability of OM after permafrost thaw and on its temperature sensitivity. Thus, we here provide evidence that OM temperature sensitivity can be attenuated by MOA in permafrost soils. © 2018 John Wiley & Sons Ltd.

Grounding Lines Detecting Using LANDSAT8 Oli and CRYOSAT-2 Data Fusion

NASA Astrophysics Data System (ADS)

Li, F.; Guo, Y.; Zhang, Y.; Zhang, S.

2018-04-01

The grounding zone is the region where ice transitions from grounded ice sheet to freely floating ice shelf, grounding lines are actually more of a zone, typically over several kilometers. The mass loss from Antarctica is strongly linked to changes in the ice shelves and their grounding lines, since the variation in the grounding line can result in very rapid changes in glacier and ice-shelf behavior. Based on remote sensing observations, five global Antarctic grounding line products have been released internationally, including MOA, ASAID, ICESat, MEaSUREs, and Synthesized grounding lines. However, the five products could not provide the annual grounding line products of the whole Antarctic, even some products have stopped updating, which limits the time series analysis of Antarctic material balance to a certain extent. Besides, the accurate of single remote-sensing data based grounding line products is far from satisficed. Therefore, we use algorithms to extract grounding lines with SAR and Cryosat-2 data respectively, and combine the results of two kinds of grounding lines to obtain new products, we obtain a mature grounding line extraction algorithm process, so that we can realize the extraction of grounding line of the Antarctic each year in the future. The comparison between fusion results and the MOA product results indicate that there is a maximum deviation of 188.67 meters between the MOA product and the fusion result.

Are herbicides a once in a century method of weed control?

PubMed

Davis, Adam S; Frisvold, George B

2017-11-01

The efficacy of any pesticide is an exhaustible resource that can be depleted over time. For decades, the dominant paradigm - that weed mobility is low relative to insect pests and pathogens, that there is an ample stream of new weed control technologies in the commercial pipeline, and that technology suppliers have sufficient economic incentives and market power to delay resistance - supported a laissez faire approach to herbicide resistance management. Earlier market data bolstered the belief that private incentives and voluntary actions were sufficient to manage resistance. Yet, there has been a steady growth in resistant weeds, while no new commercial herbicide modes of action (MOAs) have been discovered in 30 years. Industry has introduced new herbicide tolerant crops to increase the applicability of older MOAs. Yet, many weed species are already resistant to these compounds. Recent trends suggest a paradigm shift whereby herbicide resistance may impose greater costs to farmers, the environment, and taxpayers than earlier believed. In developed countries, herbicides have been the dominant method of weed control for half a century. Over the next half-century, will widespread resistance to multiple MOAs render herbicides obsolete for many major cropping systems? We suggest it would be prudent to consider the implications of such a low-probability, but high-cost development. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Mode-of-action evaluation for the effect of trans fatty acids on low-density lipoprotein cholesterol.

PubMed

Reichard, John F; Haber, Lynne T

2016-12-01

The purpose of this work is to systematically consider the data relating to the mode of action (MOA) for the effects of industrially produced trans fatty acid (iTFA) on plasma low-density lipoprotein (LDL) levels. The hypothesized MOA is composed of two key events: increased LDL production and decreased LDL clearance. A substantial database supports this MOA, although the key events are likely to be interdependent, rather than sequential. Both key events are functions of nonlinear biological processes including rate-limited clearance, receptor-mediated transcription, and both positive and negative feedback regulation. Each key event was evaluated based on weight-of-evidence analysis and for human relevance. We conclude that the data are inadequate for a detailed dose-response analysis in the context of the evolved Bradford Hill considerations; however, the weight of evidence is strong and the overall shape of the dose-response curves for markers of the key events and the key determinants of those relationships is well understood in many cases and is nonlinear. Feedback controls are responsible for maintaining homeostasis of cholesterol and triglyceride levels and underlie both of the key events, resulting in a less-than-linear or thresholded relationship between TFA and LDL-C. The inconsistencies and gaps in the database are discussed. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Minimum datasets to establish a CAR-mediated mode of action for rodent liver tumors.

PubMed

Peffer, Richard C; LeBaron, Matthew J; Battalora, Michael; Bomann, Werner H; Werner, Christoph; Aggarwal, Manoj; Rowe, Rocky R; Tinwell, Helen

2018-04-16

Methods for investigating the Mode of Action (MoA) for rodent liver tumors via constitutive androstane receptor (CAR) activation are outlined here, based on current scientific knowledge about CAR and feedback from regulatory agencies globally. The key events (i.e., CAR activation, altered gene expression, cell proliferation, altered foci and increased adenomas/carcinomas) can be demonstrated by measuring a combination of key events and associative events that are markers for the key events. For crop protection products, a primary dataset typically should include a short-term study in the species/strain that showed the tumor response at dose levels that bracket the tumorigenic and non-tumorigenic dose levels. The dataset may vary depending on the species and the test compound. As examples, Case Studies with nitrapyrin (in mice) and metofluthrin (in rats) are described. Based on qualitative differences between the species, the key events leading to tumors in mice or rats by this MoA are not operative in humans. In the future, newer approaches such as a CAR biomarker signature approach and/or in vitro CAR3 reporter assays for mouse, rat and human CAR may eventually be used to demonstrate a CAR MoA is operative, without the need for extensive additional studies in laboratory animals. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

PubMed Central

Scullion, Paul; del Pino, Ricardo C.; Vincent, Isabel M.; Zhang, Yong-Kang; Alley, Michael R. K.; Jacobs, Robert T.; Read, Kevin D.

2018-01-01

Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in Trypanosoma brucei. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds. PMID:29425238

Back from the Brink with Something for Everyone - The Final Executed Memorandum of Agreement for Interpretation of the East Tennessee Technology Park and the K-25 Building - 13370

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cusick, Lesley T.

When the Environmental Management (EM) Program at the Oak Ridge Office of the Department of Energy (DOE) began its major decontamination and decommissioning (D and D) program activities in the mid-1990's, it was understood that the work to demolish the gaseous diffusion process buildings at the K-25 Site, as it was then known, would be challenging. Nothing of that size and breadth had ever been done within the DOE complex and the job brought about a full menu of unique attributes: radiological contamination with enriched materials entrained in certain areas of the system, a facility that was never designed notmore » to operate but had been shut down since 1964, and a loyal following of individuals and organizations who were committed to the physical preservation of at least some portion of the historic Manhattan Project property. DOE was able to solve and resolve the issues related to nuclear materials management, contamination control, and determining the best way to safely and efficiently deconstruct the massive building. However, for a variety of reasons, resolution of the historic preservation questions - what and how much to preserve, how to preserve it, where to preserve it, how to interpret it, how much to spend on preservation, and by and for whom preservation should occur - remained open to debate for over a decade. After a dozen years, countless meetings, phone calls, discussions and other exchanges, and four National Historic Preservation Act (NHPA) [1] Memoranda of Agreement (MOA), a final MOA [2] has been executed. The final executed MOA's measures are robust, creative, substantive, and will be effective. They include a multi-story replica of a portion of the K-25 Building, the dedication of the K-25 Building footprint for preservation purposes, an equipment building to house authentic Manhattan Project and Cold War equipment, a virtual museum, an on-site history center, a grant to preserve a historically-significant Manhattan Project-era hotel in Oak Ridge, and more. The MOA was designed to offer something for everyone. The MOA for the K- 25 Building and interpretation of the East Tennessee Technology Park (ETTP; formerly the K-25 Site) was executed by all of the signatory parties on August 7, 2012 - almost 67 years to-the-day after the 'product' of the K-25 process building became known to more than just a small group of scientists and engineers working on a secret project for the Army Corps of Engineers Manhattan District. (authors)« less

Toxicity of organic compounds from unresolved complex mixtures (UCMs) to primary fish hepatocytes.

PubMed

Petersen, Karina; Hultman, Maria T; Rowland, Steven J; Tollefsen, Knut Erik

2017-09-01

Many environmental matrices contaminated with organic pollutants derived from crude oil or degraded petroleum contain mixtures so complex that they are typically unresolved by conventional analytical techniques such as gas chromatography. The resulting chromatographic features have become known as 'humps' or unresolved complex mixtures (UCMs). These UCMs often dominate the organic contaminants of polluted environmental samples: for example, in oil sands produced water up to 150mgL -1 of 'naphthenic acids' appear as UCMs when examined by gas chromatography as the esters. In oil-contaminated mussels, aromatic hydrocarbon UCMs may comprise almost all of the total toxic hydrocarbons, with over 7000μgg -1 dry weight reported in some samples. Over the last 25 years, efforts to resolve and thus identify, or at least to produce average structures, for some UCM components, have proved fruitful. Numerous non-polar UCM hydrocarbons and more polar UCM acids have been identified, then synthesised or purchased from commercial suppliers. As UCMs have been proposed to represent a risk to aquatic organisms, the need for assessment of the ecotoxicological effects and characterisation of the mode of action (MoA) of these environmental pollutants has arisen. In the present study, several chemicals with structures typical of those found in some UCMs, were assessed for their potential to disrupt membrane integrity, inhibit metabolic activity, activate the aryl hydrocarbon receptor (AhR), and activate the estrogen receptor (ER) in primary rainbow trout hepatocytes (Oncorhynchus mykiss). These endpoints were determined in order to screen for common toxic modes of action (MoA) in this diverse group of chemicals. The results from the in vitro screening indicated that of the endpoints tested, the predominant toxic MoA was cytotoxicity. EC 50 values for cytotoxicity were obtained for 16 compounds and ranged from 77μM-24mM, whereof aliphatic monocyclic acids, monoaromatic acids, polycyclic monoaromatic acids and alkylnaphthalenes were the most toxic. The observed cytotoxicity of the chemicals correlated well with the hydrophobicity (LogK OW ) suggesting that the toxicity was predominantly due to a non-specific MoA. Interestingly, two compounds induced the ER-mediated production of vitellogenin (Vtg) and six compounds induced the AhR-mediated Ethoxyresorufin-O-deethylase (EROD) enzymatic activity to >20% of the positive control; by doing so suggesting that they may act as ER or AhR agonists in fish. The heterogeneous group of 'UCM compounds' tested exhibited multiple MoA that may potentially cause adverse effects in fish. Additional studies to determine if these compounds may cause adverse effects in vivo at environmentally relevant concentrations, are warranted to identify if such compounds are indeed of potential environmental concern. Copyright © 2017 Elsevier B.V. All rights reserved.

Mode of action of ethyl tertiary-butyl ether hepatotumorigenicity in the rat: Evidence for a role of oxidative stress via activation of CAR, PXR and PPAR signaling pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kakehashi, Anna, E-mail: anna@med.osaka-cu.ac.jp; Hagiwara, Akihiro; Imai, Norio

To elucidate possible mode of action (MOA) and human relevance of hepatotumorigenicity in rats for ethyl tertiary-butyl ether (ETBE), male F344 rats were administered ETBE at doses of 0, 150 and 1000 mg/kg body weight twice a day by gavage for 1 and 2 weeks. For comparison, non-genotoxic carcinogen phenobarbital (PB) was applied at a dose of 500 ppm in diet. Significant increase of P450 total content and hydroxyl radical levels by low, high doses of ETBE and PB treatments at weeks 1 and 2, and 8-OHdG formation at week 2, accompanied accumulation of CYP2B1/2B2, CYP3A1/3A2 and CYP2C6, and downregulationmore » of DNA oxoguanine glycosylase 1, induction of apoptosis and cell cycle arrest in hepatocytes, respectively. Up-regulation of CYP2E1 and CYP1A1 at weeks 1 and 2, and peroxisome proliferation at week 2 were found in high dose ETBE group. Results of proteome analysis predicted activation of upstream regulators of gene expression altered by ETBE including constitutive androstane receptor (CAR), pregnane-X-receptor (PXR) and peroxisome proliferator-activated receptors (PPARs). These results indicate that the MOA of ETBE hepatotumorigenicity in rats may be related to induction of oxidative stress, 8-OHdG formation, subsequent cell cycle arrest, and apoptosis, suggesting regenerative cell proliferation after week 2, predominantly via activation of CAR and PXR nuclear receptors by a mechanism similar to that of PB, and differentially by activation of PPARs. The MOA for ETBE hepatotumorigenicity in rats is unlikely to be relevant to humans. - Highlights: • We focus on MOA and human relevance of hepatotumorigenicity in rats for ETBE. • ETBE was administered to F344 rats for 1 and 2 weeks. • Oxidative stress formation, proliferation and apoptosis in the liver are analyzed. • ETBE-induced changes of gene and protein expression in the liver are examined. • The effects are compared with those induced by non-genotoxic carcinogen PB.« less

Usability Testing of a National Substance Use Screening Tool Embedded in Electronic Health Records.

PubMed

Press, Anne; DeStio, Catherine; McCullagh, Lauren; Kapoor, Sandeep; Morley, Jeanne; Conigliaro, Joseph

2016-07-08

Screening, brief intervention, and referral to treatment (SBIRT) is currently being implemented into health systems nationally via paper and electronic methods. The purpose of this study was to evaluate the integration of an electronic SBIRT tool into an existing paper-based SBIRT clinical workflow in a patient-centered medical home. Usability testing was conducted in an academic ambulatory clinic. Two rounds of usability testing were done with medical office assistants (MOAs) using a paper and electronic version of the SBIRT tool, with two and four participants, respectively. Qualitative and quantitative data was analyzed to determine the impact of both tools on clinical workflow. A second round of usability testing was done with the revised electronic version and compared with the first version. Personal workflow barriers cited in the first round of testing were that the electronic health record (EHR) tool was disruptive to patient's visits. In Round 2 of testing, MOAs reported favoring the electronic version due to improved layout and the inclusion of an alert system embedded in the EHR. For example, using the system usability scale (SUS), MOAs reported a grade "1" for the statement, "I would like to use this system frequently" during the first round of testing but a "5" during the second round of analysis. The importance of testing usability of various mediums of tools used in health care screening is highlighted by the findings of this study. In the first round of testing, the electronic tool was reported as less user friendly, being difficult to navigate, and time consuming. Many issues faced in the first generation of the tool were improved in the second generation after usability was evaluated. This study demonstrates how usability testing of an electronic SBRIT tool can help to identify challenges that can impact clinical workflow. However, a limitation of this study was the small sample size of MOAs that participated. The results may have been biased to Northwell Health workers' perceptions of the SBIRT tool and their specific clinical workflow.

A theropod dinosaur embryo and the affinities of the flaming cliffs dinosaur eggs.

PubMed

Norell, M A; Clark, J M; Demberelyin, D; Rhinchen, B; Chiappe, L M; Davidson, A R; McKenna, M C; Altangerel, P; Novacek, M J

1994-11-04

An embryonic skeleton of a nonavian theropod dinosaur was found preserved in an egg from Upper Cretaceous rocks in the Gobi Desert of Mongolia. Cranial features identify the embryo as a member of Oviraptoridae. Two embryo-sized skulls of dromaeosaurids, similar to that of Velociraptor, were also recovered in the nest. The eggshell microstructure is similar to that of ratite birds and is of a type common in the Djadokhta Formation at the Flaming Cliffs (Bayn Dzak). Discovery of a nest of such eggs at the Flaming Cliffs in 1923, beneath the Oviraptor philoceratops holotype, suggests that this dinosaur may have been a brooding adult.

Anchorage regional ITS architecture : summary report

DOT National Transportation Integrated Search

2004-10-14

The Municipality of Anchorage (MOA) initiated the development of a regional Intelligent : Transportation System (ITS) architecture to manage implementation of a range of technologies that will improve transportation within the municipality. ITS is th...

Multiparametric Phenotypic Screening System for Profiling Bioactive Compounds Using Human Fetal Hippocampal Neural Stem/Progenitor Cells.

PubMed

Tabata, Yoshikuni; Murai, Norio; Sasaki, Takeo; Taniguchi, Sachie; Suzuki, Shuichi; Yamazaki, Kazuto; Ito, Masashi

2015-10-01

Stem cell research has been progressing rapidly, contributing to regenerative biology and regenerative medicine. In this field, small-molecule compounds affecting stem cell proliferation/differentiation have been explored to understand stem cell biology and support regenerative medicine. In this study, we established a multiparametric screening system to detect bioactive compounds affecting the cell fate of human neural stem/progenitor cells (NSCs/NPCs), using human fetal hippocampal NSCs/NPCs, HIP-009 cells. We examined effects of 410 compounds, which were collected based on mechanisms of action (MOAs) and chemotypes, on HIP-009's cell fate (self-renewal, neuronal and astrocytic differentiation) and morphology by automated multiparametric assays and profiled induced cellular phenotypes. We found that this screening classified compounds with the same MOAs into subgroups according to additional pharmacological effects (e.g., mammalian target of rapamycin complex 1 [mTORC1] inhibitors and mTORC1/mTORC2 dual inhibitors among mTOR inhibitors). Moreover, it identified compounds that have off-target effects under matrix analyses of MOAs and structure similarities (e.g., neurotropic effects of amitriptyline among tri- and tetracyclic compounds). Therefore, this automated, medium-throughput and multiparametric screening system is useful for finding compounds that affect the cell fate of human NSCs/NPCs for supporting regenerative medicine and to fingerprint compounds based on human stem cells' multipotency, leading to understanding of stem cell biology. © 2015 Society for Laboratory Automation and Screening.

Analysis of carbonaceous biomarkers with the Mars Organic Analyzer microchip capillary electrophoresis system: carboxylic acids.

PubMed

Stockton, Amanda M; Tjin, Caroline Chandra; Chiesl, Thomas N; Mathies, Richard A

2011-01-01

The oxidizing surface chemistry on Mars argues that any comprehensive search for organic compounds indicative of life requires methods to analyze higher oxidation states of carbon with very low limits of detection. To address this goal, microchip capillary electrophoresis (μCE) methods were developed for analysis of carboxylic acids with the Mars Organic Analyzer (MOA). Fluorescent derivatization was achieved by activation with the water soluble 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) followed by reaction with Cascade Blue hydrazide in 30 mM borate, pH 3. A standard containing 12 carboxylic acids found in terrestrial life was successfully labeled and separated in 30 mM borate at pH 9.5, 20 °C by using the MOA CE system. Limits of detection were 5-10 nM for aliphatic monoacids, 20 nM for malic acid (diacid), and 230 nM for citric acid (triacid). Polyacid benzene derivatives containing 2, 3, 4, and 6 carboxyl groups were also analyzed. In particular, mellitic acid was successfully labeled and analyzed with a limit of detection of 300 nM (5 ppb). Analyses of carboxylic acids sampled from a lava tube cave and a hydrothermal area demonstrated the versatility and robustness of our method. This work establishes that the MOA can be used for sensitive analyses of a wide range of carboxylic acids in the search for extraterrestrial organic molecules. © Mary Ann Liebert, Inc.

Genotoxicity assessment of a selected cytostatic drug mixture in human lymphocytes: A study based on concentrations relevant for occupational exposure.

PubMed

Gajski, Goran; Ladeira, Carina; Gerić, Marko; Garaj-Vrhovac, Vera; Viegas, Susana

2018-02-01

Cytostatic drugs are highly cytotoxic agents used in cancer treatment and although their benefit is unquestionable, they have been recognized as hazardous to healthcare professionals in occupational settings. In a working environment, simultaneous exposure to cytostatics may occur creating a higher risk than that of a single substance. Hence, the present study evaluated the combined cyto/genotoxicity of a mixture of selected cytostatics with different mechanisms of action (MoA; 5-fluorouracil, cyclophosphamide and paclitaxel) towards human lymphocytes in vitro at a concentration range relevant for occupational as well as environmental exposure. The results suggest that the selected cytostatic drug mixture is potentially cyto/genotoxic and that it can induce cell and genome damage even at low concentrations. This indicates not only that such mixture may pose a risk to cell and genome integrity, but also that single compound toxicity data are not sufficient for the prediction of toxicity in a complex working environment. The presence of drugs in different amounts and with different MoA suggests the need to study the relationship between the presence of genotoxic components in the mixture and the resulting effects, taking into account the MoA of each component by itself. Therefore, this study provides new data sets necessary for scientifically-based risk assessments of cytostatic drug mixtures in occupational as well as environmental settings. Copyright © 2017 Elsevier Inc. All rights reserved.

32 CFR Appendix A to Part 989 - Glossary of References, Abbreviations, Acronyms, and Terms

Code of Federal Regulations, 2011 CFR

2011-07-01

... MAJCOM Major Command MGM Materiel Group Manager MOA Military Operating Area MOU Memorandum of... Air Force for Installations, Environment & Logistics SAF/IEE Deputy Assistant Secretary of the Air...

32 CFR Appendix A to Part 989 - Glossary of References, Abbreviations, Acronyms, and Terms

Code of Federal Regulations, 2014 CFR

2014-07-01

... MAJCOM Major Command MGM Materiel Group Manager MOA Military Operating Area MOU Memorandum of... Air Force for Installations, Environment & Logistics SAF/IEE Deputy Assistant Secretary of the Air...

32 CFR Appendix A to Part 989 - Glossary of References, Abbreviations, Acronyms, and Terms

Code of Federal Regulations, 2013 CFR

2013-07-01

... MAJCOM Major Command MGM Materiel Group Manager MOA Military Operating Area MOU Memorandum of... Air Force for Installations, Environment & Logistics SAF/IEE Deputy Assistant Secretary of the Air...

32 CFR Appendix A to Part 989 - Glossary of References, Abbreviations, Acronyms, and Terms

Code of Federal Regulations, 2012 CFR

2012-07-01

... MAJCOM Major Command MGM Materiel Group Manager MOA Military Operating Area MOU Memorandum of... Air Force for Installations, Environment & Logistics SAF/IEE Deputy Assistant Secretary of the Air...

Federal Aviation Administration Memorandum of Agreement to Address Aircraft-Wildlife Strikes

EPA Pesticide Factsheets

This Memorandum of Agreement (MOA) establish procedures necessary to coordinate the signatory agencies missions to more effectively address existing and future environmental conditions contributing to aircraft-wildlife strikes throughout the United States.

An Isolated Microlens Observed from K2, Spitzer, and Earth

NASA Astrophysics Data System (ADS)

Zhu, Wei; Udalski, A.; Huang, C. X.; Calchi Novati, S.; Sumi, T.; Poleski, R.; Skowron, J.; Mróz, P.; Szymański, M. K.; Soszyński, I.; Pietrukowicz, P.; Kozłowski, S.; Ulaczyk, K.; Pawlak, M.; OGLE Collaboration; Beichman, C.; Bryden, G.; Carey, S.; Gaudi, B. S.; Gould, A.; Henderson, C. B.; Shvartzvald, Y.; Yee, J. C.; Spitzer Team; Bond, I. A.; Bennett, D. P.; Suzuki, D.; Rattenbury, N. J.; Koshimoto, N.; Abe, F.; Asakura, Y.; Barry, R. K.; Bhattacharya, A.; Donachie, M.; Evans, P.; Fukui, A.; Hirao, Y.; Itow, Y.; Kawasaki, K.; Li, M. C. A.; Ling, C. H.; Masuda, K.; Matsubara, Y.; Miyazaki, S.; Munakata, H.; Muraki, Y.; Nagakane, M.; Ohnishi, K.; Ranc, C.; Saito, To.; Sharan, A.; Sullivan, D. J.; Tristram, P. J.; Yamada, T.; Yonehara, A.; MOA Collaboration

2017-11-01

We present the result of microlensing event MOA-2016-BLG-290, which received observations from the two-wheel Kepler (K2), Spitzer, as well as ground-based observatories. A joint analysis of data from K2 and the ground leads to two degenerate solutions of the lens mass and distance. This degeneracy is effectively broken once the (partial) Spitzer light curve is included. Altogether, the lens is found to be an extremely low-mass star or brown dwarf ({77}-23+34 {M}{{J}}) located in the Galactic bulge (6.8+/- 0.4 kpc). MOA-2016-BLG-290 is the first microlensing event for which we have signals from three well-separated (∼1 au) locations. It demonstrates the power of two-satellite microlensing experiment in reducing the ambiguity of lens properties, as pointed out independently by S. Refsdal and A. Gould several decades ago.

The Natural Product Osthole Attenuates Yeast Growth by Extensively Suppressing the Gene Expressions of Mitochondrial Respiration Chain.

PubMed

Wang, Zhe; Shen, Yan

2017-03-01

The fast growing evidences have indicated that the natural product osthole is a promising drug candidate for fighting several serious human diseases, for example, cancer and inflammation. However, the mode-of-action (MoA) of osthole remains largely incomplete. In this study, we investigated the growth inhibition activity of osthole using fission yeast as a model, with the goal of understanding the osthole's mechanism of action, especially from the molecular level. Microarray analysis indicated that osthole has significant impacts on gene transcription levels (In total, 214 genes are up-regulated, and 97 genes are down-regulated). Gene set enrichment analysis (GSEA) indicated that 11 genes belong to the "Respiration module" category, especially including the components of complex III and V of mitochondrial respiration chain. Based on GSEA and network analysis, we also found that 54 up-regulated genes belong to the "Core Environmental Stress Responses" category, particularly including many transporter genes, which suggests that the rapidly activated nutrient exchange between cell and environment is part of the MoA of osthole. In summary, osthole can greatly impact on fission yeast transcriptome, and it primarily represses the expression levels of the genes in respiration chain, which next causes the inefficiency of ATP production and thus largely explains osthole's growth inhibition activity in Schizosaccharomyces pombe (S. pombe). The complexity of the osthole's MoA shown in previous studies and our current research demonstrates that the omics approach and bioinformatics tools should be applied together to acquire the complete landscape of osthole's growth inhibition activity.

Development and validation of a new population-based simulation model of osteoarthritis in New Zealand.

PubMed

Wilson, R; Abbott, J H

2018-04-01

To describe the construction and preliminary validation of a new population-based microsimulation model developed to analyse the health and economic burden and cost-effectiveness of treatments for knee osteoarthritis (OA) in New Zealand (NZ). We developed the New Zealand Management of Osteoarthritis (NZ-MOA) model, a discrete-time state-transition microsimulation model of the natural history of radiographic knee OA. In this article, we report on the model structure, derivation of input data, validation of baseline model parameters against external data sources, and validation of model outputs by comparison of the predicted population health loss with previous estimates. The NZ-MOA model simulates both the structural progression of radiographic knee OA and the stochastic development of multiple disease symptoms. Input parameters were sourced from NZ population-based data where possible, and from international sources where NZ-specific data were not available. The predicted distributions of structural OA severity and health utility detriments associated with OA were externally validated against other sources of evidence, and uncertainty resulting from key input parameters was quantified. The resulting lifetime and current population health-loss burden was consistent with estimates of previous studies. The new NZ-MOA model provides reliable estimates of the health loss associated with knee OA in the NZ population. The model structure is suitable for analysis of the effects of a range of potential treatments, and will be used in future work to evaluate the cost-effectiveness of recommended interventions within the NZ healthcare system. Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens

PubMed Central

Hernández, Lya G.; van Benthem, Jan; Johnson, George E.

2013-01-01

Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-β-oestradiol (E2). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E2 and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment. PMID:23675539

Reactive transport model of the formation of oxide-type Ni-laterite profiles (Punta Gorda, Moa Bay, Cuba)

NASA Astrophysics Data System (ADS)

Domènech, Cristina; Galí, Salvador; Villanova-de-Benavent, Cristina; Soler, Josep M.; Proenza, Joaquín A.

2017-10-01

Oxide-type Ni-laterite deposits are characterized by a dominant limonite zone with goethite as the economically most important Ni ore mineral and a thin zone of hydrous Mg silicate-rich saprolite beneath the magnesium discontinuity. Fe, less soluble, is mainly retained forming goethite, while Ni is redeposited at greater depth in a Fe(III) and Ni-rich serpentine (serpentine II) or in goethite, where it adsorbs or substitutes for Fe in the mineral structure. Here, a 1D reactive transport model, using CrunchFlow, of Punta Gorda oxide-type Ni-laterite deposit (Moa Bay, Cuba) formation is presented. The model reproduces the formation of the different laterite horizons in the profile from an initial, partially serpentinized peridotite, in 106 years, validating the conceptual model of the formation of this kind of deposits in which a narrow saprolite horizon rich in Ni-bearing serpentine is formed above peridotite parent rock and a thick limonite horizon is formed over saprolite. Results also confirm that sorption of Ni onto goethite can explain the weight percent of Ni found in the Moa goethite. Sensitivity analyses accounting for the effect of key parameters (composition, dissolution rate, carbonate concentration, quartz precipitation) on the model results are also presented. It is found that aqueous carbonate concentration and quartz precipitation significantly affects the laterization process rate, while the effect of the composition of secondary serpentine or of mineral dissolution rates is minor. The results of this reactive transport modeling have proven useful to validate the conceptual models derived from field observations.

What are the arguments for and against rational therapy for epilepsy?

PubMed

Barker-Haliski, Melissa; Sills, Graeme J; White, H Steve

2014-01-01

Although more than a dozen new anti-seizure drugs (ASDs) have entered the market since 1993, a substantial proportion of patients (~30 %) remain refractory to current treatments. Thus, a concerted effort to identify and develop new therapies that will help these patients continues. Until this effort succeeds, it is reasonable to re-assess the use of currently available therapies and to consider how these therapies might be utilized in a more efficacious manner. This applies to the selection of monotherapies in newly-diagnosed epilepsy, but perhaps, more importantly, to the choice of combination treatments in otherwise drug-refractory epilepsy. Rational polytherapy is a concept that is predicated on the combination of drugs with complementary mechanisms of action (MoAs) that work synergistically to maximize efficacy and minimize the potential for adverse events. Furthermore, rational polytherapy requires a detailed understanding of the MoA subclasses amongst available ASDs and an appreciation of the empirical evidence that supports the use of specific combinations. The majority of ASDs can be loosely categorized into those that target neurotransmission and network hyperexcitability, modulate intrinsic neuronal properties through ion channels, or possess broad-spectrum efficacy as a result of multiple mechanisms. Within each of these categories, there are discrete pharmacological profiles that differentiate individual ASDs. This chapter will consider how knowledge of MoA can help guide therapy in a rational manner, both in the selection of monotherapies for specific seizure types and syndromes, but also in the choice of drug combinations for patients whose epilepsy is not optimally controlled with a single ASD.

Dietary Toxicity Thresholds and Ecological Risks for Birds and Mammals Based on Species Sensitivity Distributions.

PubMed

Korsman, John C; Schipper, Aafke M; Hendriks, A Jan

2016-10-04

Species sensitivity distributions (SSDs) are commonly used in regulatory procedures and ecological risk assessments. Yet, most toxicity threshold and risk assessment studies are based on invertebrates and fish. In the present study, no observed effect concentrations (NOECs) specific to birds and mammals were used to derive SSDs and corresponding hazardous concentrations for 5% of the species (HC5 values). This was done for 41 individual substances as well as for subsets of substances aggregated based on their toxic Mode of Action (MoA). In addition, potential differences in SSD parameters (mean and standard deviation) were investigated in relation to MoA and end point (growth, reproduction, and survival). The means of neurotoxic and respirotoxic compounds were significantly lower than those of narcotics, whereas no differences were found between end points. The standard deviations of the SSDs were similar across MoA's and end points. Finally, the SSDs obtained were used in a case study by calculating Ecological Risks (ER) and multisubstance Potentially Affected Fractions of species (msPAF) based on 19 chemicals in 10 Northwestern European estuaries and coastal areas. The assessment showed that the risks were all below 2.6 × 10 -2 . However, the calculated risks underestimate the actual risks of chemicals in these areas because the potential impacts of substances that were not measured in the field or for which no SSD was available were not included in the risk assessment. The SSDs obtained can be used in regulatory procedures and for assessing the impacts of contaminants on birds and mammals from fish contaminants monitoring programs.

Predictive ecotoxicity of MoA 1 of organic chemicals using in silico approaches.

PubMed

de Morais E Silva, Luana; Alves, Mateus Feitosa; Scotti, Luciana; Lopes, Wilton Silva; Scotti, Marcus Tullius

2018-05-30

Persistent organic products are compounds used for various purposes, such as personal care products, surfactants, colorants, industrial additives, food, pesticides and pharmaceuticals. These substances are constantly introduced into the environment and many of these pollutants are difficult to degrade. Toxic compounds classified as MoA 1 (Mode of Action 1) are low toxicity compounds that comprise nonreactive chemicals. In silico methods such as Quantitative Structure-Activity Relationships (QSARs) have been used to develop important models for prediction in several areas of science, as well as aquatic toxicity studies. The aim of the present study was to build a QSAR model-based set of theoretical Volsurf molecular descriptors using the fish acute toxicity values of compounds defined as MoA 1 to identify the molecular properties related to this mechanism. The selected Partial Least Squares (PLS) results based on the values of cross-validation coefficients of determination (Q cv 2 ) show the following values: Q cv 2 = 0.793, coefficient of determination (R 2 ) = 0.823, explained variance in external prediction (Q ext 2 ) = 0.87. From the selected descriptors, not only the hydrophobicity is related to the toxicity as already mentioned in previously published studies but other physicochemical properties combined contribute to the activity of these compounds. The symmetric distribution of the hydrophobic moieties in the structure of the compounds as well as the shape, as branched chains, are important features that are related to the toxicity. This information from the model can be useful in predicting so as to minimize the toxicity of organic compounds. Copyright © 2018. Published by Elsevier Inc.

Resistance mutation conserved between insects and mites unravels the benzoylurea insecticide mode of action on chitin biosynthesis.

PubMed

Douris, Vassilis; Steinbach, Denise; Panteleri, Rafaela; Livadaras, Ioannis; Pickett, John Anthony; Van Leeuwen, Thomas; Nauen, Ralf; Vontas, John

2016-12-20

Despite the major role of chitin biosynthesis inhibitors such as benzoylureas (BPUs) in the control of pests in agricultural and public health for almost four decades, their molecular mode of action (MoA) has in most cases remained elusive. BPUs interfere with chitin biosynthesis and were thought to interact with sulfonylurea receptors that mediate chitin vesicle transport. Here, we uncover a mutation (I1042M) in the chitin synthase 1 (CHS1) gene of BPU-resistant Plutella xylostella at the same position as the I1017F mutation reported in spider mites that confers etoxazole resistance. Using a genome-editing CRISPR/Cas9 approach coupled with homology-directed repair (HDR) in Drosophila melanogaster, we introduced both substitutions (I1056M/F) in the corresponding fly CHS1 gene (kkv). Homozygous lines bearing either of these mutations were highly resistant to etoxazole and all tested BPUs, as well as buprofezin-an important hemipteran chitin biosynthesis inhibitor. This provides compelling evidence that BPUs, etoxazole, and buprofezin share in fact the same molecular MoA and directly interact with CHS. This finding has immediate effects on resistance management strategies of major agricultural pests but also on mosquito vectors of serious human diseases such as Dengue and Zika, as diflubenzuron, the standard BPU, is one of the few effective larvicides in use. The study elaborates on how genome editing can directly, rapidly, and convincingly elucidate the MoA of bioactive molecules, especially when target sites are complex and hard to reconstitute in vitro.

Resistance mutation conserved between insects and mites unravels the benzoylurea insecticide mode of action on chitin biosynthesis

PubMed Central

Steinbach, Denise; Panteleri, Rafaela; Livadaras, Ioannis; Van Leeuwen, Thomas; Nauen, Ralf; Vontas, John

2016-01-01

Despite the major role of chitin biosynthesis inhibitors such as benzoylureas (BPUs) in the control of pests in agricultural and public health for almost four decades, their molecular mode of action (MoA) has in most cases remained elusive. BPUs interfere with chitin biosynthesis and were thought to interact with sulfonylurea receptors that mediate chitin vesicle transport. Here, we uncover a mutation (I1042M) in the chitin synthase 1 (CHS1) gene of BPU-resistant Plutella xylostella at the same position as the I1017F mutation reported in spider mites that confers etoxazole resistance. Using a genome-editing CRISPR/Cas9 approach coupled with homology-directed repair (HDR) in Drosophila melanogaster, we introduced both substitutions (I1056M/F) in the corresponding fly CHS1 gene (kkv). Homozygous lines bearing either of these mutations were highly resistant to etoxazole and all tested BPUs, as well as buprofezin—an important hemipteran chitin biosynthesis inhibitor. This provides compelling evidence that BPUs, etoxazole, and buprofezin share in fact the same molecular MoA and directly interact with CHS. This finding has immediate effects on resistance management strategies of major agricultural pests but also on mosquito vectors of serious human diseases such as Dengue and Zika, as diflubenzuron, the standard BPU, is one of the few effective larvicides in use. The study elaborates on how genome editing can directly, rapidly, and convincingly elucidate the MoA of bioactive molecules, especially when target sites are complex and hard to reconstitute in vitro. PMID:27930336

Consideration of Rat Chronic Progressive Nephropathy in Regulatory Evaluations for Carcinogenicity

PubMed Central

Hard, Gordon C.

2013-01-01

Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies. It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein. The weight of evidence supports an absence of a renal counterpart in humans. There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT). The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression. As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions. Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development. CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently. In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment. Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical. PMID:23104430

Advancing human health risk assessment: Integrating recent advisory committee recommendations

PubMed Central

Becker, Richard A.; Haber, Lynne T.; Pottenger, Lynn H.; Bredfeldt, Tiffany; Fenner-Crisp, Penelope A.

2013-01-01

Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose–response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose–response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches. PMID:23844697

Hydrological and sedimentary analyses of well-preserved paleofluvial-paleolacustrine systems at Moa Valles, Mars

NASA Astrophysics Data System (ADS)

Salese, Francesco; Di Achille, Gaetano; Neesemann, Adrian; Ori, Gian Gabriele; Hauber, Ernst

2016-02-01

Moa Valles is a well-preserved, likely Amazonian (younger than 2 Ga old), paleodrainage system that is nearly 300 km long and carved into ancient highland terrains west of Idaeus Fossae. The fluvial system apparently originated from fluidized ejecta blankets, and it consists of a series of dam breach paleolakes with associated fan-shaped sedimentary deposits. The paleolakes are interconnected and drain eastward into Liberta crater, forming a complex and multilobate deltaic deposit exhibiting a well-developed channelized distributary pattern with evidence of switching on the delta plain. A breach area, consisting of three spillover channels, is present in the eastern part of the crater rim. These channels connect the Liberta crater to the eastward portion of the valley system, continuing toward Moa Valles with a complex pattern of anabranching channels that is more than 180 km long. Based on hydrological calculations of infilling and spillover discharges of the Liberta crater lake, the formation of the whole fluvial system is compatible with short to medium (<1000 year) timescales, although the length and morphology of the observed fluvial-lacustrine features suggest long-term periods of activity based on terrestrial analogs. Water for the 300 km long fluvial system may have been primarily sourced by the melting of shallow ice due to the thermal anomaly produced by impact craters. The occurrence of relatively recent (likely Amazonian) hydrological activity, which could have been primarily supported by groundwater replenishment, supports the hypothesis that hydrological activity could have been possible after the Noachian-Hesperian boundary, which is commonly considered as the onset epoch of the present cold-dry climate.

SUMMARY REPORT OF AIR QUALITY MODELING RESEARCH ACTIVITIES FOR 2006

EPA Science Inventory

Through a Memorandum of Understanding (MOU) and Memorandum of Agreement (MOA) between the Department of Commerce (DOC) and U.S. Environmental Protection Agency (EPA), the Atmospheric Sciences Modeling Division (ASMD) of National Oceanic and Atmospheric Administration's (NOAA's) ...

Bioassays for Evaluating Water Quality-Technical Brief

EPA Pesticide Factsheets

Bioassays are a potential solution for assessing complex samples since they screen for total bioactivity for a given pathway or mode of action (MOA), such as estrogen receptor activation, in the samples. EPA has made considerable progress in the developmen

Comparative effects of in ovo versus subcutaneous administration of the Marek's disease vaccine and pre-placement holding time on the early post-hatch quality of Ross × Ross 708 broiler chicks.

PubMed

Peebles, E D; Barbosa, T M; Cummings, T S; Dickson, J; Womack, S K

2016-09-01

Effects of method of administration [moa; in ovo (i.o.) or s.c.] of the Marek's disease vaccine and pre-placement holding time (pht) on early post-hatch male broiler chick quality was investigated. Sixty-five Ross × Ross 708 broiler hatching eggs were randomly set in each of 15 replicate trays (blocks) belonging to each of 4 pre-assigned moa and pht treatment combinations (3,900 total eggs) in a single stage Jamesway incubator. Eggs that were i.o.-vaccinated received injections at 18 d of incubation and male chicks from eggs that were not i.o.-injected were vaccinated by s.c. injection at hatch. The i.o. injections (50 μL) were delivered by a commercial multi-egg injector and the s.c. injections (200 μL) were delivered by an automatic pneumatic s.c. injector. Male chicks from each moa group also were subjected to either a 4 or 18 h pht. At hatch and placement total and yolk-free BW; body length; body mass index; yolk sac weight; yolk-free body and yolk sac weights as percentages of total BW; and yolk-free body and yolk moisture concentrations were determined. Chick BW also was determined at 7 d of age. Hatchability of fertile eggs was not affected by i.o. injection. However, at hatch, body length was increased and body mass index was decreased in response to i.o. injection. No main effect of moa or an interactive effect with pht was observed for the above variables at placement. However, body length was longer and body mass was lower in the 18 h than in the 4 h pht chicks. Placement yolk sac and body weights, and the 7 d BW of 18 h pht chicks was also lower than that of 4 h pht chicks. In conclusion, prolonging pht for 14 h adversely affected early chick quality, whereas i.o. injection did not negatively affect the early post-hatch quality of Ross × Ross 708 broiler chicks whether or not they were held for 4 or 18 h prior to placement. © 2016 Poultry Science Association Inc.

Multiple Resistance Evolution in Bipyridylium-Resistant Epilobium ciliatum After Recurrent Selection.

PubMed

Tahmasebi, Berhoz K; Alcántara-de la Cruz, Ricardo; Alcántara, Esteban; Torra, Joel; Domínguez-Valenzuela, José A; Cruz-Hipólito, Hugo E; Rojano-Delgado, Antonia M; De Prado, Rafael

2018-01-01

The use of herbicides with different modes of action is the primary strategy used to control weeds possessing resistance to a single mechanism of action (MOA). However, this practice can lead to selection for generalist resistance mechanisms and may cause resistance to all MOAs. In this research, we characterized the resistance to diquat/paraquat (bipyridiliums) in an Epilobium ciliatum biotype (R1) collected in an olive orchard from Chile, where alternatives herbicides (2,4-D, glyphosate, glufosinate, flazasulfuron and pyraflufen-ethyl) with different MOAs were used, but they have also showed failure in controlling this species. Because the resistance/susceptibility patterns of the R1 biotype to glufosinate, 2,4-D and pyraflufen-ethyl were not clear, a recurrent resistance selection was carried out in field and greenhouse using these herbicides on R1 plants for three generations (R2 biotype). One biotype that was never treated with herbicides (S) was included as control. Results indicated that the S biotype was controlled at the field dose of all herbicides tested. The biotype R1 exhibited resistance to diquat, paraquat and flazasulfuron and natural tolerance to glyphosate. The R2 biotype displayed resistance to glufosinate, 2,4-D and pyraflufen-ethyl with LD 50 (herbicide dose to kill 50% of plants) values higher than field doses in all assays. Physiological and biochemical studies determined the resistance to diquat of the R1 biotype, which was due to impaired translocation. The resistance to flazasulfuron in the R1 and R2 biotypes was confirmed by the low sensitivity of the acetolactate synthase (ALS) activity compared to the S biotype. The similar accumulation of shikimate in treated S, R1, and R2 plants with glyphosate supported the existence of innate tolerance to this herbicide in E. ciliatum . Resistance to glufosinate, 2,4-D and pyraflufen-ethyl in the R2 biotype, acquired after recurrent selection, was determined by low sensitivity of the glutamine synthetase, low accumulation of ethylene and protoporphyrinogen IX oxidase, respectively, in comparison to the S biotype. Epilobium ciliatum from Chilean olive orchards had resistance to only two MAOs (photosystem I and ALS inhibitors), but resistance to five MOAs could occur in the next cropping seasons, if alternatives to weed management, other than herbicides, are not included.

Exploration of amino acid biomarkers in polar ice with the Mars Organic Analyzer

NASA Astrophysics Data System (ADS)

Jayarajah, C.; Botta, O.; Aubrey, A.; Parker, E.; Bada, J.; Mathies, R.

2009-05-01

A portable microfabricated capillary electrophoresis (CE) system named the Mars Organic Analyzer (MOA) has been developed to analyze fluorescently-labeled biomarkers including amino acids, amines, nucleobases, and amino sugars with the goal of life detection on Mars (1,2). This technology has also been shown to be effective in screening the formation of biogenic amines during fermentation (3). The MOA is a part of the Urey instrument package that has been selected for the 2016 European ExoMars mission by ESA. The identification of recent gully erosion sites, observations of ice on and beneath the surface of Mars, and the discovery of large reservoirs of sub-surface ice on Mars point to water-ice as an important target for astrobiological analyses. In addition, the ice samples on the Moon, Mercury, Europa and Enceladus are of interest due to the possibility that they may contain information on biogenic material relevant to the evolution of life. We explore here the use of the MOA instrument for the analysis of amino acids in polar ice samples. The amino acids valine, alanine/serine, glycine, glutamic acid, and aspartic acid were found in the parts-per-billion range from Greenland ice-core samples. Chiral analysis of these samples yielded D/L ratios of 0.51/0.09 for alanine/serine and 0.14/0.06 for aspartic acid. Individual amino acids in the parts-per-trillion range were found in Antarctic ice samples collected from the surface of a meteorite collection area. The distinct amino acid and amine content of these samples indicates that further biomarker characterization of ice samples as a function of sampling location, depth, and structural features will be highly informative. The rapid sensitive analysis capabilities demonstrated here establish the feasibility of using the MOA to analyze the biomarker content of ice samples in planetary exploration. 1. Skelley, A. M.; Scherer, J. R.; Aubrey, A. D.; Grover, W. H.; Ivester, R. H. C., Ehrenfreund, P.; Grunthaner, F. J.; Bada, J. L.; Mathies, R. A. PNAS, 2005, 192, 1041. 2. Skelley, A. M., Cleaves, H. J., Jayarajah, C. N., Bada, J. L. and Mathies, R. A., Astrobiology 2006, 6, 824. 3. Jayarajah, C.N., Skelley, A.M., Fortner, A.D., and Mathies, R.A., Anal. Chem. 2007, 79, 21, 8162.

DoD Pest Management Program

DTIC Science & Technology

2008-05-29

Plant Health Inspection Service / Animal Damage Control Memorandum of Agreement on Animal Damage Control, April 19905 (am) Army Regulation 40-905...Services shall manage vertebrate pests in accordance with the DoD-USDA/Animal and Plant Health Inspection Service / Animal Damage Control MOA (Reference

24 CFR 901.135 - Memorandum of Agreement.

Code of Federal Regulations, 2010 CFR

2010-04-01

... DEVELOPMENT PUBLIC HOUSING MANAGEMENT ASSESSMENT PROGRAM § 901.135 Memorandum of Agreement. (a) After..., the training of PHA employees in specific management areas or assistance in the resolution of.../Area Office. (c) The Department encourages the inclusion of the resident leadership in MOA negotiations...

MOA between EPA, Interior, and Commerce on Establishment of an Interagency Working Group to Coordinate ESA Consultations for Pesticide Registrations and Registration Review

EPA Pesticide Factsheets

MEMORANDUM OF AGREEMENT between EPA, Interior, and Commerce on Establishment of an Interagency Working Group to Coordinate Endangered Species Act Consultations for Pesticide Registrations and Registration Review

Summary Report of Air Quality Modeling Research Activities for 2007

EPA Science Inventory

Through a Memorandum of Understanding (MOU) and Memorandum of Agreement (MOA) between the U.S. Department of Commerce (DOC) and the U.S. Environmental Protection Agency (EPA), the Atmospheric Sciences Modeling Division (ASMD) of the National Oceanic and Atmospheric Administration...

Response to Comment on “Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches”

EPA Science Inventory

This letter to the editor that does not have an abstract. It explains mode of action in aquatic toxicology, and rebuts comments about our mode of action classification caused by confusion of the commenter.

Customizing the Connectivity Map Approach for Functional Evaluation in Toxicogenomics Studies (SOT)

EPA Science Inventory

Evaluating effects on the transcriptome can provide insight on putative chemical-specific mechanisms of action (MOAs). With whole genome transcriptomics technologies becoming more amenable to high-throughput screening, libraries of chemicals can be evaluated in vitro to produce l...

Assessment of possible carcinogenicity of oxyfluorfen to humans using mode of action analysis of rodent liver effects.

PubMed

Stagg, Nicola J; LeBaron, Matthew J; Eisenbrandt, David L; Gollapudi, B Bhaskar; Klaunig, James E

2012-08-01

Oxyfluorfen is a herbicide that is not genotoxic and produces liver toxicity in rodents, following repeated administration at high dose levels. Lifetime rodent feeding studies reported in 1977 with low-purity oxyfluorfen (85%) showed no increase in any tumor type in rats (800 ppm, high dose) and only a marginally increased incidence of hepatocellular tumors in male CD-1 mice at the highest dose (200 ppm). To evaluate the potential carcinogenicity of the currently registered oxyfluorfen (> 98% purity), we conducted a series of short-term liver mode of action (MOA) toxicology studies in male CD-1 mice administered dietary doses of 0, 40, 200, 800, and 1600 ppm for durations of 3, 7, 10, or 28 days. MOA endpoints examined included liver weight, histopathology, cell proliferation, nuclear receptor-mediated gene expression, and other peroxisome proliferator-specific endpoints and their reversibility. Minimal liver effects were observed in mice administered doses at or below 200 ppm for up to 28 days. Increased liver weight, single-cell necrosis, cell proliferation, and peroxisomal acyl-CoA oxidase (ACO) were observed at 800 ppm after 28 days, but there was no increase in peroxisomes. Expression of Cyp2b10 and Cyp4a10 transcripts, markers of constitutive androstane receptor and peroxisome proliferator activated receptor α nuclear receptor activation, respectively, were increased at 800 and 1600 ppm after 3 or 10 days. Collectively, these data along with the negative genotoxicity demonstrate that oxyfluorfen (> 98% purity) has the potential to induce mouse liver tumors through a nongenotoxic, mitogenic MOA with a clear threshold and is not predicted to be carcinogenic in humans at relevant exposure levels.

Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer?

PubMed Central

Li, Fengzhi; Jiang, Tao; Li, Qingyong; Ling, Xiang

2017-01-01

Camptothecin (CPT) was discovered from plant extracts more than 60 years ago. Since then, only two CPT analogues (irinotecan and topotecan) have been approved for cancer treatment, although several thousand CPT derivatives have been synthesized and many of them were actively studied in our research community over the past 6+ decades. In this review article, we briefly summarize: (1) the discovery and early development of CPTs, (2) the recognized CPT mechanism of action (MOA), (3) the synthesis of CPT and CPT analogues, and (4) the structure-activity relationship (SAR) of CPT and its analogues. Next, we provide evidence that certain CPT analogues can exert improved efficacy with low toxicity independently of topoisomerase I (Top1) inhibition; instead, these CPT analogues use novel MOAs by targeting important cancer survival-associated oncogenic proteins and/or by bypassing various treatment-resistant mechanisms. We then present a comprehensive review of the most advanced CPT analogues in clinical development, with the goal of resolving why no new CPTs have been FDA approved for cancer treatment, beyond irinotecan and topotecan. We argue that new CPT Top1 inhibitor drugs are unlikely being found to be significantly better than irinotecan and/or topotecan in terms of the overall antitumor activity and toxicity. The significance of CPT analogues that possess novel MOAs has not been sufficiently recognized so far. In our opinion, this is a research area with great potential to make a breakthrough for development of the next generation of CPT analogues that possess high efficacy (due to novel targets) and low toxicity (due to low inhibition of Top1 activity/function) for effective treatment of human disease, including cancer. PMID:29312794

A human relevance investigation of PPARα-mediated key events in the hepatocarcinogenic mode of action of propaquizafop in rats.

PubMed

Strupp, Christian; Bomann, Werner H; Spézia, François; Gervais, Frédéric; Forster, Roy; Richert, Lysiane; Singh, Pramila

2018-06-01

Propaquizafop is an herbicide with demonstrated hepatocarcinogenic activity in rodents. A rodent-specific mode of action (MOA) in the liver via activation of peroxisome proliferator-activated receptor α (PPARα) has been postulated based on existing data. Experience with PPARα-inducing pharmaceuticals indicates a lack of human relevance of this MOA. The objective of the present investigation was to evaluate the dependency of early key events leading to liver tumors on PPARα activation in wildtype (WT) compared to PPARα-knockout (KO) rats following 2 weeks exposure to 75, 500 and 1000 ppm propaquizafop in the diet. In WT rats, both WY-14643 (50 mg/kg bw/day) and propaquizafop (dose-dependently) induced marked increases in liver weights, correlating with liver enlargement and hepatocellular hypertrophy, along with increased CYP4A and acyl-CoA oxidase mRNA expression and enzyme activities versus controls, while in KO rats liver weight was mildly increased only at the high dose with minimal microscopic correlates and without any changes in liver peroxisomal or CYP4A activities. In addition, BrdU labeling resulted in higher numbers and density of positive hepatocytes versus controls in WT but not in KO rats, indicating increased mitotic activity and cell proliferation only in WT rats, thus confirming the PPARα-dependency of the biochemical and histological changes in the liver. Based on an assessment of the results of this investigation, together with existing propaquizafop data according to the MOA-Human Relevance Framework, we conclude that liver tumors observed in rodents after dietary administration of propaquizafop do not pose a relevant health risk to humans. Copyright © 2018 Elsevier Inc. All rights reserved.

Synchrotron-based imaging of chromium and  γ-H2AX immunostaining in the duodenum following repeated exposure to Cr(VI) in drinking water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thompson, Chad M.; Seiter, Jennifer; Chappell, Mark A.

Current drinking water standards for chromium are for the combined total of both hexavalent and trivalent chromium (Cr(VI) and Cr(III)). However, recent studies have shown that Cr(III) is not carcinogenic to rodents, whereas mice chronically exposed to high levels of Cr(VI) developed duodenal tumors. These findings may suggest the need for environmental standards specific for Cr(VI). Whether the intestinal tumors arose through a mutagenic or non-mutagenic mode of action (MOA) greatly impacts how drinking water standards for Cr(VI) are derived. Herein, X-ray fluorescence (spectro)microscopy (µ-XRF) was used to image the Cr content in the villus and crypt regions of duodenamore » from B6C3F1 mice exposed to 180 mg/l Cr(VI) in drinking water for 13 weeks. DNA damage was also assessed by γ-H2AX immunostaining. Exposure to Cr(VI) induced villus blunting and crypt hyperplasia in the duodenum—the latter evidenced by lengthening of the crypt compartment by ~2-fold with a concomitant 1.5-fold increase in the number of crypt enterocytes. γ-H2AX immunostaining was elevated in villi, but not in the crypt compartment. µ-XRF maps revealed mean Cr levels >30 times higher in duodenal villi than crypt regions; mean Cr levels in crypt regions were only slightly above background signal. Despite the presence of Cr and elevated γ-H2AX immunoreactivity in villi, no aberrant foci indicative of transformation were evident. Lastly, these findings do not support a MOA for intestinal carcinogenesis involving direct Cr-DNA interaction in intestinal stem cells, but rather support a non-mutagenic MOA involving chronic wounding of intestinal villi and crypt cell hyperplasia.« less

Discovery of metabolic signatures for predicting whole organism toxicology.

PubMed

Hines, Adam; Staff, Fred J; Widdows, John; Compton, Russell M; Falciani, Francesco; Viant, Mark R

2010-06-01

Toxicological studies in sentinel organisms frequently use biomarkers to assess biological effect. Development of "omic" technologies has enhanced biomarker discovery at the molecular level, providing signatures unique to toxicant mode-of-action (MOA). However, these signatures often lack relevance to organismal responses, such as growth or reproduction, limiting their value for environmental monitoring. Our primary objective was to discover metabolic signatures in chemically exposed organisms that can predict physiological toxicity. Marine mussels (Mytilus edulis) were exposed for 7 days to 12 and 50 microg/l copper and 50 and 350 microg/l pentachlorophenol (PCP), toxicants with unique MOAs. Physiological responses comprised an established measure of organism energetic fitness, scope for growth (SFG). Metabolic fingerprints were measured in the same individuals using nuclear magnetic resonance-based metabolomics. Metabolic signatures predictive of SFG were sought using optimal variable selection strategies and multivariate regression and then tested upon independently field-sampled mussels from rural and industrialized sites. Copper and PCP induced rational metabolic and physiological changes. Measured and predicted SFG were highly correlated for copper (r(2) = 0.55, P = 2.82 x 10(-7)) and PCP (r(2) = 0.66, P = 3.20 x 10(-6)). Predictive metabolites included methionine and arginine/phosphoarginine for copper and allantoin, valine, and methionine for PCP. When tested on field-sampled animals, metabolic signatures predicted considerably reduced fitness of mussels from the contaminated (SFG = 6.0 J/h/g) versus rural (SFG = 15.2 J/h/g) site. We report the first successful discovery of metabolic signatures in chemically exposed environmental organisms that inform on molecular MOA and that can predict physiological toxicity. This could have far-reaching implications for monitoring impacts on environmental health.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Henderson, C. B.; Gould, A.; Gaudi, B. S.

The mass of the lenses giving rise to Galactic microlensing events can be constrained by measuring the relative lens-source proper motion and lens flux. The flux of the lens can be separated from that of the source, companions to the source, and unrelated nearby stars with high-resolution images taken when the lens and source are spatially resolved. For typical ground-based adaptive optics (AO) or space-based observations, this requires either inordinately long time baselines or high relative proper motions. We provide a list of microlensing events toward the Galactic bulge with high relative lens-source proper motion that are therefore good candidatesmore » for constraining the lens mass with future high-resolution imaging. We investigate all events from 2004 to 2013 that display detectable finite-source effects, a feature that allows us to measure the proper motion. In total, we present 20 events with μ ≳ 8 mas yr{sup –1}. Of these, 14 were culled from previous analyses while 6 are new, including OGLE-2004-BLG-368, MOA-2005-BLG-36, OGLE-2012-BLG-0211, OGLE-2012-BLG-0456, MOA-2012-BLG-532, and MOA-2013-BLG-029. In ≲12 yr from the time of each event the lens and source of each event will be sufficiently separated for ground-based telescopes with AO systems or space telescopes to resolve each component and further characterize the lens system. Furthermore, for the most recent events, comparison of the lens flux estimates from images taken immediately to those estimated from images taken when the lens and source are resolved can be used to empirically check the robustness of the single-epoch method currently being used to estimate lens masses for many events.« less

Synchrotron-Based Imaging of Chromium and γ-H2AX Immunostaining in the Duodenum Following Repeated Exposure to Cr(VI) in Drinking Water

PubMed Central

Thompson, Chad M.; Seiter, Jennifer; Chappell, Mark A.; Tappero, Ryan V.; Proctor, Deborah M.; Suh, Mina; Wolf, Jeffrey C.; Haws, Laurie C.; Vitale, Rock; Mittal, Liz; Kirman, Christopher R.; Hays, Sean M.; Harris, Mark A.

2015-01-01

Current drinking water standards for chromium are for the combined total of both hexavalent and trivalent chromium (Cr(VI) and Cr(III)). However, recent studies have shown that Cr(III) is not carcinogenic to rodents, whereas mice chronically exposed to high levels of Cr(VI) developed duodenal tumors. These findings may suggest the need for environmental standards specific for Cr(VI). Whether the intestinal tumors arose through a mutagenic or non-mutagenic mode of action (MOA) greatly impacts how drinking water standards for Cr(VI) are derived. Herein, X-ray fluorescence (spectro)microscopy (µ-XRF) was used to image the Cr content in the villus and crypt regions of duodena from B6C3F1 mice exposed to 180 mg/l Cr(VI) in drinking water for 13 weeks. DNA damage was also assessed by γ-H2AX immunostaining. Exposure to Cr(VI) induced villus blunting and crypt hyperplasia in the duodenum—the latter evidenced by lengthening of the crypt compartment by ∼2-fold with a concomitant 1.5-fold increase in the number of crypt enterocytes. γ-H2AX immunostaining was elevated in villi, but not in the crypt compartment. µ-XRF maps revealed mean Cr levels >30 times higher in duodenal villi than crypt regions; mean Cr levels in crypt regions were only slightly above background signal. Despite the presence of Cr and elevated γ-H2AX immunoreactivity in villi, no aberrant foci indicative of transformation were evident. These findings do not support a MOA for intestinal carcinogenesis involving direct Cr-DNA interaction in intestinal stem cells, but rather support a non-mutagenic MOA involving chronic wounding of intestinal villi and crypt cell hyperplasia. PMID:25352572

Synchrotron-based imaging of chromium and  γ-H2AX immunostaining in the duodenum following repeated exposure to Cr(VI) in drinking water

DOE PAGES

Thompson, Chad M.; Seiter, Jennifer; Chappell, Mark A.; ...

2014-10-28

Current drinking water standards for chromium are for the combined total of both hexavalent and trivalent chromium (Cr(VI) and Cr(III)). However, recent studies have shown that Cr(III) is not carcinogenic to rodents, whereas mice chronically exposed to high levels of Cr(VI) developed duodenal tumors. These findings may suggest the need for environmental standards specific for Cr(VI). Whether the intestinal tumors arose through a mutagenic or non-mutagenic mode of action (MOA) greatly impacts how drinking water standards for Cr(VI) are derived. Herein, X-ray fluorescence (spectro)microscopy (µ-XRF) was used to image the Cr content in the villus and crypt regions of duodenamore » from B6C3F1 mice exposed to 180 mg/l Cr(VI) in drinking water for 13 weeks. DNA damage was also assessed by γ-H2AX immunostaining. Exposure to Cr(VI) induced villus blunting and crypt hyperplasia in the duodenum—the latter evidenced by lengthening of the crypt compartment by ~2-fold with a concomitant 1.5-fold increase in the number of crypt enterocytes. γ-H2AX immunostaining was elevated in villi, but not in the crypt compartment. µ-XRF maps revealed mean Cr levels >30 times higher in duodenal villi than crypt regions; mean Cr levels in crypt regions were only slightly above background signal. Despite the presence of Cr and elevated γ-H2AX immunoreactivity in villi, no aberrant foci indicative of transformation were evident. Lastly, these findings do not support a MOA for intestinal carcinogenesis involving direct Cr-DNA interaction in intestinal stem cells, but rather support a non-mutagenic MOA involving chronic wounding of intestinal villi and crypt cell hyperplasia.« less

Interlaboratory Evaluation of a Multiplexed High Information Content In Vitro Genotoxicity Assay

PubMed Central

Bryce, Steven M.; Bernacki, Derek T.; Bemis, Jeffrey C.; Spellman, Richard A.; Engel, Maria E.; Schuler, Maik; Lorge, Elisabeth; Heikkinen, Pekka T.; Hemmann, Ulrike; Thybaud, Véronique; Wilde, Sabrina; Queisser, Nina; Sutter, Andreas; Zeller, Andreas; Guérard, Melanie; Kirkland, David; Dertinger, Stephen D.

2017-01-01

We previously described a multiplexed in vitro genotoxicity assay based on flow cytometric analysis of detergent-liberated nuclei that are simultaneously stained with propidium iodide and labeled with fluorescent antibodies against p53, γH2AX, and phospho-histone H3. Inclusion of a known number of microspheres provides absolute nuclei counts. The work described herein was undertaken to evaluate the interlaboratory transferability of this assay, commercially known as MultiFlow™ DNA Damage Kit— p53, γH2AX, Phospho-histone H3. For these experiments seven laboratories studied reference chemicals from a group of 84 representing clastogens, aneugens, and non-genotoxicants. TK6 cells were exposed to chemicals in 96-well plates over a range of concentrations for 24 hrs. At 4 and 24 hrs cell aliquots were added to the MultiFlow reagent mix and following a brief incubation period flow cytometric analysis occurred, in most cases directly from a 96-well plate via a robotic walk-away data acquisition system. Multiplexed response data were evaluated using two analysis approaches, one based on global evaluation factors (i.e., cutoff values derived from all inter-laboratory data), and a second based on multinomial logistic regression that considers multiple biomarkers simultaneously. Both data analysis strategies were devised to categorize chemicals as predominately exhibiting a clastogenic, aneugenic, or non-genotoxic mode of action (MoA). Based on the aggregate 231 experiments that were performed, assay sensitivity, specificity, and concordance in relation to a priori MoA grouping were ≥ 92%. These results are encouraging as they suggest that two distinct data analysis strategies can rapidly and reliably predict new chemicals’ predominant genotoxic MoA based on data from an efficient and transferable multiplexed in vitro assay. PMID:28370322

Studies of styrene, styrene oxide and 4-hydroxystyrene toxicity in CYP2F2 knockout and CYP2F1 humanized mice support lack of human relevance for mouse lung tumors.

PubMed

Cruzan, G; Bus, J; Hotchkiss, J; Sura, R; Moore, C; Yost, G; Banton, M; Sarang, S

2013-06-01

Styrene (S) is lung tumorigenic in mice but not in rats. S and its alkene-oxidized metabolite styrene oxide (SO) were not lung toxic in CYP2F2(-/-) [knockout] mice, indicating S-induced mouse lung tumors are mediated through mouse-specific CYP2F2-generated ring-oxidized metabolite(s) in lung bronchioles. The human relevance of the CYP2F MOA was assessed by insertion of a human CYP2F1, 2A13, 2B6 transgene into CYP2F2(-/-) mice; CYP2F1 expression and activity were confirmed in the transgenic (TG) mice. No evidence of cytotoxicity or increased cell proliferation (BrdU labeling) was seen in TG mice treated with either S or SO (200mg/kg/day ip for 5days). In contrast to S and SO, 4HS (105mg/kg/day ip for 5days) increased BrdU labeling 5-10-fold in WT mice, <3-fold increase in KO mice and 2-4-fold in TG mice. The limited response of 4HS in KO and TG mice may result from intrinsic toxicity or from further metabolism; regardless of the MOA, these findings indicate that the CYP2F-mediated tumorigenic MOA in WT mice is not operative for S, SO, or for 4HS putatively derived from metabolism of S by CYP2F1 in humans, and thus S-induced mouse lung tumors are unlikely to be relevant to human risk. Copyright © 2013. Published by Elsevier Inc.

J-GEM follow-up observations of the gravitational wave source GW151226*

NASA Astrophysics Data System (ADS)

Yoshida, Michitoshi; Utsumi, Yousuke; Tominaga, Nozomu; Morokuma, Tomoki; Tanaka, Masaomi; Asakura, Yuichiro; Matsubayashi, Kazuya; Ohta, Kouji; Abe, Fumio; Chimasu, Sho; Furusawa, Hisanori; Itoh, Ryosuke; Itoh, Yoichi; Kanda, Yuka; Kawabata, Koji S.; Kawabata, Miho; Koshida, Shintaro; Koshimoto, Naoki; Kuroda, Daisuke; Moritani, Yuki; Motohara, Kentaro; Murata, Katsuhiro L.; Nagayama, Takahiro; Nakaoka, Tatsuya; Nakata, Fumiaki; Nishioka, Tsubasa; Saito, Yoshihiko; Terai, Tsuyoshi; Tristram, Paul J.; Yanagisawa, Kenshi; Yasuda, Naoki; Doi, Mamoru; Fujisawa, Kenta; Kawachi, Akiko; Kawai, Nobuyuki; Tamura, Yoichi; Uemura, Makoto; Yatsu, Yoichi

2017-02-01

We report the results of optical-infrared follow-up observations of the gravitational wave (GW) event GW151226 detected by the Advanced LIGO in the framework of J-GEM (Japanese collaboration for Gravitational wave ElectroMagnetic follow-up). We performed wide-field optical imaging surveys with the Kiso Wide Field Camera (KWFC), Hyper Suprime-Cam (HSC), and MOA-cam3. The KWFC survey started at 2.26 d after the GW event and covered 778 deg2 centered at the high Galactic region of the skymap of GW151226. We started the HSC follow-up observations from ˜12 d after the event and covered an area of 63.5 deg2 of the highest probability region of the northern sky with limiting magnitudes of 24.6 and 23.8 for the i and z bands, respectively. MOA-cam3 covered 145 deg2 of the skymap with the MOA-red filter ˜2.5 mon after the GW alert. The total area covered by the wide-field surveys was 986.5 deg2. The integrated detection probability for the observed area was ˜29%. We also performed galaxy-targeted observations with six optical and near-infrared telescopes from 1.61 d after the event. A total of 238 nearby (≤100 Mpc) galaxies were observed with a typical I band limiting magnitude of ˜19.5. We detected 13 supernova candidates with the KWFC survey, and 60 extragalactic transients with the HSC survey. Two thirds of the HSC transients were likely supernovae and the remaining one third were possible active galactic nuclei. With our observational campaign, we found no transients that are likely to be associated with GW151226.

Key Issues in the Role of Peroxisome Proliferator–Activated Receptor Agonism and Cell Signaling in Trichloroethylene Toxicity

PubMed Central

Keshava, Nagalakshmi; Caldwell, Jane C.

2006-01-01

Peroxisome proliferator–activated receptor α (PPARα) is thought to be involved in several different diseases, toxic responses, and receptor pathways. The U.S. Environmental Protection Agency 2001 draft trichloroethylene (TCE) risk assessment concluded that although PPAR may play a role in liver tumor induction, the role of its activation and the sequence of subsequent events important to tumorigenesis are not well defined, particularly because of uncertainties concerning the extraperoxisomal effects. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we summarize some of the scientific literature published since that time on the effects and actions of PPARα that help inform and illustrate the key scientific questions relevant to TCE risk assessment. Recent analyses of the role of PPARα in gene expression changes caused by TCE and its metabolites provide only limited data for comparison with other PPARα agonists, particularly given the difficulties in interpreting results involving PPARα knockout mice. Moreover, the increase in data over the last 5 years from the broader literature on PPARα agonists presents a more complex array of extraperoxisomal effects and actions, suggesting the possibility that PPARα may be involved in modes of action (MOAs) not only for liver tumors but also for other effects of TCE and its metabolites. In summary, recent studies support the conclusion that determinations of the human relevance and susceptibility to PPARα-related MOA(s) of TCE-induced effects cannot rely on inferences regarding peroxisome proliferation per se and require a better understanding of the interplay of extraperoxisomal events after PPARα agonism. PMID:16966106

Economic evaluation within a factorial-design randomised controlled trial of exercise, manual therapy, or both interventions for osteoarthritis of the hip or knee: study protocol.

PubMed

Pinto, Daniel; Robertson, M Clare; Hansen, Paul; Abbott, J Haxby

2011-06-17

Clinical guidelines for the treatment of hip and knee osteoarthritis recommend non-pharmacological and non-surgical treatments. Exercise treatments are recommended as primary strategies, but specific exercise programme components have not been specified. Early evidence indicates that manual physiotherapy is effective for hip and knee osteoarthritis. The Management of Osteoarthritis (MOA) Trial was designed to evaluate the effectiveness and cost-effectiveness of physiotherapist-led, individualised exercise, manual physiotherapy and a combination of these two interventions in the treatment of adults with hip or knee osteoarthrits. This paper describes the methods that will be used to conduct the economic evaluation of these interventions within the MOA Trial. This comprehensive economic evaluation will assess the incremental cost-effectiveness of physiotherapy plus usual care versus usual care alone from a societal perspective. The authors will conduct a cost-consequences analysis using end-points such as Outcomes Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International responder criteria and quality-adjusted life years. The evaluation will have a time horizon of 1 year (and so discounting will not be necessary). All costs will be reported in 2009 New Zealand dollars. The authors will address uncertainty via bootstrapping to calculate CIs for the mean incremental cost-effectiveness ratios and by performing sensitivity analyses. Ethical approval was granted by the Lower South Regional Ethics Committee of the New Zealand Ministry of Health (ethics reference: LRS/07/11/044). All participants of the MOA Trial provided written informed consent for the capture of their healthcare costs. We will submit the results of the study for publication irrespective of outcome. Clinical trials registration number ACTRN12608000130369.

Linkage Of Exposure And Effects Using Genomics, Proteomics, And Metabolomics In Small Fish Models

EPA Science Inventory

Poster for the BOSC Computational Toxicology Research Program review. Knowledge of possible toxic mechanisms/modes of action (MOA) of chemicals can provide valuable insights as to appropriate methods for assessing exposure and effects, thereby reducing uncertainties related to e...

Triaryl Benzimidazoles as a New Class of Antibacterial Agents against Resistant Pathogenic Microorganisms.

PubMed

Picconi, Pietro; Hind, Charlotte; Jamshidi, Shirin; Nahar, Kazi; Clifford, Melanie; Wand, Matthew E; Sutton, J Mark; Rahman, Khondaker Miraz

2017-07-27

A new class of nontoxic triaryl benzimidazole compounds, derived from existing classes of DNA minor groove binders, were designed, synthesized, and evaluated for their antibacterial activity against multidrug resistant (MDR) Gram-positive and Gram-negative species. Molecular modeling experiments suggest that the newly synthesized class cannot be accommodated within the minor groove of DNA due to a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of the series, with MICs in the range of 0.5-4 μg/mL against the MDR Staphylococci and Enterococci species. Compound 13 showed moderate activity against the MDR Gram-negative strains, with MICs in the range of 16-32 μg/mL. Active compounds showed a bactericidal mode of action, and a mechanistic study suggested the inhibition of bacterial gyrase as the mechanism of action (MOA) of this chemical class. The MOA was further supported by the molecular modeling study.

Were Viking Dry-dock methods in the Americas used earlier to Build Pyramids, with Outflow Eroding the Sphinx, and were Stonehenge, the Obelisks, and Moas Similarly Erected?

NASA Astrophysics Data System (ADS)

McLeod, Edward; McLeod, Roger

2006-03-01

Chisel-quarried recycled granite in MA is datable by runes to 1069 CE; it could corroborate dating by a LIDAR. Associated sites, possibly used by Vikings to dry-dock their ships, could have exploited lock-like controls, possibly a continued technology. Site-leveling at the Giza Pyramids proves water was used. `Locks' and body-immersion worked for building, moving, erecting, or watering, at sites like Stonehenge, The Hanging Gardens at Babylon, the Moas of Easter Island, or The Pyramids, where the eroding water discharge was deliberately flushed over the Sphinx complex. It enhance the electromagnetically excited blue light signals we can detect, especially at sites frequented by Molocket of ME. Information, as at America's Stonehenge, in NH, and constructions at Acton MA, at Giza or at Rumford ME proves that the Pyramids and Sphinx were engineered and built about 4500 BP.

Use of Chemical Mixtures to Differentiate Mechanisms of Endocrine Action in a Small Fish Model

EPA Science Inventory

Various assays with adult fish have been developed to identify potential endocrine-disrupting chemicals (EDCs) which may cause toxicity via alterations in the hypothalamic-pituitary-gonadal (HPG) axis via different mechanisms/modes of action (MOA). These assays can be sensitive ...

Comparison of Global and Mode of Action-Based Models for Aquatic Toxicity

EPA Science Inventory

The ability to estimate aquatic toxicity for a wide variety of chemicals is a critical need for ecological risk assessment and chemical regulation. The consensus in the literature is that mode of action (MOA) based QSAR (Quantitative Structure Activity Relationship) models yield ...

40 CFR 52.82 - Extensions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 3 2011-07-01 2011-07-01 false Extensions. 52.82 Section 52.82... PROMULGATION OF IMPLEMENTATION PLANS Alaska § 52.82 Extensions. The Administrator, by authority delegated under..., 1996) the attainment date for the MOA, Alaska CO nonattainment area. [61 FR 33678, June 28, 1996] ...

40 CFR 52.82 - Extensions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 3 2012-07-01 2012-07-01 false Extensions. 52.82 Section 52.82... PROMULGATION OF IMPLEMENTATION PLANS Alaska § 52.82 Extensions. The Administrator, by authority delegated under..., 1996) the attainment date for the MOA, Alaska CO nonattainment area. [61 FR 33678, June 28, 1996] ...

40 CFR 52.82 - Extensions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 3 2014-07-01 2014-07-01 false Extensions. 52.82 Section 52.82... PROMULGATION OF IMPLEMENTATION PLANS Alaska § 52.82 Extensions. The Administrator, by authority delegated under..., 1996) the attainment date for the MOA, Alaska CO nonattainment area. [61 FR 33678, June 28, 1996] ...

40 CFR 52.82 - Extensions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 3 2010-07-01 2010-07-01 false Extensions. 52.82 Section 52.82... PROMULGATION OF IMPLEMENTATION PLANS Alaska § 52.82 Extensions. The Administrator, by authority delegated under..., 1996) the attainment date for the MOA, Alaska CO nonattainment area. [61 FR 33678, June 28, 1996] ...

40 CFR 52.82 - Extensions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 3 2013-07-01 2013-07-01 false Extensions. 52.82 Section 52.82... PROMULGATION OF IMPLEMENTATION PLANS Alaska § 52.82 Extensions. The Administrator, by authority delegated under..., 1996) the attainment date for the MOA, Alaska CO nonattainment area. [61 FR 33678, June 28, 1996] ...

OPPTS Meeting: Linkage Of Exposure And Effects Using Genomics, Proteomics, And Metabolomics In Small Fish Models

EPA Science Inventory

Poster for the OPPTS Science Forum. Knowledge of possible toxic mechanisms/modes of action (MOA) of chemicals can provide valuable insights as to appropriate methods for assessing exposure and effects, thereby reducing uncertainties related to extrapolation across species, endpoi...

INSIGHTS INTO THE CARCINOGENIC MODE OF ACTION OF ARSENIC

EPA Science Inventory

That arsenic can induce cancer in humans has been known since the late 17th century, yet how arsenic induces cancer has been the subject of numerous scientific publications. Various modes of action (MOA) have been proposed for arsenic's carcinogenicity. In this paper we review o...

A TOXICOLOGICAL VIEW OF ISSUES AND APPROACHES

EPA Science Inventory

Mode of action (MOA) is a powerful approach which can be used to improve extrapolations and understanding of relevance from studies of animals to humans, to inform differential susceptible states, and from high to low doses. In using mode of action, a key event is identified whi...

APPROACHES TO EXTRAPOLATING EFFECTS OF EDCS ACROSS BIOLOGICAL LEVELS OF ORGANIZATION IN FISH

EPA Science Inventory

A challenge in ecological risk assessments is to obtain, in a resource-effective manner, information that provides insight both into chemical mode/mechanism of action (MOA) and adverse effects in individual animals, which are indicative of potential population-level responses. T...

Report: EPA Should Revise Outdated or Inconsistent EPA-State Clean Water Act Memoranda of Agreement

EPA Pesticide Factsheets

Report #10-P-0224, September 14, 2010. NPDES MOAs between EPA and States do not ensure Agency management control and effective oversight over a national program administered by States that is capable of providing equal protection to all Americans.

Triclosan Alters Thyroid Hormone Homeostasis via Up-regulation of Hepatic Catabolism

EPA Science Inventory

Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) decreases serum thyroxine (T4) in the weanling rat. Scientific uncertainties include: by what mode of action (MOA) does triclosan decrease T4, and does triclosan induce hypothyroxinemia in dams and neonates? To test the hypothes...

2008 Memorandum on Revised Coordination between EPA Regional Offices and Headquarters on Clean Water Act Section 404(q) Actions

EPA Pesticide Factsheets

The purpose of this memorandum is to revise and streamline EPA's internal coordination procedures established in 2006 for the review of proposed Section 404(q) actions under the joint EPA/Army Memorandum of Agreement (MOA).

ARSENIC MODE OF ACTION AND DEVELOPING A BBDR MODEL

EPA Science Inventory

The current USEPA cancer risk assessment for inorganic arsenic is based on a linear extrapolation of the epidemiological data from exposed populations in Taiwan. However, proposed key events in the mode of action (MoA) for arsenic-induced cancer (which may include altered DNA me...

Human Systems Integration Requirements

DTIC Science & Technology

2009-09-01

52 Stratofortress, C/ KC -135 Stratotanker, E-3 Sentry and contractor logistics support aircraft; as well as a substantial jet engine inventory...www.hqda.army.mil/ teo /Sutability%20Terms%20MOA%20Oct%2005.pdf q. ISO 9241-11, Ergonomic requirements for office work with visual display terminals (VDTs

Identification and validation nucleolin as a target of curcumol in nasopharyngeal carcinoma cells.

PubMed

Wang, Juan; Wu, Jiacai; Li, Xumei; Liu, Haowei; Qin, Jianli; Bai, Zhun; Chi, Bixia; Chen, Xu

2018-06-30

Identification of the specific protein target(s) of a drug is a critical step in unraveling its mechanisms of action (MOA) in many natural products. Curcumol, isolated from well known Chinese medicinal plant Curcuma zedoary, has been shown to possess multiple biological activities. It can inhibit nasopharyngeal carcinoma (NPC) proliferation and induce apoptosis, but its target protein(s) in NPC cells remains unclear. In this study, we employed a mass spectrometry-based chemical proteomics approach reveal the possible protein targets of curcumol in NPC cells. Cellular thermal shift assay (CETSA), molecular docking and cell-based assay was used to validate the binding interactions. Chemical proteomics capturing uncovered that NCL is a target of curcumol in NPC cells, Molecular docking showed that curcumol bound to NCL with an -7.8 kcal/mol binding free energy. Cell function analysis found that curcumol's treatment leads to a degradation of NCL in NPC cells, and it showed slight effects on NP69 cells. In conclusion, our results providing evidences that NCL is a target protein of curcumol. We revealed that the anti-cancer effects of curcumol in NPC cells are mediated, at least in part, by NCL inhibition. Many natural products showed high bioactivity, while their mechanisms of action (MOA) are very poor or completely missed. Understanding the MOA of natural drugs can thoroughly exploit their therapeutic potential and minimize their adverse side effects. Identification of the specific protein target(s) of a drug is a critical step in unraveling its MOA. Compound-centric chemical proteomics is a classic chemical proteomics approach which integrates chemical synthesis with cell biology and mass spectrometry (MS) to identify protein targets of natural products determine the drug mechanism of action, describe its toxicity, and figure out the possible cause of off-target. It is an affinity-based chemical proteomics method to identify small molecule-protein interactions through affinity chromatography approach coupled with mass spectrometry, has been conventionally used to identify target proteins and has yielded good results. Curcumol, has shown effective inhibition on Nasopharyngeal Carcinoma (NPC) Cells, interacted with NCL and then initiated the anti-tumor biological effect. This research demonstrated the effectiveness of chemical proteomics approaches in natural drugs molecular target identification, revealing and understanding of the novel mechanism of actions of curcumol is crucial for cancer prevention and treatment in nasopharynx cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

Methyl isobutyl ketone-induced hepatocellular carcinogenesis in B6C3F1 mice: A constitutive androstane receptor (CAR)-mediated mode of action.

PubMed

Hughes, B J; Thomas, J; Lynch, A M; Borghoff, S J; Green, S; Mensing, T; Sarang, S S; LeBaron, M J

2016-11-01

In a National Toxicology Program (NTP) chronic inhalation study with methyl isobutyl ketone (MIBK), increases in hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were observed in male and female B6C3F 1 mice at 1800 ppm. A DNA reactive Mode-of-Action (MOA) for this liver tumor response is not supported by the evidence as MIBK and its major metabolites lack genotoxicity in both in vitro and in vivo studies. Constitutive androstane receptor (CAR) nuclear receptor-mediated activation has been hypothesized as the MOA for MIBK-induced mouse liver tumorigenesis. To further investigate the MOA for MIBK-induced murine liver tumors, male and female B6C3F1, C57BL/6, and CAR/PXR Knockout (KO) mice were exposed to either 0 or 1800 ppm MIBK for 6 h/day, 5 days/week for a total of 10 days. On day 1, mice were implanted with osmotic mini-pumps containing 5-Bromo-2-deoxyuridine (BrdU) 1 h following exposure and humanely euthanized 1-3 h following the final exposure. B6C3F 1 and C57BL/6 mice had statistically significant increases in liver weights compared to controls that corresponded with hepatocellular hypertrophy and increased mitotic figures. Hepatocellular proliferation data indicated induction of S-phase DNA synthesis in B6C3F 1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to control, and no increase was observed in MIBK exposed CAR/PXR KO mice. Liver gene expression changes indicated a maximally-induced Cyp2b10 (CAR-associated) transcript and a slight increase in Cyp3a11(PXR-associated) transcript in B6C3F 1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to controls, but not in Cyp1a1 (AhR-associated) or Cyp4a10 (PPAR-α-associated) transcripts. CAR/PXR KO mice exposed to 1800 ppm MIBK showed no evidence of activation of AhR, CAR, PXR or PPAR-α nuclear receptors via their associated transcripts. MIBK induced hepatic effects are consistent with a phenobarbital-like MOA where the initiating events are activation of the CAR and PXR nuclear receptors and resultant hepatocellular proliferation leading to rodent liver tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

mtDNA from fossils reveals a radiation of Hawaiian geese recently derived from the Canada goose (Branta canadensis)

PubMed Central

Paxinos, Ellen E.; James, Helen F.; Olson, Storrs L.; Sorenson, Michael D.; Jackson, Jennifer; Fleischer, Robert C.

2002-01-01

Phylogenetic analysis of 1.35 kb of mtDNA sequence from fossils revealed a previously unknown radiation of Hawaiian geese, of which only one representative remains alive (the endangered Hawaiian goose or nene, Branta sandvicensis). This radiation is nested phylogenetically within a living species, the Canada goose (Branta canadensis) and is related most closely to the large-bodied lineage within that species. The barnacle goose (Branta leucopsis) is also nested within the Canada goose species and is related most closely to the small-bodied lineage of Canada geese. The peripheral isolation of the barnacle goose in the Palearctic apparently allowed the evolution of its distinctive plumage pattern, whereas the two Nearctic lineages of Canada geese share a primitive plumage pattern. The Hawaiian lineage of Canada geese diverged more dramatically, splitting into at least three species that differ in body size, body proportions, and flight ability. One fossil species, limited to the island of Hawaii, was related closely to the nene but was over four times larger, flightless, heavy-bodied and had a much more robust cranium. Application of a rate calibration to levels of DNA divergence suggests that this species evolved on the island of Hawaii in less than 500,000 years. This date is consistent with the potassium/argon-based age of the island of Hawaii of 430,000–500,000 years. The giant Hawaii goose resembles the moa-nalos, a group of massive, extinct, flightless ducks that lived on older Hawaiian Islands and thus is an example of convergent evolution of similar morphologies in island ecosystems. PMID:11818543

An evaluation of the mode of action framework for mutagenic carcinogens: chromium (VI)

EPA Science Inventory

In response to the 2005 revised U.S Environmental Protection Agency’s (EPA) Cancer Guidelines, a strategy is being developed to determine whether a carcinogen operates through a mutagenic mode of action (MOA). This information is necessary for EPA to decide whether age-dependent ...

Merging Adverse Outcome Pathway (AOP) and Mode of Action (MOA) Frameworks: Assembling Knowledge for Use in Risk Assessment

EPA Science Inventory

The Adverse Outcome Pathway has emerged as an internationally harmonized mechanism for organizing biological information in a chemical agnostic manner. This construct is valuable for interpreting the results from high-throughput toxicity (HTT) assessment by providing a mechanisti...

40 CFR 233.51 - Waiver of review.

Code of Federal Regulations, 2012 CFR

2012-07-01

... REGULATIONS Federal Oversight § 233.51 Waiver of review. (a) The MOA with the Regional Administrator shall... discharge for which EPA will waive review. The Regional Administrator shall consult with the Corps, FWS, and... reasonable potential for adverse impacts on waters of another State; (4) Discharges known or suspected to...

Cytogenetic insights into DNA damage and repair of lesions induced by a monomethylated trivalent arsenical

EPA Science Inventory

Arsenic is a human carcinogen, and only recently have animal models been developed that are useful in investigating its carcinogenic mode ofaction (MOA). However, how arsenic induces cancer is still an open question. In a previous paper, we proposed a model detailing how arsenic ...

Mode of Action (MOA) and Dose-Response Approaches for Nuclear Receptors

EPA Science Inventory

Abstract: The presence of sub-threshold doses for non-cancer and (in appropriate cases) cancer has been the dominant paradigm for the practice of risk assessment, but the application of dose-response modeling approaches that include a threshold have been questioned in a 2009 NRC ...

44 CFR 208.2 - Definitions of terms used in this part.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Force personnel compensation, itemized fringe benefit rates and amounts including calculations, and... State or Local Government that has executed an MOA with DHS to organize and administer a Task Force. Stafford Act means the Robert T. Stafford Disaster Relief and Emergency Assistance Act, 42 U.S.C. 5121...

Endocrine disrupting chemicals in fish: developing exposure indicators and predictive models of effects based on mechanism of action

EPA Science Inventory

Knowledge of possible toxic mechanisms/modes of action (MOA) of chemicals can provide valuable insights as to appropriate methods for assessing exposure and effects, such as reducing uncertainties related to extrapolation across species, endpoints and chemical structure. However,...

Development of a Quantitative Model Incorporating Key Events in a Hepatoxic Mode of Action to Predict Tumor Incidence

EPA Science Inventory

Biologically-Based Dose Response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically described as either genotoxic or non-genotoxic. One common...

Bioassays for Evaluating Water Quality: Screening for total bioactivity to assess water safety

EPA Science Inventory

Bioassays are a potential solution for assessing complex samples since they screen for total bioactivity for a given pathway or mode of action (MOA), such as estrogen receptor activation, in the samples. Overall, they can account for the three challenges listed above, and can sim...

US forest service technical cooperation visit Badia Rangeland and irrigation analysis

USDA-ARS?s Scientific Manuscript database

A US Forest Service (USFS) team comprised of a rangeland management advisor, a dryland water resource, and irrigation specialist, and a Middle East program specialist visited Jordan to provide technical assistance to the Ministry of Agriculture-Water Harvesting Directorate (MoA) and the Hashemite Fu...

Relationships between aquatic toxicity, chemical hydrophobicity and mode of action: log kow QSARs revisited

EPA Science Inventory

Relationships between chemical hydrophobicity and toxicity have been shown for nearly 100 years in both mammals and fish, typically using the log of the octanol:water partition coefficient (kow). The current study reassessed the influence of mode of action (MOA) on aquatic toxici...

Jingqiu Moa and Xinrong Ren check out Pennsylvania State University's Airborne Tropospheric Hydrogen Oxides Sensor instrument during the ARCTAS mission upload

NASA Image and Video Library

2008-03-07

Climate researchers from the National Center for Atmospheric Research (NCAR) and several universities install and perform functional checkouts of a variety of sensitive atmospheric instruments on NASA's DC-8 airborne laboratory prior to beginning the ARCTAS mission.

Memorandum of Agreement Between the Department of Defense and the Department of Transportation : Civil Use of the Global Positioning System

DOT National Transportation Integrated Search

2008-01-01

This Memorandum of Agreement (MOA) establishes policies and procedures to ensure an effective working relationship between the Department of Defense (DoD) and the Department of Transportation (DOT) regarding civil use of the Navstar Global Positionin...

Identification of Androgen Receptor Antagonists in Fish Using a Simple Bioassay with the Fathead Minnow Pimephales promelas .

EPA Science Inventory

Considerable effort has been expended on the development of bioassays to detect chemicals that affect endocrine function controlled by the vertebrate hypothalamic-pituitary-gonadal (HPG) axis via different mechanisms/modes of action (MOA). Antagonism of the androgen receptor (AR)...

An evaluation of the mode of action framework for mutagenic carcinogens: Chromium (VI): SOT.

EPA Science Inventory

In response to the 2005 revised U.S Environmental Protection Agency’s (EPA) Cancer Guidelines, a strategy is being developed to determine whether a carcinogen operates through a mutagenic mode of action (MOA). This information is necessary for EPA to decide whether age-dependent ...

Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity

EPA Science Inventory

To support a paradigm shift in regulatory toxicology testing and risk assessment, the Adverse Outcome Pathway (AOP) concept has recently been proposed. This concept is similar to that for Mode of Action (MOA), describing a sequence of measurable key events triggered by a molecula...

MOAtox: A comprehensive mode of action and acute aquatic toxicity database for predictive model development (SETAC abstract)

EPA Science Inventory

The mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, the development of quantitative structure activity relationship (QSAR) and other models has been limit...

MOAtox: A Comprehensive Mode of Action and Acute Aquatic Toxicity Database for Predictive Model Development

EPA Science Inventory

tThe mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity andas an alternative to chemical class-based predictive toxicity modeling. However, the development ofquantitative structure activity relationship (QSAR) and other models has been limite...

Systems Biology Approach for Understanding MOA, Dose-Response and Susceptibility to Environmental Chemicals

EPA Science Inventory

There is an increasing need for assays for the rapid and efficient assessment of toxicities of large numbers of environmental chemicals. To meet this need, we have developed a battery of cell-based reporter assays that measure the activation of key cellular stress pathways. These...

Medical Office Assistants' Handbook. Second Edition.

ERIC Educational Resources Information Center

British Columbia Dept. of Education, Victoria.

This handbook is intended both as a text for use in medical office assistant (MOA) training programs in colleges and as a handbook for people working in medical offices. Addressed in the individual sections of the manual are the following topics: responsibilities of the medical office assistant, office organization, appointments and the waiting…

Detection of trace amino acid biomarkers in ice from extreme environments with the Mars Organic Analyzer

NASA Astrophysics Data System (ADS)

Jayarajah, Christine; Jayarajah, Christine; Botta, Oliver; Aubrey, Andrew; Parker, Eric; Bada, Jeffrey; Mathies, Richard

A portable microfabricated capillary electrophoresis (CE) system named the Mars Organic Analyzer (MOA) has been developed to analyze fluorescently-labeled biomarkers including amino acids, amines, nucleobases, and amino sugars with the goal of life detection on Mars (1,2). This system consists of a multilayer microfabricated glass wafer containing electrophoresis channels as well as microfluidic valves and pumps for sample manipulation, a confocal laser excitation and fluorescence detection system, and integrated CE power supplies. The MOA has been successfully field tested in the Panoche Valley, CA and in the Atacama Desert, Chile, detecting amino acids at the ppb levels (3). In addition, this technology has been shown to be effective in screening the formation of biogenic amines during fermentation (4). The MOA is a part of the Urey instrument package that has been selected for the 2013 European ExoMars mission by ESA. The identification of recent gully erosion sites, observations of ice on and beneath the surface of Mars, and the discovery of large reservoirs of sub-surface ice on Mars point to water-ice as an important target for astrobiological analyses (5). In addition, the ice moons Europa and Enceladus are of astrobiological interest due to the possibility that they may contain liquid water under their ice crusts. Consequently, we explore here the use of the MOA instrument for the analysis of amino acids in polar ice samples. Soil extracts as well as concentrated icecore samples tend to be highly saline and inhomogeneous. Furthermore, brine pockets in ice form potential refugia for extant extra-terrestrial life, rendering near surface ice a key target for the search for a record of past life on the planet (6). Therefore, we have determined the effect of salinity on sample injection parameters in ice-core samples retrieved from Greenland. The amino acids valine, alanine/serine, glycine, glutamic acid, and aspartic acid were found in the parts-per-billion range from these ice-core samples. Chiral analysis of these samples yielded D/L ratios of 0.51/0.09 for alanine/serine and 0.14/0.06 for aspartic acid. Individual amino acids in the parts-per-trillion range were found in Antarctic ice samples collected from the surface of a meteorite collection area. The distinct amino acid and amine content of these samples indicates that further biomarker characterization of ice samples as a function of sampling location, depth, and structural features will be highly informative. The rapid sensitive analysis capabilities demonstrated here establish the feasibility of using the MOA to analyze the biomarker content of ice samples in planetary exploration. 1. Skelley, A. M.; Scherer, J. R.; Aubrey, A. D.; Grover, W. H.; Ivester, R. H. C., Ehrenfreund, P.; Grunthaner, F. J.; Bada, J. L.; Mathies, R. A. Proceedings of the National Academy of Sciences, U.S.A., 2005, 192, 1041-1046. 2. Skelley, A. M., Cleaves, H. J., Jayarajah, C. N., Bada, J. L. and Mathies, R. A., Astrobiology 2006, 6, 824-837. 3. Skelley, A. M., Aubrey, A. D., Willis, P. A., Amashukeli, X., Ehrenfreuend, P. , Bada, J. L., Grunthaner, F. J. and Mathies, R. A. Journal of Geophysical Research 2007, 112, G04S11 4. Jayarajah, C.N., Skelley, A.M., Fortner, A.D., and Mathies, R.A., Analytical Chemistry, 2007, 79, 21, 8162-8169. 5. Sanderson, K., Nature 2006, 414. 800-801. 6. Price, B.P. Proceedings of the National Academy of Sciences, U.S.A., 2000, 97, 1247-1251.

Elucidating the Aβ42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer's Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data.

PubMed

Kocis, Petr; Tolar, Martin; Yu, Jeremy; Sinko, William; Ray, Soumya; Blennow, Kaj; Fillit, Howard; Hey, John A

2017-06-01

Amyloid beta (Aβ) oligomers play a critical role in the pathogenesis of Alzheimer's disease (AD) and represent a promising target for drug development. Tramiprosate is a small-molecule Aβ anti-aggregation agent that was evaluated in phase III clinical trials for AD but did not meet the primary efficacy endpoints; however, a pre-specified subgroup analysis revealed robust, sustained, and clinically meaningful cognitive and functional effects in patients with AD homozygous for the ε4 allele of apolipoprotein E4 (APOE4/4 homozygotes), who carry an increased risk for the disease. Therefore, to build on this important efficacy attribute and to further improve its pharmaceutical properties, we have developed a prodrug of tramiprosate ALZ-801 that is in advanced stages of clinical development. To elucidate how tramiprosate works, we investigated its molecular mechanism of action (MOA) and the translation to observed clinical outcomes. The two main objectives of this research were to (1) elucidate and characterize the MOA of tramiprosate via an integrated application of three independent molecular methodologies and (2) present an integrated translational analysis that links the MOA, conformation of the target, stoichiometry, and pharmacokinetic dose exposure to the observed clinical outcome in APOE4/4 homozygote subjects. We used three molecular analytical methods-ion mobility spectrometry-mass spectrometry (IMS-MS), nuclear magnetic resonance (NMR), and molecular dynamics-to characterize the concentration-related interactions of tramiprosate versus Aβ42 monomers and the resultant conformational alterations affecting aggregation into oligomers. The molecular stoichiometry of the tramiprosate versus Aβ42 interaction was further analyzed in the context of clinical pharmacokinetic dose exposure and central nervous system Aβ42 levels (i.e., pharmacokinetic-pharmacodynamic translation in humans). We observed a multi-ligand interaction of tramiprosate with monomeric Aβ42, which differs from the traditional 1:1 binding. This resulted in the stabilization of Aβ42 monomers and inhibition of oligomer formation and elongation, as demonstrated by IMS-MS and molecular dynamics. Using NMR spectroscopy and molecular dynamics, we also showed that tramiprosate bound to Lys16, Lys28, and Asp23, the key amino acid side chains of Aβ42 that are responsible for both conformational seed formation and neuronal toxicity. The projected molar excess of tramiprosate versus Aβ42 in humans using the dose effective in patients with AD aligned with the molecular stoichiometry of the interaction, providing a clear clinical translation of the MOA. A consistent alignment of these preclinical-to-clinical elements describes a unique example of translational medicine and supports the efficacy seen in symptomatic patients with AD. This unique "enveloping mechanism" of tramiprosate also provides a potential basis for tramiprosate dose selection for patients with homozygous AD at earlier stages of disease. We have identified the molecular mechanism that may account for the observed clinical efficacy of tramiprosate in patients with APOE4/4 homozygous AD. In addition, the integrated application of the molecular methodologies (i.e., IMS-MS, NMR, and thermodynamics analysis) indicates that it is feasible to modulate and control the Aβ42 conformational dynamics landscape by a small molecule, resulting in a favorable Aβ42 conformational change that leads to a clinically relevant amyloid anti-aggregation effect and inhibition of oligomer formation. This novel enveloping MOA of tramiprosate has potential utility in the development of disease-modifying therapies for AD and other neurodegenerative diseases caused by misfolded proteins.

Scaling of Convex Hull Volume to Body Mass in Modern Primates, Non-Primate Mammals and Birds

PubMed Central

Brassey, Charlotte A.; Sellers, William I.

2014-01-01

The volumetric method of ‘convex hulling’ has recently been put forward as a mass prediction technique for fossil vertebrates. Convex hulling involves the calculation of minimum convex hull volumes (vol CH) from the complete mounted skeletons of modern museum specimens, which are subsequently regressed against body mass (M b) to derive predictive equations for extinct species. The convex hulling technique has recently been applied to estimate body mass in giant sauropods and fossil ratites, however the biomechanical signal contained within vol CH has remained unclear. Specifically, when vol CH scaling departs from isometry in a group of vertebrates, how might this be interpreted? Here we derive predictive equations for primates, non-primate mammals and birds and compare the scaling behaviour of M b to vol CH between groups. We find predictive equations to be characterised by extremely high correlation coefficients (r 2 = 0.97–0.99) and low mean percentage prediction error (11–20%). Results suggest non-primate mammals scale body mass to vol CH isometrically (b = 0.92, 95%CI = 0.85–1.00, p = 0.08). Birds scale body mass to vol CH with negative allometry (b = 0.81, 95%CI = 0.70–0.91, p = 0.011) and apparent density (vol CH/M b) therefore decreases with mass (r 2 = 0.36, p<0.05). In contrast, primates scale body mass to vol CH with positive allometry (b = 1.07, 95%CI = 1.01–1.12, p = 0.05) and apparent density therefore increases with size (r 2 = 0.46, p = 0.025). We interpret such departures from isometry in the context of the ‘missing mass’ of soft tissues that are excluded from the convex hulling process. We conclude that the convex hulling technique can be justifiably applied to the fossil record when a large proportion of the skeleton is preserved. However we emphasise the need for future studies to quantify interspecific variation in the distribution of soft tissues such as muscle, integument and body fat. PMID:24618736

The wild ostrich (Struthio camelus): a review.

PubMed

Cooper, R G; Mahrose, Kh M A; Horbańczuk, J O; Villegas-Vizcaíno, R; Kennou Sebei, S; Faki Mohammed, A E

2009-12-01

The aim of the current report was to study the literature pertinent to wild populations of ostriches and their ecological and behavioural adaptations in the wild. Selected areas included palaeontology; ostrich distribution; conservation status and relationships with humans and habitat. There is an immediate and urgent need to conserve and protect the apparently rapidly declining populations of wild ostriches with the committed involvement of governments and funding bodies. Wildlife management is an important complement to the farming of livestock. Scientists need to understand the elements of ostrich behaviour in the wild in order to make informed decisions on their management and contact with other animals. Information of the like should be included in readily-accessible and annually updated wildlife manuals. We deemed that such information was an essential part in the conservation of this dwindling ratite.

24 CFR 902.75 - Referral to a Troubled Agency Recovery Center (TARC).

Code of Federal Regulations, 2010 CFR

2010-04-01

... Recovery Center (TARC). 902.75 Section 902.75 Housing and Urban Development Regulations Relating to Housing... § 902.75 Referral to a Troubled Agency Recovery Center (TARC). (a) General. Upon a PHA's designation of... of the preliminary MOA. (d) Maximum recovery period—(1) Expiration of one-year recovery period. Upon...

Metabolite Profiling and a Transcriptional Activation Assay Provide Direct Evidence of Androgen Receptor Antagonism by Bisphenol A in Fish.

EPA Science Inventory

Widespread environmental contamination by bisphenol A (BPA) has created the need to fully define its potential toxic mechanisms of action (MOA) to properly assess human health and ecological risks from exposure. Although long recognized as an estrogen receptor (ER) agonist, some ...

77 FR 43819 - Memorandum of Agreement With the Kalispel Tribe on Columbia Basin Fish Accords

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-26

... Tribe on Columbia Basin Fish Accords AGENCY: Bonneville Power Administration (BPA), Department of Energy... Agreement With Kalispel Tribe SUMMARY: This notice announces the availability of the BPA's ROD for entering... Bonner Counties, Idaho. BPA has decided to enter into the MOA to pursue mutual goals with the Kalispel...

Triclosan Decreases Rat Thyroxine: Mode-of-Action, Developmental Susceptibility and Human Relevance

EPA Science Inventory

Triclosan (TCS) decreases serum thyroxine (T4) in the rat. In vivo and in vitro approaches were used to address three uncertainties: by what mode-of-action (MOA) does TCS decrease T4; does TCS decrease T4 developmentally; and, are effects observed in rats relevant to humans? To t...

Triclosan Disrupts Thyroxine: Contribution of Hepatic Transport to the Mode of Action

EPA Science Inventory

Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) (TCS) decreases serum thyroxine (T4) in rats. In previous work, TCS upregulated Phase I and II hepatic metabolism after 4-day exposures in rats. A major data gap in our characterization of the mode of action (MOA) of TCS-induced ...

Developmental Triclosan Exposure Decreases Maternal,Fetal, and Early Neonatal Thyroxine: Dynamic and Kinetic Data Support for a Mode-of-Action

EPA Science Inventory

This work tests the mode-of-action (MOA) hypothesis that perinatal triclosan (TCS) exposure decreases circulating thyroxine (T4) concentrations via activation of pregnane X and/or constitutive androstane receptors (PXR, CAR), resulting in up-regulation of hepatic catabolism and e...

OVERVIEW: USING MODE OF ACTION AND LIFE STAGE INFORMATION TO EVALUATE THE HUMAN RELEVANCE OF ANIMAL TOXICITY DATA.

EPA Science Inventory

A manuscript summarizes a workshop aimed at developing a framework to determine the relevancy of animal modes-of-action for extrapolation to humans. A complete mode of action human relevance analysis - as distinct from mode of action (MOA) analysis alone - depends on robust info...

Steering Committee Progress Report on Hydrogen Sensor Performance Testing and Evaluation under the Memorandum of Agreement between NREL, U.S. DOE and JRC-IET, EC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buttner, W.; Post, M.; Burgess, R.

This progress report is a programmatic summary of a formal MOA between NREL and the European Union Joint Research Center, Institute for Energy and Transport to be presented at the Steering Committee Meeting, December 3, 2012.

ARSENIC IS A GENOTOXIC CARCINOGEN -- ACTING AS A CLASTOGEN AND A MITOTIC INHIBITOR

EPA Science Inventory

Introduction


The ability of arsenic to induce cancer in humans is beyond dispute. How arsenic induces cancer is the subject of much conjecture. Various modes of action (MOA) have been proposed for arsenic¿s carcinogenicity including, its ability to alter DNA me...

40 CFR 147.1350 - State-administered programs-Class II wells.

Code of Federal Regulations, 2014 CFR

2014-07-01

...://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. (1) Montana...) Letter dated March 8, 1996, from MBOGC independent counsel to USEPA, Region VIII; “Re: EPA comments of... Administrator of the MBOGC and the attached proposed replacement language for the MOA; “Re: Responses to EPA...

40 CFR 147.1350 - State-administered programs-Class II wells.

Code of Federal Regulations, 2012 CFR

2012-07-01

...://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. (1) Montana...) Letter dated March 8, 1996, from MBOGC independent counsel to USEPA, Region VIII; “Re: EPA comments of... Administrator of the MBOGC and the attached proposed replacement language for the MOA; “Re: Responses to EPA...

40 CFR 147.1350 - State-administered programs-Class II wells.

Code of Federal Regulations, 2010 CFR

2010-07-01

...://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. (1) Montana...) Letter dated March 8, 1996, from MBOGC independent counsel to USEPA, Region VIII; “Re: EPA comments of... Administrator of the MBOGC and the attached proposed replacement language for the MOA; “Re: Responses to EPA...

40 CFR 147.1350 - State-administered programs-Class II wells.

Code of Federal Regulations, 2013 CFR

2013-07-01

...://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. (1) Montana...) Letter dated March 8, 1996, from MBOGC independent counsel to USEPA, Region VIII; “Re: EPA comments of... Administrator of the MBOGC and the attached proposed replacement language for the MOA; “Re: Responses to EPA...

40 CFR 147.1350 - State-administered programs-Class II wells.

Code of Federal Regulations, 2011 CFR

2011-07-01

...://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. (1) Montana...) Letter dated March 8, 1996, from MBOGC independent counsel to USEPA, Region VIII; “Re: EPA comments of... Administrator of the MBOGC and the attached proposed replacement language for the MOA; “Re: Responses to EPA...

DEVELOPMENT AND VALIDATION OF A 2,000 GENE MICROARRAY FOR THE FATHEAD MINNOW, PIMEPHALES PROMELAS

EPA Science Inventory

The development of the gene microarray has provided the field of ecotoxicology a new tool to identify modes of action (MOA) of chemicals and chemical mixtures. Herein we describe the development and application of a 2,000 gene oligonucleotide microarray for the fathead minnow (P...

Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives.

PubMed

Mahapatra, Debarshi Kar; Asati, Vivek; Bharti, Sanjay Kumar

2015-03-06

Diabetes Mellitus (DM) is the fastest growing metabolic disorder affecting about 387 million people across the globe and is estimated to affect 592 million people by year 2030. The search for newer anti-diabetic agents is the foremost need to control the accelerating diabetic population. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates that act by modulating the therapeutic targets PPAR-γ, DPP-4, α-glucosidase, PTP1B, aldose reductase, and stimulate insulin secretion and tissue sensitivity. In this review, a comprehensive study (from January 1977 to October 2014) of anti-diabetic chalcones, their molecular targets, structure activity relationships (SARs), mechanism of actions (MOAs) and patents have been described. The compounds which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-diabetic agents. They should be evaluated critically at all clinical stages to ensure their therapeutic and toxicological profile to meet the demand of diabetics. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Culture, local capacity, and outside aid: a community perspective on disaster response after the 2009 tsunami in American Sāmoa.

PubMed

Binder, Sherri Brokopp; Baker, Charlene K

2017-04-01

Research on diverse cultural contexts has indicated that aid organisations often fail to leverage local, culturally-grounded resources and capacities in disaster-affected communities. Case-study methodology was employed to explore the relationship between local and external disaster response efforts in American Sāmoa following the earthquake and tsunami on 29 September 2009 in the southern Pacific Ocean, with a specific focus on the role of culture in defining that relationship. Interview and focus group data from 37 participants, along with observational data, suggested that the local response to the event was swift and grounded in Samoan cultural systems and norms. External aid was viewed as helpful in some respects, although, on the whole, it was seen as a disruption to village hierarchies, social networks, and local response efforts. The study discusses the implications for the role of outside aid in diverse cultural contexts, and makes suggestions for improving the ecological fit of post-disaster interventions. © 2017 The Author(s). Disasters © Overseas Development Institute, 2017.

Tripolar Laplacian electrocardiogram and moment of activation isochronal mapping.

PubMed

Besio, W; Chen, T

2007-05-01

The electrocardiogram (ECG) provides useful global temporal assessment of the cardiac activity, but has limited spatial capabilities. The Laplacian electrocardiogram (LECG), an improvement over the ECG, provides high spatiotemporal distributed information about cardiac electrical activation. We designed and developed LECG tripolar concentric ring electrode active sensors based on the finite element algorithm 'nine-point method' (NPM). The active sensors were used in an array of 6 by 12 (72) locations to record bipolar and tripolar LECG from the body surface over the anterolateral chest. Compared to bipolar LECG, tripolar LECG showed significantly higher spatial selectivity which may be helpful in inferring information about cardiac activations detected on the body surface. In this study the moment of activation (MOA), an indicator of a depolarization wave passing below the active sensors, was used to surmise possible timing information of the cardiac electrical activation below the active sensors' recording sites. The MOA on the body surface was used to generate isochronal maps that may some day be used by clinicians in diagnosing arrhythmias and assessing the efficacy of therapies.

Control of autoclave scaling during acid pressure leaching of nickeliferous laterite ore

NASA Astrophysics Data System (ADS)

Queneau, P. B.; Doane, R. E.; Cooperrider, M. W.; Berggren, M. H.; Rey, P.

1984-09-01

An operating problem encountered at the Moa Bay operation in Cuba, where nickeliferous laterite ore is processed by sulfuric acid pressure leaching, is the formation of alunite and hematite deposits on the autoclave walls. The AMAX Extractive Research & Development, Inc., metallurgical laboratory (Golden, Colorado) has made substantial improvements in the Moa Bay process in the area of metal recovery, energy consumption, and feed versatility. One of the advantages of AMAX's process is its ability to treat substantial portions of nickel-and magnesium-rich serpentine while maintaining acid utilization efficiency. Scale formation is minimized by combining staged acid addition with vigorous agitation and 270 °C operation. This paper describes how advantage can be taken of MgSO4· XH2O precipitation both to inhibit alunite scaling and to disperse hematite scale within the MgSO4 · XH2O matrix. Cooling the autoclave from its 270 ·C operating temperature down to 180 ·C takes advantage of the reverse solubility of magnesium sulfate. The magnesium dissolves, liberating entrained hematite, thus providing a means for control of autoclave scale with minimum process disruption.

Mode of action characterization for adverse effect of propranolol in Daphnia magna based on behavior and physiology monitoring and metabolite profiling.

PubMed

Jeong, Tae-Yong; Yoon, Dahye; Kim, Suhkmann; Kim, Hyun Young; Kim, Sang Don

2018-02-01

Studies are underway to gather information about the mode of action (MOA) of emerging pollutants that could guide practical environmental decision making. Previously, we showed that propranolol, an active pharmaceutical ingredient, had adverse effects on Daphnia magna that were similar to its pharmaceutical action. In order to characterize the mode of action of propranolol in D. magna, which is suspected to be organ-specific pharmaceutical action or baseline toxicity, we performed time-series monitoring of behavior along with heart rate measurements and nuclear magnetic resonance (NMR) based metabolite profiling. Principle component analysis (PCA) and hierarchical clustering were used to categorize the mode of action of propranolol among 5 chemicals with different modes of action. The findings showed that the mode of action of propranolol in D. magna is organ-specific and vastly different from those of narcotics, even though metabolite regulation is similar between narcotic and non-narcotic candidates. The method applied in this study seems applicable to rapid characterization of the MOA of other cardiovascular pharmaceutical ingredients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cholesterol and fatty acid composition of longissimus thoracis from water buffalo (Bubalus bubalis) and Brahman-influenced cattle raised under savannah conditions.

PubMed

Giuffrida-Mendoza, Maria; Arenas de Moreno, Lilia; Huerta-Leidenz, Nelson; Uzcátegui-Bracho, Sojan; Valero-Leal, Kutchynskaya; Romero, Sonia; Rodas-González, Argenis

2015-08-01

Male (n=66) water buffalo (Buffalo) and Brahman-influenced cattle (Brahman) were born, raised, weaned, fattened on grazing savannah and harvested at two different ages (19 and 24months) to compare lipid composition of the longissimus thoracis muscle. Half of the animals were castrated at seven months of age (MOA) to examine the castration effects. At 24 MOA Brahman steers showed the highest content of total lipids (P<0.05). No significant variation was detected in cholesterol content for either the main or interaction effects in the age groups. Some individual fatty acids varied with the species (P<0.05), however, interspecific similarities were found in fatty acid ratios. For health-related indices, only atherogenic index (AI) showed lower values in favor of Buffalo meat (P<0.05) at both harvesting ages. Although, meat derived from both bovid groups was leaner and showed lower cholesterol level, AI indicates that Buffalo meat might be beneficial from a human health standpoint. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cognitive behavioral therapy to reduce overt aggression behavior in Chinese young male violent offenders.

PubMed

Chen, Chen; Li, Chun; Wang, Hong; Ou, Jian-Jun; Zhou, Jian-Song; Wang, Xiao-Ping

2014-01-01

This 9-week study was designed to determine whether a commercial cognitive-behavioral training program could effectively reduce overt aggression behavior in Chinese young male violent offenders. Sixty-six participants were randomly assigned to receive routine intervention alone (control group) or routine intervention plus Williams LifeSkills Training (WLST group) in a 1:1 ratio. The primary outcome was change scores on the Modified Overt Aggression Scale (MOAS) from baseline to one week following end of training. Secondary outcomes were change scores on the Barratt Impulsiveness Scale-11 (BIS-11) and Cook-Medley Hostility Scale (CMHS). There were significant between-group differences in change of MOAS total score (P < .001) and all sub-scores (Ps < .01) except aggression against property. Between-group differences were also observed in change of BIS-11 and CMHS total score (Ps < 0.05). All results favored the WLST group. These findings suggest WLST has the potential to be an effective intervention to reduce overt aggressive behavior in young male violent offenders. © 2013 Wiley Periodicals, Inc.

A Spectroscopic and Photometric Study of Gravitational Microlensing Events

NASA Astrophysics Data System (ADS)

Kane, Stephen R.

2000-08-01

Gravitational microlensing has generated a great deal of scientific interest over recent years. This has been largely due to the realization of its wide-reaching applications, such as the search for dark matter, the detection of planets, and the study of Galactic structure. A significant observational advance has been that most microlensing events can be identified in real-time while the source is still being lensed. More than 400 microlensing events have now been detected towards the Galactic bulge and Magellanic Clouds by the microlensing survey teams EROS, MACHO, OGLE, DUO, and MOA. The real-time detection of these events allows detailed follow-up observations with much denser sampling, both photometrically and spectroscopically. The research undertaken in this project on photometric studies of gravitational microlensing events has been performed as a member of the PLANET (Probing Lensing Anomalies NETwork) collaboration. This is a worldwide collaboration formed in the early part of 1995 to study microlensing anomalies - departures from an achromatic point source, point lens light curve - through rapidly-sampled, multi-band, photometry. PLANET has demonstrated that it can achieve 1% photometry under ideal circumstances, making PLANET observations sensitive to detection of Earth-mass planets which require characterization of 1%--2% deviations from a standard microlensing light curve. The photometric work in this project involved over 5 months using the 1.0 m telescope at Canopus Observatory in Australia, and 3 separate observing runs using the 0.9 m telescope at the Cerro Tololo Inter-American Observatory (CTIO) in Chile. Methods were developed to reduce the vast amount of photometric data using the image analysis software MIDAS and the photometry package DoPHOT. Modelling routines were then written to analyse a selection of the resulting light curves in order to detect any deviation from an achromatic point source - point lens light curve. The photometric results presented in this thesis are from observations of 34 microlensing events over three consecutive bulge seasons. These results are presented along with a discussion of the observations and the data reduction procedures. The colour-magnitude diagrams indicate that the microlensed sources are main sequence and red clump giant stars. Most of the events appear to exhibit standard Paczynski point source - point lens curves whilst a few deviate significantly from the standard model. Various microlensing models that include anomalous structure are fitted to a selection of the observed events resulting in the discovery of a possible binary source event. These fitted events are used to estimate the sensitivity to extra-solar planets and it is found that the sampling rate for these events was insufficient by about a factor of 7.5 for detecting a Jupiter-mass planet. This result assumes that deviations of 5% can be reliably detected. If microlensing is caused predominantly by bulge stars, as has been suggested by Kiraga and Paczynski, the lensed stars should have larger extinction than other observed stars since they would preferentially be located at the far side of the Galactic bulge. Hence, spectroscopy of Galactic microlensing events may be used as a tool for studying the kinematics and extinction effects in the Galactic bulge. The spectroscopic work in this project involved using Kurucz model spectra to create theoretical extinction effects for various spectral classes towards the Galactic centre. These extinction effects are then used to interpret spectroscopic data taken with the 3.6 m ESO telescope. These data consist of a sample of microlensed stars towards the Galactic bulge and are used to derive the extinction offsets of the lensed source with respect to the average population and a measurement of the fraction of bulge-bulge lensing is made. Hence, it is shown statistically that the microlensed sources are generally located on the far side of the Galactic bulge. Measurements of the radial velocities of these sources are used to determine the kinematic properties of the far side of the Galactic bulge.

Characterization of the transcriptional regulator Rv3124 of Mycobacterium tuberculosis identifies it as a positive regulator of molybdopterin biosynthesis and defines the functional consequences of a non-synonymous SNP in the Mycobacterium bovis BCG orthologue

PubMed Central

Mendoza Lopez, Pablo; Golby, Paul; Wooff, Esen; Garcia, Javier Nunez; Garcia Pelayo, M. Carmen; Conlon, Kevin; Gema Camacho, Ana; Hewinson, R. Glyn; Polaina, Julio; Suárez García, Antonio; Gordon, Stephen V.

2010-01-01

A number of single-nucleotide polymorphisms (SNPs) have been identified in the genome of Mycobacterium bovis BCG Pasteur compared with the sequenced strain M. bovis 2122/97. The functional consequences of many of these mutations remain to be described; however, mutations in genes encoding regulators may be particularly relevant to global phenotypic changes such as loss of virulence, since alteration of a regulator's function will affect the expression of a wide range of genes. One such SNP falls in bcg3145, encoding a member of the AfsR/DnrI/SARP class of global transcriptional regulators, that replaces a highly conserved glutamic acid residue at position 159 (E159G) with glycine in a tetratricopeptide repeat (TPR) located in the bacterial transcriptional activation (BTA) domain of BCG3145. TPR domains are associated with protein–protein interactions, and a conserved core (helices T1–T7) of the BTA domain seems to be required for proper function of SARP-family proteins. Structural modelling predicted that the E159G mutation perturbs the third α-helix of the BTA domain and could therefore have functional consequences. The E159G SNP was found to be present in all BCG strains, but absent from virulent M. bovis and Mycobacterium tuberculosis strains. By overexpressing BCG3145 and Rv3124 in BCG and H37Rv and monitoring transcriptome changes using microarrays, we determined that BCG3145/Rv3124 acts as a positive transcriptional regulator of the molybdopterin biosynthesis moa1 locus, and we suggest that rv3124 be renamed moaR1. The SNP in bcg3145 was found to have a subtle effect on the activity of MoaR1, suggesting that this mutation is not a key event in the attenuation of BCG. PMID:20378651

Synchrotron-based imaging of chromium and γ-H2AX immunostaining in the duodenum following repeated exposure to Cr(VI) in drinking water.

PubMed

Thompson, Chad M; Seiter, Jennifer; Chappell, Mark A; Tappero, Ryan V; Proctor, Deborah M; Suh, Mina; Wolf, Jeffrey C; Haws, Laurie C; Vitale, Rock; Mittal, Liz; Kirman, Christopher R; Hays, Sean M; Harris, Mark A

2015-01-01

Current drinking water standards for chromium are for the combined total of both hexavalent and trivalent chromium (Cr(VI) and Cr(III)). However, recent studies have shown that Cr(III) is not carcinogenic to rodents, whereas mice chronically exposed to high levels of Cr(VI) developed duodenal tumors. These findings may suggest the need for environmental standards specific for Cr(VI). Whether the intestinal tumors arose through a mutagenic or non-mutagenic mode of action (MOA) greatly impacts how drinking water standards for Cr(VI) are derived. Herein, X-ray fluorescence (spectro)microscopy (µ-XRF) was used to image the Cr content in the villus and crypt regions of duodena from B6C3F1 mice exposed to 180 mg/l Cr(VI) in drinking water for 13 weeks. DNA damage was also assessed by γ-H2AX immunostaining. Exposure to Cr(VI) induced villus blunting and crypt hyperplasia in the duodenum--the latter evidenced by lengthening of the crypt compartment by ∼2-fold with a concomitant 1.5-fold increase in the number of crypt enterocytes. γ-H2AX immunostaining was elevated in villi, but not in the crypt compartment. µ-XRF maps revealed mean Cr levels >30 times higher in duodenal villi than crypt regions; mean Cr levels in crypt regions were only slightly above background signal. Despite the presence of Cr and elevated γ-H2AX immunoreactivity in villi, no aberrant foci indicative of transformation were evident. These findings do not support a MOA for intestinal carcinogenesis involving direct Cr-DNA interaction in intestinal stem cells, but rather support a non-mutagenic MOA involving chronic wounding of intestinal villi and crypt cell hyperplasia. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology.

Patient and Oncology Nurse Preferences for the Treatment Options in Advanced Melanoma: A Discrete Choice Experiment.

PubMed

Liu, Frank Xiaoqing; Witt, Edward A; Ebbinghaus, Scot; DiBonaventura Beyer, Grace; Basurto, Enrique; Joseph, Richard W

2017-10-25

Understanding the perceptions of patients and oncology nurses about the relative importance of benefits and risks associated with newer treatments of advanced melanoma can help to inform clinical decision-making. The aims of this study were to quantify and compare the views of patients and oncology nurses regarding the importance of attributes of treatments of advanced melanoma. A discrete choice experiment (DCE) was conducted in US-based oncology nurses and patients diagnosed with advanced melanoma. Patients and nurses were enlisted through online panels. In a series of scenarios, respondents had to choose between 2 hypothetical treatments, each with 7 attributes: mode of administration (MoA), dosing schedule (DS), median duration of therapy (DoT), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and grade 3 or 4 adverse events (AEs). Hierarchical Bayesian logistic regression models were used to estimate preference weights. A total of 200 patients with advanced melanoma and 150 oncology nurses participated. The relative importance estimates of attributes by patients and nurses, respectively, were as follows: OS, 33% and 28%; AEs, 29% and 26%; ORR, 25% and 27%; PFS, 12% and 15%; DS, 2% and 3%; DoT, 0% and 0%; and MoA, 0% and 0%. Both patients and oncology nurses valued OS, ORR, and AEs as the most important treatment attributes for advanced melanoma, followed by PFS, whereas DS, DoT, and MoA were given less value in their treatment decisions. Oncology nurses and patients have similar views on important treatment considerations for advanced melanoma, which can help build trust in shared decision-making.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

A survey of current ostrich handling and transport practices in North America with reference to ostrich welfare and transportation guidelines set up in other countries.

PubMed

Bejaei, M; Cheng, K M

2014-02-01

Appropriate management of an ostrich's exposure to stressors during preslaughter handling and transport practices can improve its well-being and product quality. Because of the lack of information about ostrich farming and transportation in North America and lack of developed Codes of Practice for ratite transport in Canada and the United States, the first objective of our research was to identify current preslaughter handling and transport practices of the ostrich industry in Canada and the United States, and to identify potential welfare issues based on the current practices. The second objective of this research was to review ostrich transport welfare standards and guidelines from Australia, European Union, New Zealand, and South Africa to investigate if those guidelines are applicable to Canadian and American ostrich production systems. Preliminary producer interviews, on-farm visits, and literature review information sources were used to design a producer questionnaire that was used to survey producers by Internet and mail surveying methods to identify existing ostrich transport norms in Canada and the United States. Based on the results of our producer survey and review of the transport standards and guidelines, we conclude that following factors are potential ostrich handling and transport welfare issues in Canada and the United States: lack of scientific information about welfare of ostriches during handling and transport; unfamiliarity of handlers and birds with handling and transport practices; not considering birds' social bounds, sex, behavior, and physical state in mixing them during handling and transport process; lack of an established specific maximum water and feed withdrawal duration for ostrich transport in Canada and the United States; lack of a specific vehicle designed for ratite transportation in Canada and the United States considering different physical body characteristics of ostriches compared with other species; exposure of birds to natural light during transport inside the trailer; overcrowding; and long transportation in Canada and the United States. Results of this research will contribute toward developing Codes of Practice for preslaughter handling, transportation, and slaughter of ostriches in Canada and the United States.

75 FR 44719 - Amendment and Establishment of Restricted Areas and Other Special Use Airspace, Razorback Range...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-29

... airspace needed for military aircraft to conduct medium to high altitude standoff weapon delivery profiles... existing restricted area, and amends the boundaries description of the Special Use Airspace (SUA) Hog High..., MOAs are not rulemaking airspace actions. However, since the proposed R-2402B airspace and the Hog High...

DIFFICULTY OF MODE OF ACTION DETERMINATION FOR TRICHLOROETHYLENE: AN EXAMPLE OF COMPLEX INTERACTIONS OF METABOLITES AND OTHER CHEMICAL EXPOSURES (Journal Article)

EPA Science Inventory

The mode(s) of action (MOA) of a pollutant for adverse health effects may be dependent on the mixture of metabolites resulting from exposure to a single agent and may also be affected by co-exposure to pollutants that have similar targets or affected pathways. Trichloroethylene ...

77 FR 20575 - Approval and Promulgation of Air Quality Implementation Plans; Wisconsin; Forest County...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-05

... redesignated area must determine by an analysis whether their emissions will have an adverse impact on those... of the MOA allows for restricting the requirements normally associated with Class I areas as these... demonstration that the emissions from the proposed new major source or major modification would have an adverse...

One State's Use of Prior Learning Assessment to Augment Its Workforce Development Agenda

ERIC Educational Resources Information Center

Boyle, Mike; Gotcher, David; Otts, David

2018-01-01

In 2008, the Tennessee Higher Education Commission (THEC) formed a special committee to make recommendations to increase the educational attainment of Tennessee adults. Called the Making Opportunity Affordable-Tennessee (MOA-TN) Adult Strategies Group, the new committee was convened with 23 higher education officials from across the state with…

Developing Toxicogenomics as a Research Tool by Applying Benchmark Dose-Response Modeling to inform Chemical Mode of Action and Tumorigenic Potency

EPA Science Inventory

ABSTRACT Results of global gene expression profiling after short-term exposures can be used to inform tumorigenic potency and chemical mode of action (MOA) and thus serve as a strategy to prioritize future or data-poor chemicals for further evaluation. This compilation of cas...

76 FR 80910 - Revised Notice of Intent To Prepare an Environmental Impact Statement for Military Training...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-27

... Boardman Northeast MOA would have two parts, A and B, with the current Boardman Air Traffic Control.... Civilian or other nonparticipating air traffic flying with an air traffic control clearance and under... civilian or other nonparticipating air traffic flying under VFR, or under IFR without air traffic control...

Elucidating compound mechanism of action by network perturbation analysis | Office of Cancer Genomics

Cancer.gov

Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins.

77 FR 5780 - Record of Decision for the White Elk Military Operations Area White Pine and Elko Counties...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-06

... DEPARTMENT OF DEFENSE Department of the Air Force Record of Decision for the White Elk Military... Availability (NOA) of a Record of Decision (ROD). SUMMARY: On November 4, 2011, the United States Air Force... states the Air Force decision to select the Proposed Action to establish the White Elk MOA airspace...

The functional therapeutic chemical classification system.

PubMed

Croset, Samuel; Overington, John P; Rebholz-Schuhmann, Dietrich

2014-03-15

Drug repositioning is the discovery of new indications for compounds that have already been approved and used in a clinical setting. Recently, some computational approaches have been suggested to unveil new opportunities in a systematic fashion, by taking into consideration gene expression signatures or chemical features for instance. We present here a novel method based on knowledge integration using semantic technologies, to capture the functional role of approved chemical compounds. In order to computationally generate repositioning hypotheses, we used the Web Ontology Language to formally define the semantics of over 20 000 terms with axioms to correctly denote various modes of action (MoA). Based on an integration of public data, we have automatically assigned over a thousand of approved drugs into these MoA categories. The resulting new resource is called the Functional Therapeutic Chemical Classification System and was further evaluated against the content of the traditional Anatomical Therapeutic Chemical Classification System. We illustrate how the new classification can be used to generate drug repurposing hypotheses, using Alzheimers disease as a use-case. https://www.ebi.ac.uk/chembl/ftc; https://github.com/loopasam/ftc. croset@ebi.ac.uk Supplementary data are available at Bioinformatics online.

The Beauty and Complexity of the Brunt Ice Shelf from MOA and ICESat

NASA Technical Reports Server (NTRS)

Humbert, Angelika; Shuman, Christopher A.

2005-01-01

Beginning in February 2003, NASA's Ice, Cloud, and land Elevation Satellite (ICESat) has determined surface elevations from approx. 86degN to 86degS latitude. To date, altimetry data have been acquired in a series of observation periods in repeated track patterns using all three Geoscience Laser Altimeter System (GLAS) lasers. This paper will focus on ice shelf elevation data that were obtained in 2003 across the Brunt Ice Shelf and the Stancomb-Wills Ice Tongue. Integrating the altimetry with the recently available MODIS Mosaic of Antarctica (MOA), quantifies the relative accuracy and precision of the resulting ice shelf elevations. Furthermore, the elevation data was processed onto an elevation grid, by regional interpolation across the area s complex glacial features only. Ice thickness estimation from the altimetry of the floating ice is discussed. ICESat operates at 40Hz and its elevation data is obtained every 172m along track. These elevations have a relative accuracy of about 14cm based on the standard deviation of low-slope crossover differences and a precision of close to 2cm for the Laser 2a, Release 21, GLA12 data used here.

Synthesis, XRD crystal structure, spectroscopic characterization, local reactive properties using DFT and molecular dynamics simulations and molecular docking study of (E)-1-(4-bromophenyl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one

NASA Astrophysics Data System (ADS)

Arshad, Suhana; Raveendran Pillai, Renjith; Zainuri, Dian Alwani; Khalib, Nuridayanti Che; Razak, Ibrahim Abdul; Armaković, Stevan; Armaković, Sanja J.; Renjith, Rishikesh; Panicker, C. Yohannan; Van Alsenoy, C.

2017-06-01

In the present study, the title compound named as (E)-1-(4-bromophenyl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one was synthesized and structurally characterized by single-crystal X-ray diffraction. The FT-IR spectrum was recorded and interpreted in details with the aid of Density Functional Theory (DFT) calculations and Potential Energy Distribution (PED) analysis. Average local ionization energies (ALIE) and Fukui functions have been used as quantum-molecular descriptors to locate the molecule sites that could be of importance from the aspect of reactivity. Degradation properties have been assessed by calculations of bond dissociation energies (BDE) for hydrogen abstraction and the rest of the single acyclic bonds, while molecular dynamics (MD) simulations were used in order to calculate radial distribution functions and determine the atoms with significant interactions with water. In order to understand how the title molecule inhibits and hence increases the catalytic efficiency of MOA-B enzyme, molecular docking study was performed to fit the title compound into the binding site of MOA-B enzyme.

Ground-based Parallax Confirmed by Spitzer: Binary Microlensing Event MOA-2015-BLG-020

NASA Astrophysics Data System (ADS)

Wang, Tianshu; Zhu, Wei; Mao, Shude; Bond, I. A.; Gould, A.; Udalski, A.; Sumi, T.; Bozza, V.; Ranc, C.; Cassan, A.; Yee, J. C.; Han, C.; Abe, F.; Asakura, Y.; Barry, R.; Bennett, D. P.; Bhattacharya, A.; Donachie, M.; Evans, P.; Fukui, A.; Hirao, Y.; Itow, Y.; Kawasaki, K.; Koshimoto, N.; Li, M. C. A.; Ling, C. H.; Masuda, K.; Matsubara, Y.; Miyazaki, S.; Muraki, Y.; Nagakane, M.; Ohnishi, K.; Rattenbury, N.; Saito, To.; Sharan, A.; Shibai, H.; Sullivan, D. J.; Suzuki, D.; Tristram, P. J.; Yamada, T.; Yonehara, A.; MOA Collaboration; KozŁowski, S.; Mróz, P.; Pawlak, M.; Pietrukowicz, P.; Poleski, R.; Skowron, J.; Soszyński, I.; Szymański, M. K.; Ulaczyk, K.; OGLE Collaboration; Beichman, C.; Bryden, G.; Calchi Novati, S.; Carey, S.; Fausnaugh, M.; Gaudi, B. S.; Henderson, C. B.; Shvartzvald, Y.; Wibking, B.; Spitzer Team; Albrow, M. D.; Chung, S.-J.; Hwang, K.-H.; Jung, Y. K.; Ryu, Y.-H.; Shin, I.-G.; Cha, S.-M.; Kim, D.-J.; Kim, H.-W.; Kim, S.-L.; Lee, C.-U.; Lee, Y.; Park, B.-G.; Pogge, R. W.; KMTNet Collaboration; Street, R. A.; Tsapras, Y.; Hundertmark, M.; Bachelet, E.; Dominik, M.; Horne, K.; Figuera Jaimes, R.; Wambsganss, J.; Bramich, D. M.; Schmidt, R.; Snodgrass, C.; Steele, I. A.; Menzies, J.; RoboNet Collaboration

2017-08-01

We present the analysis of the binary gravitational microlensing event MOA-2015-BLG-020. The event has a fairly long timescale (˜63 days) and thus the light curve deviates significantly from the lensing model that is based on the rectilinear lens-source relative motion. This enables us to measure the microlensing parallax through the annual parallax effect. The microlensing parallax parameters constrained by the ground-based data are confirmed by the Spitzer observations through the satellite parallax method. By additionally measuring the angular Einstein radius from the analysis of the resolved caustic crossing, the physical parameters of the lens are determined. It is found that the binary lens is composed of two dwarf stars with masses {M}1=0.606+/- 0.028 {M}⊙ and {M}2=0.125 +/- 0.006 {M}⊙ in the Galactic disk. Assuming that the source star is at the same distance as the bulge red clump stars, we find the lens is at a distance {D}L=2.44+/- 0.10 {kpc}. We also provide a summary and short discussion of all of the published microlensing events in which the annual parallax effect is confirmed by other independent observations.

Polycyclic aromatic hydrocarbon analysis with the Mars organic analyzer microchip capillary electrophoresis system.

PubMed

Stockton, Amanda M; Chiesl, Thomas N; Scherer, James R; Mathies, Richard A

2009-01-15

The Mars Organic Analyzer (MOA), a portable microchip capillary electrophoresis (CE) instrument developed for sensitive amino acid analysis on Mars, is used to analyze laboratory standards and real-world samples for polycyclic aromatic hydrocarbons (PAHs). The microfabricated CE separation and analysis method for these hydrophobic analytes is optimized, resulting in a separation buffer consisting of 10 mM sulfobutylether-beta-cyclodextrin, 40 mM methyl-beta-cyclodextrin, 5 mM carbonate buffer at pH 10, 5 degrees C. A PAH standard consisting of seven PAHs found in extraterrestrial matter and two terrestrial PAHs is successfully baseline separated. Limits of detection for the components of the standard ranged from 2000 ppm to 6 ppb. Analysis of an environmental contamination standard from Lake Erie and of a hydrothermal vent chimney sample from the Guaymas Basin agreed with published composition. A Martian analogue sample from the Yungay Hills region of the Atacama Desert was analyzed and found to contain 9,10-diphenylanthracene, anthracene, anthanthrene, fluoranthene, perylene, and benzo[ghi]fluoranthene at ppm levels. This work establishes the viability of the MOA for detecting and analyzing PAHs in in situ planetary exploration.

An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors.

PubMed

Pagano, Nicholas; Teriete, Peter; Mattmann, Margrith E; Yang, Li; Snyder, Beth A; Cai, Zhaohui; Heil, Marintha L; Cosford, Nicholas D P

2017-12-01

Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanism of action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents. Copyright © 2017. Published by Elsevier Ltd.

Medical-Dental Health Clerical Support Staff (C-4). Dental Receptionist-DR. Hospital Clerical Worker-MCW. Medical Office Assistant-MOA. Medical Stenographer-MS. Course Outlines.

ERIC Educational Resources Information Center

Vancouver Community Coll., British Columbia.

These course outlines are intended to assist instructors in the development of curricula for college programs to train medical-dental health clerical support staff. The course outlines consist of a combined profile and four occupational profiles--dental receptionist, hospital clerical worker, medical office assistant, and medical stenographer.…

F-22 Plus-Up Environmental Assessment Joint Base Elmendorf-Richardson, Alaska

DTIC Science & Technology

2011-06-01

Page 1-3 The F-22 has enhanced low visibilty, speed, maneuverability, electronics , and maintainability. The proposal is to beddown six primary...tactics, radar employment, identification, weapons employment, defensive response, electronic countermeasures, and electronic counter countermeasures...flare, and electronic countermeasures. Warning Area, MOA, and ATCAA 2,000 AGL to 60,000 MSL 0.75 to 1.5 hour F-22 Plus-Up Environmental

F-22 Operational Squadron and T-38 Detachment Beddown at Tyndall Air Force Base, Florida

DTIC Science & Technology

2011-08-01

tactics, radar employment, identification, weapons employment, defensive response, electronic countermeasures, and electronic counter...use, and electronic countermeasures. Warning Area, MOA, and ATCAA 2,000 AGL to 60,000 MSL 0.75 to 1.5 hour (Dissimilar) Air Combat...night), air refueling, and strike-force rendezvous, conducting air-to-ground strikes, strike force defense and escort, air intercepts, electronic

Student Flow Analysis: CSU Student Progress toward Graduation. Report to the California State University as Part of the "Making Opportunity Affordable" Planning Year

ERIC Educational Resources Information Center

Institute for Higher Education Leadership & Policy, 2009

2009-01-01

The CSU (California State University) Chancellor's Office received a grant from the Lumina Foundation to engage in a year of planning activities to increase productivity within the CSU system. The grant is part of the Making Opportunity Affordable (MOA) initiative of the Lumina Foundation that is aimed at improving higher education productivity…

Evaluating the genotoxicity of topoisomerase-targeted antibiotics

PubMed Central

Smart, Daniel J.; Lynch, Anthony M.

2012-01-01

Antibiotics like fluoroquinolones (FQs) that target bacterial type II topoisomerases pose a potential genotoxic risk due to interactions with mammalian topoisomerase II (TOPO II) counterparts. Inhibition of TOPO II can lead to the generation of clastogenic DNA double-strand breaks (DSBs) that can in turn manifest in mutagenesis. Thus, methods that allow early identification of drugs that present the greatest hazard are warranted. A rapid, medium-throughput and predictive genotoxicity screen that can be applied to bacterial type II topoisomerase inhibitors is described herein. Maximal induction of the DSB biomarker serine139-phosphorylated histone H2AX (γH2AX) in L5178Y cells was quantified via flow cytometry and correlated with data derived from the mouse lymphoma screen (MLS), a default assay used to rank genotoxic potential. When applied to a class of novel bacterial type II topoisomerase inhibitors (NBTIs) in lead-optimisation, maximal γH2AX induction >1.4-fold (relative to controls) identified 22/27 NBTIs that induced >6-fold relative mutation frequency (MF) in MLS. Moreover, response signatures comprising of γH2AX induction and G2M cell cycle arrest elucidated using this approach suggested that these NBTIs, primarily of the H class, operated via a TOPO II poison-like mechanism of action (MoA) similar to FQs. NBTIs that induced ≤6-fold relative MF, which were mainly A class-derived, had less impact on γH2AX (≤1.4-fold) and also evoked G1 arrest, indicating that their cytotoxic effects were likely mediated through a non-poison MoA. Concordance between assays was 86% (54/63) when 1.4- and 6-fold ‘cut offs’ were applied. These findings were corroborated through inspection of human TOPO IIα IC50 data as NBTIs exhibiting equivalent inhibitory capacities had differing genotoxic potencies. Deployed in an early screening capacity, the γH2AX by flow assay coupled with structure–activity relationship evaluation can provide insight into MoA and impact medicinal chemistry efforts, ultimately leading to the production of inherently safer molecules. PMID:22155972

Application of a novel integrated toxicity testing strategy incorporating "3R" principles of animal research to evaluate the safety of a new agrochemical sulfoxaflor.

PubMed

Terry, Claire; Rasoulpour, Reza J; Saghir, Shakil; Marty, Sue; Gollapudi, B Bhaskar; Billington, Richard

2014-05-01

Plant protection products (PPPs) and the active substance(s) contained within them are rigorously and comprehensively tested prior to registration to ensure that human health is not impacted by their use. In recent years, there has been a widespread drive to have more relevant testing strategies (e.g., ILSI/HESI-ACSA and new EU Directives), which also take account of animal welfare, including the 3R (replacement, refinement, and reduction) principles. The toxicity potential of one such new active substance, sulfoxaflor, a sulfoximine insecticide (CAS #946578-00-3), was evaluated utilizing innovative testing strategies comprising: (1) an integrated testing scheme to optimize information obtained from as few animals as possible (i.e., 3R principles) through modifications of standard protocols, such as enhanced palatability study design, to include molecular endpoints, additional neurotoxicity and immunotoxicity parameters in a subchronic toxicity study, and combining multiple test guidelines into one study protocol; (2) generation of toxicokinetic data across dose levels, sexes, study durations, species, strains and life stages, without using satellite animals, which was a first for PPP development, and (3) addition of prospective mode of action (MoA) endpoints within repeat dose toxicity studies as well as proactive inclusion of specific MoA studies as an integral part of the development program. These novel approaches to generate key data early in the safety evaluation program facilitated informed decision-making on the need for additional studies and contributed to a more relevant human health risk assessment. This supplement also contains papers which describe in more detail the approach taken to establish the MoA and human relevance framework related to toxicities elicited by sulfoxaflor in the mammalian toxicology studies: developmental toxicity in rats mediated via the fetal muscle nicotinic acetylcholine receptor (nAChR) ( Ellis-Hutchings et al. 2014 ); liver tumors in rodents mediated via CAR/PXR ( LeBaron et al. 2014 ); and Leydig cell tumors in Fischer 344 rats ( Rasoulpour et al. 2014 ).

Weak silica nanomaterial-induced genotoxicity can be explained by indirect DNA damage as shown by the OGG1-modified comet assay and genomic analysis.

PubMed

Pfuhler, Stefan; Downs, Thomas R; Allemang, Ashley J; Shan, Yuching; Crosby, Meredith E

2017-01-01

In a previous study, 15-nm silica nanoparticles (NPs) caused small increases in DNA damage in liver as measured in the in vivo comet and micronucleus assays after intravenous administration to rats at their maximum tolerated dose, a worst-case exposure scenario. Histopathological examination supported a particle-induced, tissue damage-mediated inflammatory response. This study used a targeted approach to provide insight into the mode of action (MoA) by examining transcriptional regulation of genes in liver in a time and dose-dependent manner at 1, 2, 4, 8 and 24 h after intravenous administration of 15-nm silica NPs. DNA damage was assessed using the standard comet assay and hOGG1 glycosylase-modified comet assay that also measures oxidative DNA damage. Potassium bromate, an IARC Class 2B carcinogen that specifically operates via an oxidative stress MoA, was used as a positive control for the hOGG1 comet assay and gave a strong signal in its main target organ, the kidney, while showing less activity in liver. Treatment of rats with silica NPs at 50 mg/kg body weight (bw) caused small, statistically insignificant increases in DNA damage in liver measured by the standard comet assay, while a statistically significant increase was observed at 4 h with the hOGG1 comet assay, consistent with a MoA involving reactive oxygen species. Histopathology showed liver damage and neutrophil involvement while genomic analysis and response pattern of key genes involved in inflammation and oxidative stress supported a tissue damage-mediated inflammatory response involving the complement system for removing/phagocytising damaged cells. No changes were observed for histopathology or gene array for the low-dose (5 mg/kg bw) silica NPs. The results of this study confirm our hypothesis that the weak DNA damage observed by silica NPs occurs secondary to inflammation/immune response, indicating that a threshold can be applied in the risk assessment of these materials. © The Author 2016. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

U-Th Burial Dates on Ostrich Eggshell

NASA Astrophysics Data System (ADS)

Sharp, W. D.; Fylstra, N. D.; Tryon, C. A.; Faith, J. T.; Peppe, D. J.

2015-12-01

Obtaining precise and accurate dates at archaeological sites beyond the range of radiocarbon dating is challenging but essential for understanding human origins. Eggshells of ratites (large flightless birds including ostrich, emu and others) are common in many archaeological sequences in Africa, Australia and elsewhere. Ancient eggshells are geochemically suitable for the U-Th technique (1), which has about ten times the range of radiocarbon dating (>500 rather than 50 ka), making eggshells attractive dating targets. Moreover, C and N isotopic studies of eggshell provide insights into paleovegetation and paleoprecipitation central to assessing past human-environment interactions (2,3). But until now, U-Th dates on ratite eggshell have not accounted for the secondary origin of essentially all of their U. We report a novel approach to U-Th dating of eggshell that explicitly accounts for secondary U uptake that begins with burial. Using ostrich eggshell (OES) from Pleistocene-Holocene east African sites, we have measured U and 232Th concentration profiles across OES by laser ablation ICP-MS. U commonly peaks at 10s to 100s of ppb and varies 10-fold or more across the ~2 mm thickness of OES, with gradients modulated by the layered structure of the eggshell. Common Th is high near the shell surfaces, but low in the middle "pallisade" layer of OES, making it optimal for U-Th dating. We determine U-Th ages along the U concentration gradient by solution ICP-MS analyses of two or more fractions of the pallisade layer. We then estimate OES burial dates using a simple model for diffusive uptake of uranium. Comparing such "U-Th burial dates" with radiocarbon dates for OES calcite from the same shells, we find good agreement in 7 out of 9 cases, consistent with rapid burial and confirming the accuracy of the approach. The remaining 2 eggshells have anomalous patterns of apparent ages that reveal they are unsuitable for U-Th dating, thereby providing reliability criteria innate to the U-Th data. The oldest OES we have analyzed yields a U-Th burial date of ~140 ka, indicating that U-Th burial dating of OES may be applicable throughout the Late Pleistocene. 1. Magee, J.W. et al. (2009) Quatern. Geochron. 4, 84-89. 2. Johnson, B.J. et al. (1998) Geochim. Cosmochim. Acta 62, 2451-2461. 3. Miller, G.H. et al. (2005) Science 309, 287-290.

Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care.

PubMed

Candy, Bridget; Jones, Louise; Vickerstaff, Victoria; Larkin, Philip J; Stone, Patrick

2018-06-05

Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care. To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data. We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced. Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE. We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (RR 2.77, 95% CI 1.91 to 4.04. I² = 0%; moderate-quality evidence). In combined analysis, we found methylnaltrexone induced more laxation responses over two weeks (RR 9.98, 95% CI 4.96 to 20.09. I² = 0%; moderate-quality evidence). The proportion of participants who had a rescue-free laxation response within 24 hours of the first dose was 59.1% in the methylnaltrexone arms and 19.1% in the placebo arm. There was moderate-quality evidence that the rate of opioid withdrawal was not affected. Methylnaltrexone did not increase the likelihood of a serious adverse event; there were fewer in the intervention arm (RR 0.59, 95% CI 0.38 to 0.93; I² = 0%; moderate-quality evidence). There was no difference in the proportion of participants experiencing an adverse event (RR 1.17, 95% CI 0.94 to 1.45; I² = 74%; low-quality evidence). Methylnaltrexone increased the likelihood of abdominal pain and flatulence.Two trials compared differing methylnaltrexone schedules of higher doses with lower doses. For early laxation, there was low-quality evidence of no clear difference between doses on analgesia and adverse events. Both trials measured laxation response within 24 hours of first dose (trial one: RR 0.82, 95% CI 0.41 to 1.66; trial two: RR 1.07, 95% CI 0.81 to 1.42). In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.

Speech Quality Measurement

DTIC Science & Technology

1977-06-10

characterize. To detect distortion related to phonemic perception, spectral distance measures seem most important. Since the pitch contour plays such an...only gross gain errors should be detected. 10 In the caeas oi wavoform coders, the distortions are not so ea ily related to percoptlon. Pitci...e• ctral distanco moa.sures and related Lt measures were studied in this project. Let V(O), -1Tesw, be the short time power spectral envelope for a

Environmental Assessment: Building 3001 Tinker Air Force Base, Oklahoma

DTIC Science & Technology

2008-09-01

developing a Memorandum of Agreement (MOA) with the SHPO and the Oklahoma Archaeological Survey regarding the potential effects the Proposed Action...3.3.5.4 Electrical System Tinker AFB receives its electrical power from Oklahoma Gas and Electric, which delivers power through a looped 138... gas , with diesel fuel used as the backup supply. The steam line system is primarily underground, with a limited number of lines extending

Environmental Assessment for Watershed Enhancements at Joint Base Elmendorf-Richardson

DTIC Science & Technology

2013-07-03

Potassium permanganate would be utilized to prevent lethal dose of rotenone migrating beyond the largest beaver dam on Otter Creek. Lowering the lake level...Finding of No Significant Impact JBER Joint Base Elmendorf-Richardson KMnO4 potassium permanganate MOA Municipality of Anchorage NEPA National...Potassium permanganate would be utilized to prevent lethal dose of rotenone migrating beyond the largest beaver dam on Otter Creek. Lowering the lake

Development of risk-based nanomaterial groups for occupational exposure control

NASA Astrophysics Data System (ADS)

Kuempel, E. D.; Castranova, V.; Geraci, C. L.; Schulte, P. A.

2012-09-01

Given the almost limitless variety of nanomaterials, it will be virtually impossible to assess the possible occupational health hazard of each nanomaterial individually. The development of science-based hazard and risk categories for nanomaterials is needed for decision-making about exposure control practices in the workplace. A possible strategy would be to select representative (benchmark) materials from various mode of action (MOA) classes, evaluate the hazard and develop risk estimates, and then apply a systematic comparison of new nanomaterials with the benchmark materials in the same MOA class. Poorly soluble particles are used here as an example to illustrate quantitative risk assessment methods for possible benchmark particles and occupational exposure control groups, given mode of action and relative toxicity. Linking such benchmark particles to specific exposure control bands would facilitate the translation of health hazard and quantitative risk information to the development of effective exposure control practices in the workplace. A key challenge is obtaining sufficient dose-response data, based on standard testing, to systematically evaluate the nanomaterials' physical-chemical factors influencing their biological activity. Categorization processes involve both science-based analyses and default assumptions in the absence of substance-specific information. Utilizing data and information from related materials may facilitate initial determinations of exposure control systems for nanomaterials.

Leveraging existing data for prioritization of the ecological risks of human and veterinary pharmaceuticals to aquatic organisms

PubMed Central

LaLone, Carlie A.; Berninger, Jason P.; Villeneuve, Daniel L.; Ankley, Gerald T.

2014-01-01

Medicinal innovation has led to the discovery and use of thousands of human and veterinary drugs. With this comes the potential for unintended effects on non-target organisms exposed to pharmaceuticals inevitably entering the environment. The impracticality of generating whole-organism chronic toxicity data representative of all species in the environment has necessitated prioritization of drugs for focused empirical testing as well as field monitoring. Current prioritization strategies typically emphasize likelihood for exposure (i.e. predicted/measured environmental concentrations), while incorporating only rather limited consideration of potential effects of the drug to non-target organisms. However, substantial mammalian pharmacokinetic and mechanism/mode of action (MOA) data are produced during drug development to understand drug target specificity and efficacy for intended consumers. An integrated prioritization strategy for assessing risks of human and veterinary drugs would leverage available pharmacokinetic and toxicokinetic data for evaluation of the potential for adverse effects to non-target organisms. In this reiview, we demonstrate the utility of read-across approaches to leverage mammalian absorption, distribution, metabolism and elimination data; analyse cross-species molecular target conservation and translate therapeutic MOA to an adverse outcome pathway(s) relevant to aquatic organisms as a means to inform prioritization of drugs for focused toxicity testing and environmental monitoring. PMID:25405975

Developing and applying the adverse outcome pathway ...

EPA Pesticide Factsheets

To support a paradigm shift in regulatory toxicology testing and risk assessment, the Adverse Outcome Pathway (AOP) concept has recently been proposed. This concept is similar to that for Mode of Action (MOA), describing a sequence of measurable key events triggered by a molecular initiating event in which a stressor interacts with a biological target. The resulting cascade of key events includes molecular, cellular, structural and functional changes in biological systems, resulting in a measurable adverse outcome. Thereby, an AOP ideally provides information relevant to chemical structure-activity relationships as a basis to predict effects for structurally similar compounds. AOPs could potentially also form the basis for qualitative and quantitative predictive modeling of the human adverse outcome resulting from molecular initiating or other key events for which higher-throughput testing methods are available or can be developed.A variety of cellular and molecular processes are known to be critical to normal function of the central (CNS) and peripheral nervous systems (PNS). Because of the biological and functional complexity of the CNS and PNS, it has been challenging to establish causative links and quantitative relationships between key events that comprise the pathways leading from chemical exposure to an adverse outcome in the nervous system. Following introduction of principles of the description and assessment of MOA and AOPs, examples of adverse out

Development of a Platform to Enable Fully Automated Cross-Titration Experiments.

PubMed

Cassaday, Jason; Finley, Michael; Squadroni, Brian; Jezequel-Sur, Sylvie; Rauch, Albert; Gajera, Bharti; Uebele, Victor; Hermes, Jeffrey; Zuck, Paul

2017-04-01

In the triage of hits from a high-throughput screening campaign or during the optimization of a lead compound, it is relatively routine to test compounds at multiple concentrations to determine potency and maximal effect. Additional follow-up experiments, such as agonist shift, can be quite valuable in ascertaining compound mechanism of action (MOA). However, these experiments require cross-titration of a test compound with the activating ligand of the receptor requiring 100-200 data points, severely limiting the number tested in MOA assays in a screening triage. We describe a process to enhance the throughput of such cross-titration experiments through the integration of Hewlett Packard's D300 digital dispenser onto one of our robotics platforms to enable on-the-fly cross-titration of compounds in a 1536-well plate format. The process handles all the compound management and data tracking, as well as the biological assay. The process relies heavily on in-house-built software and hardware, and uses our proprietary control software for the platform. Using this system, we were able to automate the cross-titration of compounds for both positive and negative allosteric modulators of two different G protein-coupled receptors (GPCRs) using two distinct assay detection formats, IP1 and Ca 2+ detection, on nearly 100 compounds for each target.

Phragmites australis root secreted phytotoxin undergoes photo-degradation to execute severe phytotoxicity

PubMed Central

Rudrappa, Thimmaraju; Choi, Yong Seok; Levia, Delphis F; Legates, David R; Lee, Kelvin H

2009-01-01

Our study organism, Phragmites australis (common reed), is a unique invader in that both native and introduced lineages are found coexisting in North America. This allows one to make direct assessments of physiological differences between these different subspecies and examine how this relates to invasiveness. Recent efforts to understand plant invasive behavior show that some invasive plants secrete a phytotoxin to ward-off encroachment by neighboring plants (allelopathy) and thus provide the invaders with a competitive edge in a given habitat. Here we show that a varying climatic factor like ultraviolet (UV) light leads to photo-degradation of secreted phytotoxin (gallic acid) in P. australis rhizosphere inducing higher mortality of susceptible seedlings. The photo-degraded product of gallic acid (hereafter GA), identified as mesoxalic acid (hereafter MOA), triggered a similar cell death cascade in susceptible seedlings as observed previously with GA. Further, we detected the biological concentrations of MOA in the natural stands of exotic and native P. australis. Our studies also show that the UV degradation of GA is facilitated at an alkaline pH, suggesting that the natural habitat of P. australis may facilitate the photo-degradation of GA. The study highlights the persistence of the photo-degraded phytotoxin in the P. australis's rhizosphere and its inhibitory effects against the native plants. PMID:19816146

Phragmites australis root secreted phytotoxin undergoes photo-degradation to execute severe phytotoxicity.

PubMed

Rudrappa, Thimmaraju; Choi, Yong Seok; Levia, Delphis F; Legates, David R; Lee, Kelvin H; Bais, Harsh P

2009-06-01

Our study organism, Phragmites australis (common reed), is a unique invader in that both native and introduced lineages are found coexisting in North America. This allows one to make direct assessments of physiological differences between these different subspecies and examine how this relates to invasiveness. Recent efforts to understand plant invasive behavior show that some invasive plants secrete a phytotoxin to ward-off encroachment by neighboring plants (allelopathy) and thus provide the invaders with a competitive edge in a given habitat. Here we show that a varying climatic factor like ultraviolet (UV) light leads to photo-degradation of secreted phytotoxin (gallic acid) in P. australis rhizosphere inducing higher mortality of susceptible seedlings. The photo-degraded product of gallic acid (hereafter GA), identified as mesoxalic acid (hereafter MOA), triggered a similar cell death cascade in susceptible seedlings as observed previously with GA. Further, we detected the biological concentrations of MOA in the natural stands of exotic and native P. australis. Our studies also show that the UV degradation of GA is facilitated at an alkaline pH, suggesting that the natural habitat of P. australis may facilitate the photo-degradation of GA. The study highlights the persistence of the photo-degraded phytotoxin in the P. australis's rhizosphere and its inhibitory effects against the native plants.

Key NASA, USAF and federal officials sign a Memorandum of Agreement on groundwater cleanup

NASA Technical Reports Server (NTRS)

1999-01-01

Walter W. Kovalick Jr., Ph.D., director of Technology Innovation Office for the U.S. Environmental Protection Agency, addresses representatives from Kennedy Space Center, the 45th Space Wing, and various federal environmental agencies gathered to attend a Memorandum of Agreement (MOA) signing, taking place at the site of Launch Complex 34. The MOA formalizes the cooperative efforts of the federal agencies in ground-water cleanup initiatives. NASA, the U.S. Air Force and the agencies have formed a consortium and are participating in a comparative study of three innovative techniques to be used in cleaning a contaminated area of Launch Complex 34. The study will be used to help improve groundwater cleanup processes nationally. Other attendees included Timothy Oppelt, director, National Risk Management Research Laboratory, U.S. Environmental Protection Agency; Tom Heenan, assistant manager of environmental management, Savannah River Site, U.S. Department of Energy; Col. James Heald, Vice Commander, Air Force Research Laboratory, U.S. Air Force; Gerald Boyd, acting deputy assistant secretary, Office of Science and Technology, U.S. Department of Energy; James Fiore, acting deputy assistant secretary, Office of Environmental Restoration, Department of Energy; Brig. Gen. Randall R. Starbuck, Commander 45th Space Wing, U.S. Air Force; and Roy Bridges Jr., director of John F. Kennedy Space Center.

The JaCVAM international validation study on the in vivo comet assay: Selection of test chemicals.

PubMed

Morita, Takeshi; Uno, Yoshifumi; Honma, Masamitsu; Kojima, Hajime; Hayashi, Makoto; Tice, Raymond R; Corvi, Raffaella; Schechtman, Leonard

2015-07-01

The Japanese Center for the Validation of Alternative Methods (JaCVAM) sponsored an international prevalidation and validation study of the in vivo rat alkaline pH comet assay. The main objective of the study was to assess the sensitivity and specificity of the assay for correctly identifying genotoxic carcinogens, as compared with the traditional rat liver unscheduled DNA synthesis assay. Based on existing carcinogenicity and genotoxicity data and chemical class information, 90 chemicals were identified as primary candidates for use in the validation study. From these 90 chemicals, 46 secondary candidates and then 40 final chemicals were selected based on a sufficiency of carcinogenic and genotoxic data, differences in chemical class or genotoxic or carcinogenic mode of action (MOA), availability, price, and ease of handling. These 40 chemicals included 19 genotoxic carcinogens, 6 genotoxic non-carcinogens, 7 non-genotoxic carcinogens and 8 non-genotoxic non-carcinogens. "Genotoxicity" was defined as positive in the Ames mutagenicity test or in one of the standard in vivo genotoxicity tests (primarily the erythrocyte micronucleus assay). These chemicals covered various chemicals classes, MOAs, and genotoxicity profiles and were considered to be suitable for the purpose of the validation study. General principles of chemical selection for validation studies are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

A Framework for Assessing Health Risk of Environmental ...

EPA Pesticide Factsheets

EPA released the final report entitled, A Framework for Assessing Health Risk of Environmental Exposures to Children, which examines the impact of potential exposures during developmental lifestages and subsequent lifestages, while emphasizing the iterative nature of the analysis phase with a multidisciplinary team. Major findings and conclusions: This report outlines the framework in which mode of action(s) (MOA) can be considered across life stages. The framework is based upon existing approaches adopted in the Framework on Cumulative Risk Assessment and identifies existing guidance, guidelines and policy papers that relate to children's health risk assessment. It emphasizes the importance of an iterative approach between hazard, dose response, and exposure analyses. In addition, it includes discussion of principles for weight of evidence consideration across life stages for the hazard characterization database.Key science/assessment issues:This framework addresses the questions of why and how an improved children's health risk assessment will strengthen the overall risk assessment process across the Agency. This approach improves the scientific explanation of children's risk and will add value by: 1) providing for a more complete evaluation of the potential for vulnerability at different life stages, including a focus on the underlying biological events and critical developmental periods for incorporating MOA considerations; 2) evaluating of the potential fo

KSC-99pp0389

NASA Image and Video Library

1999-04-06

Walter W. Kovalick Jr., Ph.D., director of Technology Innovation Office for the U.S. Environmental Protection Agency, addresses representatives from Kennedy Space Center, the 45th Space Wing, and various federal environmental agencies gathered to attend a Memorandum of Agreement (MOA) signing, taking place at the site of Launch Complex 34. The MOA formalizes the cooperative efforts of the federal agencies in ground-water cleanup initiatives. NASA, the U.S. Air Force and the agencies have formed a consortium and are participating in a comparative study of three innovative techniques to be used in cleaning a contaminated area of Launch Complex 34. The study will be used to help improve groundwater cleanup processes nationally. Other attendees included Timothy Oppelt, director, National Risk Management Research Laboratory, U.S. Environmental Protection Agency; Tom Heenan, assistant manager of environmental management, Savannah River Site, U.S. Department of Energy; Col. James Heald, Vice Commander, Air Force Research Laboratory, U.S. Air Force; Gerald Boyd, acting deputy assistant secretary, Office of Science and Technology, U.S. Department of Energy; James Fiore, acting deputy assistant secretary, Office of Environmental Restoration, Department of Energy; Brig. Gen. Randall R. Starbuck, Commander 45th Space Wing, U.S. Air Force; and Roy Bridges Jr., director of John F. Kennedy Space Center

Assessing the Parameters for Determining Mission Accomplishment of the Philippine Marine Corps in Internal Security Operations

DTIC Science & Technology

2009-01-01

country in order to establish a physically and psychologically secured environment conducive to national development."g Challenges to Inter.naI Security...be accommodated under the present Constitution and laws particularly the powers conceded by the MOA-AD to the 5 Bangsamoro Juridical Entity (BJE, an...AFP under Magsaysay underwent organizational changes with the introduction of psychological warfare activities that .complemented the usual combat

A Next Generation Repository for Sharing Sensitive Network and Security Data

DTIC Science & Technology

2018-01-01

submission, and 5 yearly IRB reviews d. Provided legal support for MOA data provider and host agreements and amendments e. Feedback and bug reporting...intrusion detection methods and systems , b) event- reconstruction and evidence-based insights into global trends (e.g., DDoS attacks and malware...propagation), and c) situational awareness (e.g., outage detection). We have leveraged IMPACT’s policy and legal framework to minimize any risks associated

A Strategic Decision Matrix for Analyzing Food Service Operations at Air Force Bases

DTIC Science & Technology

2006-12-01

substitute product can replace your product, for example high - fructose corn syrup can substitute for sugar. Substitutes may negatively affect...dining facility closed and receive BAS. Customers can be happy with customer service and the quality of the food (a high customer satisfaction level...Services squadron may achieve significant cost savings by pursuing the NAF MOA but must also weigh the dollar savings against the threat of high

Palmdale International Airport, Palmdale, California. Airport Development Program

DTIC Science & Technology

1982-01-01

and ONT have rendered this system concept academic. • Concept B, described starting on page 209, is basically a reflection of the current situation...very different, and impacts the PIA in a very different manner. For example, the almost continuous use of the Complex 1 and Complex 4 MOAs will render ...been described in considerable detail by Underhill (n.d.), Strong (1929), and others ( Heizer 1978). Groups were subdivided into s~all bands

Sleep Deprivation Disrupts Recall of Conditioned Fear Extinction.

PubMed

Straus, Laura D; Acheson, Dean T; Risbrough, Victoria B; Drummond, Sean P A

2017-03-01

Learned fear is crucial in the development and maintenance of posttraumatic stress disorder (PTSD) and other anxiety disorders, and extinction of learned fear is necessary for response to exposure-based treatments. In humans, research suggests disrupted sleep impairs consolidation of extinction, though no studies have examined this experimentally using total sleep deprivation. Seventy-one healthy controls underwent a paradigm to acquire conditioned fear to a visual cue. Twenty-four hours after fear conditioning, participants underwent extinction learning. Twenty-four hours after extinction learning, participants underwent extinction recall. Participants were randomized to three groups: 1) well-rested throughout testing ("normal sleep"; n = 21); 2) 36 hours total sleep deprivation before extinction learning ("pre-extinction deprivation"; n = 25); or 3) 36 hours total sleep deprivation after extinction learning and before extinction recall ("post-extinction deprivation"; n = 25). The groups were compared on blink EMG reactivity to the condition stimulus during extinction learning and recall. There were no differences among the three groups during extinction learning. During extinction recall, the pre-extinction deprivation group demonstrated significantly less extinction recall than the normal sleep group. There was no significant difference between the normal sleep and post-extinction deprivation group during extinction recall. Results indicated sleep deprivation prior to extinction training significantly disrupts extinction recall. These findings suggest that (1) sleep deprivation in the immediate aftermath of trauma could be a potential contributor to PTSD development and maintenance via interference with natural extinction processes and (2) management of sleep symptoms should be considered during extinction-based therapy.

Developmental triclosan exposure decreases maternal, fetal, and early neonatal thyroxine: a dynamic and kinetic evaluation of a putative mode-of-action.

PubMed

Paul, Katie B; Hedge, Joan M; Bansal, Ruby; Zoeller, R Thomas; Peter, Robert; DeVito, Michael J; Crofton, Kevin M

2012-10-09

This work tests the mode-of-action (MOA) hypothesis that maternal and developmental triclosan (TCS) exposure decreases circulating thyroxine (T4) concentrations via up-regulation of hepatic catabolism and elimination of T4. Time-pregnant Long-Evans rats received TCS po (0-300mg/kg/day) from gestational day (GD) 6 through postnatal day (PND) 21. Serum and liver were collected from dams (GD20, PND22) and offspring (GD20, PND4, PND14, PND21). Serum T4, triiodothyronine (T3), and thyroid-stimulating hormone (TSH) concentrations were measured by radioimmunoassay. Ethoxy-O-deethylase (EROD), pentoxyresorufin-O-depentylase (PROD) and uridine diphosphate glucuronyltransferase (UGT) enzyme activities were measured in liver microsomes. Custom Taqman(®) qPCR arrays were employed to measure hepatic mRNA expression of select cytochrome P450s, UGTs, sulfotransferases, transporters, and thyroid hormone-responsive genes. TCS was quantified by LC/MS/MS in serum and liver. Serum T4 decreased approximately 30% in GD20 dams and fetuses, PND4 pups and PND22 dams (300mg/kg/day). Hepatic PROD activity increased 2-3 fold in PND4 pups and PND22 dams, and UGT activity was 1.5 fold higher in PND22 dams only (300mg/kg/day). Minor up-regulation of Cyp2b and Cyp3a expression in dams was consistent with hypothesized activation of the constitutive androstane and/or pregnane X receptor. T4 reductions of 30% for dams and GD20 and PND4 offspring with concomitant increases in PROD (PND4 neonates and PND22 dams) and UGT activity (PND22 dams) suggest that up-regulated hepatic catabolism may contribute to TCS-induced hypothyroxinemia during development. Serum and liver TCS concentrations demonstrated greater fetal than postnatal internal exposure, consistent with the lack of T4 changes in PND14 and PND21 offspring. These data support the MOA hypothesis that TCS exposure leads to hypothyroxinemia via increased hepatic catabolism; however, the minor effects on thyroid hormone metabolism may reflect the low efficacy of TCS as thyroid hormone disruptor or highlight the possibility that other MOAs may also contribute to the observed maternal and early neonatal hypothyroxinemia. Published by Elsevier Ireland Ltd.

Sedimentology and hydrology of a well-preserved paleoriver systems with a series of dam-breach paleolakes at Moa Valles, Mars

NASA Astrophysics Data System (ADS)

Salese, Francesco; Di Achille, Gaetano; Neesemann, Adrian; Ori, Gian Gabriele; Hauber, Ernst

2016-04-01

Moa Valles is a well-preserved paleodrainage system that is nearly 300-km-long and carved into ancient highland terrains west of Idaeus Fossae. The paleofluvial system apparently originated from fluidized ejecta blankets, and it consists of a series of dam-breach paleolakes with associated fan-shaped sedimentary deposits. This paleofluvial system shows a rich morphological record of hydrologic activity in the highlands of Mars. Based on crater counting the latter activity seems to be Amazonian in age (2.43 - 1.41 Ga). This work is based on a digital elevation model (DEM) derived from Context camera (CTX) and High Resolution Imaging Science Experiment (HiRISE) stereo images. Our goals are to (a) study the complex channel flow paths draining into Idaeus Fossae after forming a series of dam-breach paleolakes and to (b) investigate the origin and evolution of this valley system with its implications for climate and tectonic control. The first part of the system is characterized by many paleolakes, which are interconnected and drain eastward into Liberta crater, forming a complex and multilobate deltaic deposit exhibiting a well-developed channelized distributary pattern with evidence of switching on the delta plain. A breach area, consisting of three spillover channels, is present in the eastern part of the crater rim. These channels connect the Liberta crater to the eastward portion of the valley system, continuing toward Moa Valles with a complex pattern of anabranching channels that is more than 180-km-long. Our crater counting results and hydrological calculations of infilling and spillover discharges of the Liberta crater-lake suggest that the system is the result of an Early Amazonian water-rich environment that was likely sustained by relatively short fluvial events (<102 years), thereby supporting the hypotheses that water-related erosion might have been active on Mars (at least locally) during the Amazonian. The most important water source for the system could have been shallow ice melting triggered by impact craters. Indeed, the stratigraphic relationships between channels and crater ejecta show very clearly that the channels cut through the ejecta thus postdating them. The occurrence of relatively recent (likely Amazonian) hydrological activity supports the hypothesis that hydrological activity could have been possible, at least locally, after the Noachian-Hesperian boundary.

Effects of United States Department of Agriculture carcass maturity on sensory attributes of steaks produced by cattle representing two dental age classes.

PubMed

Semler, M L; Woerner, D R; Belk, K E; Enns, K J; Tatum, J D

2016-05-01

This study examined the effects of USDA carcass maturity on sensory properties of LM steaks produced by cattle representing 2 dental age classes. Carcasses identified for use in the experiment were produced by steers and heifers classified as either <30 mo of age (MOA) or ≥30 MOA at the time of slaughter using dentition. Within each dental age class, carcasses were selected to represent 2 maturity groups and 3 marbling categories, resulting in 12 dental age × maturity × marbling subclasses, each consisting of 50 carcasses. Maturity groups consisted of carcasses classified by USDA graders as either A to A (A) overall maturity or B to D (B-D) overall maturity; marbling categories consisted of carcasses with instrument marbling scores of Slight to Slight (SL), Small to Small (SM), or Modest to Moderate (MT-MD). Carcasses were selected in pairs so that each carcass chosen to represent the B-D-maturity group was paired with an A-maturity carcass of the same sex and marbling score (±50 marbling units). Strip loin (LM) steaks were obtained from both sides of each carcass. After a 14-d aging period, 1 LM steak was measured for Warner-Bratzler shear force (WBSF) and slice shear force (SSF), whereas the other LM steak was used for sensory analysis by a trained descriptive attribute panel. No differences ( > 0.05) in LM tenderness, juiciness, or flavor were detected between carcass maturity groups in either dental age class. Advanced dental age (≥30 MOA), however, was associated with more intense ( < 0.05) grassy and bloody/serumy flavors and decreased ( < 0.05) tenderness within the SL marbling group. Marbling score effectively stratified carcasses (MT-MD > SM > SL) according to differences ( < 0.0001) in LM tenderness, juiciness, beefy/brothy flavor, and buttery/beef fat flavor. In addition, increased marbling was associated with lesser ( < 0.01) intensities of bloody/serumy, livery/organy, and grassy flavors as well as smaller ( < 0.0001) values for WBSF and SSF. Results of this study suggest that USDA carcass maturity does not effectively identify differences in LM sensory attributes in the population of beef carcasses routinely offered for grading in today's U.S. commercial beef processing facilities.

Extinctions of life

NASA Technical Reports Server (NTRS)

Sepkoski, J. J. Jr; Sepkoski JJ, J. r. (Principal Investigator)

1988-01-01

This meeting presentation examines mass extinctions through earth's history. Extinctions are charted for marine families and marine genera. Timing of marine genera extinctions is discussed. Periodicity in extinctions during the Mesozoic and Cenozoic eras is plotted and compared with Paleozoic extinction peaks. The role of extinction in evolution and mankind's role in present extinctions are examined.

Overview of US Navy UAS Programs of Record to TTCP, MAD UAS Meeting

DTIC Science & Technology

2012-07-01

Development / integration / maintenance / sustainment of software code  Rapid integration of new capabilities across the Family of Systems...Operations & Support • Maintenance - GH • Basing - GH • Training - GH • Manpower - GH • COTS Hardware Communication • Ku band SATCOM • CDL • ARC...210 • Inmarsat • CAMA Operations & Support • Maintenance – MPRF/GH • Basing – MPRF/GH • Training – MPRF/GH • Manpower – MPRF/GH MOA

State Enforcement of Civil Rights in Vocational Education: Partner or Stepchild? A Report on Implementation of Section II of the 1979 Vocational Education Guidelines by the Office for Civil Rights, U.S. Department of Education.

ERIC Educational Resources Information Center

Chachkin, Norman

An investigation was conducted of state enforcement of the Vocational Education Guidelines issued in 1979 to prevent discrimination on the basis of race, national origin, sex, or handicap in vocational training. The guidelines are administered by the Office of Civil Rights (OCR) through methods of administration (MOA) developed by the states that…

Environmental Assessment: Transforming the 49th Fighter Wing’s Combat Capability, Holloman Air Force Base, New Mexico

DTIC Science & Technology

2006-08-01

estimated 321 positions. The Proposed Action includes enhancements to training airspace within 100 nautical miles (nm) of Holloman AFB. The F-22A...Airspace enhancements within 100 nautical miles (nm) of Holloman AFB would permit the F-22A to realistically train and deploy RR-188 (or equivalent...nautical miles (nm) of Holloman AFB. This training would occur in restricted airspace, Military Operations Areas (MOAs) and Air Traffic Control

Pre-Clinical Testing of Real-Time PCR Assays for Diarrheal Disease Agents of Genera Escherichia and Shigella

DTIC Science & Technology

2014-05-16

FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA May 16, 2014 Reporting Period: October 1, 2010 to September 30, 2013...10-2010 - 30-09-2013 PRE-CLINICAL TESTING OF REAL-TIME PCR ASSAYS FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA ...Texas (MOA 2007 - 2013. Agreement No.: DODI 4000.19; AFI 25-201). Pre-clinical test results qualify ETEC and Shigella real-time PCR assays as lead

The Frequency of Snowline-Region Planets from Four Years of OGLE-MOA-Wise Second-Generation Microlensing

NASA Technical Reports Server (NTRS)

Shvartzvald, Y.; Maoz, D.; Udalski, A.; Sumi, T.; Friedmann, M.; Kaspi, S.; Poleski, R.; Szymanski, M. K.; Skowron, J.; Kozlowski, S.;

dsrAB-based analysis of sulphate-reducing bacteria in moving bed biofilm reactor (MBBR) wastewater treatment plants.

PubMed

Biswas, Kristi; Taylor, Michael W; Turner, Susan J

2014-08-01

Sulphate-reducing bacteria (SRB) are important members of the sulphur cycle in wastewater treatment plants (WWTPs). In this study, we investigate the diversity and activity of SRB within the developing and established biofilm of two moving bed biofilm reactor (MBBR) systems treating municipal wastewater in New Zealand. The larger of the two WWTPs (Moa Point) generates high levels of sulphide relative to the smaller Karori plant. Clone libraries of the dissimilatory (bi)sulphite reductase (dsrAB) genes and quantitative real-time PCR targeting dsrA transcripts were used to compare SRB communities between the two WWTPs. Desulfobulbus (35-53 % of total SRB sequences) and genera belonging to the family Desulfobacteraceae (27-41 %) dominated the SRB fraction of the developing biofilm on deployed plastic carriers at both sites, whereas Desulfovibrio and Desulfomicrobium were exclusively found at Moa Point. In contrast, the established biofilms from resident MBBR carriers were largely dominated by Desulfomonile tiedjei-like organisms (58-100 % of SRB sequences). The relative transcript abundance of dsrA genes (signifying active SRBs) increased with biofilm weight yet remained low overall, even in the mature biofilm stage. Our results indicate that although SRB are both present and active in the microbial community at both MBBR study sites, differences in the availability of sulphate may be contributing to the observed differences in sulphide production at these two plants.

Global Mapping of Traditional Chinese Medicine into Bioactivity Space and Pathways Annotation Improves Mechanistic Understanding and Discovers Relationships between Therapeutic Action (Sub)classes

PubMed Central

Mohamad Zobir, Siti Zuraidah; Mohd Fauzi, Fazlin; Liggi, Sonia; Drakakis, Georgios; Fu, Xianjun; Fan, Tai-Ping; Bender, Andreas

2016-01-01

Traditional Chinese medicine (TCM) still needs more scientific rationale to be proven for it to be accepted further in the West. We are now in the position to propose computational hypotheses for the mode-of-actions (MOAs) of 45 TCM therapeutic action (sub)classes from in silico target prediction algorithms, whose target was later annotated with Kyoto Encyclopedia of Genes and Genomes pathway, and to discover the relationship between them by generating a hierarchical clustering. The results of 10,749 TCM compounds showed 183 enriched targets and 99 enriched pathways from Estimation Score ≤ 0 and ≥ 5% of compounds/targets in a (sub)class. The MOA of a (sub)class was established from supporting literature. Overall, the most frequent top three enriched targets/pathways were immune-related targets such as tyrosine-protein phosphatase nonreceptor type 2 (PTPN2) and digestive system such as mineral absorption. We found two major protein families, G-protein coupled receptor (GPCR), and protein kinase family contributed to the diversity of the bioactivity space, while digestive system was consistently annotated pathway motif, which agreed with the important treatment principle of TCM, “the foundation of acquired constitution” that includes spleen and stomach. In short, the TCM (sub)classes, in many cases share similar targets/pathways despite having different indications. PMID:26989424

Therapeutic Decisions In Multiple Sclerosis: Moving Beyond Efficacy

PubMed Central

Brück, Wolfgang; Ralf, Gold; Lund, Brett T.; Celia, Oreja-Guevara; Prat, Alexandre; Spencer, Collin M.; Steinman, Lawrence; Mar, Tintoré; Vollmer, Timothy; Weber, Martin S.; Weiner, Leslie P.; Ziemssen, Tjalf; Zamvil, Scott S.

2014-01-01

Importance Several innovative disease-modifying treatments (DMTs) for relapsing remitting multiple sclerosis (RRMS) have been licensed recently, or are in late-stage development. The molecular targets of several of these DMTs are well defined. All affect at least one of four properties: (1) immune cell trafficking, (2) cell depletion, (3) immune cell function, or (4) cell replication. In contrast to β-interferons and glatiramer acetate, the first generation DMTs, several newer therapies are imbued with safety issues. In addition to efficacy, understanding the relationship between the mechanism of action (MOA) of the DMTs and their safety profile is essential for decision-making in patient care. Objective In this article, we relate safety issues of newer DMTs to their pharmacological characteristics, including molecular targets, MOA, chemical structure, and metabolism. Some newer DMTs also represent repurposing or modifications of previous treatments used in other diseases. Here, we describe how identification and understanding of adverse events (AEs) observed with these established drugs within the same class, provide clues regarding safety and toxicities of newer MS therapeutics. Conclusions and relevance While understanding mechanisms underlying DMT toxicities is incomplete, it is important to further develop this knowledge to minimize risk to patients, and to ensure future therapies have the most advantageous risk-benefit profiles. Recognizing the individual classes of DMTs described here may be beneficial when considering use of such agents sequentially and possibly in combination. PMID:23921521

Combination use of atomoxetine hydrochloride and olanzapine in the treatment of attention-deficit/hyperactivity disorder with comorbid disruptive behavior disorder in children and adolescents 10-18 years of age.

PubMed

Holzer, Barry; Lopes, Vasco; Lehman, Robert

2013-08-01

The aim of this study was to assess the use of atomoxetine and olanzapine in combination to treat attention-deficit/hyperactivity disorder (ADHD) and comorbid disruptive behaviors in children and adolescents 10-18 years of age. Eleven subjects ages 10-18 received open-label atomoxetine and olanzapine for a 10 week treatment period. Patients were assessed at baseline, 2 weeks, 4 weeks, 6 weeks, and 10 weeks (posttreatment). ADHD improvement was measured through the ADHD Rating Scale (ADHD-RS) (Investigator and Parent ratings). Aggression was measured through the Modified Overt Aggression Scale (MOAS). The combined use of atomoxetine and olanzapine resulted in statistically significant improvement in ADHD symptoms and overt aggression from baseline to posttreatment. As evidenced by a 33% reduction in symptoms on the ADHD-RS-I and the MOAS, 73% of patients were considered responders to ADHD treatment, whereas 55% responded to treatment for aggression. Both medications were generally well tolerated. Olanzapine treatment was associated with significant weight gain. Patients gained, on average, 3.9 kg. throughout the treatment period. These data provide initial evidence that combination use of atomoxetine and olanzapine for the treatment of ADHD and comorbid disruptive behaviors was effective in reducing ADHD symptoms and aggressive behavior in a 10 week treatment period.

Analysis of carbonaceous biomarkers with the Mars Organic Analyzer microchip capillary electrophoresis system: aldehydes and ketones.

PubMed

Stockton, Amanda M; Tjin, Caroline Chandra; Huang, Grace L; Benhabib, Merwan; Chiesl, Thomas N; Mathies, Richard A

2010-11-01

A microchip CE method is developed for the analysis of two oxidized forms of carbon, aldehydes and ketones, with the Mars Organic Analyzer (MOA). Fluorescent derivitization is achieved in ∼ 15 min by hydrazone formation with Cascade Blue hydrazide in 30 mM borate pH 5-6. The microchip CE separation and analysis method is optimized via separation in 30 mM borate buffer, pH 9.5, at 20°C. A carbonyl standard consisting of ten aldehydes and ketones found in extraterrestrial matter is successfully separated; the resulting LOD depends on the reactivity of the compound and range from 70 pM for formaldehyde to 2 μM for benzophenone. To explore the utility of this method for analyzing complex samples, analyses of several fermented beverages are conducted, identifying ten aldehydes and ketones ranging from 30 nM to 5 mM. A Martian regolith simulant sample, consisting of a basalt matrix spiked with soluble ions and acetone, is designed and analyzed, but acetone is found to have a limited detectable lifetime under simulant Martian conditions. This work establishes the capability of the MOA for studying aldehydes and ketones, a critical class of oxidized organic molecules of interest in planetary and in terrestrial environmental and health studies. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Improving the Flexibility of Optimization-Based Decision Aiding Frameworks for Integrated Water Resource Management

NASA Astrophysics Data System (ADS)

Guillaume, J. H.; Kasprzyk, J. R.

2013-12-01

Deep uncertainty refers to situations in which stakeholders cannot agree on the full suite of risks for their system or their probabilities. Additionally, systems are often managed for multiple, conflicting objectives such as minimizing cost, maximizing environmental quality, and maximizing hydropower revenues. Many objective analysis (MOA) uses a quantitative model combined with evolutionary optimization to provide a tradeoff set of potential solutions to a planning problem. However, MOA is often performed using a single, fixed problem conceptualization. Focus on development of a single formulation can introduce an "inertia" into the problem solution, such that issues outside the initial formulation are less likely to ever be addressed. This study uses the Iterative Closed Question Methodology (ICQM) to continuously reframe the optimization problem, providing iterative definition and reflection for stakeholders. By using a series of directed questions to look beyond a problem's existing modeling representation, ICQM seeks to provide a working environment within which it is easy to modify the motivating question, assumptions, and model identification in optimization problems. The new approach helps identify and reduce bottle-necks introduced by properties of both the simulation model and optimization approach that reduce flexibility in generation and evaluation of alternatives. It can therefore help introduce new perspectives on the resolution of conflicts between objectives. The Lower Rio Grande Valley portfolio planning problem is used as a case study.

Preliminary studies of primary ostrich fibroblasts for the isolation of ratite viruses.

PubMed

Rodgers, S J; Vanhooser, S L; Welsh, R D; Silkwood, T G

1994-01-01

An ostrich egg at 21 days of development was used to propagate primary embryo cell cultures. Primary cultures of skeletal muscle cells (for fibroblasts) were prepared by routine typsinization techniques. The ostrich embryo fibroblasts were tested for their ability to propagate stock avian viruses of infectious bronchitis virus, paramyxiovirus-1 (PMV-1), PMV-2, PMV-3, infectious bursal disease virus, quail bronchitis virus, avian reovirus, turkey coronavirus, and two ostrich-originating specimens (one of which was a possible coronavirus identified by electron microscopy). Cytopathic effects were seen by light microscopy in cell cultures inoculated with PMV-1, turkey coronavirus, and the two ostrich specimens. Hemaglutinating titers of 4 or more were determined for PMV-1, turkey coronavrius, and the two ostrich specimens after inoculation onto monolayers of ostrich embryo fibroblasts. Hemagglutination-inhibition tests confirmed the identification of PMV-1 when homologous antisera were used as the specific inhibitor. Bovine coronavirus antisera inhibited the hemagglutination of one of the cultured ostrich specimens.

“Terror Birds” (Phorusrhacidae) from the Eocene of Europe Imply Trans-Tethys Dispersal

PubMed Central

Angst, Delphine; Buffetaut, Eric; Lécuyer, Christophe; Amiot, Romain

2013-01-01

Background Phorusrhacidae was a clade including middle-sized to giant terrestrial carnivorous birds, known mainly from the Cenozoic of South America, but also occurring in the Plio-Pleistocene of North America and the Eocene of Africa. Previous reports of small phorusrhacids in the Paleogene of Europe have been dismissed as based on non-phorusrhacid material. Methodology we have re-examined specimens of large terrestrial birds from the Eocene (late Lutetian) of France and Switzerland previously referred to gastornithids and ratites and have identified them as belonging to a phorusrhacid for which the name Eleutherornis cotei should be used. Conclusions/Significance The occurrence of a phorusrhacid in the late Lutetian of Europe indicates that these flightless birds had a wider geographical distribution than previously recognized. The likeliest interpretation is that they dispersed from Africa, where the group is known in the Eocene, which implies crossing the Tethys Sea. The Early Tertiary distribution of phorusrhacids can be best explained by transoceanic dispersal, across both the South Atlantic and the Tethys. PMID:24312212

Facilitation of extinction and re-extinction of operant behavior in mice by chlordiazepoxide and D-cycloserine.

PubMed

Leslie, Julian C; Norwood, Kelly

2013-05-01

The aim was to compare operant extinction with re-extinction following re-acquisition and to investigate neuropharmacological mechanisms through administration of drugs potentiating GABAergic or glutamatergic systems. Groups of C57Bl/6 mice were trained to lever press for food on a fixed ratio schedule, then extinguished with or without pre-session chlordiazepoxide or post-session d-cycloserine administration (15mg/kg in each case), then retrained to lever press for food, then re-extinguished with or without pre-session chlordiazepoxide or post-session d-cycloserine. Under vehicle injections, extinction and re-extinction curves were indistinguishable, but drug treatments showed that there was less resistance to extinction in the re-extinction phase. Chlordiazepoxide facilitated extinction and re-extinction, with an earlier effect during re-extinction. d-Cycloserine also facilitated extinction and re-extinction, with some evidence of an earlier effect during re-extinction. These results replicate and extend earlier findings with operant extinction, but differ from some previous reports of d-cycloserine on re-extinction of Pavlovian conditioned fear. Implications for accounts of the similarities and differences between neural mechanisms of extinction following either Pavlovian or operant conditioning, and applications of these findings, are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

Extinction in multiple contexts: Effects on the rate of extinction and the strength of response recovery.

PubMed

Bustamante, Javier; Uengoer, Metin; Thorwart, Anna; Lachnit, Harald

2016-09-01

In two human predictive-learning experiments, we investigated the effects of extinction in multiple contexts on the rate of extinction and the strength of response recovery. In each experiment, participants initially received acquisition training with a target cue in one context, followed by extinction either in a different context (extinction in a single context) or in three different contexts (extinction in multiple contexts). The results of both experiments showed that conducting extinction in multiple contexts led to higher levels of responding during extinction than did extinction in a single context. Additionally, Experiment 2 showed that extinction in multiple contexts prevented ABC renewal but had no detectable impact on ABA renewal. Our results are discussed within the framework of contemporary learning theories of contextual control and extinction.

The KMTNet/K2-C9 (Kepler) Data Release

NASA Astrophysics Data System (ADS)

Kim, H.-W.; Hwang, K.-H.; Kim, D.-J.; Albrow, M. D.; Cha, S.-M.; Chung, S.-J.; Gould, A.; Han, C.; Jung, Y. K.; Kim, S.-L.; Lee, C.-U.; Lee, D.-J.; Lee, Y.; Park, B.-G.; Pogge, R. W.; Ryu, Y.-H.; Shin, I.-G.; Shvartzvald, Y.; Yee, J. C.; Zang, W.; Zhu, W.; KMTNet Collaboration

2018-05-01

We present Korea Microlensing Telescope Network (KMTNet) light curves for microlensing-event candidates in the Kepler K2 C9 field having peaks within three effective timescales of the Kepler observations. These include 181 “clear microlensing” and 84 “possible microlensing” events found by the KMTNet event finder, plus 56 other events found by OGLE and/or MOA that were not found by KMTNet. All data for the first two classes are immediately available for public use without restriction.

MX Missile MOA Between Four Corners Regional Commission and the United States Air Force.

DTIC Science & Technology

1981-08-20

Mountains east of Beaver. The impact of hunting pres- sure and potential poaching has also ncz been addressed. 0 Despite the fact that phea- sant... impacted by both increased hunting pressure and poach - ing. Pheasant populations in the Delta area will be impacted by the loss of habitat due to...go. Water 0’ is very limiting. 4-780 1 Upland game birds will be impacted by both increased hunting pressure and poach - ing. Pheasant populations in

Intra-Theater Air Mobility and Theater Distribution for the Joint Force Commander: Is the United States Central Command Model the Best (Revised)

DTIC Science & Technology

2011-06-01

to ASOCs, each Army Corps possesses Air Mobility Liaison Officers ( AMLO ) at the corps, division, regiment, and brigade levels. These AMLOs may... AMLOs In PACOM, the DIRMOBFOR is expected to be an advisor to the COMAFFOR, JFACC and the JFACC’s AMD Chief, primarily with respect to integration...the AOR, PACAF will provide intra-theater AMLOs in accordance with AMLO -specific directives and theater MOAs. Specifically, PACAF will provide

Final Environmental Impact Statement for Development of Facilities to Support Basing US Pacific Fleet F/A-18E/F Aircraft on the West Coast of the United States, Volume 1.

DTIC Science & Technology

1998-05-01

ROG reactive organic compound RONA Record of Non -applicability RTV rational threshold value RWQCB Regional Water Quality Control Board SARA...over water. The ranges are either scheduled via a designated military or civilian controlling agency (for restricted or warning areas) or are used...operations areas (MOAs), and air traffic control authorized airspace (ATCAA). Airspace designations throughout the United States are controlled by the Federal

Test and Evaluation of the Malicious Activity Simulation Tool (MAST) in a Local Area Network (LAN) Running the Common PC Operating System Environment (COMPOSE)

DTIC Science & Technology

2013-09-01

Malicious Activity Simulation Tool MMORPG Massively Multiplayer Online Role-Playing Game MMS Mission Management Server MOA Memorandum of Agreement MS...conferencing, and massively multiplayer online role- playing games (MMORPG). During all of these Internet-based exchanges and transactions, the Internet user...In its 2011 Internet Crime Report, the Internet Crime Complaint Center (IC3) stated there were more than 300,000 complaints of online criminal

A list of tables summarizing various Cmap analysis, from which the final tables in the manuscript are based on

EPA Pesticide Factsheets

Various Cmap analyses within and across species and microarray platforms conducted and summarized to generate the tables in the publication.This dataset is associated with the following publication:Wang , R., A. Biales , N. Garcia-Reyero, E. Perkins, D. Villeneuve, G. Ankley, and D. Bencic. Fish Connectivity Mapping: Linking Chemical Stressors by Their MOA-Driven Transcriptomic Profiles. BMC Genomics. BioMed Central Ltd, London, UK, 17(84): 1-20, (2016).

Earthquake-Induced Liquefaction of Confined Soil Zones: A Centrifuge Study

DTIC Science & Technology

1993-12-09

8217. 4.2 Pore pressure transducers (PPT) Pore pressures in the saturated soil were monitored by Druck PDCR 81 pore pressure transducers. This type of pore...PPT5406 -20 MTn-23.3 2 3 4 5 6 7 a 2 10 II 12 Mo, 34 .8 PPT6270 20~ Mlm=-I .2 1 2 3 4 5 6 8 a 1 0 II 12 4 M....7 0 PPT6263 A 3d Moa20.S PPT6260 7 -0 1 2 3

Environmental Assessment for the Expansion of the Yukon Measurement and Debriefing System in the Fox and Yukon MOAs

DTIC Science & Technology

2006-05-01

River, Porcupine River, Chandalar River, and the upper portion of the Yukon River. The southern portion of the area is drained by the Fortymile River...physiographic features in the central 17 EA for Expansion of YMDS April2006 portion are the Porcupine Plateau and the Yukon Flats. The Yukon Flats...mile. The Fortymile caribou herd utilizes the surrounding area as its principle winter range. Since 1995, the Fortymile caribou herd has increased

2005 Tri-Service Infrastructure Systems Conference and Exhibition. Volume 2, Track 2

DTIC Science & Technology

2005-08-04

not produce toxic by-products, including: – UV – E-Beam – Pulsed Corona Discharge R&D Simulation of Fate & Transport of a CB Agent in a Water...Nationwide network of sensors with integration with ASOCC or CATS . – CHPPM - Soldier health, sensors, and fate of agent. – Congressional line-item with Hach...west Nile virus ), birds (avian flu) Public meeting Aug 10. Construction start ~ late Aug – early Sep pending signed MOA P & S complete, some

Retrieval and Reconsolidation Accounts of Fear Extinction

PubMed Central

Ponnusamy, Ravikumar; Zhuravka, Irina; Poulos, Andrew M.; Shobe, Justin; Merjanian, Michael; Huang, Jeannie; Wolvek, David; O’Neill, Pia-Kelsey; Fanselow, Michael S.

2016-01-01

Extinction is the primary mode for the treatment of anxiety disorders. However, extinction memories are prone to relapse. For example, fear is likely to return when a prolonged time period intervenes between extinction and a subsequent encounter with the fear-provoking stimulus (spontaneous recovery). Therefore there is considerable interest in the development of procedures that strengthen extinction and to prevent such recovery of fear. We contrasted two procedures in rats that have been reported to cause such deepened extinction. One where extinction begins before the initial consolidation of fear memory begins (immediate extinction) and another where extinction begins after a brief exposure to the consolidated fear stimulus. The latter is thought to open a period of memory vulnerability similar to that which occurs during initial consolidation (reconsolidation update). We also included a standard extinction treatment and a control procedure that reversed the brief exposure and extinction phases. Spontaneous recovery was only found with the standard extinction treatment. In a separate experiment we tested fear shortly after extinction (i.e., within 6 h). All extinction procedures, except reconsolidation update reduced fear at this short-term test. The findings suggest that strengthened extinction can result from alteration in both retrieval and consolidation processes. PMID:27242459

Long-Term Maintenance of Immediate or Delayed Extinction Is Determined by the Extinction-Test Interval

ERIC Educational Resources Information Center

Johnson, Justin S.; Escobar, Martha; Kimble, Whitney L.

2010-01-01

Short acquisition-extinction intervals (immediate extinction) can lead to either more or less spontaneous recovery than long acquisition-extinction intervals (delayed extinction). Using rat subjects, we observed less spontaneous recovery following immediate than delayed extinction (Experiment 1). However, this was the case only if a relatively…

No impact of repeated extinction exposures on operant responding maintained by different reinforcer rates.

PubMed

Bai, John Y H; Podlesnik, Christopher A

2017-05-01

Greater rates of intermittent reinforcement in the presence of discriminative stimuli generally produce greater resistance to extinction, consistent with predictions of behavioral momentum theory. Other studies reveal more rapid extinction with higher rates of reinforcers - the partial reinforcement extinction effect. Further, repeated extinction often produces more rapid decreases in operant responding due to learning a discrimination between training and extinction contingencies. The present study examined extinction repeatedly with training with different rates of intermittent reinforcement in a multiple schedule. We assessed whether repeated extinction would reverse the pattern of greater resistance to extinction with greater reinforcer rates. Counter to this prediction, resistance to extinction was consistently greater across twelve assessments of training followed by six successive sessions of extinction. Moreover, patterns of responding during extinction resembled those observed during satiation tests, which should not alter discrimination processes with repeated testing. These findings join others suggesting operant responding in extinction can be durable across repeated tests. Copyright © 2017 Elsevier B.V. All rights reserved.

Amount of fear extinction changes its underlying mechanisms.

PubMed

An, Bobae; Kim, Jihye; Park, Kyungjoon; Lee, Sukwon; Song, Sukwoon; Choi, Sukwoo

2017-07-03

There has been a longstanding debate on whether original fear memory is inhibited or erased after extinction. One possibility that reconciles this uncertainty is that the inhibition and erasure mechanisms are engaged in different phases (early or late) of extinction. In this study, using single-session extinction training and its repetition (multiple-session extinction training), we investigated the inhibition and erasure mechanisms in the prefrontal cortex and amygdala of rats, where neural circuits underlying extinction reside. The inhibition mechanism was prevalent with single-session extinction training but faded when single-session extinction training was repeated. In contrast, the erasure mechanism became prevalent when single-session extinction training was repeated. Moreover, ablating the intercalated neurons of amygdala, which are responsible for maintaining extinction-induced inhibition, was no longer effective in multiple-session extinction training. We propose that the inhibition mechanism operates primarily in the early phase of extinction training, and the erasure mechanism takes over after that.

Acute nicotine disrupts consolidation of contextual fear extinction and alters long-term memory-associated hippocampal kinase activity.

PubMed

Kutlu, Munir Gunes; Garrett, Brendan; Gadiwalla, Sana; Tumolo, Jessica M; Gould, Thomas J

2017-11-01

Previous research has shown that acute nicotine, an agonist of nAChRs, impaired fear extinction. However, the effects of acute nicotine on consolidation of contextual fear extinction memories and associated cell signaling cascades are unknown. Therefore, we examined the effects of acute nicotine injections before (pre-extinction) and after (post-extinction) contextual fear extinction on behavior and the phosphorylation of dorsal and ventral hippocampal ERK1/2 and JNK1 and protein levels on the 1st and 3rd day of extinction. Our results showed that acute nicotine administered prior to extinction sessions downregulated the phosphorylated forms of ERK1/2 in the ventral hippocampus, but not dorsal hippocampus, and JNK1 in both dorsal and ventral hippocampus on the 3rd extinction day. These effects were absent on the 1st day of extinction. We also showed that acute nicotine administered immediately and 30 min, but not 6 h, following extinction impaired contextual fear extinction suggesting that acute nicotine disrupts consolidation of contextual fear extinction memories. Finally, acute nicotine injections immediately after extinction sessions upregulated the phosphorylated forms of ERK1/2 in the ventral hippocampus, but did not affect JNK1. These results show that acute nicotine impairs contextual fear extinction potentially by altering molecular processes responsible for the consolidation of extinction memories. Copyright © 2017 Elsevier Inc. All rights reserved.

Immediate extinction causes a less durable loss of performance than delayed extinction following either fear or appetitive conditioning.

PubMed

Woods, Amanda M; Bouton, Mark E

2008-12-01

Five experiments with rat subjects compared the effects of immediate and delayed extinction on the durability of extinction learning. Three experiments examined extinction of fear conditioning (using the conditioned emotional response method), and two experiments examined extinction of appetitive conditioning (using the food-cup entry method). In all experiments, conditioning and extinction were accomplished in single sessions, and retention testing took place 24 h after extinction. In both fear and appetitive conditioning, immediate extinction (beginning 10 min after conditioning) caused a faster loss of responding than delayed extinction (beginning 24 h after conditioning). However, immediate extinction was less durable than delayed extinction: There was stronger spontaneous recovery during the final retention test. There was also substantial renewal of responding when the physical context was changed between immediate extinction and testing (Experiment 1). The results suggest that, in these two widely used conditioning preparations, immediate extinction does not erase or depotentiate the original learning, and instead creates a less permanent reduction in conditioned responding. Results did not support the possibility that the strong recovery after immediate extinction was due to a mismatch in the recent "context" provided by the presence or absence of a recent conditioning experience. Several other accounts are considered.

Biostratigraphic case studies of six major extinctions

NASA Technical Reports Server (NTRS)

Sloan, R. E.

1988-01-01

Biostratigraphic case studies of six major extinctions show all are gradual save one, which is a catastrophic extinction of terrestrial origin. These extinctions show a continuum of environmental insults from major to minor. The major causes of these extinctions are positive and negative eustatic sea level changes, temperature, or ecological competition. Extraterrestrial causes should not be posited without positive association with a stratigraphically sharp extinction. The Cretaceous-Tertiary terrestrial extinction is considerably smaller in percentage of extinction than the marine extinction and is spread over 10 my of the Cretaceous and 1 my of the Tertiary. Sixty percent of the 30 dinosaurs in the northern Great Plains of the U.S. and Canada had become extinct in the 9 my before the late Maastrichtian sea level drop. The best data on the Permo-Triassic terrestrial extinction are from the Karoo basin of South Africa. This is a series of 6 extinctions in some 8 my, recorded in some 2800 meters of sediment. Precision of dating is enhanced by the high rate of accumulation of these sediments. Few data are readily available on the timing of the marine Permo-Triassic extinction, due to the very restricted number of sequences of Tatarian marine rocks. The terminal Ordovician extinction at 438 my is relatively rapid, taking place over about 0.5 my. The most significant aspect of this extinction is a eustatic sea level lowering associated with a major episode of glaciation. New data on this extinction is the reduction from 61 genera of trilobites in North America to 14, for a 77 percent extinction. Another Ordovician extinction present over 10 percent of the North American craton occurs at 454 my in the form of a catastrophic extinction due to a volcanic eruption which blanketed the U.S. east of the Transcontinental Arch. This is the only other sizeable extinction in the Ordovician.

Habitat Evaluation Procedures (HEP) Report : Malheur River Wildlife Mitigation, 2000-2002 Technical Report.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gonzalez, Daniel; Wenick, Jess

The development of hydropower systems within the Columbia and Snake River basins has affected a tremendous amount of fish and wildlife species. The dams have played a major role in the rapid extinction of anadromous runs of salmon and steelhead as well as other native salmonids. Inundation of these dams and the construction of reservoirs for irrigation have also severely impacted wildlife species. In some cases, fluctuating water levels caused by dam and reservoir operations have created barren vegetation zones that expose wildlife to predation and a reduction in recruitment. In association with hydropower activities, secondary impacts have also challengedmore » and highly impacted a majority of wildlife species. The construction of roads, facilities, urban development, channelization, and diversions of streams and rivers often have negative long-term effects on fish, wildlife, and vegetation. In response to these concerns, the United States Congress passed the Pacific Electric Power Planning Conservation Act (Act) in 1980. The Act authorized four states (Idaho, Montana, Oregon and Washington) and 13 Indian Tribes (including the Burns Paiute Tribe) to create the Northwest Power Planning Council (Council). The role of the Council is to prepare a program in conjunction with several participants that protects, mitigates and enhances affected species within the Columbia River Basin and its tributaries. The Council's program, known as the Columbia River Basin's Fish and Wildlife Program (Program), has evolved over the years into a basin-wide approach that incorporates management plans for 52 subbasins. The Program includes a public involvement component that requires Program participants to provide the public with meaningful opportunities to comment on specific management proposals. Participants in this Program include the region's fish and wildlife agencies, Indian tribes, the public and an 11-member panel of scientists referred to as the Independent Scientific Review Panel (ISRP). Program participants are responsible for creating management plans for each of the 52 subbasins. Upon approval by the Council, the management plan is then incorporated into the Program. In 1998, the Tribe submitted two land acquisition proposals for funding through Bonneville's Wildlife Mitigation Program, the Logan Valley and Malheur River Wildlife Mitigation Projects. After several months of rigorous scrutiny and defense of its project presentations, the Tribe was awarded both acquisitions. In February of 2000, the Tribe and BPA entered into a Memorandum of Agreement (MOA) to fund the acquisition and management of Logan Valley and the Malheur River Projects. In April and November of 2000, the Tribe acquired the Logan Valley property (Project) and the Malheur River Wildlife Mitigation Project, respectively. The MOA requires the Tribe to dedicate the Project to wildlife habitat protection. Project management must be consistent with the term and conditions of the MOA and a site-specific management plan (Plan) that is to be prepared by the Tribe. The Malheur River Wildlife Mitigation Project (Denny Jones Ranch) allows the Tribe to manage 6,385 acres of meadow, wetland, and sagebrush steppe habitats along the Malheur River. The deeded property includes seven miles of the Malheur River, the largest private landholding along this waterway between Riverside and Harper. The property came with approximately 938 acres of senior water rights and 38,377 acres of federal and state grazing allotments. The project will benefit a diverse population of fish, wildlife, and plant species. Objectives include reviving and improving critical habitat for fish and wildlife populations, controlling/ eradicating weed populations, improving water quality, maintaining Bureau of Land Management (BLM) allotments, and preserving cultural resources. Before the Tribe acquired the project site, a combination of high levels of cattle stocking rates, management strategy, and a disruption of natural disturbance regimes compromised the property's ability to provide quality habitat to wildlife species found in the area. As a result, rangeland condition was depleted, exotic annual grasses and other noxious weeds began to invade native plant communities and many riparian areas were generally degraded. Native meadow communities were also leveled and planted with introduced species shortly after settlement and wildlife use and historic home ranges for migratory species have been severely altered. Current management is actively seeking to enhance the ability of the site's plant communities to support resident fauna that are known to have thrived in the area prior to settlement. The Tribe is utilizing a baseline approach to its overall land management by recognizing the importance of plant succession in achieving wildlife goal.« less

Origination, diversity, and extinction metrics essential for analysis of mass biotic crisis events: An example from cretaceous ammonoidea

NASA Technical Reports Server (NTRS)

Collom, Christopher J.

1988-01-01

Traditional mass extinction research has predominently concentrated on statistically demonstrating that mass extinction intervals are significantly above background levels of familial and generic extinction in terms of extinction percentage, extinction rate, and per-taxon extinction rate; mass extinction intervals occur on a set periodicity throughout geologic time, which is estimated to be some 30 MYR in duration. The published literature has given little emphasis to equally important considerations and metrics such as origination rate, standing diversity, and rate of generation of new taxa DURING mass extinction intervals. The extent to which a mass extinction affects the regional or global biota, must ultimately be gauged by taking into consideration both the number of taxa which become extinct at or near the event (stage) boundary, and the number of taxa which are either not affected at all by the extinction or actually evolved during or shortly before/after the extinction interval. These effects can be seen in Cretaceous Ammonoidea (at the genus level), and their combined usage allow better insight into paleobiological dynamics and responses to mass extinction and its affect on this dominant Molluscan organism.

Fear extinction requires Arc/Arg3.1 expression in the basolateral amygdala.

PubMed

Onoue, Kousuke; Nakayama, Daisuke; Ikegaya, Yuji; Matsuki, Norio; Nomura, Hiroshi

2014-04-23

Prolonged re-exposure to a fear-eliciting cue in the absence of an aversive event extinguishes the fear response to the cue, and has been clinically used as an exposure therapy. Arc (also known as Arg3.1) is implicated in synaptic and experience-dependent plasticity. Arc is regulated by the transcription factor cAMP response element binding protein, which is upregulated with and necessary for fear extinction. Because Arc expression is also activated with fear extinction, we hypothesized that Arc expression is required for fear extinction. Extinction training increased the proportion of Arc-labeled cells in the basolateral amygdala (BLA). Arc was transcribed during latter part of extinction training, which is possibly associated with fear extinction, as well as former part of extinction training. Intra-BLA infusions of Arc antisense oligodeoxynucleotide (ODN) before extinction training impaired long-term but not short-term extinction memory. Intra-BLA infusions of Arc antisense ODN 3 h after extinction training had no effect on fear extinction. Our findings demonstrate that Arc is required for long-term extinction of conditioned fear and contribute to the understanding of extinction as a therapeutic manner.

Expanding the Intertrial Interval During Extinction: Response Cessation and Recovery

PubMed Central

Orinstein, Alyssa J.; Urcelay, Gonzalo P.; Miller, Ralph R.

2010-01-01

We examined trial spacing during extinction following a human contingency learning task. Specifically, we assessed if an expanding retrieval practice schedule (Bjork & Bjork, 1992, 2006), in which the spacing between extinction trials was progressively increased, would result in faster immediate extinction and less recovery from extinction than uniformly spaced extinction trials. We used an ABB vs. ABA renewal design and observed that, whereas the expanding group extinguished faster during extinction treatment, the expanding and constant groups showed the same level of extinction with an immediate test in the extinction context (ABB) and the two groups showed equivalent ABA renewal at test in the training context. We conclude that the faster extinction observed in the expanding groups could be misleading in clinical treatment, if the therapist used the absence of fear during extinction as the basis for terminating treatment. PMID:20171324

Inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear.

PubMed

Jiang, Lizhu; Mao, Rongrong; Tong, Jianbin; Li, Jinnan; Chai, Anping; Zhou, Qixin; Yang, Yuexiong; Wang, Liping; Li, Lingjiang; Xu, Lin

2016-10-01

Promoting extinction of fear memory is the main treatment of fear disorders, especially post-traumatic stress disorder (PTSD). However, fear extinction is often incomplete in these patients. Our previous study had shown that Rac1 activity in hippocampus plays a crucial role in the learning of contextual fear memory in rats. Here, we further investigated whether Rac1 activity also modulated the extinction of contextual fear memory. We found that massed extinction obviously upregulated hippocampal Rac1 activity and induced long-term extinction of contextual fear in rats. Intrahippocampal injection of the Rac1 inhibitor NSC23766 prevents extinction of contextual fear in massed extinction training rats. In contrast, long-spaced extinction downregulated Rac1 activity and caused less extinction. And Rac1 activator CN04-A promotes extinction of contextual fear in long-spaced extinction rats. Our study demonstrates that inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear, suggesting that modulating Rac1 activity of the hippocampus may be promising therapy of fear disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fear extinction can be made state-dependent on peripheral epinephrine: role of norepinephrine in the nucleus tractus solitarius.

PubMed

Rosa, Jessica; Myskiw, Jociane C; Furini, Cristiane R G; Sapiras, Gerson G; Izquierdo, Ivan

2014-09-01

We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)→locus coeruleus→hippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24 h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6 min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100 μg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50 μg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01 μg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1 μg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1 μg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTS→locus coeruleus→HIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning. Copyright © 2013 Elsevier Inc. All rights reserved.

Extinction and anti-extinction: the "attentional waiting" hypothesis.

PubMed

Watling, Rosamond; Danckert, James; Linnell, Karina J; Cocchini, Gianna

2013-03-01

Patients with visual extinction have difficulty detecting a single contralesional stimulus when a second stimulus is simultaneously presented on the ipsilesional side. The rarely reported phenomenon of visual anti-extinction describes the opposite behavior, in which patients show greater difficulty in reporting a stimulus presented in isolation than they do in reporting 2 simultaneously presented stimuli. S. J. Goodrich and R. Ward (1997, Anti-extinction following unilateral parietal damage, Cognitive Neuropsychology, Vol. 14, pp. 595-612) suggested that visual anti-extinction is the result of a task-specific mechanism in which processing of the ipsilesional stimulus facilitates responses to the contralesional stimulus; in contrast, G. W. Humphreys, M. J. Riddoch, G. Nys, and D. Heinke (2002, Transient binding by time: Neuropsychological evidence from anti-extinction, Cognitive Neuropsychology, Vol. 19, pp. 361-380) suggested that temporal binding groups contralesional and ipsilesional stimuli together at brief exposure durations. We investigated extinction and anti-extinction phenomena in 3 brain-damaged patients using an extinction paradigm in which the stimulus exposure duration was systematically manipulated. Two patients showed both extinction and anti-extinction depending on the exposure duration of stimuli. Data confirmed the crucial role of duration in modulating the effect of extinction and anti-extinction. However, contrary to Humphreys and colleagues' (2002) single case, our patients showed extinction for short and anti-extinction for long exposure durations, suggesting that different mechanisms might underlie our patients' pattern of data. We discuss a novel "attentional waiting" hypothesis, which proposes that anti-extinction may be observed in patients showing extinction if the exposure duration of stimuli is increased. PsycINFO Database Record (c) 2013 APA, all rights reserved.

The effects of compound stimulus extinction and inhibition of noradrenaline reuptake on the renewal of alcohol seeking

PubMed Central

Furlong, T M; Pan, M J; Corbit, L H

2015-01-01

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli can reduce their impact on relapse; however, the expression of extinction can be disrupted when testing occurs outside the context where extinction learning took place, an effect termed renewal. Behavioral and pharmacological methods have recently been shown to augment extinction learning; yet, it is not known whether the improved expression of extinction following these treatments remains context-dependent. Here we examined whether two methods, compound–stimulus extinction and treatment with the noradrenaline reuptake inhibitor atomoxetine, would reduce the vulnerability of extinction to a change in context. Following alcohol self-administration, responding was extinguished in a distinct context. After initial extinction, further extinction was given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg kg−1; Experiment 2). A stimulus extinguished as part of a compound elicited less responding than a stimulus receiving equal extinction alone regardless of whether animals were tested in the training or extinction context; however, reliable renewal was not observed in this paradigm. Importantly, atomoxetine enhanced extinction relative to controls even in the presence of a reliable renewal effect. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Importantly, both methods improve extinction even when the context is changed between extinction training and test, and thus could be utilized to enhance the outcome of extinction-based treatments for alcohol-use disorders. PMID:26327688

Amount of fear extinction changes its underlying mechanisms

PubMed Central

An, Bobae; Kim, Jihye; Park, Kyungjoon; Lee, Sukwon; Song, Sukwoon; Choi, Sukwoo

2017-01-01

There has been a longstanding debate on whether original fear memory is inhibited or erased after extinction. One possibility that reconciles this uncertainty is that the inhibition and erasure mechanisms are engaged in different phases (early or late) of extinction. In this study, using single-session extinction training and its repetition (multiple-session extinction training), we investigated the inhibition and erasure mechanisms in the prefrontal cortex and amygdala of rats, where neural circuits underlying extinction reside. The inhibition mechanism was prevalent with single-session extinction training but faded when single-session extinction training was repeated. In contrast, the erasure mechanism became prevalent when single-session extinction training was repeated. Moreover, ablating the intercalated neurons of amygdala, which are responsible for maintaining extinction-induced inhibition, was no longer effective in multiple-session extinction training. We propose that the inhibition mechanism operates primarily in the early phase of extinction training, and the erasure mechanism takes over after that. DOI: http://dx.doi.org/10.7554/eLife.25224.001 PMID:28671550

Extinction rates in North American freshwater fishes, 1900-2010

USGS Publications Warehouse

Burkhead, Noel M.

2012-01-01

Widespread evidence shows that the modern rates of extinction in many plants and animals exceed background rates in the fossil record. In the present article, I investigate this issue with regard to North American freshwater fishes. From 1898 to 2006, 57 taxa became extinct, and three distinct populations were extirpated from the continent. Since 1989, the numbers of extinct North American fishes have increased by 25%. From the end of the nineteenth century to the present, modern extinctions varied by decade but significantly increased after 1950 (post-1950s mean = 7.5 extinct taxa per decade). In the twentieth century, freshwater fishes had the highest extinction rate worldwide among vertebrates. The modern extinction rate for North American freshwater fishes is conservatively estimated to be 877 times greater than the background extinction rate for freshwater fishes (one extinction every 3 million years). Reasonable estimates project that future increases in extinctions will range from 53 to 86 species by 2050.

Temporal Dynamics of Recovery from Extinction Shortly after Extinction Acquisition

ERIC Educational Resources Information Center

Archbold, Georgina E.; Dobbek, Nick; Nader, Karim

2013-01-01

Evidence suggests that extinction is new learning. Memory acquisition involves both short-term memory (STM) and long-term memory (LTM) components; however, few studies have examined early phases of extinction retention. Retention of auditory fear extinction was examined at various time points. Shortly (1-4 h) after extinction acquisition…

Erosion of lizard diversity by climate change and altered thermal niches.

PubMed

Sinervo, Barry; Méndez-de-la-Cruz, Fausto; Miles, Donald B; Heulin, Benoit; Bastiaans, Elizabeth; Villagrán-Santa Cruz, Maricela; Lara-Resendiz, Rafael; Martínez-Méndez, Norberto; Calderón-Espinosa, Martha Lucía; Meza-Lázaro, Rubi Nelsi; Gadsden, Héctor; Avila, Luciano Javier; Morando, Mariana; De la Riva, Ignacio J; Victoriano Sepulveda, Pedro; Rocha, Carlos Frederico Duarte; Ibargüengoytía, Nora; Aguilar Puntriano, César; Massot, Manuel; Lepetz, Virginie; Oksanen, Tuula A; Chapple, David G; Bauer, Aaron M; Branch, William R; Clobert, Jean; Sites, Jack W

2010-05-14

It is predicted that climate change will cause species extinctions and distributional shifts in coming decades, but data to validate these predictions are relatively scarce. Here, we compare recent and historical surveys for 48 Mexican lizard species at 200 sites. Since 1975, 12% of local populations have gone extinct. We verified physiological models of extinction risk with observed local extinctions and extended projections worldwide. Since 1975, we estimate that 4% of local populations have gone extinct worldwide, but by 2080 local extinctions are projected to reach 39% worldwide, and species extinctions may reach 20%. Global extinction projections were validated with local extinctions observed from 1975 to 2009 for regional biotas on four other continents, suggesting that lizards have already crossed a threshold for extinctions caused by climate change.

Bidirectional effects of inhibiting or activating NMDA receptors on extinction after cocaine self-administration in rats

PubMed Central

Hafenbreidel, Madalyn; Todd, Carolynn Rafa; Twining, Robert C.; Tuscher, Jennifer J.; Mueller, Devin

2014-01-01

Rationale Extinction of drug seeking is facilitated by NMDA receptor (NMDAr) agonists, but it remains unclear whether extinction is dependent on NMDAr activity. Objectives We investigated the necessity of NMDArs for extinction of cocaine seeking, and whether extinction altered NMDAr expression within extinction-related neuroanatomical loci. Methods Rats were trained to lever press for i.v. infusions of cocaine or sucrose reinforcement prior to extinction training or withdrawal. Results Administration of the NMDAr competitive antagonist CPP prior to four brief extinction sessions impaired subsequent extinction retention. In contrast, post-extinction administration of the NMDAr coagonist D-serine attenuated lever pressing across days as compared to saline administration, indicative of facilitated consolidation of extinction. Furthermore, expression of the NMDAr subunits, GluN2A and GluN2B, was not altered in the ventromedial prefrontal cortex. However, both GluN2A and GluN2B subunit expression in the nucleus accumbens was increased following cocaine self-administration, and this increased expression was relatively resistant to modulation by extinction. Conclusions Our findings demonstrate that extinction of cocaine seeking is bidirectionally mediated by NMDArs and suggest that selective modulation of NMDAr activity could facilitate extinction-based therapies for treatment of cocaine abuse. PMID:24847958

The role of the medial prefrontal cortex in trace fear extinction

PubMed Central

Kwapis, Janine L.; Jarome, Timothy J.

2015-01-01

The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that supports extinction of this memory has received very little attention. Recent research has indicated that trace fear extinction requires a different neural circuit than delay extinction; trace extinction requires the participation of the retrosplenial cortex, but not the amygdala, as noted in a previous study. Here, we tested the roles of the prelimbic and infralimbic regions of the medial prefrontal cortex in trace and delay fear extinction by blocking NMDA receptors during extinction learning. We found that the prelimbic cortex is necessary for trace, but not for delay fear extinction, whereas the infralimbic cortex is involved in both types of extinction. These results are consistent with the idea that trace fear associations require plasticity in multiple cortical areas for successful extinction. Further, the infralimbic cortex appears to play a role in extinction regardless of whether the animal was initially trained in trace or delay conditioning. Together, our results provide new information about how the neural circuits supporting trace and delay fear extinction differ. PMID:25512576

Structural studies of viperin, an antiviral radical SAM enzyme.

PubMed

Fenwick, Michael K; Li, Yue; Cresswell, Peter; Modis, Yorgo; Ealick, Steven E

2017-06-27

Viperin is an IFN-inducible radical S -adenosylmethionine (SAM) enzyme that inhibits viral replication. We determined crystal structures of an anaerobically prepared fragment of mouse viperin (residues 45-362) complexed with S -adenosylhomocysteine (SAH) or 5'-deoxyadenosine (5'-dAdo) and l-methionine (l-Met). Viperin contains a partial (βα) 6 -barrel fold with a disordered N-terminal extension (residues 45-74) and a partially ordered C-terminal extension (residues 285-362) that bridges the partial barrel to form an overall closed barrel structure. Cys84, Cys88, and Cys91 located after the first β-strand bind a [4Fe-4S] cluster. The active site architecture of viperin with bound SAH (a SAM analog) or 5'-dAdo and l-Met (SAM cleavage products) is consistent with the canonical mechanism of 5'-deoxyadenosyl radical generation. The viperin structure, together with sequence alignments, suggests that vertebrate viperins are highly conserved and that fungi contain a viperin-like ortholog. Many bacteria and archaebacteria also express viperin-like enzymes with conserved active site residues. Structural alignments show that viperin is similar to several other radical SAM enzymes, including the molybdenum cofactor biosynthetic enzyme MoaA and the RNA methyltransferase RlmN, which methylates specific nucleotides in rRNA and tRNA. The viperin putative active site contains several conserved positively charged residues, and a portion of the active site shows structural similarity to the GTP-binding site of MoaA, suggesting that the viperin substrate may be a nucleoside triphosphate of some type.

Rescuing mutant CFTR: a multi-task approach to a better outcome in treating cystic fibrosis.

PubMed

Amaral, Margarida D; Farinha, Carlos M

2013-01-01

Correcting multiple defects of mutant CFTR with small molecule compounds has been the goal of an increasing number of recent Cystic Fibrosis (CF) drug discovery programmes. However, the mechanism of action (MoA) by which these molecules restore mutant CFTR is still poorly understood, in particular of CFTR correctors, i.e., compounds rescuing to the cells surface the most prevalent mutant in CF patients--F508del-CFTR. However, there is increasing evidence that to fully restore the multiple defects associated with F508del-CFTR, different small molecules with distinct corrective properties may be required. Towards this goal, a better insight into MoA of correctors is needed and several constraints should be addressed. The methodological approaches to achieve this include: 1) testing the combined effect of compounds with that of other (non-pharmacological) rescuing strategies (e.g., revertants or low temperature); 2) assessing effects in multiple cellular models (non-epithelial vs epithelial, non-human vs human, immortalized vs primary cultures, polarized vs non polarized, cells vs tissues); 3) assessing compound effects on isolated CFTR domains (e.g., compound binding by surface plasmon resonance, assessing effects on domain folding and aggregation); and finally 4) assessing compounds specificity in rescuing different CFTR mutants and other mutant proteins. These topics are reviewed and discussed here so as to provide a state-of-the art review on how to combine multiple ways of rescuing mutant CFTR to the ultimate benefit of CF patients.

BRCA-Monet: a breast cancer specific drug treatment mode-of-action network for treatment effective prediction using large scale microarray database.

PubMed

Ma, Chifeng; Chen, Hung-I; Flores, Mario; Huang, Yufei; Chen, Yidong

2013-01-01

Connectivity map (cMap) is a recent developed dataset and algorithm for uncovering and understanding the treatment effect of small molecules on different cancer cell lines. It is widely used but there are still remaining challenges for accurate predictions. Here, we propose BRCA-MoNet, a network of drug mode of action (MoA) specific to breast cancer, which is constructed based on the cMap dataset. A drug signature selection algorithm fitting the characteristic of cMap data, a quality control scheme as well as a novel query algorithm based on BRCA-MoNet are developed for more effective prediction of drug effects. BRCA-MoNet was applied to three independent data sets obtained from the GEO database: Estrodial treated MCF7 cell line, BMS-754807 treated MCF7 cell line, and a breast cancer patient microarray dataset. In the first case, BRCA-MoNet could identify drug MoAs likely to share same and reverse treatment effect. In the second case, the result demonstrated the potential of BRCA-MoNet to reposition drugs and predict treatment effects for drugs not in cMap data. In the third case, a possible procedure of personalized drug selection is showcased. The results clearly demonstrated that the proposed BRCA-MoNet approach can provide increased prediction power to cMap and thus will be useful for identification of new therapeutic candidates.

Residual Acute Toxicity of Some Modern Insecticides Toward Two Mirid Predators of Tomato Pests.

PubMed

Wanumen, Andrea C; Carvalho, Geraldo A; Medina, Pilar; Viñuela, Elisa; Adán, Ángeles

2016-03-31

The successful integration of chemical and biological control strategies for crop pests depends on a thorough evaluation of the effects of pesticides on the natural enemies of pests. A case-by-case review is difficult to achieve because of the many combinations of pests, natural enemies, and crops that need to be tested. Within this framework, we tested and compared seven insecticides representative of four different modes of action (MoAs) groups on closely related predators (Miridae): flubendiamide, spirotetramat, metaflumizone, and sulfoxaflor onNesidiocoris tenuisReuter and flubendiamide, spiromesifen, indoxacarb, and imidacloprid onMacrolophus basicornis(Stal). We follow the standardized methodology of the International Organization for Biological Control, a sequential testing exposure scheme. The lethal effect of each insecticide was evaluated in adults after three days of contact with treated surfaces in the laboratory, extended laboratory, and semifield tests (inert substrate, tomato leaves, and tomato plant as the treated surface, respectively). Flubendiamide, spiromesifen, and spirotetramat were classified as harmless (class 1), metaflumizone was slightly harmful (class 2) but persistent, indoxacarb was harmless (class 1), and sulfoxaflor and imidacloprid were toxic (class 4) and exhibited a long residual activity. Our results suggest similarities in the acute toxicities of insecticides from the same MoA group on related species of natural enemies. © The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment

PubMed Central

McHale, Cliona M.; Zhang, Luoping; Smith, Martyn T.

2012-01-01

Benzene causes acute myeloid leukemia and probably other hematological malignancies. As benzene also causes hematotoxicity even in workers exposed to levels below the US permissible occupational exposure limit of 1 part per million, further assessment of the health risks associated with its exposure, particularly at low levels, is needed. Here, we describe the probable mechanism by which benzene induces leukemia involving the targeting of critical genes and pathways through the induction of genetic, chromosomal or epigenetic abnormalities and genomic instability, in a hematopoietic stem cell (HSC); stromal cell dysregulation; apoptosis of HSCs and stromal cells and altered proliferation and differentiation of HSCs. These effects modulated by benzene-induced oxidative stress, aryl hydrocarbon receptor dysregulation and reduced immunosurveillance, lead to the generation of leukemic stem cells and subsequent clonal evolution to leukemia. A mode of action (MOA) approach to the risk assessment of benzene was recently proposed. This approach is limited, however, by the challenges of defining a simple stochastic MOA of benzene-induced leukemogenesis and of identifying relevant and quantifiable parameters associated with potential key events. An alternative risk assessment approach is the application of toxicogenomics and systems biology in human populations, animals and in vitro models of the HSC stem cell niche, exposed to a range of levels of benzene. These approaches will inform our understanding of the mechanisms of benzene toxicity and identify additional biomarkers of exposure, early effect and susceptibility useful for risk assessment. PMID:22166497

Application of the Activity Framework for Assessing Aquatic Ecotoxicology Data for Organic Chemicals.

PubMed

Thomas, Paul; Dawick, James; Lampi, Mark; Lemaire, Philippe; Presow, Shaun; van Egmond, Roger; Arnot, Jon A; Mackay, Donald; Mayer, Philipp; Galay Burgos, Malyka

2015-10-20

Toxicological research in the 1930s gave the first indications of the link between narcotic toxicity and the chemical activity of organic chemicals. More recently, chemical activity has been proposed as a novel exposure parameter that describes the fraction of saturation and that quantifies the potential for partitioning and diffusive uptake. In the present study, more than 2000 acute and chronic algal, aquatic invertebrates and fish toxicity data, as well as water solubility and melting point values, were collected from a series of sources. The data were critically reviewed and grouped by mode of action (MoA). We considered 660 toxicity data to be of acceptable quality. The 328 data which applied to the 72 substances identified as MoA 1 were then evaluated within the activity-toxicity framework: EC50 and LC50 values for all three taxa correlated generally well with (subcooled) liquid solubilities. Acute toxicity was typically exerted within the chemical activity range of 0.01-0.1, whereas chronic toxicity was exerted in the range of 0.001-0.01. These results confirm that chemical activity has the potential to contribute to the determination, interpretation and prediction of toxicity to aquatic organisms. It also has the potential to enhance regulation of organic chemicals by linking results from laboratory tests, monitoring and modeling programs. The framework can provide an additional line of evidence for assessing aquatic toxicity, for improving the design of toxicity tests, reducing animal usage and addressing chemical mixtures.

Implementation of Mass Cytometry as a Tool for Mechanism of Action Studies in Inflammatory Bowel Disease.

PubMed

Tyler, Christopher J; Pérez-Jeldres, Tamara; Ehinger, Erik; Capaldo, Brian; Karuppuchamy, Thangaraj; Boyer, Joshua D; Patel, Derek; Dulai, Parambir; Boland, Brigid S; Lannigan, Joanne; Eckmann, Lars; Ernst, Peter B; Sandborn, William J; Ho, Samuel B; Rivera-Nieves, Jesús

2018-06-08

Novel therapeutics for inflammatory bowel disease (IBD) are under development, yet mechanistic readouts at the tissue level are lacking. Techniques to assess intestinal immune composition could represent a valuable tool for mechanism of action (MOA) studies of novel drugs. Mass cytometry enables analysis of intestinal inflammatory cell infiltrate and corresponding molecular fingerprints with unprecedented resolution. Here, we aimed to optimize the methodology for isolation and cryopreservation of cells from intestinal tissue to allow for the potential implementation of mass cytometry in MOA studies. We investigated key technical issues, including minimal tissue requirements, cell isolation protocols, and cell storage, using intestinal biopsies and peripheral blood from healthy individuals. High-dimensional mass cytometry was employed for the analyses of biopsy-derived intestinal cellular subsets. Dithiothreitol and mechanical dissociation decreased epithelial cell contamination and allowed for isolation of adequate cell numbers from 2 to 4 colonic or ileal biopsies (6 × 104±2 × 104) after a 20-minute collagenase digestion, allowing for reliable detection of most major immune cell subsets. Biopsies and antibody-labeled mononuclear cells could be cryopreserved for later processing and acquisition (viability > 70%; P < 0.05). Mass cytometry represents a unique tool for deep immunophenotyping intestinal cell composition. This technique has the potential to facilitate analysis of drug actions at the target tissue by identifying specific cellular subsets and their molecular signatures. Its widespread implementation may impact not only IBD research but also other gastrointestinal conditions where inflammatory cells play a role in pathogenesis.

Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats.

PubMed

Maeng, Lisa Y; Cover, Kara K; Taha, Mohamad B; Landau, Aaron J; Milad, Mohammed R; Lebrón-Milad, Kelimer

2017-01-02

There is growing evidence that estradiol (E2) enhances fear extinction memory consolidation. However, it is unclear how E2 influences the nodes of the fear extinction network to enhance extinction memory. This study begins to delineate the neural circuits underlying the influence of E2 on fear extinction acquisition and consolidation in female rats. After fear conditioning (day 1), naturally cycling female rats underwent extinction learning (day 2) in a low-E2 state, receiving a systemic administration of either E2 or vehicle prior to extinction training. Extinction memory recall was then tested 24 hr later (day 3). We measured immediate early gene c-fos expression within the extinction network during fear extinction learning and extinction recall. During extinction learning, E2 treatment increased centrolateral amygdala c-fos activity and reduced lateral amygdala activity relative to vehicle. During extinction recall, E2-treated rats exhibited reduced c-fos expression in the centromedial amygdala. There were no group differences in c-fos expression within the medial prefrontal cortex or dorsal hippocampus. Examining c-fos ratios with the infralimbic cortex (IL) revealed that, despite the lack of group differences within the IL, E2 treatment induced greater IL activity relative to both prelimbic cortex and central amygdala (CeA) activity during extinction memory recall. Only the relationship between IL and CeA activity positively correlated with extinction retention. In conclusion, E2 appears to modify interactions between the IL and the CeA in females, shifting from stronger amygdalar modulation of fear during extinction learning to stronger IL control during extinction recall. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

PubMed Central

Chai, Ning; Liu, Jian-Feng; Xue, Yan-Xue; Yang, Chang; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao; Shi, Hai-Shui; Wang, Ji-Shi; Bao, Yan-Ping; Meng, Shi-Qiu; Ding, Zeng-Bo; Wang, Xue-Yi; Lu, Lin

2014-01-01

Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the β-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the β-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another β-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM. PMID:24553734

Associative learning versus fear habituation as predictors of long-term extinction retention.

PubMed

Brown, Lily A; LeBeau, Richard T; Chat, Ka Yi; Craske, Michelle G

2017-06-01

Violation of unconditioned stimulus (US) expectancy during extinction training may enhance associative learning and result in improved long-term extinction retention compared to within-session habituation. This experiment examines variation in US expectancy (i.e., expectancy violation) as a predictor of long-term extinction retention. It also examines within-session habituation of fear-potentiated startle (electromyography, EMG) and fear of conditioned stimuli (CS) throughout extinction training as predictors of extinction retention. Participants (n = 63) underwent fear conditioning, extinction and retention and provided continuous ratings of US expectancy and EMG, as well as CS fear ratings before and after each phase. Variation in US expectancy throughout extinction and habituation of EMG and fear was entered into a regression as predictors of retention and reinstatement of levels of expectancy and fear. Greater variation in US expectancy throughout extinction training was significantly predictive of enhanced extinction performance measured at retention test, although not after reinstatement test. Slope of EMG and CS fear during extinction did not predict retention of extinction. Within-session habituation of EMG and self-reported fear is not sufficient for long-term retention of extinction learning, and models emphasizing expectation violation may result in enhanced outcomes.

Preventing the return of fear using reconsolidation updating and methylene blue is differentially dependent on extinction learning

PubMed Central

Auchter, Allison M.; Shumake, Jason; Gonzalez-Lima, Francisco; Monfils, Marie H.

2017-01-01

Many factors account for how well individuals extinguish conditioned fears, such as genetic variability, learning capacity and conditions under which extinction training is administered. We predicted that memory-based interventions would be more effective to reduce the reinstatement of fear in subjects genetically predisposed to display more extinction learning. We tested this hypothesis in rats genetically selected for differences in fear extinction using two strategies: (1) attenuation of fear memory using post-retrieval extinction training, and (2) pharmacological enhancement of the extinction memory after extinction training by low-dose USP methylene blue (MB). Subjects selectively bred for divergent extinction phenotypes were fear conditioned to a tone stimulus and administered either standard extinction training or retrieval + extinction. Following extinction, subjects received injections of saline or MB. Both reconsolidation updating and MB administration showed beneficial effects in preventing fear reinstatement, but differed in the groups they targeted. Reconsolidation updating showed an overall effect in reducing fear reinstatement, whereas pharmacological memory enhancement using MB was an effective strategy, but only for individuals who were responsive to extinction. PMID:28397861

Cumulative frequency distribution of past species extinctions

NASA Technical Reports Server (NTRS)

Raup, D. M.

1991-01-01

Analysis of Sepkoski's compendium of the time ranges of 30,000+ taxa yields a mean duration of 28.4 ma for genera of fossil invertebrates. This converts to an average extinction rate of 3.5 percent per million years or about one percent every 286,000 years. Using survivorship techniques, these estimates can be converted to the species level, yielding a Phanerozoic average of one percent species extinction every 40,000 years. Variation in extinction rates through time is far greater than the null expectation of a homogeneous birth-death model and this reflects the well-known episodicity of extinction ranging from a few large mass extinctions to so-called background extinction. The observed variation in rates can be used to construct a cumulative frequency distribution of extinction intensity, and this distribution, in the form of a kill curve for species, shows the expected waiting times between extinction events of a given intensity. The kill curve is an average description of the extinction events of a given intensity. The kill curve is an average description of the extinction record and does not imply any cause or causes of extinction. The kill curve shows, among other things, that only about five percent of total species extinctions in the Phanerozoic were involved in the five largest mass extinctions. The other 95 percent were distributed among large and small events not normally called mass extinctions. As an exploration of the possibly absurd proposition that most past extinctions were produced by the effects of large-body impact, the kill curve for species was mapped on the comparable distribution for comet and asteroid impacts. The result is a curve predicting the species kill for a given size of impacting object (expressed as crater size). The results are reasonable in that impacts producing craters less than 30 km (diameter) cause negligible extinction but those producing craters 100-150 km (diameter) cause extinction of species in the range of 45-60 percent.

Nature and causes of the immediate extinction deficit: a brief review.

PubMed

Maren, Stephen

2014-09-01

Recent data in both rodents and humans suggests that the timing of extinction trials after conditioning influences the magnitude and duration of extinction. For example, administering extinction trials soon after Pavlovian fear conditioning in rats, mice, and humans results in minimal fear suppression - the so-called immediate extinction deficit. Here I review recent work examining the behavioral and neural substrates of the immediate extinction deficit. I suggest that extinction is most effective at some delay after conditioning, because brain systems involved in encoding and retrieving extinction memories function sub-optimally under stress. Copyright © 2013 Elsevier Inc. All rights reserved.

Nature and Causes of the Immediate Extinction Deficit: A Brief Review

PubMed Central

Maren, Stephen

2013-01-01

Recent data in both rodents and humans suggests that the timing of extinction trials after conditioning influences the magnitude and duration of extinction. For example, administering extinction trials soon after Pavlovian fear conditioning in rats, mice, and humans results in minimal fear suppression--the so-called immediate extinction deficit. Here I review recent work examining the behavioral and neural substrates of the immediate extinction deficit. I suggest that extinction is most effective at some delay after conditioning, because brain systems involved in encoding and retrieving extinction memories function sub-optimally under stress. PMID:24176924

The effects of instructions on the sensitivity of negatively reinforced human behavior to extinction.

PubMed

Alessandri, Jérôme; Cançado, Carlos R X

2017-03-01

The effects of instructions on the sensitivity of negatively reinforced (escape) behavior to extinction were studied. Initially, responding produced timeouts from pressing a force cell on a variable-ratio (VR) schedule, which was then discontinued (extinction). Based on extinction data, participants were distributed into two groups. Participants in the Persistence Group (for which response rates were low in extinction) were instructed that the experimenter expected them to continue responding in extinction after a second exposure to the VR schedule. Participants in the Extinction group (for which response rates were high in extinction) were instructed that the experimenter expected them to stop responding in extinction. Relative to the condition in which instructions were absent, extinction-response rates increased and decreased, respectively, for participants in the Persistence and Extinction groups. These results replicate and extend to negatively reinforced responding previous findings that showed behavioral control by instructions formulated as explicit experimenter demands or expectations. Copyright © 2017 Elsevier B.V. All rights reserved.

Extinction and the fossil record

NASA Technical Reports Server (NTRS)

Sepkoski, J. J. Jr; Sepkoski JJ, ,. J. r. (Principal Investigator)

1994-01-01

The author examines evidence of mass extinctions in the fossil record and searches for reasons for such large extinctions. Five major mass extinctions eliminated at least 40 percent of animal genera in the oceans and from 65 to 95 percent of ocean species. Questions include the occurrence of gradual or catastrophic extinctions, causes, environment, the capacity of a perturbation to cause extinctions each time it happens, and the possibility and identification of complex events leading to a mass extinction.

Greenhouse-icehouse transition in the Late Ordovician marks a step change in extinction regime in the marine plankton.

PubMed

Crampton, James S; Cooper, Roger A; Sadler, Peter M; Foote, Michael

2016-02-09

Two distinct regimes of extinction dynamic are present in the major marine zooplankton group, the graptolites, during the Ordovician and Silurian periods (486-418 Ma). In conditions of "background" extinction, which dominated in the Ordovician, taxonomic evolutionary rates were relatively low and the probability of extinction was highest among newly evolved species ("background extinction mode"). A sharp change in extinction regime in the Late Ordovician marked the onset of repeated severe spikes in the extinction rate curve; evolutionary turnover increased greatly in the Silurian, and the extinction mode changed to include extinction that was independent of species age ("high-extinction mode"). This change coincides with a change in global climate, from greenhouse to icehouse conditions. During the most extreme episode of extinction, the Late Ordovician Mass Extinction, old species were selectively removed ("mass extinction mode"). Our analysis indicates that selective regimes in the Paleozoic ocean plankton switched rapidly (generally in <0.5 My) from one mode to another in response to environmental change, even when restoration of the full ecosystem was much slower (several million years). The patterns observed are not a simple consequence of geographic range effects or of taxonomic changes from Ordovician to Silurian. Our results suggest that the dominant primary controls on extinction throughout the lifespan of this clade were abiotic (environmental), probably mediated by the microphytoplankton.

Greenhouse−icehouse transition in the Late Ordovician marks a step change in extinction regime in the marine plankton

PubMed Central

Crampton, James S.; Cooper, Roger A.; Sadler, Peter M.; Foote, Michael

2016-01-01

Two distinct regimes of extinction dynamic are present in the major marine zooplankton group, the graptolites, during the Ordovician and Silurian periods (486−418 Ma). In conditions of “background” extinction, which dominated in the Ordovician, taxonomic evolutionary rates were relatively low and the probability of extinction was highest among newly evolved species (“background extinction mode”). A sharp change in extinction regime in the Late Ordovician marked the onset of repeated severe spikes in the extinction rate curve; evolutionary turnover increased greatly in the Silurian, and the extinction mode changed to include extinction that was independent of species age (“high-extinction mode”). This change coincides with a change in global climate, from greenhouse to icehouse conditions. During the most extreme episode of extinction, the Late Ordovician Mass Extinction, old species were selectively removed (“mass extinction mode”). Our analysis indicates that selective regimes in the Paleozoic ocean plankton switched rapidly (generally in <0.5 My) from one mode to another in response to environmental change, even when restoration of the full ecosystem was much slower (several million years). The patterns observed are not a simple consequence of geographic range effects or of taxonomic changes from Ordovician to Silurian. Our results suggest that the dominant primary controls on extinction throughout the lifespan of this clade were abiotic (environmental), probably mediated by the microphytoplankton. PMID:26811471

Neural circuits via which single prolonged stress exposure leads to fear extinction retention deficits

PubMed Central

Stanfield, Briana R.; Staib, Jennifer M.; David, Nina P.; Keller, Samantha M.; DePietro, Thomas

2016-01-01

Single prolonged stress (SPS) has been used to examine mechanisms via which stress exposure leads to post-traumatic stress disorder symptoms. SPS induces fear extinction retention deficits, but neural circuits critical for mediating these deficits are unknown. To address this gap, we examined the effect of SPS on neural activity in brain regions critical for extinction retention (i.e., fear extinction circuit). These were the ventral hippocampus (vHipp), dorsal hippocampus (dHipp), basolateral amygdala (BLA), prelimbic cortex (PL), and infralimbic cortex (IL). SPS or control rats were fear conditioned then subjected to extinction training and testing. Subsets of rats were euthanized after extinction training, extinction testing, or immediate removal from the housing colony (baseline condition) to assay c-Fos levels (measure of neural activity) in respective brain region. SPS induced extinction retention deficits. During extinction training SPS disrupted enhanced IL neural activity and inhibited BLA neural activity. SPS also disrupted inhibited BLA and vHipp neural activity during extinction testing. Statistical analyses suggested that SPS disrupted functional connectivity within the dHipp during extinction training and increased functional connectivity between the BLA and vHipp during extinction testing. Our findings suggest that SPS induces extinction retention deficits by disrupting both excitatory and inhibitory changes in neural activity within the fear extinction circuit and inducing changes in functional connectivity within the Hipp and BLA. PMID:27918273

HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner.

PubMed

Malvaez, Melissa; McQuown, Susan C; Rogge, George A; Astarabadi, Mariam; Jacques, Vincent; Carreiro, Samantha; Rusche, James R; Wood, Marcelo A

2013-02-12

Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.

The biology of mass extinction: a palaeontological view

NASA Technical Reports Server (NTRS)

Jablonski, D.; Raup, D. M. (Principal Investigator)

1989-01-01

Extinctions are not biologically random: certain taxa or functional/ecological groups are more extinction-prone than others. Analysis of molluscan survivorship patterns for the end-Cretaceous mass extinctions suggests that some traits that tend to confer extinction resistance during times of normal ('background') levels of extinction are ineffectual during mass extinction. For genera, high species-richness and possession of widespread individual species imparted extinction-resistance during background times but not during the mass extinction, when overall distribution of the genus was an important factor. Reanalysis of Hoffman's (1986) data (Neues Jb. Geol. Palaont. Abh. 172, 219) on European bivalves, and preliminary analysis of a new northern European data set, reveals a similar change in survivorship rules, as do data scattered among other taxa and extinction events. Thus taxa and adaptations can be lost not because they were poorly adapted by the standards of the background processes that constitute the bulk of geological time, but because they lacked--or were not linked to--the organismic, species-level or clade-level traits favoured under mass-extinction conditions. Mass extinctions can break the hegemony of species-rich, well-adapted clades and thereby permit radiation of taxa that had previously been minor faunal elements; no net increase in the adaptation of the biota need ensue. Although some large-scale evolutionary trends transcend mass extinctions, post extinction evolutionary pathways are often channelled in directions not predictable from evolutionary patters during background times.

Immediate Extinction Causes a Less Durable Loss of Performance than Delayed Extinction following Either Fear or Appetitive Conditioning

ERIC Educational Resources Information Center

Woods, Amanda M.; Bouton, Mark E.

2008-01-01

Five experiments with rat subjects compared the effects of immediate and delayed extinction on the durability of extinction learning. Three experiments examined extinction of fear conditioning (using the conditioned emotional response method), and two experiments examined extinction of appetitive conditioning (using the food-cup entry method). In…

Activation of orexin/hypocretin neurons is associated with individual differences in cued fear extinction.

PubMed

Sharko, Amanda C; Fadel, Jim R; Kaigler, Kris F; Wilson, Marlene A

2017-09-01

Identifying the neurobiological mechanisms that underlie differential sensitivity to stress is critical for understanding the development and expression of stress-induced disorders, such as post-traumatic stress disorder (PTSD). Preclinical studies have suggested that rodents display different phenotypes associated with extinction of Pavlovian conditioned fear responses, with some rodent populations being resistant to extinction. An emerging literature also suggests a role for orexins in the consolidation processes associated with fear learning and extinction. To examine the possibility that the orexin system might be involved in individual differences in fear extinction, we used a Pavlovian conditioning paradigm in outbred Long-Evans rats. Rats showed significant variability in the extinction of cue-conditioned freezing and extinction recall, and animals were divided into groups based on their extinction profiles based on a median split of percent freezing behavior during repeated exposure to the conditioned cue. Animals resistant to extinction (high freezers) showed more freezing during repeated cue presentations during the within trial and between trial extinction sessions compared with the group showing significant extinction (low freezers), although there were no differences between these groups in freezing upon return to the conditioned context or during the conditioning session. Following the extinction recall session, activation of orexin neurons was determined using dual label immunohistochemistry for cFos in orexin positive neurons in the hypothalamus. Individual differences in the extinction of cue conditioned fear were associated with differential activation of hypothalamic orexin neurons. Animals showing poor extinction of cue-induced freezing (high freezers) had significantly greater percentage of orexin neurons with Fos in the medial hypothalamus than animals displaying significant extinction and good extinction recall (low freezers). Further, the freezing during extinction learning was positively correlated with the percentage of activated orexin neurons in both the lateral and medial hypothalamic regions. No differences in the overall density of orexin neurons or Fos activation were seen between extinction phenotypes. Although correlative, our results support other studies implicating a role of the orexinergic system in regulating extinction of conditioned responses to threat. Copyright © 2016 Elsevier Inc. All rights reserved.

Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy.

PubMed

MacPherson, Kathryn; Whittle, Nigel; Camp, Marguerite; Gunduz-Cinar, Ozge; Singewald, Nicolas; Holmes, Andrew

2013-07-05

Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. While there is growing evidence that fear extinction is influenced by certain procedural variables, it is unclear how these influences might vary across individuals and subpopulations. To model individual differences in fear extinction, prior studies identified a strain of inbred mouse, 129S1/SvImJ (S1), which exhibits a profound deficit in fear extinction, as compared to other inbred strains, such as C57BL/6J (B6). Here, we assessed the effects of procedural variables on the impaired extinction phenotype of the S1 strain and, by comparison, the extinction-intact B6 strain. The variables studied were 1) the interval between conditioning and extinction, 2) the interval between cues during extinction training, 3) single-cue exposure before extinction training, and 4) extinction of a second-order conditioned cue. Conducting extinction training soon after ('immediately') conditioning attenuated fear retrieval in S1 mice and impaired extinction in B6 mice. Spacing cue presentations with long inter-trial intervals during extinction training augmented fear in S1 and B6 mice. The effect of spacing was lost with one-trial fear conditioning in B6, but not S1 mice. A single exposure to a conditioned cue before extinction training did not alter extinction retrieval, either in B6 or S1 mice. Both the S1 and B6 strains exhibited robust second-order fear conditioning, in which a cue associated with footshock was sufficient to serve as a conditioned exciter to condition a fear association to a second cue. B6 mice extinguished the fear response to the second-order conditioned cue, but S1 mice failed to do so. These data provide further evidence that fear extinction is strongly influenced by multiple procedural variables and is so in a highly strain-dependent manner. This suggests that the efficacy of extinction-based behavioral interventions, such as exposure therapy, for trauma-related anxiety disorders will be determined by the procedural parameters employed and the degree to which the patient can extinguish.

Can Transcranial Direct Current Stimulation Augment Extinction of Conditioned Fear?

PubMed Central

van ’t Wout, Mascha; Mariano, Timothy Y.; Garnaat, Sarah L.; Reddy, Madhavi K.; Rasmussen, Steven A.; Greenberg, Benjamin D.

2016-01-01

Background Exposure-based therapy parallels extinction learning of conditioned fear. Prior research points to the ventromedial prefrontal cortex as a potential site for the consolidation of extinction learning and subsequent retention of extinction memory. Objective/hypothesis The present study aimed to evaluate whether the application of non-invasive transcranial direct current stimulation (tDCS) during extinction learning enhances late extinction and early recall in human participants. Methods Forty-four healthy volunteers completed a 2-day Pavlovian fear conditioning, extinction, and recall paradigm while skin conductance activity was continuously measured. Twenty-six participants received 2 mA anodal tDCS over EEG coordinate AF3 during extinction of a first conditioned stimulus. The remaining 18 participants received similar tDCS during extinction of a second conditioned stimulus. Sham stimulation was applied for the balance of extinction trials in both groups. Normalized skin conductance changes were analyzed using linear mixed models to evaluate effects of tDCS over late extinction and early recall trials. Results We observed a significant interaction between timing of tDCS during extinction blocks and changes in skin conductance reactivity over late extinction trials. These data indicate that tDCS was associated with accelerated late extinction learning of a second conditioned stimulus after tDCS was combined with extinction learning of a previous conditioned stimulus. No significant effects of tDCS timing were observed on early extinction recall. Conclusions Results could be explained by an anxiolytic aftereffect of tDCS and extend previous studies on tDCS-induced modulation of fear and threat related learning processes. These findings support further exploration of the clinical use of tDCS. PMID:27037186

Biological extinction in earth history

NASA Technical Reports Server (NTRS)

Raup, D. M.

1986-01-01

Virtually all plant and animal species that have ever lived on the earth are extinct. For this reason alone, extinction must play an important role in the evolution of life. The five largest mass extinctions of the past 600 million years are of greatest interest, but there is also a spectrum of smaller events, many of which indicate biological systems in profound stress. Extinction may be episodic at all scales, with relatively long periods of stability alternating with short-lived extinction events. Most extinction episodes are biologically selective, and further analysis of the victims and survivors offers the greatest chance of deducing the proximal causes of extinction. A drop in sea level and climatic change are most frequently invoked to explain mass extinctions, but new theories of collisions with extraterrestrial bodies are gaining favor. Extinction may be constructive in a Darwinian sense or it may only perturb the system by eliminating those organisms that happen to be susceptible to geologically rare stresses.

Erasing fear memories with extinction training

PubMed Central

Quirk, Gregory J.; Paré, Denis; Richardson, Rick; Herry, Cyril; Monfils, Marie H.; Schiller, Daniela; Vicentic, Aleksandra

2012-01-01

Decades of behavioral studies have confirmed that extinction does not erase classically-conditioned fear memories. For this reason, research efforts have focused on the mechanisms underlying the development of extinction-induced inhibition within fear circuits. However, recent studies in rodents have uncovered mechanisms that stabilize and destabilize fear memories, opening the possibility that extinction might be used to erase fear memories. This symposium focuses on several of these new developments, which involve the timing of extinction training. Extinction-induced erasure of fear occurs in very young rats, but is lost with the development of perineuronal nets in the amygdala that render fear memories impervious to extinction. Moreover, extinction administered during the reconsolidation phase, when fear memory is destabilized, updates the fear association as safe, thereby preventing the return of fear, in both rats and humans. The use of modified extinction protocols to eliminate fear memories complements existing pharmacological strategies for strengthening extinction. PMID:21068303

Extinction rates in North American freshwater fishes, 1900-2010

USGS Publications Warehouse

Burkhead, Noel M.

2012-01-01

Widespread evidence shows that the modern rates of extinction in many plants and animals exceed background rates in the fossil record. In the present article, I investigate this issue with regard to North American freshwater fishes. From 1898 to 2006, 57 taxa became extinct, and three distinct populations were extirpated from the continent. Since 1989, the numbers of extinct North American fishes have increased by 25%. From the end of the nineteenth century to the present, modern extinctions varied by decade but significantly increased after 1950 (post-1950s mean = 7.5 extinct taxa per decade). The modern extinction rate for North American freshwater fishes is conservatively estimated to be 877 times greater than the background extinction rate for freshwater fishes (one extinction every 3 million years). Reasonable estimates project that future increases in extinctions will range from 53 to 86 species by 2050.

The changing role of mammal life histories in Late Quaternary extinction vulnerability on continents and islands

PubMed Central

Miller, Joshua H.; Fraser, Danielle; Smith, Felisa A.; Boyer, Alison; Lindsey, Emily; Mychajliw, Alexis M.

2016-01-01

Understanding extinction drivers in a human-dominated world is necessary to preserve biodiversity. We provide an overview of Quaternary extinctions and compare mammalian extinction events on continents and islands after human arrival in system-specific prehistoric and historic contexts. We highlight the role of body size and life-history traits in these extinctions. We find a significant size-bias except for extinctions on small islands in historic times. Using phylogenetic regression and classification trees, we find that while life-history traits are poor predictors of historic extinctions, those associated with difficulty in responding quickly to perturbations, such as small litter size, are good predictors of prehistoric extinctions. Our results are consistent with the idea that prehistoric and historic extinctions form a single continuing event with the same likely primary driver, humans, but the diversity of impacts and affected faunas is much greater in historic extinctions. PMID:27330176

The changing role of mammal life histories in Late Quaternary extinction vulnerability on continents and islands.

PubMed

Lyons, S Kathleen; Miller, Joshua H; Fraser, Danielle; Smith, Felisa A; Boyer, Alison; Lindsey, Emily; Mychajliw, Alexis M

2016-06-01

Understanding extinction drivers in a human-dominated world is necessary to preserve biodiversity. We provide an overview of Quaternary extinctions and compare mammalian extinction events on continents and islands after human arrival in system-specific prehistoric and historic contexts. We highlight the role of body size and life-history traits in these extinctions. We find a significant size-bias except for extinctions on small islands in historic times. Using phylogenetic regression and classification trees, we find that while life-history traits are poor predictors of historic extinctions, those associated with difficulty in responding quickly to perturbations, such as small litter size, are good predictors of prehistoric extinctions. Our results are consistent with the idea that prehistoric and historic extinctions form a single continuing event with the same likely primary driver, humans, but the diversity of impacts and affected faunas is much greater in historic extinctions. © 2016 The Author(s).

Biological Extinction in Earth History

NASA Astrophysics Data System (ADS)

Raup, David M.

1986-03-01

Virtually all plant and animal species that have ever lived on the earth are extinct. For this reason alone, extinction must play an important role in the evolution of life. The five largest mass extinctions of the past 600 million years are of greatest interest, but there is also a spectrum of smaller events, many of which indicate biological systems in profound stress. Extinction may be episodic at all scales, with relatively long periods of stability alternating with short-lived extinction events. Most extinction episodes are biologically selective, and further analysis of the victims and survivors offers the greatest chance of deducing the proximal causes of extinction. A drop in sea level and climatic change are most frequently invoked to explain mass extinctions, but new theories of collisions with extraterrestrial bodies are gaining favor. Extinction may be constructive in a Darwinian sense or it may only perturb the system by eliminating those organisms that happen to be susceptible to geologically rare stresses.

Pharmacological evidence that a failure to recruit NMDA receptors contributes to impaired fear extinction retention in adolescent rats.

PubMed

Baker, Kathryn D; Richardson, Rick

2017-09-01

Adolescents, both humans and rodents, exhibit a marked impairment in extinction of fear relative to younger and older groups which could be caused by a failure to efficiently recruit NMDA receptors (NMDARs) in adolescence. It is well-established that systemic administration of NMDAR antagonists (e.g., MK801) before extinction training impairs the retention of extinction in adult and juvenile rodents, but it is unknown whether this is also the case for adolescents. Therefore, in the present study we investigated the effect of pharmacologically manipulating the NMDAR on extinction retention in adolescent rats. When extinction retention is typically impaired (i.e., after one session of extinction training) adolescent male rats given d-cycloserine (a partial NMDAR agonist) showed enhanced extinction retention relative to saline-treated animals while animals given MK801 (a non-competitive antagonist) did not exhibit any further impairment of extinction retention relative to the controls. In a further two experiments we demonstrated that when two sessions of extinction training separated by either 4 or 24h intervals were given to adolescent rats, saline-treated animals exhibited good extinction retention and the animals given MK801 before the second session exhibited impaired extinction retention. These findings suggest that extinction in adolescence does not initially involve NMDARs and this is a likely mechanism that contributes to the impaired fear inhibition observed at this age. However, NMDARs appear to be recruited with extended extinction training or after administration of a partial agonist, both of which lead to effective extinction retention. Copyright © 2016 Elsevier Inc. All rights reserved.

Forming competing fear learning and extinction memories in adolescence makes fear difficult to inhibit

PubMed Central

Richardson, Rick

2015-01-01

Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats (n = 170) were tested for extinction retention after conditioning and extinction at different ages. We examined neural correlates of impaired extinction retention by detection of phosphorylated mitogen-activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions. Unexpectedly, adolescent rats exhibited good extinction retention if fear was acquired before adolescence. Further, fear acquired in adolescence could be successfully extinguished in adulthood but not within adolescence. Adolescent rats did not show extinction-induced increases in pMAPK-IR in the medial prefrontal cortex or the basolateral amygdala, or a pattern of reduced caudal central amygdala pMAPK-IR, as was observed in juveniles. This dampened prefrontal and basolateral amygdala MAPK activation following extinction in adolescence occurred even when there was no impairment in extinction retention. In contrast, only adolescent animals that exhibited impaired extinction retention showed elevated pMAPK-IR in the posterior paraventricular thalamus. These data suggest that neither the animal's age at the time of fear acquisition or extinction determines whether impaired extinction retention is exhibited. Rather, it appears that forming competing fear conditioning and extinction memories in adolescence renders this a vulnerable developmental period in which fear is difficult to inhibit. Furthermore, even under conditions that promote good extinction, the neural correlates of extinction in adolescence are different than those recruited in animals of other ages. PMID:26472643

Effects of sleep on memory for conditioned fear and fear extinction

PubMed Central

Pace-Schott, Edward F.; Germain, Anne; Milad, Mohammed R.

2015-01-01

Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. REM may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep’s effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. PMID:25894546

Effects of sleep on memory for conditioned fear and fear extinction.

PubMed

Pace-Schott, Edward F; Germain, Anne; Milad, Mohammed R

2015-07-01

Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning, and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. Rapid eye movement (REM) may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction, and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep's effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

VizieR Online Data Catalog: Coefficients for passband extinctions (Sale+, 2015)

NASA Astrophysics Data System (ADS)

Sale, S. E.; Magorrian, J.

2017-11-01

We have considered how one should measure the distance and extinction to individual stars for use in constructing extinction maps of the whole Galaxy. We advocate the use of monochromatic extinctions, since, unlike bandpass measures such as AV and E(B-V), monochromatic extinctions are linear functions of the dust column density and are independent of the source SED. In particular we suggest the use of A4000, the monochromatic extinction at 4000Å because of its insensitivity to the dust grain size distribution. Files for converting from A_4000 to passband extinctions at 35 RV extinction law value and for 11 photometric systems. (2 data files).

Metapopulation extinction risk: dispersal's duplicity.

PubMed

Higgins, Kevin

2009-09-01

Metapopulation extinction risk is the probability that all local populations are simultaneously extinct during a fixed time frame. Dispersal may reduce a metapopulation's extinction risk by raising its average per-capita growth rate. By contrast, dispersal may raise a metapopulation's extinction risk by reducing its average population density. Which effect prevails is controlled by habitat fragmentation. Dispersal in mildly fragmented habitat reduces a metapopulation's extinction risk by raising its average per-capita growth rate without causing any appreciable drop in its average population density. By contrast, dispersal in severely fragmented habitat raises a metapopulation's extinction risk because the rise in its average per-capita growth rate is more than offset by the decline in its average population density. The metapopulation model used here shows several other interesting phenomena. Dispersal in sufficiently fragmented habitat reduces a metapopulation's extinction risk to that of a constant environment. Dispersal between habitat fragments reduces a metapopulation's extinction risk insofar as local environments are asynchronous. Grouped dispersal raises the effective habitat fragmentation level. Dispersal search barriers raise metapopulation extinction risk. Nonuniform dispersal may reduce the effective fraction of suitable habitat fragments below the extinction threshold. Nonuniform dispersal may make demographic stochasticity a more potent metapopulation extinction force than environmental stochasticity.

Climate change. Accelerating extinction risk from climate change.

PubMed

Urban, Mark C

2015-05-01

Current predictions of extinction risks from climate change vary widely depending on the specific assumptions and geographic and taxonomic focus of each study. I synthesized published studies in order to estimate a global mean extinction rate and determine which factors contribute the greatest uncertainty to climate change-induced extinction risks. Results suggest that extinction risks will accelerate with future global temperatures, threatening up to one in six species under current policies. Extinction risks were highest in South America, Australia, and New Zealand, and risks did not vary by taxonomic group. Realistic assumptions about extinction debt and dispersal capacity substantially increased extinction risks. We urgently need to adopt strategies that limit further climate change if we are to avoid an acceleration of global extinctions. Copyright © 2015, American Association for the Advancement of Science.

Gradients of Fear Potentiated Startle During Generalization, Extinction, and Extinction Recall--and Their Relations With Worry.

PubMed

Dunning, Jonathan P; Hajcak, Greg

2015-09-01

It is well established that fear conditioning plays a role in the development and maintenance of anxiety disorders. Moreover, abnormalities in fear generalization, extinction, and extinction recall have also been associated with anxiety. The present study used a generalization paradigm to examine fear processing during phases of generalization, extinction, and extinction recall. Specifically, participants were shocked following a CS+ and were also presented with stimuli that ranged in perceptual similarity to the CS+ (i.e., 20%, 40%, or 60% smaller or larger than the CS+) during a fear generalization phase. Participants were also presented with the same stimuli during an extinction phase and an extinction recall phase 1week later; no shocks were presented during extinction or recall. Lastly, participants completed self-report measures of worry and trait anxiety. Results indicated that fear potentiated startle (FPS) to the CS+ and GS±20% shapes was present in generalization and extinction, suggesting that fear generalization persisted into extinction. FPS to the CS+ was also evident 1 week later during extinction recall. Higher levels of worry were associated with greater FPS to the CS+ during generalization and extinction phases. Moreover, individuals high in worry had fear response gradients that were steeper during both generalization and extinction. This suggests that high levels of worry are associated with greater discriminative fear conditioning to threatening compared to safe stimuli and less fear generalization to perceptually similar stimuli. Copyright © 2015. Published by Elsevier Ltd.

Neural circuits via which single prolonged stress exposure leads to fear extinction retention deficits.

PubMed

Knox, Dayan; Stanfield, Briana R; Staib, Jennifer M; David, Nina P; Keller, Samantha M; DePietro, Thomas

2016-12-01

Single prolonged stress (SPS) has been used to examine mechanisms via which stress exposure leads to post-traumatic stress disorder symptoms. SPS induces fear extinction retention deficits, but neural circuits critical for mediating these deficits are unknown. To address this gap, we examined the effect of SPS on neural activity in brain regions critical for extinction retention (i.e., fear extinction circuit). These were the ventral hippocampus (vHipp), dorsal hippocampus (dHipp), basolateral amygdala (BLA), prelimbic cortex (PL), and infralimbic cortex (IL). SPS or control rats were fear conditioned then subjected to extinction training and testing. Subsets of rats were euthanized after extinction training, extinction testing, or immediate removal from the housing colony (baseline condition) to assay c-Fos levels (measure of neural activity) in respective brain region. SPS induced extinction retention deficits. During extinction training SPS disrupted enhanced IL neural activity and inhibited BLA neural activity. SPS also disrupted inhibited BLA and vHipp neural activity during extinction testing. Statistical analyses suggested that SPS disrupted functional connectivity within the dHipp during extinction training and increased functional connectivity between the BLA and vHipp during extinction testing. Our findings suggest that SPS induces extinction retention deficits by disrupting both excitatory and inhibitory changes in neural activity within the fear extinction circuit and inducing changes in functional connectivity within the Hipp and BLA. © 2016 Knox et al.; Published by Cold Spring Harbor Laboratory Press.

Immediate Extinction Attenuates Spontaneous Recovery and Reinstatement in a Passive Avoidance Paradigm.

PubMed

Briggs, James F; Fava, Devin A

2016-08-01

Recent research suggests that extinction occurring shortly after fear conditioning attenuates spontaneous recovery and reinstatement of fear. Two experiments investigated whether immediate extinction would prevent spontaneous recovery and reinstatement of fear using a passive avoidance paradigm. In Experiment 1, naive female adult rats (N = 40) received extinction training either immediately or 24 hours (delayed) after fear conditioning. Both extinction groups showed a significant reduction in fear at a 1-day test. At a 15-day test, spontaneous recovery was observed in the delayed extinction group while the immediate extinction group continued to show significant extinction. In Experiment 2, using a naive group of adult female rats (N = 16), the extinction result was replicated in both the immediate and delayed extinction groups at the 1-day interval. Reinstatement of fear, elicited by foot-shock in a neutral environment, was observed for the delayed group but not for the immediate group. By utilizing the passive-avoidance paradigm, these experiments replicate and extend previous findings that immediate extinction attenuates spontaneous recovery and reinstatement of fear. © The Author(s) 2016.

Impact as a general cause of extinction: A feasibility test

NASA Technical Reports Server (NTRS)

Raup, David M.

1988-01-01

Large body impact has been implicated as the possible cause of several extinction events. This is entirely plausible if one accepts two propositions: (1) that impacts of large comets and asteroids produce environmental effects severe enough to cause significant species extinctions and (2) that the estimates of comet and asteroid flux for the Phanerozoic are approximately correct. A resonable next step is to investigate the possibility that impact could be a significant factor in the broader Phanerozoic extinction record, not limited merely to a few events of mass extinction. Monte Carlo simulation experiments based on existing flux estimates and reasonable predictions of the relationship between bolide diameter and extinction are discussed. The simulation results raise the serious possibility that large body impact may be a more pervasive factor in extinction than has been assumed heretofore. At the very least, the experiments show that the comet and asteroid flux estimates combined with a reasonable kill curve produces a reasonable extinction record, complete with occasional mass extinctions and the irregular, lower intensity extinctions commonly called background extinction.

Environmental Assessment for Lowering Base Altitude of Military Operations Areas

DTIC Science & Technology

2010-11-01

collection of information if it does not display a currently valid OMB control number. 1. REPORT DATE NOV 2010 2. REPORT TYPE 3. DATES COVERED 00-00...single T-38C overflight at 8,700 feet AGL (i.e., the current base altitude of the MOAs) is 63 dBA, while the noise from the aircraft at 6,700 feet AGL... Current Bird Census for Salt Plains National Wildlife Refuge: May 6, 2010 ....... 3-24  Table 3-13 Washita Wildlife Refuge 2008 Christmas Bird Count

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gould, A.; Yee, J. C.; Pinsonneault, M. H.

The Galactic bulge source MOA-2010-BLG-523S exhibited short-term deviations from a standard microlensing light curve near the peak of an A {sub max} {approx} 265 high-magnification microlensing event. The deviations originally seemed consistent with expectations for a planetary companion to the principal lens. We combine long-term photometric monitoring with a previously published high-resolution spectrum taken near peak to demonstrate that this is an RS CVn variable, so that planetary microlensing is not required to explain the light-curve deviations. This is the first spectroscopically confirmed RS CVn star discovered in the Galactic bulge.

Cytoscape file of chemical networks

EPA Pesticide Factsheets

The maximum connectivity scores of pairwise chemical conditions summarized from Cmap results in a file with Cytoscape format (http://www.cytoscape.org/). The figures in the publication were generated from this file. The Cytoscape file is formed from importing the eight text file therein.This dataset is associated with the following publication:Wang , R., A. Biales , N. Garcia-Reyero, E. Perkins, D. Villeneuve, G. Ankley, and D. Bencic. Fish Connectivity Mapping: Linking Chemical Stressors by Their MOA-Driven Transcriptomic Profiles. BMC Genomics. BioMed Central Ltd, London, UK, 17(84): 1-20, (2016).

The ghosts of mammals past: biological and geographical patterns of global mammalian extinction across the Holocene.

PubMed

Turvey, Samuel T; Fritz, Susanne A

2011-09-12

Although the recent historical period is usually treated as a temporal base-line for understanding patterns of mammal extinction, mammalian biodiversity loss has also taken place throughout the Late Quaternary. We explore the spatial, taxonomic and phylogenetic patterns of 241 mammal species extinctions known to have occurred during the Holocene up to the present day. To assess whether our understanding of mammalian threat processes has been affected by excluding these taxa, we incorporate extinct species data into analyses of the impact of body mass on extinction risk. We find that Holocene extinctions have been phylogenetically and spatially concentrated in specific taxa and geographical regions, which are often not congruent with those disproportionately at risk today. Large-bodied mammals have also been more extinction-prone in most geographical regions across the Holocene. Our data support the extinction filter hypothesis, whereby regional faunas from which susceptible species have already become extinct now appear less threatened; they may also suggest that different processes are responsible for driving past and present extinctions. We also find overall incompleteness and inter-regional biases in extinction data from the recent fossil record. Although direct use of fossil data in future projections of extinction risk is therefore not straightforward, insights into extinction processes from the Holocene record are still useful in understanding mammalian threat.

Calcineurin inhibition blocks within-, but not between-session fear extinction in mice

PubMed Central

Moulin, Thiago C.; Carneiro, Clarissa F. D.; Gonçalves, Marina M. C.; Junqueira, Lara S.; Amaral, Olavo B.

2015-01-01

Memory extinction involves the formation of a new associative memory that inhibits a previously conditioned association. Nonetheless, it could also depend on weakening of the original memory trace if extinction is assumed to have multiple components. The phosphatase calcineurin (CaN) has been described as being involved in extinction but not in the initial consolidation of fear learning. With this in mind, we set to study whether CaN could have different roles in distinct components of extinction. Systemic treatment with the CaN inhibitors cyclosporin A (CsA) or FK-506, as well as i.c.v. administration of CsA, blocked within-session, but not between-session extinction or initial learning of contextual fear conditioning. Similar effects were found in multiple-session extinction of contextual fear conditioning and in auditory fear conditioning, indicating that CaN is involved in different types of short-term extinction. Meanwhile, inhibition of protein synthesis by cycloheximide (CHX) treatment did not affect within-session extinction, but disrupted fear acquisition and slightly impaired between-session extinction. Our results point to a dissociation of within- and between-session extinction of fear conditioning, with the former being more dependent on CaN activity and the latter on protein synthesis. Moreover, the modulation of within-session extinction did not affect between-session extinction, suggesting that these components are at least partially independent. PMID:25691516

The ghosts of mammals past: biological and geographical patterns of global mammalian extinction across the Holocene

PubMed Central

Turvey, Samuel T.; Fritz, Susanne A.

2011-01-01

Although the recent historical period is usually treated as a temporal base-line for understanding patterns of mammal extinction, mammalian biodiversity loss has also taken place throughout the Late Quaternary. We explore the spatial, taxonomic and phylogenetic patterns of 241 mammal species extinctions known to have occurred during the Holocene up to the present day. To assess whether our understanding of mammalian threat processes has been affected by excluding these taxa, we incorporate extinct species data into analyses of the impact of body mass on extinction risk. We find that Holocene extinctions have been phylogenetically and spatially concentrated in specific taxa and geographical regions, which are often not congruent with those disproportionately at risk today. Large-bodied mammals have also been more extinction-prone in most geographical regions across the Holocene. Our data support the extinction filter hypothesis, whereby regional faunas from which susceptible species have already become extinct now appear less threatened; they may also suggest that different processes are responsible for driving past and present extinctions. We also find overall incompleteness and inter-regional biases in extinction data from the recent fossil record. Although direct use of fossil data in future projections of extinction risk is therefore not straightforward, insights into extinction processes from the Holocene record are still useful in understanding mammalian threat. PMID:21807737

Extinguishing trace fear engages the retrosplenial cortex rather than the amygdala

PubMed Central

Kwapis, Janine L.; Jarome, Timothy J.; Lee, Jonathan L.; Gilmartin, Marieke R.; Helmstetter, Fred J.

2013-01-01

Extinction learning underlies the treatment for a variety of anxiety disorders. Most of what is known about the neurobiology of extinction is based on standard “delay” fear conditioning, in which awareness is not required for learning. Little is known about how complex, explicit associations extinguish, however. “Trace” conditioning is considered to be a rodent model of explicit fear because it relies on both the cortex and hippocampus and requires explicit contingency awareness in humans. Here, we explore the neural circuit supporting trace fear extinction in order to better understand how complex memories extinguish. We first show that the amygdala is selectively involved in delay fear extinction; blocking intra-amygdala glutamate receptors disrupted delay, but not trace extinction. Further, ERK phosphorylation was increased in the amygdala after delay, but not trace extinction. We then identify the retrosplenial cortex (RSC) as a key structure supporting trace extinction. ERK phosphorylation was selectively increased in the RSC following trace extinction and blocking intra-RSC NMDA receptors impaired trace, but not delay extinction. These findings indicate that delay and trace extinction require different neural circuits; delay extinction requires plasticity in the amygdala whereas trace extinction requires the RSC. Anxiety disorders linked to explicit memory may therefore depend on cortical processes that have not been traditionally targeted by extinction studies based on delay fear. PMID:24055593

Effects of D-cycloserine on the extinction of appetitive operant learning

PubMed Central

Vurbic, Drina; Gold, Benjamin; Bouton, Mark E.

2011-01-01

Four experiments with rat subjects examined whether D-cycloserine (DCS), a partial NMDA agonist, facilitates the extinction of operant lever-pressing reinforced by food. Previous research has demonstrated that DCS facilitates extinction learning with methods that involve Pavlovian extinction. In the current experiments, operant conditioning occurred in Context A, extinction in Context B, and then testing occurred in both the extinction and conditioning contexts. Experiments 1a and 1b tested the effects of three doses of DCS (5, 15, and 30 mg/kg) on the extinction of lever pressing trained as a free operant. Experiment 2 examined their effects when extinction of the free operant was conducted in the presence of non-response-contingent deliveries of the reinforcer (which theoretically reduced the role of generalization decrement in suppressing responding). Experiment 3 examined their effects on extinction of a discriminated operant, i.e., one that had been reinforced in the presence of a discriminative stimulus, but not in its absence. A strong ABA renewal effect was observed in all four experiments during testing. However, despite the use of DCS doses and a drug administration procedure that facilitates the extinction of Pavlovian learning, there was no evidence in any experiment that DCS facilitated operant extinction learning assessed in either the extinction or the conditioning context. DCS may primarily facilitate learning processes that underlie Pavlovian, rather than purely operant, extinction. PMID:21688894

Extinction from a paleontological perspective

NASA Technical Reports Server (NTRS)

Raup, D. M.

1993-01-01

Extinction of widespread species is common in evolutionary time (millions of years) but rare in ecological time (hundreds or thousands of years). In the fossil record, there appears to be a smooth continuum between background and mass extinction; and the clustering of extinctions at mass extinctions cannot be explained by the chance coincidence of independent events. Although some extinction is selective, much is apparently random in that survivors have no recognizable superiority over victims. Extinction certainly plays an important role in evolution, but whether it is constructive or destructive has not yet been determined.

Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model

PubMed Central

Whittle, Nigel; Schmuckermair, Claudia; Gunduz Cinar, Ozge; Hauschild, Markus; Ferraguti, Francesco; Holmes, Andrew; Singewald, Nicolas

2013-01-01

Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled ‘Cognitive Enhancers’. PMID:22722028

Opposing effects of D-cycloserine on fear despite a common extinction duration: interactions between brain regions and behavior.

PubMed

Bolkan, Scott S; Lattal, K Matthew

2014-09-01

A number of studies have reported that D-cycloserine (DCS), a partial agonist of the N-methyl-D-aspartate glutamate receptor, can facilitate the loss of conditioned fear if it is administered during an extinction trial. Here we examine the effects of DCS injected into the hippocampus or amygdala on extinction of context-evoked freezing after contextual fear conditioning in C57BL/6 mice. We find that DCS administered prior to an extinction session decreased freezing from the outset of the session regardless of which brain region was targeted. Retention tests revealed opposite effects on fear expression despite identical behavioral treatments: intra-hippocampal DCS inhibited fear expression while intra-amygdala DCS potentiated fear expression. Following post-extinction session injections of DCS, we found a similar though less pronounced effect. Closer inspection of the data revealed that the effects of DCS interacted with the behavior of the subjects during extinction. Intra-hippocampal injections of DCS enhanced extinction in those mice that showed the greatest amount of within-session extinction, but had less pronounced effects on mice that showed the least within-session extinction. Intra-amygdala injections of DCS impaired extinction in those mice that showed the least within-session extinction, but there was some evidence that the effect in the amygdala did not depend on behavior during extinction. These findings demonstrate that even with identical extinction trial durations, the effects of DCS administered into the hippocampus and amygdala can heavily depend on the organism's behavior during the extinction session. The broader implication of these findings is that the effects of pharmacological treatments designed to enhance extinction by targeting hippocampal or amygdalar processes may depend on the responsivity of the subject to the behavioral treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder

PubMed Central

Milad, Mohammed R.; Pitman, Roger K.; Ellis, Cameron B.; Gold, Andrea L.; Shin, Lisa M; Lasko, Natasha B.; Zeidan, Mohamed A.; Handwerger, Kathryn; Orr, Scott P.; Rauch, Scott L.

2009-01-01

Background: A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). Methods: Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD controls (TENCs) underwent a two-day fear conditioning and extinction protocol in a 3T fMRI scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response. Results: SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of fMRI data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC, and greater activation in dACC, was observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing. Conclusions: These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment. PMID:19748076

Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy

PubMed Central

2013-01-01

Background Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. While there is growing evidence that fear extinction is influenced by certain procedural variables, it is unclear how these influences might vary across individuals and subpopulations. To model individual differences in fear extinction, prior studies identified a strain of inbred mouse, 129S1/SvImJ (S1), which exhibits a profound deficit in fear extinction, as compared to other inbred strains, such as C57BL/6J (B6). Methods Here, we assessed the effects of procedural variables on the impaired extinction phenotype of the S1 strain and, by comparison, the extinction-intact B6 strain. The variables studied were 1) the interval between conditioning and extinction, 2) the interval between cues during extinction training, 3) single-cue exposure before extinction training, and 4) extinction of a second-order conditioned cue. Results Conducting extinction training soon after (‘immediately’) conditioning attenuated fear retrieval in S1 mice and impaired extinction in B6 mice. Spacing cue presentations with long inter-trial intervals during extinction training augmented fear in S1 and B6 mice. The effect of spacing was lost with one-trial fear conditioning in B6, but not S1 mice. A single exposure to a conditioned cue before extinction training did not alter extinction retrieval, either in B6 or S1 mice. Both the S1 and B6 strains exhibited robust second-order fear conditioning, in which a cue associated with footshock was sufficient to serve as a conditioned exciter to condition a fear association to a second cue. B6 mice extinguished the fear response to the second-order conditioned cue, but S1 mice failed to do so. Conclusions These data provide further evidence that fear extinction is strongly influenced by multiple procedural variables and is so in a highly strain-dependent manner. This suggests that the efficacy of extinction-based behavioral interventions, such as exposure therapy, for trauma-related anxiety disorders will be determined by the procedural parameters employed and the degree to which the patient can extinguish. PMID:23830244

Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats

PubMed Central

Cruz, Emmanuel; Soler-Cedeño, Omar; Negrón, Geovanny; Criado-Marrero, Marangelie; Chompré, Gladys

2015-01-01

Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase. PMID:26354908

Amygdala-ventral striatum circuit activation decreases long-term fear

PubMed Central

Correia, Susana S; McGrath, Anna G; Lee, Allison; Graybiel, Ann M; Goosens, Ki A

2016-01-01

In humans, activation of the ventral striatum, a region associated with reward processing, is associated with the extinction of fear, a goal in the treatment of fear-related disorders. This evidence suggests that extinction of aversive memories engages reward-related circuits, but a causal relationship between activity in a reward circuit and fear extinction has not been demonstrated. Here, we identify a basolateral amygdala (BLA)-ventral striatum (NAc) pathway that is activated by extinction training. Enhanced recruitment of this circuit during extinction learning, either by pairing reward with fear extinction training or by optogenetic stimulation of this circuit during fear extinction, reduces the return of fear that normally follows extinction training. Our findings thus identify a specific BLA-NAc reward circuit that can regulate the persistence of fear extinction and point toward a potential therapeutic target for disorders in which the return of fear following extinction therapy is an obstacle to treatment. DOI: http://dx.doi.org/10.7554/eLife.12669.001 PMID:27671733

Bilateral Alternating Auditory Stimulations Facilitate Fear Extinction and Retrieval.

PubMed

Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie

2017-01-01

Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR.

Bilateral Alternating Auditory Stimulations Facilitate Fear Extinction and Retrieval

PubMed Central

Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie

2017-01-01

Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR. PMID:28659851

Relapse processes after the extinction of instrumental learning: Renewal, resurgence, and reacquisition

PubMed Central

Bouton, Mark E.; Winterbauer, Neil E.; Todd, Travis P.

2012-01-01

It is widely recognized that extinction (the procedure in which a Pavlovian conditioned stimulus or an instrumental action is repeatedly presented without its reinforcer) weakens behavior without erasing the original learning. Most of the experiments that support this claim have focused on several “relapse” effects that occur after Pavlovian extinction, which collectively suggest that the original learning is saved through extinction. However, although such effects do occur after instrumental extinction, they have not been explored there in as much detail. This article reviews recent research in our laboratory that has investigated three relapse effects that occur after the extinction of instrumental (operant) learning. In renewal, responding returns after extinction when the behavior is tested in a different context; in resurgence, responding recovers when a second response that has been reinforced during extinction of the first is itself put on extinction; and in rapid reacquisition, extinguished responding returns rapidly when the response is reinforced again. The results provide new insights into extinction and relapse, and are consistent with principles that have been developed to explain extinction and relapse as they occur after Pavlovian conditioning. Extinction of instrumental learning, like Pavlovian learning, involves new learning that is relatively dependent on the context for expression. PMID:22450305

Mixed evidence for the potential of non-invasive transcutaneous vagal nerve stimulation to improve the extinction and retention of fear.

PubMed

Burger, A M; Verkuil, B; Fenlon, H; Thijs, L; Cools, L; Miller, H C; Vervliet, B; Van Diest, I

2017-10-01

Extinction memories are fragile and their formation has been proposed to partially rely on vagus nerve activity. We tested whether stimulating the auricular branch of the vagus (transcutaneous VNS; tVNS) accelerates extinction and reduces spontaneous recovery of fear. Forty-two healthy students participated in a 3-day fear conditioning study, where we tested fear acquisition (day 1), fear extinction (day 2) and the retention of the extinction memory (day 3). During extinction, participants were randomly allocated to receive tVNS or sham stimulation concurrently with each CS presentation. During the acquisition and retention phases, all participants received sham stimulation. Indexes of fear included US-expectancy, startle blink EMG and skin conductance responses. Results showed successful acquisition and extinction of fear in all measures. tVNS facilitated the extinction of declarative fear (US expectancy ratings), but did not promote a stronger retention of the declarative extinction memory. No clear effects of tVNS on extinction and retention of extinction were found for the psychophysiological indexes. The present findings provide tentative indications that tVNS could be a promising tool to improve fear extinction and call for larger scale studies to replicate these effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

The effect of hippocampal NMDA receptor blockade by MK-801 on cued fear extinction.

PubMed

Zhang, Bo; Li, Chuan-Yu; Wang, Xiu-Song

2017-08-14

Extinction of conditioned fear has been suggested to be a new form of learning instead of erasure of what was originally learned, and the process is NMDA (N-methyl d-aspartate) receptor (NMDAR) dependent. Most of studies have so far revealed the important roles of NMDARs in the amygdala and medial prefrontal cortex (mPFC) in cued fear extinction. Although the ventral hippocampus has intimately reciprocal connections with the amygdala and mPFC, the role of its NMDARs in cued fear extinction remains unclear. The present experiment explored the issue by bilateral pre-extinction microinjection of the noncompetitive NMDAR antagonist MK-801 into the ventral hippocampus. Four groups of rats were given habituation, tone cued fear conditioning, fear extinction training and extinction test. Prior to extinction training, rats received bilateral infusions of either MK-801 (1.5, 3, or 6μg/0.5μl) or saline. Our results showed that MK-801 reduced freezing on the first trial of extinction training with no impact on within-session acquisition of extinction, and that the lower doses of MK-801 resulted in increased freezing on the extinction retrieval test. These findings suggest that ventral hippocampal NMDARs are necessary for the consolidation of tone cued fear extinction. Copyright © 2017 Elsevier B.V. All rights reserved.

Rescaling of temporal expectations during extinction

PubMed Central

Drew, Michael R.; Walsh, Carolyn; Balsam, Peter D

2016-01-01

Previous research suggests that extinction learning is temporally specific. Changing the CS duration between training and extinction can facilitate the loss of the CR within the extinction session but impairs long-term retention of extinction. In two experiments using conditioned magazine approach with rats, we examined the relation between temporal specificity of extinction and CR timing. In Experiment 1 rats were trained on a 12-s, fixed CS-US interval and then extinguished with CS presentations that were 6, 12, or 24 s in duration. The design of Experiment 2 was the same except rats were trained using partial rather than continuous reinforcement. In both experiments, extending the CS duration in extinction facilitated the diminution of CRs during the extinction session, but shortening the CS duration failed to slow extinction. In addition, extending (but not shortening) the CS duration caused temporal rescaling of the CR, in that the peak CR rate migrated later into the trial over the course of extinction training. This migration partially accounted for the faster loss of the CR when the CS duration was extended. Results are incompatible with the hypothesis that extinction is driven by cumulative CS exposure and suggest that temporally extended nonreinforced CS exposure reduces conditioned responding via temporal displacement rather than through extinction per se. PMID:28045291