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Both qualitative and quantitative modeling methods relating chemical structure to biological activity, called structure-activity relationship analyses or SAR, are applied to the prediction and characterization of chemical toxicity. This minireview will discuss some generic issue...
Introducing Spectral Structure Activity Relationship (S-SAR) Analysis. Application to Ecotoxicology
Putz, Mihai V.; Lacrămă, Ana-Maria
A novel quantitative structure-activity (property) relationship model, namely Spectral-SAR, is presented in an exclusive algebraic way replacing the old-fashioned multi-regression one. The actual S-SAR method interprets structural descriptors as vectors in a generic data space that is further mapped into a full orthogonal space by means of the Gram-Schmidt algorithm. Then, by coordinated transformation between the data and orthogonal spaces, the S-SAR equation is given under simple determinant form for any chemical-biological interactions under study. While proving to give the same analytical equation and correlation results with standard multivariate statistics, the actual S-SAR frame allows the introduction of the spectral norm as a valid substitute for the correlation factor, while also having the advantage to design the various related SAR models through the introduced "minimal spectral path" rule. An application is given performing a complete S-SAR analysis upon the Tetrahymena pyriformis ciliate species employing its reported eco-toxicity activities among relevant classes of xenobiotics. By representing the spectral norm of the endpoint models against the concerned structural coordinates, the obtained S-SAR endpoints hierarchy scheme opens the perspective to further design the ecotoxicological test batteries with organisms from different species.
The review is an introduction to methods for evaluating structure-activity relationships (SARs), and, in particular, to those methods that have been applied to study mutagenicity and carcinogenicity. A brief history and some background material on the earliest attempts to correla...
Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity
de Araújo, Rodrigo S. A.; Guerra, Felipe Q. S.; de O. Lima, Edeltrudes; de Simone, Carlos A.; Tavares, Josean F.; Scotti, Luciana; Scotti, Marcus T.; de Aquino, Thiago M.; de Moura, Ricardo O.; Mendonça, Francisco J. B.; Barbosa-Filho, José M.
The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 μg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO2 and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2cv of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity. PMID:23306152
HomoSAR: bridging comparative protein modeling with quantitative structural activity relationship to design new peptides.
Borkar, Mahesh R; Pissurlenkar, Raghuvir R S; Coutinho, Evans C
Peptides play significant roles in the biological world. To optimize activity for a specific therapeutic target, peptide library synthesis is inevitable; which is a time consuming and expensive. Computational approaches provide a promising way to simply elucidate the structural basis in the design of new peptides. Earlier, we proposed a novel methodology termed HomoSAR to gain insight into the structure activity relationships underlying peptides. Based on an integrated approach, HomoSAR uses the principles of homology modeling in conjunction with the quantitative structural activity relationship formalism to predict and design new peptide sequences with the optimum activity. In the present study, we establish that the HomoSAR methodology can be universally applied to all classes of peptides irrespective of sequence length by studying HomoSAR on three peptide datasets viz., angiotensin-converting enzyme inhibitory peptides, CAMEL-s antibiotic peptides, and hAmphiphysin-1 SH3 domain binding peptides, using a set of descriptors related to the hydrophobic, steric, and electronic properties of the 20 natural amino acids. Models generated for all three datasets have statistically significant correlation coefficients (r(2)) and predictive r2 (r(pred)2) and cross validated coefficient ( q(LOO)2). The daintiness of this technique lies in its simplicity and ability to extract all the information contained in the peptides to elucidate the underlying structure activity relationships. The difficulties of correlating both sequence diversity and variation in length of the peptides with their biological activity can be addressed. The study has been able to identify the preferred or detrimental nature of amino acids at specific positions in the peptide sequences. PMID:24105965
Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.
Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush
In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition. PMID:17077558
Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: lead optimization.
Alonso, Juan Antonio; Andrés, Miriam; Bravo, Mónica; Calbet, Marta; Eastwood, Paul R; Eichhorn, Peter; Esteve, Cristina; Ferrer, Manel; Gómez, Elena; González, Jacob; Mir, Marta; Moreno, Imma; Petit, Silvia; Roberts, Richard S; Sevilla, Sara; Vidal, Bernat; Vidal, Laura; Vilaseca, Pere; Zanuy, Miriam
Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles. PMID:25437505
Synthesis, insecticidal activity, and structure-activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings.
Li, Yuhao; Zhu, Hongjun; Chen, Kai; Liu, Rui; Khallaf, Abdalla; Zhang, Xiangning; Ni, Jueping
A series of anthranilic diamides analogs (3–11, 16–24) containing 1,2,4- or 1,3,4-oxadiazole rings were synthesized and characterized by (1)H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (18, CCDC-) was determined by X-ray diffraction crystallography. The insecticidal activities against Plutella xylostella and Spodoptera exigua were evaluated. The results showed that most of title compounds displayed good larvicidal activities against P. xylostella, especially compound 3-bromo-N-(4-chloro-2-methyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (6), which displayed 71.43% activity against P. xylostella at 0.4 μg mL(-1) and 33.33% against S. exigua at 1 μg mL(-1). The structure-activity relationship showed that compounds decorated with a 1,3,4-oxadiazole were more potent than compounds decorated with a 1,2,4-oxadiazole, and different substituents attached to the oxadiazole ring also affected the insecticidal activity. This work provides some hints for further structure modification and the enhancement of insecticidal activity. PMID:23657615
Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies.
Bach, Anders; Pizzirani, Daniela; Realini, Natalia; Vozella, Valentina; Russo, Debora; Penna, Ilaria; Melzig, Laurin; Scarpelli, Rita; Piomelli, Daniele
Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads. PMID:26560855
Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies.
Nuzzi, Andrea; Fiasella, Annalisa; Ortega, Jose Antonio; Pagliuca, Chiara; Ponzano, Stefano; Pizzirani, Daniela; Bertozzi, Sine Mandrup; Ottonello, Giuliana; Tarozzo, Glauco; Reggiani, Angelo; Bandiera, Tiziano; Bertozzi, Fabio; Piomelli, Daniele
4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate (3b) is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, we describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivatives, which have led to the identification of 3b, and expand these studies to elucidate the principal structural and stereochemical features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of 3ak, a novel inhibitor of human NAAA that shows an improved physicochemical and drug-like profile relative to 3b. This favourable profile, along with the structural diversity of the carbamic acid chain of 3b, identify this compound as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation. PMID:26866968
Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study
Sepsova, Vendula; Karasova, Jana Zdarova; Korabecny, Jan; Dolezal, Rafael; Zemek, Filip; Bennion, Brian J.; Kuca, Kamil
Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring. PMID:23959117
Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of pyrrolopiperidinone acetic acids as CRTh2 antagonists.
Andrés, Miriam; Buil, Maria Antonia; Calbet, Marta; Casado, Oscar; Castro, Jordi; Eastwood, Paul R; Eichhorn, Peter; Ferrer, Manel; Forns, Pilar; Moreno, Imma; Petit, Silvia; Roberts, Richard S
Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs. PMID:25437503
Thinking in Terms of Structure-Activity-Relationships (T-SAR): A Tool to Better Understand Nanofiltration Membranes
Fernández, José F.; Jastorff, Bernd; Störmann, Reinhold; Stolte, Stefan; Thöming, Jorg
A frontier to be conquered in the field of membrane technology is related to the very limited scientific base for the rational and task-specific design of membranes. This is especially true for nanofiltration membranes with properties that are based on several solute-membrane interaction mechanisms. "Thinking in terms of Structure-Activity-Relationships" (T-SAR) is a methodology which applies a systematic analysis of a chemical entity based on its structural formula. However, the analysis become more complex with increasing size of the molecules considered. In this study, T-SAR was combined with classical membrane characterization methods, resulting in a new methodology which allowed us not only to explain membrane characteristics, but also provides evidence for the importance of the chemical structure for separation performance. We demonstrate an application of the combined approach and its potential to discover stereochemistry, molecular interaction potentials, and reactivity of two FilmTec nanofiltration membranes (NF-90 and NF-270). Based on these results, it was possible to predict both properties and performance in the recovery of hydrophobic ionic liquids from aqueous solution. PMID:24957730
Approach to using mechanism-based structure activity relationship (SAR) analysis to assess human health hazard potential of nanomaterials.
Lai, David Y
With the increasing use and development of engineered nanoparticles in electronics, consumer products, pesticides, food and pharmaceutical industries, there is a growing concern about potential human health hazards of these materials. A number of studies have demonstrated that nanoparticle toxicity is extremely complex, and that the biological activity of nanoparticles will depend on a variety of physicochemical properties such as particle size, shape, agglomeration state, crystal structure, chemical composition, surface area and surface properties. Nanoparticle toxicity can be attributed to nonspecific interaction with biological structures due to their physical properties (e.g., size and shape) and biopersistence, or to specific interaction with biomolecules through their surface properties (e.g., surface chemistry and reactivity) or release of toxic ions. The toxic effects of most nanomaterials have not been adequately characterized and currently, there are many issues and challenges in toxicity testing and risk assessment of nanoparticles. Based on the possible mechanisms of action and available in vitro and in vivo toxicity database, this paper proposes an approach to using mechanism-based SAR analysis to assess the relative human health hazard/risk potential of various types of nanomaterials. PMID:26111809
Inhibition of monoamine oxidase-A activity in rat brain by synthetic hydrazines: structure-activity relationship (SAR).
Dar, Ahsana; Khan, Khalid M; Ateeq, Humayun S; Khan, Shagufta; Rahat, Shagufta; Perveen, Shahnaz; Supuran, Claudiu T
A series of hydrazine derivatives was synthesized in order to evaluate their monoamine oxidase A (MAO-A) inhibitory effects. MAO-A inhibitory activity of 4-tosyl benzoic acid carbohydrazide was quite potent, similarly to that of the corresponding 4-benzyloxy-benzoic acid carbohydrazide and its N-cyanoethylated derivative. Structural variations of these compounds, such as the replacement of the 4-substitutent, of the aromatic ring on which the carbohydrazide moiety is grafted, as well as cyclization of the hydrazide moiety in five- or six-membered rings caused either significant decline or complete loss of MAO inhibitory properties. The most active compound (4-tosyl benzoic acid carbohydrazide) was also subjected to the forced swim test, an animal model of depression, eliciting a marked reduction in immobility time in rats, without affecting the locomotor activity, implying that it possesses anti-depressant properties due to inhibition of MAO type-A. PMID:16119198
Benzoic acid derivatives with improved antifungal activity: Design, synthesis, structure-activity relationship (SAR) and CYP53 docking studies.
Berne, Sabina; Kovačič, Lidija; Sova, Matej; Kraševec, Nada; Gobec, Stanislav; Križaj, Igor; Komel, Radovan
Previously, we identified CYP53 as a fungal-specific target of natural phenolic antifungal compounds and discovered several inhibitors with antifungal properties. In this study, we performed similarity-based virtual screening and synthesis to obtain benzoic acid-derived compounds and assessed their antifungal activity against Cochliobolus lunatus, Aspergillus niger and Pleurotus ostreatus. In addition, we generated structural models of CYP53 enzyme and used them in docking trials with 40 selected compounds. Finally, we explored CYP53-ligand interactions and identified structural elements conferring increased antifungal activity to facilitate the development of potential new antifungal agents that specifically target CYP53 enzymes of animal and plant pathogenic fungi. PMID:26154240
Mode of action and the assessment of chemical hazards in the presence of limited data: use of structure-activity relationships (SAR) under TSCA, Section 5.
Auer, C M; Nabholz, J V; Baetcke, K P
Section 5 of the Toxic Substances Control Act (TSCA) requires that manufacturers and importers of new chemicals must submit a Premanufacture Notification (PMN) to the U.S. Environmental Protection Agency 90 days before they intend to commence manufacture or import. Certain information such as chemical identity, uses, etc., must be included in the notification. The submission of test data on the new substance, however, is not required, although any available health and environmental information must be provided. Nonetheless, over half of all PMNs submitted to the agency do not contain any test data; because PMN chemicals are new, no test data is generally available in the scientific literature. Given this situation, EPA has had to develop techniques for hazard assessment that can be used in the presence of limited test data. EPA's approach has been termed "structure-activity relationships" (SAR) and involves three major components: the first is critical evaluation and interpretation of available toxicity data on the chemical; the second component involves evaluation of test data available on analogous substances and/or potential metabolites; and the third component involves the use of mathematical expressions for biological activity known as "quantitative structure-activity relationships" (QSARs). At present, the use of QSARs is limited to estimating physical chemical properties, environmental toxicity, and bioconcentration factors. An important overarching element in EPA's approach is the experience and judgment of scientific assessors in interpreting and integrating the available data and information. Examples are provided that illustrate EPA's approach to hazard assessment for PMN chemicals. PMID:2269224
Development of a new Structure-Activity Relationship (SAR) for gas-phase reactions of NO3 radicals with organic compounds
NASA Astrophysics Data System (ADS)
Kerdouci, J.; Picquet-Varrault, B.; Doussin, J.
The nitrate radical (NO3) has long been recognized as the dominant night-time oxidant of organic species, in particular of unsaturated compounds. More recently, it has been shown that it can contribute significantly to the oxidation of very reactive VOC (e.g. terpenes) even during the day[1]. Volatile organic compounds are widely emitted into the atmosphere by both anthropogenic and biogenic sources. When released into the troposphere, they can undergo either photolysis or oxidation by OH and NO3 radicals and by ozone. These chemical processes are known to be responsible for the formation of photooxidants and SOA which are involved in photochemical smog events. Hence, to estimate their impact on the tropospheric chemistry, it is necessary to know their reactivity towards the atmospheric oxidants. But because of huge number of VOCs, it is impossible to perform kinetic experiments for all of them. For this reason, estimation methods have been developed to predict rate constants. A number of methods for the estimation of rate constants have been proposed. Many of them utilize the physical or chemical properties of the organic compounds such as the ionization energy[2] or the energy of molecular orbital[3]. However, these methods are restricted in their use because of the limited database concerning molecular properties and the discrepancies between the different molecular models used to calculate these parameters. For this reason, a structure-activity relationship has been developed by Atkinson[4] to predict rate constants of the OH-oxidation of VOCs. This kind of SAR is very easy to use and has been successfully integrated in chemical models[5, 6]. Concerning the reactivity of organic compounds with NO3 radicals, it has long been considered that the number of experimental data was not sufficient to use the approach proposed by Atkinson. But during the last decade, many experimental studies, in particular on the unsaturated oxygenated compounds, have enhanced the
Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists I.
Alonso, Juan Antonio; Andrés, Miriam; Bravo, Mónica; Buil, Maria Antonia; Calbet, Marta; Castro, Jordi; Eastwood, Paul R; Eichhorn, Peter; Esteve, Cristina; Gómez, Elena; González, Jacob; Mir, Marta; Petit, Silvia; Roberts, Richard S; Vidal, Bernat; Vidal, Laura; Vilaseca, Pere; Zanuy, Miriam
A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure-kinetic relationships (SKR) opened up the possibility of long receptor residence times. PMID:25437504
Seasonal dynamics of active SAR11 ecotypes in the oligotrophic Northwest Mediterranean Sea
Salter, Ian; Galand, Pierre E; Fagervold, Sonja K; Lebaron, Philippe; Obernosterer, Ingrid; Oliver, Matthew J; Suzuki, Marcelino T; Tricoire, Cyrielle
A seven-year oceanographic time series in NW Mediterranean surface waters was combined with pyrosequencing of ribosomal RNA (16S rRNA) and ribosomal RNA gene copies (16S rDNA) to examine the environmental controls on SAR11 ecotype dynamics and potential activity. SAR11 diversity exhibited pronounced seasonal cycles remarkably similar to total bacterial diversity. The timing of diversity maxima was similar across narrow and broad phylogenetic clades and strongly associated with deep winter mixing. Diversity minima were associated with periods of stratification that were low in nutrients and phytoplankton biomass and characterised by intense phosphate limitation (turnover time<5 h). We propose a conceptual framework in which physical mixing of the water column periodically resets SAR11 communities to a high diversity state and the seasonal evolution of phosphate limitation competitively excludes deeper-dwelling ecotypes to promote low diversity states dominated (>80%) by SAR11 Ia. A partial least squares (PLS) regression model was developed that could reliably predict sequence abundances of SAR11 ecotypes (Q2=0.70) from measured environmental variables, of which mixed layer depth was quantitatively the most important. Comparison of clade-level SAR11 rRNA:rDNA signals with leucine incorporation enabled us to partially validate the use of these ratios as an in-situ activity measure. However, temporal trends in the activity of SAR11 ecotypes and their relationship to environmental variables were unclear. The strong and predictable temporal patterns observed in SAR11 sequence abundance was not linked to metabolic activity of different ecotypes at the phylogenetic and temporal resolution of our study. PMID:25238399
ICAO's anti-SARS airport activities.
Finkelstein, Silvio; Curdt-Christiansen, Claus M
To prevent SARS from spreading through air travel and in order to rebuild the confidence of the traveling public in the safety of air travel, ICAO has set up an "Anti-SARS Airport Evaluation Project." The first phase of this project was to develop a set of protective measures for international airports in affected areas to adopt and implement and then to send out, on the request of Contracting States, a team of inspectors to evaluate and assess airports and issue a "statement of evaluation" that the airport inspected complies with the ICAO anti-SARS protective measures. In cooperation with the World Health Organization (WHO), the first part of phase 1 was completed in early June this year, and the second part of phase 1 followed soon after. By mid-July, five international airports in Southeast Asia had been inspected and found to be in full compliance with the ICAO anti-SARS protective measures. The success of this ICAO project is believed to have contributed significantly to the recovery of international air travel and related industries now taking place. Phase 2 of the project is now being developed. It is aimed at preventing a resurgence of SARS, but it also contains elements to make the methodology developed applicable to future outbreaks of any other communicable disease in which the mode of transmission could involve aviation and/or the need to prevent the spread of the disease by air travel. PMID:14620481
Structure activity relationships (SARs) are based on the principle that structurally similar chemicals should have similar biological activity. SARs relate specifically-defined toxicological activity of chemicals to their molecular structure and physico-chemical properties. To de...
TerraSAR InSAR Investigation of Active Crustal Deformation
NASA Astrophysics Data System (ADS)
Lei, L.; Burgmann, R.
We aim to utilize advanced analysis of TerraSAR-X data to investigate the dynamics and interactions of solid Earth deformation processes, such as earthquakes and fault creep, and Earth surface processes, such as land subsidence and groundwater movements, in a densely populated, urban region, the San Francisco Bay Area. Ongoing deformation imaging reveals a number of natural hazards including elastic strain accumulation about seismologic faults, active landsliding, land subsidence and rebound, and settling of unconsolidated sediments that are highly susceptible to liquefaction. Up to now, we have ordered and received 20 more TerraSAR-X Spotlight Single Look Complex (SLC) images and a few Stripmap SLC images delivered by DLR and got a few preliminary results. The TerraSAR-X images were acquired over the San Francisco Bay Area particularly around an area of active landsliding, coastal subsidence and shallow Hayward fault creep near the city of Berkeley. Berkeley is situated between latitude 37.45 and 38.00, longitude 237.30 and 238.00. The data acquisition interval is from November, 2008 to now. Four types of Spotlight images and one type of Stripmap images in time sequence were ordered and acquired: spot_012, spot_038, spot_049, spot_075 and strip_003, having different look angles and pass directions. Access to the SAR data is via ftp about 10 days after acquisition date. The data is supplied in TerraSAR-X standard SLC COSAR (COmplex SAR) format with orbital information in an Extensible Markup Language (XML) header. The file contains integer real-complex components with double sampling and calibration constants for values. I am using ROI_PAC to do the interferograms. But ROI_PAC was designed to process the raw data rather SLC images. So there are some problems in azimuth processing with TerraSAR SLC data especially the Spotlight data. We now have some preliminary results of Stripmap interferograms and Spotlight interferograms but still work on those problems and
Structure-Activity Relationship (SAR) and Preliminary Mode of Action Studies of 3-Substituted Benzylthioquinolinium Iodide as Anti-opportunistic Infection Agents
Bolden, Sidney; Zhu, Xue Y.; Etukala, Jagan R; Boateng, Comfort; Mazu, Tryphon; Flores-Rozas, Hernan; Jacob, Melissa R.; Khan, Shabana I; Walker, Larry A.; Ablordeppey, Seth Y.
Opportunistic infections are devastating to immunocompromised patients. And in especially sub-Saharan Africa where the AIDS epidemic is still raging, the mortality rate was recently as high as 70%. The paucity of anti-opportunistic drugs, the decreasing efficacy and the development of resistance against the azoles and even amphotericin B have stimulated the search for new drugs with new mechanisms of action. In a previous work, we showed that a new chemotype derived from the natural product cryptolepine displayed selective toxicity against opportunistic pathogens with minimal cytotoxicity to normal cells. In this manuscript, we report the design and synthesis of substituted benzylthioquinolinium iodides, evaluated their anti-infective properties and formulated some initial structure-activity relationships around phenyl ring A from the original natural product. The sensitivity of the most potent analog 10l, to selected strains of C. cerevisiae was also evaluated leading to the observation that this scaffold may have a different mode of action from its predecessor, cryptolepine. PMID:24141203
76 FR 20822 - Proposed Information Collection (Servicer's Staff Appraisal Reviewer (SAR) Application) Activity...
Federal Register 2010, 2011, 2012, 2013, 2014
... AFFAIRS Proposed Information Collection (Servicer's Staff Appraisal Reviewer (SAR) Application) Activity... (SAR) Application, VA Form 26-0829. OMB Control Number: 2900-0715. Type of Review: Extension of a... approval as Staff Appraisal Reviewer (SAR). Servicers SAR's will have the authority to review real...
In the field of environmental toxicology, structure activity relationships (SARs) have developed as scientifically-credible tools for predicting the effects of chemicals when little or no empirical data are available.
Structure-Activity Relationship Studies and their Role in Predicting and Investigating Chemical Toxicity
Structure-activity relationships (SAR) represent attempts to generalize chemical information relative to biological activity for the twin purposes of generating insigh...
Consideration of Reaction Intermediates in Structure- Activity Relationships: A Key to Understanding and Prediction
A structure-activity relationship (SAR) represents an empirical means for generalizing chemical information relative to biological activity, and is frequent...
76 FR 8847 - Proposed Information Collection (Lenders Staff Appraisal Reviewer (SAR) Application) Activity...
Federal Register 2010, 2011, 2012, 2013, 2014
... AFFAIRS Proposed Information Collection (Lenders Staff Appraisal Reviewer (SAR) Application) Activity...: Lenders Staff Appraisal Reviewer (SAR) Application, VA Form 26-0785. OMB Control Number: 2900-0658. Type... lenders to nominate employees for approval as approved Staff Appraisal Reviewer (SAR). Once approved,...
Structural interpretation of activity cliffs revealed by systematic analysis of structure-activity relationships in analog series.
Sisay, Mihiret T; Peltason, Lisa; Bajorath, Jürgen
Discontinuity in structure-activity relationships (SARs) is caused by so-called activity cliffs and represents one of the major caveats in SAR modeling and lead optimization. At activity cliffs, small structural modifications of compounds lead to substantial differences in potency that are essentially unpredictable using quantitative structure-activity relationship (QSAR) methods. In order to better understand SAR discontinuity at the molecular level of detail, we have analyzed different compound series in combinatorial analog graphs and determined substitution patterns that introduce activity cliffs of varying magnitude. So identified SAR determinants were then analyzed on the basis of complex crystal structures to enable a structural interpretation of SAR discontinuity and underlying activity cliffs. In some instances, SAR discontinuity detected within analog series could be well rationalized on the basis of structural data, whereas in others a structural explanation was not possible. This reflects the intrinsic complexity of small molecule SARs and suggests that the analysis of short-range receptor-ligand interactions seen in X-ray structures is insufficient to comprehensively account for SAR discontinuity. However, in other cases, SAR information extracted from ligands was incomplete but could be deduced taking X-ray data into account. Thus, taken together, these findings illustrate the complementarity of ligand-based SAR analysis and structural information. PMID:19761254
Structure-activity relationship of crustacean peptide hormones.
Katayama, Hidekazu
In crustaceans, various physiological events, such as molting, vitellogenesis, and sex differentiation, are regulated by peptide hormones. To understanding the functional sites of these hormones, many structure-activity relationship (SAR) studies have been published. In this review, the author focuses the SAR of crustacean hyperglycemic hormone-family peptides and androgenic gland hormone and describes the detailed results of our and other research groups. The future perspectives will be also discussed. PMID:26624010
Relationships between autofocus methods for SAR and self-survey techniques for SONAR. [Synthetic Aperture Radar (SAR)
Wahl, D.E.; Jakowatz, C.V. Jr.; Ghiglia, D.C.; Eichel, P.H.
Autofocus methods in SAR and self-survey techniques in SONAR have a common mathematical basis in that they both involve estimation and correction of phase errors introduced by sensor position uncertainties. Time delay estimation and correlation methods have been shown to be effective in solving the self-survey problem for towed SONAR arrays. Since it can be shown that platform motion errors introduce similar time-delay estimation problems in SAR imaging, the question arises as to whether such techniques could be effectively employed for autofocus of SAR imagery. With a simple mathematical model for motion errors in SAR, we will show why such correlation/time-delay techniques are not nearly as effective as established SAR autofocus algorithms such as phase gradient autofocus or sub-aperture based methods. This analysis forms an important bridge between signal processing methodologies for SAR and SONAR. 5 refs., 4 figs.
The Seamless SAR Archive (SSARA) Project and Other SAR Activities at UNAVCO
NASA Astrophysics Data System (ADS)
Baker, S.; Crosby, C. J.; Meertens, C. M.; Fielding, E. J.; Bryson, G.; Buechler, B.; Nicoll, J.; Baru, C.
The seamless synthetic aperture radar archive (SSARA) implements a seamless distributed access system for SAR data and derived data products (i.e. interferograms). SSARA provides a unified application programming interface (API) for SAR data search and results at the Alaska Satellite Facility and UNAVCO (WInSAR and EarthScope data archives) through the use of simple web services. A federated query service was developed using the unified APIs, providing users a single search interface for both archives. Interest from the international community has prompted an effort to incorporate ESA's Virtual Archive 4 Geohazard Supersites and Natural Laboratories (GSNL) collections and other archives into the federated query service. SSARA also provides Digital Elevation Model access for topographic correction via a simple web service through OpenTopography and tropospheric correction products through JPL's OSCAR service. Additionally, UNAVCO provides data storage capabilities for WInSAR PIs with approved TerraSAR-X and ALOS-2 proposals which allows easier distribution to US collaborators on associated proposals and facilitates data access through the SSARA web services. Further work is underway to incorporate federated data discovery for GSNL across SAR, GPS, and seismic datasets provided by web services from SSARA, GSAC, and COOPEUS.
76 FR 35949 - Agency Information Collection Activity (Servicer's Staff Appraisal Reviewer (SAR) Application...
Federal Register 2010, 2011, 2012, 2013, 2014
... AFFAIRS Agency Information Collection Activity (Servicer's Staff Appraisal Reviewer (SAR) Application....'' SUPPLEMENTARY INFORMATION: ] Title: Servicer's Staff Appraisal Reviewer (SAR) Application, VA Form 26-0829. OMB... 26-0829 is completed by servicers to nominate employees for approval as Staff Appraisal Reviewer...
Ecological Structure Activity Relationships
Ecological Structure Activity Relationships, v1.00a, February 2009
ECOSAR (Ecological Structure Activity Relationships) is a personal computer software program that is used to estimate the toxicity of chemicals used in industry and discharged into water. The program predicts...
Relationship of SARS-CoV to other pathogenic RNA viruses explored by tetranucleotide usage profiling
Yap, Yee Leng; Zhang, Xue Wu; Danchin, Antoine
Background The exact origin of the cause of the Severe Acute Respiratory Syndrome (SARS) is still an open question. The genomic sequence relationship of SARS-CoV with 30 different single-stranded RNA (ssRNA) viruses of various families was studied using two non-standard approaches. Both approaches began with the vectorial profiling of the tetra-nucleotide usage pattern V for each virus. In approach one, a distance measure of a vector V, based on correlation coefficient was devised to construct a relationship tree by the neighbor-joining algorithm. In approach two, a multivariate factor analysis was performed to derive the embedded tetra-nucleotide usage patterns. These patterns were subsequently used to classify the selected viruses. Results Both approaches yielded relationship outcomes that are consistent with the known virus classification. They also indicated that the genome of RNA viruses from the same family conform to a specific pattern of word usage. Based on the correlation of the overall tetra-nucleotide usage patterns, the Transmissible Gastroenteritis Virus (TGV) and the Feline CoronaVirus (FCoV) are closest to SARS-CoV. Surprisingly also, the RNA viruses that do not go through a DNA stage displayed a remarkable discrimination against the CpG and UpA di-nucleotide (z = -77.31, -52.48 respectively) and selection for UpG and CpA (z = 65.79,49.99 respectively). Potential factors influencing these biases are discussed. Conclusion The study of genomic word usage is a powerful method to classify RNA viruses. The congruence of the relationship outcomes with the known classification indicates that there exist phylogenetic signals in the tetra-nucleotide usage patterns, that is most prominent in the replicase open reading frames. PMID:14499005
Prediction of compounds in different local structure-activity relationship environments using emerging chemical patterns.
Namasivayam, Vigneshwaran; Gupta-Ostermann, Disha; Balfer, Jenny; Heikamp, Kathrin; Bajorath, Jürgen
Active compounds can participate in different local structure-activity relationship (SAR) environments and introduce different degrees of local SAR discontinuity, depending on their structural and potency relationships in data sets. Such SAR features have thus far mostly been analyzed using descriptive approaches, in particular, on the basis of activity landscape modeling. However, compounds in different local SAR environments have not yet been predicted. Herein, we adapt the emerging chemical patterns (ECP) method, a machine learning approach for compound classification, to systematically predict compounds with different local SAR characteristics. ECP analysis is shown to accurately assign many compounds to different local SAR environments across a variety of activity classes covering the entire range of observed local SARs. Control calculations using random forests and multiclass support vector machines were carried out and a variety of statistical performance measures were applied. In all instances, ECP calculations yielded comparable or better performance than controls. The approach presented herein can be applied to predict compounds that complement local SARs or prioritize compounds with different SAR characteristics. PMID:24803014
SAR studies directed toward the pyridine moiety of the sap-feeding insecticide sulfoxaflor (Isoclast™ active).
Loso, Michael R; Benko, Zoltan; Buysse, Ann; Johnson, Timothy C; Nugent, Benjamin M; Rogers, Richard B; Sparks, Thomas C; Wang, Nick X; Watson, Gerald B; Zhu, Yuanming
Sap-feeding insect pests constitute a major insect pest complex that includes a range of aphids, whiteflies, planthoppers and other insect species. Sulfoxaflor (Isoclast™ active), a new sulfoximine class insecticide, targets sap-feeding insect pests including those resistant to many other classes of insecticides. A structure activity relationship (SAR) investigation of the sulfoximine insecticides revealed the importance of a 3-pyridyl ring and a methyl substituent on the methylene bridge linking the pyridine and the sulfoximine moiety to achieving strong Myzus persicae activity. A more in depth QSAR investigation of pyridine ring substituents revealed a strong correlation with the calculated logoctanol/water partition coefficient (SlogP). Model development resulted in a highly predictive model for a set of 18 sulfoximines including sulfoxaflor. The model is consistent with and helps explain the highly optimized pyridine substitution pattern for sulfoxaflor. PMID:26706115
Follow-up: Prospective compound design using the 'SAR Matrix' method and matrix-derived conditional probabilities of activity.
Gupta-Ostermann, Disha; Hirose, Yoichiro; Odagami, Takenao; Kouji, Hiroyuki; Bajorath, Jürgen
In a previous Method Article, we have presented the 'Structure-Activity Relationship (SAR) Matrix' (SARM) approach. The SARM methodology is designed to systematically extract structurally related compound series from screening or chemical optimization data and organize these series and associated SAR information in matrices reminiscent of R-group tables. SARM calculations also yield many virtual candidate compounds that form a "chemical space envelope" around related series. To further extend the SARM approach, different methods are developed to predict the activity of virtual compounds. In this follow-up contribution, we describe an activity prediction method that derives conditional probabilities of activity from SARMs and report representative results of first prospective applications of this approach. PMID:25949808
Methods of InSAR atmosphere correction for volcano activity monitoring
Gong, W.; Meyer, F.; Webley, P.W.; Lu, Zhiming
When a Synthetic Aperture Radar (SAR) signal propagates through the atmosphere on its path to and from the sensor, it is inevitably affected by atmospheric effects. In particular, the applicability and accuracy of Interferometric SAR (InSAR) techniques for volcano monitoring is limited by atmospheric path delays. Therefore, atmospheric correction of interferograms is required to improve the performance of InSAR for detecting volcanic activity, especially in order to advance its ability to detect subtle pre-eruptive changes in deformation dynamics. In this paper, we focus on InSAR tropospheric mitigation methods and their performance in volcano deformation monitoring. Our study areas include Okmok volcano and Unimak Island located in the eastern Aleutians, AK. We explore two methods to mitigate atmospheric artifacts, namely the numerical weather model simulation and the atmospheric filtering using Persistent Scatterer processing. We investigate the capability of the proposed methods, and investigate their limitations and advantages when applied to determine volcanic processes. ?? 2011 IEEE.
Sar1 GTPase Activity Is Regulated by Membrane Curvature*♦
Hanna, Michael G.; Mela, Ioanna; Wang, Lei; Henderson, Robert M.; Chapman, Edwin R.; Edwardson, J. Michael; Audhya, Anjon
The majority of biosynthetic secretory proteins initiate their journey through the endomembrane system from specific subdomains of the endoplasmic reticulum. At these locations, coated transport carriers are generated, with the Sar1 GTPase playing a critical role in membrane bending, recruitment of coat components, and nascent vesicle formation. How these events are appropriately coordinated remains poorly understood. Here, we demonstrate that Sar1 acts as the curvature-sensing component of the COPII coat complex and highlight the ability of Sar1 to bind more avidly to membranes of high curvature. Additionally, using an atomic force microscopy-based approach, we further show that the intrinsic GTPase activity of Sar1 is necessary for remodeling lipid bilayers. Consistent with this idea, Sar1-mediated membrane remodeling is dramatically accelerated in the presence of its guanine nucleotide-activating protein (GAP), Sec23-Sec24, and blocked upon addition of guanosine-5′-[(β,γ)-imido]triphosphate, a poorly hydrolysable analog of GTP. Our results also indicate that Sar1 GTPase activity is stimulated by membranes that exhibit elevated curvature, potentially enabling Sar1 membrane scission activity to be spatially restricted to highly bent membranes that are characteristic of a bud neck. Taken together, our data support a stepwise model in which the amino-terminal amphipathic helix of GTP-bound Sar1 stably penetrates the endoplasmic reticulum membrane, promoting local membrane deformation. As membrane bending increases, Sar1 membrane binding is elevated, ultimately culminating in GTP hydrolysis, which may destabilize the bilayer sufficiently to facilitate membrane fission. PMID:26546679
Use of SAR data to study active volcanoes in Alaska
Dean, K.G.; Engle, K.; Lu, Zhiming; Eichelberger, J.; Near, T.; Doukas, M.
Synthetic Aperture Radar (SAR) data of the Westdahl, Veniaminof, and Novarupta volcanoes in the Aleutian Arc of Alaska were analysed to investigate recent surface volcanic processes. These studies support ongoing monitoring and research by the Alaska Volcano Observatory (AVO) in the North Pacific Ocean Region. Landforms and possible crustal deformation before, during, or after eruptions were detected and analysed using data from the European Remote Sensing Satellites (ERS), the Japanese Earth Resources Satellite (JERS) and the US Seasat platforms. Field observations collected by scientists from the AVO were used to verify the results from the analysis of SAR data.
Use of SAR data to study active volcanoes in Alaska
Dean, K.G.; Engle, K.; Lu, Zhiming; Eichelberger, J.; Neal, T.; Doukas, M.
Synthetic Aperture Radar (SAR) data of Westdahl, Veniaminof, and Novarupta volcanoes in the Aleutian Arc of Alaska were analyzed to investigate recent surface volcanic processes. These studies support ongoing monitoring and research by the Alaska Volcano Observatory (AVO) in the North Pacific Ocean Region. Landforms and possible crustal deformation before, during, or after eruptions were detected and analyzed using data from the European Remote Sensing Satellites (ERS), Japanese Earth Resources Satellite (JERS) and the U. S. Seasat platforms. Field observations collected by scientists from the AVO were used to verify the results from the analysis of SAR data.
Assessing sinkhole activity in the Ebro Valley mantled evaporite karst using advanced DInSAR
NASA Astrophysics Data System (ADS)
Galve, Jorge Pedro; Castañeda, Carmen; Gutiérrez, Francisco; Herrera, Gerardo
Sinkholes in karst areas may cause subsidence damage in transportation infrastructures, demolition of buildings and even the loss of human lives when they occur in a catastrophic way. Differential Interferometry (DInSAR) is a promising technology for detecting and characterizing sinkholes, as well as for reducing the associated risk when combined with other sources of data such as a sinkhole inventory. In this work, the usefulness of InSAR techniques and data for sinkhole risk management has been analyzed through the comparison of three DInSAR-derived velocity maps with a comprehensive sinkhole inventory in the Ebro Valley, NE Spain. The DInSAR maps have contributed to improve the sinkhole inventory in different ways: (1) detection of non-inventoried sinkholes; (2) revision of sinkhole areas previously classified as inactive as active; and (3) refinement of underestimated sinkhole boundaries. The obtained results suggest that DInSAR products are suitable for analyzing active dissolution-induced subsidence. The application of these techniques may help in recognizing and better characterizing previously unknown karst subsidence problems and in preventing personal and property losses. However, the analysis reveals that the available DInSAR maps combined overlook about 70% of the previously mapped active sinkholes mainly due to decorrelation.
Validation of an active transponder for KOMPSAT-5 SAR image calibration
NASA Astrophysics Data System (ADS)
Park, Durk Jong; Yeom, Kyung Whan; Ahn, Sang Il; Lim, Hyo Suk
This paper describes the development and validation of a transportable active transponder designed for the image calibration of Korea Multi-Purpose Satellite-5 (KOMPSAT-5) with a synthetic aperture radar (SAR). Ground targets are essential in SAR image calibration. The environment for the deployment of ground targets for SAR image calibration should provide uniformity and minimum interference. The Amazon or deserts are regarded as desirable environments. However, such environments for SAR image calibration are difficult to find in Korea. Thus, it will be advantageous to have an active transponder whose performance will not be severely limited by the absence of such uniform environment. We have therefore developed an active transponder which has an adjustable internal delay and into which the orbit data of an arbitrary satellite can be loaded. The stored obit data with the aid of an internal global positioning system (GPS) receiver and gyroscope enables the active transponder to point to a selected satellite. In addition, a virtual deployment of the active transponder is possible due to its adjustable internal delay. Thus, the developed active transponder can be deployed at any place without environmental constraint. The performance of the developed active transponder is validated using the satellite TerraSAR-X, which is already in operation. The test results show that the active transponder is successfully compliant with the requirements for KOMPSAT-5 image calibration.
Method for the evaluation of structure-activity relationship information associated with coordinated activity cliffs.
Dimova, Dilyana; Stumpfe, Dagmar; Bajorath, Jürgen
Activity cliffs are generally defined as pairs of active compounds having a large difference in potency. Although this definition of activity cliffs focuses on compound pairs, the vast majority of cliffs are formed in a coordinated manner. This means that multiple highly and weakly potent compounds form series of activity cliffs, which often overlap. In activity cliff networks, coordinated cliffs emerge as disjoint activity cliff clusters. Recently, we have identified all cliff clusters from current bioactive compounds and analyzed their topologies. For structure-activity relationship (SAR) analysis, activity cliff clusters are of high interest, since they contain more SAR information than cliffs that are individually considered. For medicinal chemistry applications, a key question becomes how to best extract SAR information from activity cliff clusters. This represents a challenging problem, given the complexity of many activity cliff configurations. Herein we introduce a generally applicable methodology to organize activity cliff clusters on the basis of structural relationships, prioritize clusters, and systematically extract SAR information from them. PMID:25014781
Structure-activity Relationship Analysis of N-Benzoylpyrazoles for Elastase Inhibitory Activity: A Simplified Approach Using Atom Pair Descriptors
Khlebnikov, Andrei I.; Schepetkin, Igor A.; Quinn, Mark T.
Previously, we utilized high throughput screening of a chemical diversity library to identify potent inhibitors of human neutrophil elastase and found that many of these compounds had N-benzoylpyrazole core structures. We also found individual ring substituents had significant impact on elastase inhibitory activity and compound stability. In the present study, we utilized computational structure–activity relationship (SAR) analysis of a series of 53 N-benzoylpyrazole derivatives to further optimize these lead molecules. We present an improved approach to SAR methodology based on atom pair descriptors in combination with 2-dimentional (2D) molecular descriptors. This approach utilizes the rich representation of chemical structure and leads to SAR analysis that is both accurate and intuitively easy to understand. A sequence of ANOVA, linear discriminant, and binary classification tree analyses of the molecular descriptors led to the derivation of SAR rule-based algorithms. These rules revealed that the main factors influencing elastase inhibitory activity of N-benzoylpyrazole molecules were the presence of methyl groups in the pyrazole moiety and ortho-substituents in the benzoyl radical. Furthermore, our data showed that physicochemical characteristics (energy of frontier molecular orbitals, molar refraction, lipophilicity) were not necessary for achieving good SAR, as comparable quality of SAR classification was obtained with atom pairs and 2D descriptors only. This simplified SAR approach may be useful to qualitative SAR recognition problems in a variety of data sets. PMID:18234502
Structure-activity relationship analysis of N-benzoylpyrazoles for elastase inhibitory activity: a simplified approach using atom pair descriptors.
Khlebnikov, Andrei I; Schepetkin, Igor A; Quinn, Mark T
Previously, we utilized high throughput screening of a chemical diversity library to identify potent inhibitors of human neutrophil elastase and found that many of these compounds had N-benzoylpyrazole core structures. We also found individual ring substituents had significant impact on elastase inhibitory activity and compound stability. In the present study, we utilized computational structure-activity relationship (SAR) analysis of a series of 53 N-benzoylpyrazole derivatives to further optimize these lead molecules. We present an improved approach to SAR methodology based on atom pair descriptors in combination with 2-dimensional (2D) molecular descriptors. This approach utilizes the rich representation of chemical structure and leads to SAR analysis that is both accurate and intuitively easy to understand. A sequence of ANOVA, linear discriminant, and binary classification tree analyses of the molecular descriptors led to the derivation of SAR rule-based algorithms. These rules revealed that the main factors influencing elastase inhibitory activity of N-benzoylpyrazole molecules were the presence of methyl groups in the pyrazole moiety and ortho-substituents in the benzoyl radical. Furthermore, our data showed that physicochemical characteristics (energy of frontier molecular orbitals, molar refraction, lipophilicity) were not necessary for achieving good SAR, as comparable quality of SAR classification was obtained with atom pairs and 2D descriptors only. This simplified SAR approach may be useful to qualitative SAR recognition problems in a variety of data sets. PMID:18234502
Application of Satellite SAR Imagery in Mapping the Active Layer of Arctic Permafrost
NASA Technical Reports Server (NTRS)
Li, Shu-Sun; Romanovsky, V.; Lovick, Joe; Wang, Z.; Peterson, Rorik
A method of mapping the active layer of Arctic permafrost using a combination of conventional synthetic aperture radar (SAR) backscatter and more sophisticated interferometric SAR (INSAR) techniques is proposed. The proposed research is based on the sensitivity of radar backscatter to the freeze and thaw status of the surface soil, and the sensitivity of INSAR techniques to centimeter- to sub-centimeter-level surface differential deformation. The former capability of SAR is investigated for deriving the timing and duration of the thaw period for surface soil of the active layer over permafrost. The latter is investigated for the feasibility of quantitative measurement of frost heaving and thaw settlement of the active layer during the freezing and thawing processes. The resulting knowledge contributes to remote sensing mapping of the active layer dynamics and Arctic land surface hydrology.
SARS Coronavirus 3b Accessory Protein Modulates Transcriptional Activity of RUNX1b
Varshney, Bhavna; Agnihotram, Sudhakar; Tan, Yee-Joo; Baric, Ralph; Lal, Sunil K.
Background The causative agent of severe acute respiratory syndrome, SARS coronavirus (SARS-CoV) genome encodes several unique group specific accessory proteins with unknown functions. Among them, accessory protein 3b (also known as ORF4) was lately identified as one of the viral interferon antagonist. Recently our lab uncovered a new role for 3b in upregulation of AP-1 transcriptional activity and its downstream genes. Thus, we believe that 3b might play an important role in SARS-CoV pathogenesis and therefore is of considerable interest. The current study aims at identifying novel host cellular interactors of the 3b protein. Methodology/Principal Findings In this study, using yeast two-hybrid and co-immunoprecipitation techniques, we have identified a host transcription factor RUNX1b (Runt related transcription factor, isoform b) as a novel interacting partner for SARS-CoV 3b protein. Chromatin immunoprecipitaion (ChIP) and reporter gene assays in 3b expressing jurkat cells showed recruitment of 3b on the RUNX1 binding element that led to an increase in RUNX1b transactivation potential on the IL2 promoter. Kinase assay and pharmacological inhibitor treatment implied that 3b also affect RUNX1b transcriptional activity by regulating its ERK dependent phosphorylation levels. Additionally, mRNA levels of MIP-1α, a RUNX1b target gene upregulated in SARS-CoV infected monocyte-derived dendritic cells, were found to be elevated in 3b expressing U937 monocyte cells. Conclusions/Significance These results unveil a novel interaction of SARS-CoV 3b with the host factor, RUNX1b, and speculate its physiological relevance in upregulating cytokines and chemokine levels in state of SARS virus infection. PMID:22253733
Identification and SAR Evaluation of Hemozoin-Inhibiting Benzamides Active against Plasmodium falciparum.
Wicht, Kathryn J; Combrinck, Jill M; Smith, Peter J; Hunter, Roger; Egan, Timothy J
Quinoline antimalarials target hemozoin formation causing a cytotoxic accumulation of ferriprotoporphyrin IX (Fe(III)PPIX). Well-developed SAR models exist for β-hematin inhibition, parasite activity, and cellular mechanisms for this compound class, but no comparably detailed investigations exist for other hemozoin inhibiting chemotypes. Here, benzamide analogues based on previous HTS hits have been purchased or synthesized. Only derivatives containing an electron deficient aromatic ring and capable of adopting flat conformations, optimal for π-π interactions with Fe(III)PPIX, inhibited β-hematin formation. The two most potent analogues showed nanomolar parasite activity, with little CQ cross-resistance, low cytotoxicity, and high in vitro microsomal stability. Selected analogues inhibited hemozoin formation in Plasmodium falciparum causing high levels of free heme. In contrast to quinolines, introduction of amine side chains did not lead to benzamide accumulation in the parasite. These data reveal complex relationships between heme binding, free heme levels, cellular accumulation, and in vitro activity of potential novel antimalarials. PMID:27299916
SAR imagery of the Grand Banks (Newfoundland) pack ice pack and its relationship to surface features
NASA Technical Reports Server (NTRS)
Argus, S. D.; Carsey, F. D.
Synthetic Aperture Radar (SAR) data and aerial photographs were obtained over pack ice off the East Coast of Canada in March 1987 as part of the Labrador Ice Margin Experiment (LIMEX) pilot project. Examination of this data shows that although the pack ice off the Canadian East Coast appears essentially homogeneous to visible light imagery, two clearly defined zones of ice are apparent on C-band SAR imagery. To identify factors that create the zones seen on the radar image, aerial photographs were compared to the SAR imagery. Floe size data from the aerial photographs was compared to digital number values taken from SAR imagery of the same ice. The SAR data of the inner zone acquired three days apart over the melt period was also examined. The studies indicate that the radar response is governed by floe size and meltwater distribution.
The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent
te Velthuis, Aartjan J. W.; Arnold, Jamie J.; Cameron, Craig E.; van den Worm, Sjoerd H. E.; Snijder, Eric J.
An RNA-dependent RNA polymerase (RdRp) is the central catalytic subunit of the RNA-synthesizing machinery of all positive-strand RNA viruses. Usually, RdRp domains are readily identifiable by comparative sequence analysis, but biochemical confirmation and characterization can be hampered by intrinsic protein properties and technical complications. It is presumed that replication and transcription of the ∼30-kb severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) RNA genome are catalyzed by an RdRp domain in the C-terminal part of nonstructural protein 12 (nsp12), one of 16 replicase subunits. However, thus far full-length nsp12 has proven refractory to expression in bacterial systems, which has hindered both the biochemical characterization of coronavirus RNA synthesis and RdRp-targeted antiviral drug design. Here, we describe a combined strategy involving bacterial expression of an nsp12 fusion protein and its in vivo cleavage to generate and purify stable SARS-CoV nsp12 (106 kDa) with a natural N-terminus and C-terminal hexahistidine tag. This recombinant protein possesses robust in vitro RdRp activity, as well as a significant DNA-dependent activity that may facilitate future inhibitor studies. The SARS-CoV nsp12 is primer dependent on both homo- and heteropolymeric templates, supporting the likeliness of a close enzymatic collaboration with the intriguing RNA primase activity that was recently proposed for coronavirus nsp8. PMID:19875418
Structure of the SARS coronavirus main proteinase as an active C{sub 2} crystallographic dimer
Xu, Ting; Ooi, Amy; Lee, Hooi Chen; Wilmouth, Rupert; Liu, Ding Xiang; Lescar, Julien
An orthorhombic crystal form of the SARS CoV main proteinase diffracting to a resolution of 1.9 Å is reported. The conformation of residues in the catalytic site indicates an active enzyme. The 34 kDa main proteinase (M{sup pro}) from the severe acute respiratory syndrome coronavirus (SARS-CoV) plays an important role in the virus life cycle through the specific processing of viral polyproteins. As such, SARS-CoV M{sup pro} is a key target for the identification of specific inhibitors directed against the SARS virus. With a view to facilitating the development of such compounds, crystals were obtained of the enzyme at pH 6.5 in the orthorhombic space group P2{sub 1}2{sub 1}2 that diffract to a resolution of 1.9 Å. These crystals contain one monomer per asymmetric unit and the biologically active dimer is generated via the crystallographic twofold axis. The conformation of the catalytic site indicates that the enzyme is active in the crystalline form and thus suitable for structure-based inhibition studies.
Active extreme learning machines for quad-polarimetric SAR imagery classification
NASA Astrophysics Data System (ADS)
Samat, Alim; Gamba, Paolo; Du, Peijun; Luo, Jieqiong
Supervised classification of quad-polarimetric SAR images is often constrained by the availability of reliable training samples. Active learning (AL) provides a unique capability at selecting samples with high representation quality and low redundancy. The most important part of AL is the criterion for selecting the most informative candidates (pixels) by ranking. In this paper, class supports based on the posterior probability function are approximated by ensemble learning and majority voting. This approximation is statistically meaningful when a large enough classifier ensemble is exploited. In this work, we propose to use extreme learning machines and apply AL to quad-polarimetric SAR image classification. Extreme learning machines are ideal because of their fast operation, straightforward solution and strong generalization. As inputs to the so-called active extreme learning machines, both polarimetric and spatial features (morphological profiles) are considered. In order to validate the proposed method, results and performance are compared with random sampling and state-of-the-art AL methods, such as margin sampling, normalized entropy query-by-bagging and multiclass level uncertainty. Experimental results for four quad-polarimetric SAR images collected by RADARSAT-2, AirSAR and EMISAR indicate that the proposed method achieves promising results in different scenarios. Moreover, the proposed method is faster than existing techniques in both the learning and the classification phases.
The Soil Moisture Active/Passive (SMAP) Mission Radar: A Novel Conically Scanning SAR
NASA Technical Reports Server (NTRS)
Spencer, Michael; Chan, Samuel; Veilleux, Louise; Wheeler, Kevin
The Soil Moisture Active/Passive (SMAP) mission is a NASA mission identified by the NRC "decadal survey" to measure both soil moisture and freeze/thaw state from space. The mission will use both active radar and passive radiometer instruments at L-Band. In order to achieve a wide swath at sufficiently high resolution for both active and passive chan-nels, an instrument architecture that uses a large rotating reflector is employed. The active radar will further utilize SAR processing in order to obtain the sub-footprint resolution necessary for the geophysical retrievals. The SMAP radar has a unique geometry where the antenna footprint is continuously rotated about nadir in a conical fashion, as opposed to the more common side-looking SAR design. In additional to the unconventional scan geometry, the SMAP radar must address the effects of Faraday rotation and radio frequency interference (RFI), both consequences of the L-Band frequency of operation.
Different host cell proteases activate the SARS-coronavirus spike-protein for cell-cell and virus-cell fusion
Simmons, Graham; Bertram, Stephanie; Glowacka, Ilona; Steffen, Imke; Chaipan, Chawaree; Agudelo, Juliet; Lu Kai; Rennekamp, Andrew J.; Hofmann, Heike; Bates, Paul; Poehlmann, Stefan
Severe acute respiratory syndrome coronavirus (SARS-CoV) poses a considerable threat to human health. Activation of the viral spike (S)-protein by host cell proteases is essential for viral infectivity. However, the cleavage sites in SARS-S and the protease(s) activating SARS-S are incompletely defined. We found that R667 was dispensable for SARS-S-driven virus-cell fusion and for SARS-S-activation by trypsin and cathepsin L in a virus-virus fusion assay. Mutation T760R, which optimizes the minimal furin consensus motif 758-RXXR-762, and furin overexpression augmented SARS-S activity, but did not result in detectable SARS-S cleavage. Finally, SARS-S-driven cell-cell fusion was independent of cathepsin L, a protease essential for virus-cell fusion. Instead, a so far unknown leupeptin-sensitive host cell protease activated cellular SARS-S for fusion with target cells expressing high levels of ACE2. Thus, different host cell proteases activate SARS-S for virus-cell and cell-cell fusion and SARS-S cleavage at R667 and 758-RXXR-762 can be dispensable for SARS-S activation.
Follow-up: Prospective compound design using the 'SAR Matrix' method and matrix-derived conditional probabilities of activity
Gupta-Ostermann, Disha; Hirose, Yoichiro; Odagami, Takenao; Kouji, Hiroyuki; Bajorath, Jürgen
In a previous Method Article, we have presented the 'Structure-Activity Relationship (SAR) Matrix' (SARM) approach. The SARM methodology is designed to systematically extract structurally related compound series from screening or chemical optimization data and organize these series and associated SAR information in matrices reminiscent of R-group tables. SARM calculations also yield many virtual candidate compounds that form a "chemical space envelope" around related series. To further extend the SARM approach, different methods are developed to predict the activity of virtual compounds. In this follow-up contribution, we describe an activity prediction method that derives conditional probabilities of activity from SARMs and report representative results of first prospective applications of this approach. PMID:25949808
Active landslides detection at regional scale: comparing multitemporal InSAR with "handmade" inventories
NASA Astrophysics Data System (ADS)
Derron, Marc-Henri; Michoud, Clément; Jaboyedoff, Michel; Runne Lauknes, Tom
Advanced multitemporal differential SAR interferometry has proved to be able to detect unexpected active landslides in areas difficult to access. That makes this technique very useful to complete inventories. But that does not mean that applying A-DInSAR is a sufficient tool to build an inventory. Some A-DInSAR results have been compared in areas where independent landslides inventories exists, in Norway (J. Dehls at the Geological Survey of Norway) and Italy (A. Tamburini, TRE Milano). Roughly, depending on the surface cover, geomorphology and images availability, from 0 to 50% of the already known landslides can be detected with A-DInSAR results. We are testing a similar approach in Switzerland, in the county of Vaud where two landslides inventories are available (DUTI 1985, Jaboyedoff 2009). A set of 24 Envisat ASAR images (single frame/ single track) have been processed with PS-INSAR and SBAS techniques. Because of the large variety of surface cover (urban, forested, rocky) and morphology (plane and mountainous areas), both techniques provides very different results depending on local conditions.
Development of structure-activity relationship for metal oxide nanoparticles
NASA Astrophysics Data System (ADS)
Liu, Rong; Zhang, Hai Yuan; Ji, Zhao Xia; Rallo, Robert; Xia, Tian; Chang, Chong Hyun; Nel, Andre; Cohen, Yoram
Nanomaterial structure-activity relationships (nano-SARs) for metal oxide nanoparticles (NPs) toxicity were investigated using metrics based on dose-response analysis and consensus self-organizing map clustering. The NP cellular toxicity dataset included toxicity profiles consisting of seven different assays for human bronchial epithelial (BEAS-2B) and murine myeloid (RAW 264.7) cells, over a concentration range of 0.39-100 mg L-1 and exposure time up to 24 h, for twenty-four different metal oxide NPs. Various nano-SAR building models were evaluated, based on an initial pool of thirty NP descriptors. The conduction band energy and ionic index (often correlated with the hydration enthalpy) were identified as suitable NP descriptors that are consistent with suggested toxicity mechanisms for metal oxide NPs and metal ions. The best performing nano-SAR with the above two descriptors, built with support vector machine (SVM) model and of validated robustness, had a balanced classification accuracy of ~94%. An applicability domain for the present data was established with a reasonable confidence level of 80%. Given the potential role of nano-SARs in decision making, regarding the environmental impact of NPs, the class probabilities provided by the SVM nano-SAR enabled the construction of decision boundaries with respect to toxicity classification under different acceptance levels of false negative relative to false positive predictions.Nanomaterial structure-activity relationships (nano-SARs) for metal oxide nanoparticles (NPs) toxicity were investigated using metrics based on dose-response analysis and consensus self-organizing map clustering. The NP cellular toxicity dataset included toxicity profiles consisting of seven different assays for human bronchial epithelial (BEAS-2B) and murine myeloid (RAW 264.7) cells, over a concentration range of 0.39-100 mg L-1 and exposure time up to 24 h, for twenty-four different metal oxide NPs. Various nano-SAR building models were
The relationship between localised SAR in the arm and wrist current.
Dimbylow, P J
Calculations are presented of the specific energy absorption rate, SAR, in the lower arm of the NRPB anatomically realistic voxel model. NORMAN, for induced currents from 100 kHz to 80 MHz. The wrist region has a narrow cross section and contains little high conductivity muscle, comprising mainly low conductivity bone, tendon and fat. Consequently there is a channelling of the current through the high conductivity muscle, which produces high, localised values of the SAR. Values averaged over 10 g and 100 g of tissue are calculated as a function of the current flowing through the wrist. PMID:11572647
The Structure of Sec12 Implicates Potassium Ion Coordination in Sar1 Activation*
McMahon, Conor; Studer, Sean M.; Clendinen, Chaevia; Dann, Geoffrey P.; Jeffrey, Philip D.; Hughson, Frederick M.
Coat protein II (COPII)-coated vesicles transport proteins and lipids from the endoplasmic reticulum to the Golgi. Crucial for the initiation of COPII coat assembly is Sec12, a guanine nucleotide exchange factor responsible for activating the small G protein Sar1. Once activated, Sar1/GTP binds to endoplasmic reticulum membranes and recruits COPII coat components (Sec23/24 and Sec13/31). Here, we report the 1.36 Å resolution crystal structure of the catalytically active, 38-kDa cytoplasmic portion of Saccharomyces cerevisiae Sec12. Sec12 adopts a β propeller fold. Conserved residues cluster around a loop we term the "K loop," which extends from the N-terminal propeller blade. Structure-guided site-directed mutagenesis, in conjunction with in vitro and in vivo functional studies, reveals that this region of Sec12 is catalytically essential, presumably because it makes direct contact with Sar1. Strikingly, the crystal structure also reveals that a single potassium ion stabilizes the K loop; bound potassium is, moreover, essential for optimum guanine nucleotide exchange activity in vitro. Thus, our results reveal a novel role for a potassium-stabilized loop in catalyzing guanine nucleotide exchange. PMID:23109340
A Survey of Landslide Activity in the Columbia River Gorge from InSAR
NASA Astrophysics Data System (ADS)
Tong, X.; Schmidt, D. A.
The Columbia River Gorge contains several large landslide complexes that have exhibited historical movement, both catastrophic and slow moving. Monitoring the kinematics of active movement helps to characterize the ongoing natural hazard. In this study, we document the status of several large landslide complexes along the Columbia River Gorge. We use synthetic aperture radar (SAR) data from multiple satellites (ERS, ENVISAT and ALOS) to reveal the spatial-temporal movement of slow-moving landslides over two decades, 1992-2011. To increase the spatial extent of the signal we developed a new InSAR time-series method based on pixel coherence and derived the time series of the landslides. We also investigate the ability of Persistent Scatterer InSAR to better illuminate active movement. While many historical landslide complexes show minimal or non-existent movement, we measure significant creep on the Redbluff landslide, which is part of the Cascade Landslide Complex near the Bonneville Dam. The InSAR time-series data reveal approximately 25 cm of line-of-sight movement from 5 years of ALOS observations, which translates into greater than 60 cm of downslope movement. The Redbluff landslide is seasonally activated, with accelerated movement observed during the early winter of each year. However, the amplitude of the seasonal signal is variable from year-to-year. To assess the triggering mechanisms, we compared the deformation time series data with local precipitation data. The deformation correlates well with precipitation, implying the slow movement is controlled by rainfall that infiltrates to the base of the slide. A preliminary comparison with the bare earth 2m-resolution digital elevation model from LiDAR reveals that the overall deformation pattern and the active perimeter is highly correlated with the morphology of the landslide.
Mutation of Asn28 Disrupts the Dimerization and Enzymatic Activity of SARS 3CL
Barrila, J.; Gabelli, S; Bacha, U; Amzel, M; Freire, E
Coronaviruses are responsible for a significant proportion of annual respiratory and enteric infections in humans and other mammals. The most prominent of these viruses is the severe acute respiratory syndrome coronavirus (SARS-CoV) which causes acute respiratory and gastrointestinal infection in humans. The coronavirus main protease, 3CL{sup pro}, is a key target for broad-spectrum antiviral development because of its critical role in viral maturation and high degree of structural conservation among coronaviruses. Dimerization is an indispensable requirement for the function of SARS 3CL{sup pro} and is regulated through mechanisms involving both direct and long-range interactions in the enzyme. While many of the binding interactions at the dimerization interface have been extensively studied, those that are important for long-range control are not well-understood. Characterization of these dimerization mechanisms is important for the structure-based design of new treatments targeting coronavirus-based infections. Here we report that Asn28, a residue 11 {angstrom} from the closest residue in the opposing monomer, is essential for the enzymatic activity and dimerization of SARS 3CLpro. Mutation of this residue to alanine almost completely inactivates the enzyme and results in a 19.2-fold decrease in the dimerization K{sub d}. The crystallographic structure of the N28A mutant determined at 2.35 {angstrom} resolution reveals the critical role of Asn28 in maintaining the structural integrity of the active site and in orienting key residues involved in binding at the dimer interface and substrate catalysis. These findings provide deeper insight into complex mechanisms regulating the activity and dimerization of SARS 3CL{sup pro}.
The variety of subaerial active salt deformations in the Kuqa fold-thrust belt (China) constrained by InSAR
NASA Astrophysics Data System (ADS)
Colón, Cindy; Webb, A. Alexander G.; Lasserre, Cécile; Doin, Marie-Pierre; Renard, François; Lohman, Rowena; Li, Jianghai; Baudoin, Patrick F.
Surface salt bodies in the western Kuqa fold-thrust belt of northwestern China allow study of subaerial salt kinematics and its possible correlations with weather variations. Ephemeral subaerial salt exposure during the evolution of a salt structure can greatly impact the subsequent development and deformation of its tectonic setting. Here, we present a quantitative time-lapse survey of surface salt deformation measured from interferometric synthetic aperture radar (InSAR) using Envisat radar imagery acquired between 2003 and 2010. Time series analysis and inspection of individual interferograms confirm that the majority of the salt bodies in western Kuqa are active, with significant InSAR observable displacements at 3 of 4 structures studied in the region. Subaerial salt motion toward and away from the satellite at rates up to 5 mm/yr with respect to local references. Rainfall measurements from the Tropical Rainfall Measuring Mission (TRMM) and temperature from a local weather station are used to test the relationship between seasonality and surface salt motion. We observe decoupling between surface salt motion and seasonality and interpret these observations to indicate that regional and local structural regimes exert primary control on surface salt displacement rates.
Railway deformation detected by DInSAR over active sinkholes in the Ebro Valley evaporite karst, Spain
NASA Astrophysics Data System (ADS)
Galve, J. P.; Castañeda, C.; Gutiérrez, F.
Subsidence was measured for the first time on railway tracks in the central sector of Ebro Valley (NE Spain) using Differential Synthetic Aperture Radar Interferometry (DInSAR) techniques. This area is affected by evaporite karst and the analysed railway corridors traverse active sinkholes that produce deformations in these infrastructures. One of the railway tracks affected by slight settlements is the Madrid-Barcelona high-speed line, a form of transport infrastructure highly vulnerable to ground deformation processes. Our analysis based on DInSAR measurements and geomorphological surveys indicates that this line shows dissolution-induced subsidence and compaction of anthropogenic deposits (infills and embankments). Significant sinkhole-related subsidence was also measured by DInSAR techniques on the Castejón-Zaragoza conventional railway line. This study demonstrates that DInSAR velocity maps, coupled with detailed geomorphological surveys, may help in the identification of the railway track sections that are affected by active subsidence.
Synthesis and antibacterial activity of sulfonamides. SAR and DFT studies
NASA Astrophysics Data System (ADS)
Boufas, Wahida; Dupont, Nathalie; Berredjem, Malika; Berrezag, Kamel; Becheker, Imène; Berredjem, Hajira; Aouf, Nour-Eddine
A series of substituted sulfonamide derivatives were synthesized from chlorosulfonyl isocyanate (CSI) in tree steps (carbamoylation, sulfamoylation and deprotection). Antibacterial activity in vitro of some newly formed compounds investigated against clinical strains Gram-positive and Gram-negative: Escherichia coli and Staphylococcus aureus applying the method of dilution and minimal inhibition concentration (MIC) methods. These compounds have significant bacteriostatic activity with totalities of bacterial strains used. DFT calculations with B3LYP/6-31G(d) level have been used to analyze the electronic and geometric characteristics deduced for the stable structure of three compounds presenting conjugation between a nitrogen atom N through its lone pair and an aromatic ring next to it. The principal quantum chemical descriptors have been correlated with the antibacterial activity.
Synthesis and Structure Activity Relationship of 3-Hydroxypyridin-2-thione Based Histone Deacetylase Inhibitors
Sodji, Quaovi H.; Patil, Vishal; Kornacki, James R.; Mrksich, Milan; Oyelere, Adegboyega K.
We have previously identified 3-hydroxypyridin-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but are devoid of HDAC1 inhibition. To further delineate the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds 10d and 14e with potent HDAC6 and HDAC8 activities, but that are inactive against HDAC1. These new HDACi possess anti-cancer activities against various cancer cell lines including Jurkat J-γ1 against which SAHA and the previously disclosed 3HPT-derived HDACi were inactive. PMID:24304348
Synthesis, SAR and antibacterial activity of hybrid chloro, dichloro-phenylthiazolyl-s-triazines
Gahtori, Prashant; Ghosh, Surajit Kumar; Singh, Brijesh; Singh, Udaya Pratap; Bhat, Hans Raj; Uppal, Archana
A series of hybrid novel chloro (1a–9a) and dichloro (10b–18b) phenylthiazolyl-s-triazine were synthesized and subsequently subjected to their antibacterial activity against three gram positive viz. Lactobacillus casei (NCIM-2651); Bacillus cereus (NCIM-2458); Staphylococcus aureus (NCIM-2120) and three gram negative viz Salmonella typhimurium (NCIM-2501); Escherichia coli (NCIM-2065); Klebsiella aerogenes (NCIM-2098). The SAR studies around the lead compound revealed that introduction of electron withdrawing groups and amino (–NH–) and mercapto (–S–) linker bridge seemed more promising towards antibacterial activity. Moreover, the virtual Molinspiration screenings are in compliance with Ghose's rule. PMID:23960775
A categorical structure-activity relationship analysis of GPR119 ligands
Kumar, Pritesh; Carrasquer, Carl A.; Carter, Arren; Song, Zhao-Hui; Cunningham, Albert R.
The categorical structure-activity relationship (cat-SAR) expert system has been successfully used in the analysis of chemical compounds that cause toxicity. Herein we describe the use of this fragment-based approach to model ligands for the G protein-coupled receptor 119 (GPR119). Using compounds that are known GPR119 agonists and compounds that we have confirmed experimentally that are not GPR119 agonists, four distinct cat-SAR models were developed. Using a leave-one out validation routine, the best GPR119 model had an overall concordance of 99 %, a sensitivity of 99 %, and a specificity of 100 %. Our findings from the in-depth fragment analysis of several known GPR119 agonists were consistent with previously reported GPR119 structure-activity relationship (SAR) analyses. Overall, while our results indicate that we have developed a highly predictive cat-SAR model that can be potentially used to rapidly screen for prospective GPR119 ligands the applicability domain must be taken into consideration. Moreover, our study demonstrates for the first time, that the cat-SAR expert system can be used to model G protein-coupled receptor ligands, many of which are important therapeutic agents. PMID:25401513
Crustal-scale active deformation along the Ecuadorian Andes using Persistent Scatterers SAR Interferometry
NASA Astrophysics Data System (ADS)
Champenois, J.; Baize, S.; Audin, L.; Pinel, V.; Alvarado, A.; Jomard, H.; Yepes, H. A.
Located in the Northern Andes along the active subduction zone of the Nazca plate beneath the South American continent, Ecuador is highly exposed to seismic hazard. For the last ten years, numerous multidisciplinary studies focused on major seismicity related to the subduction, whereas few investigations concentrated on M>7 crustal seismicity in the upper plate (like 1797 Riobamba earthquake, ML 8.3, 12.000 deaths). The active faults producing these earthquakes are poorly known in term of slip rate and for some cases are even not identified yet. Additionnally, Ecuador is one of the most active volcanic areas of the northern Andean volcanic zone. Three among the nine active volcanoes are actually erupting (Reventador, Tungurahua, and Sangay). For the last 5 years, geodetic networks have been deployed in Ecuador to enhance crustal deformation monitoring, but these point-wise techniques cannot provide spatially dense maps of ground deformation and are quite expensive methods. To address this issue, we applied the Persistent Scatterers SAR Interferometry technique (StaMPS/MTI freeware developed by A. Hooper) to ENVISAT SAR data between 2003 and 2009. Using these cost-effective techniques, we are able to investigate both tectonic and volcanic surface deformations with an unprecedented spatial density of measurements. This study presents new PS-InSAR results along the Ecuadorian Andes, close to the area of Riobamba. We generated average velocity maps and consistent time-series of displacements measured along the radar line of sight. These results evidence large scale deformation localized on the Pallatanga fault system (locked fault) compatible with a model of locked strike slip fault. Moreover, these results show an important growth of the Tungurahua volcanic complex (maximum rate about 9 mm/yr) with a rapid uplift prior and post 2006 explosive eruption. We investigate the time-series of displacement for 22 images. Our results permitted to propose two crustal source
(Q)SAR: A Tool for the Toxicologist.
Steinbach, Thomas; Gad-McDonald, Samantha; Kruhlak, Naomi; Powley, Mark; Greene, Nigel
A continuing education (CE) course at the 2014 American College of Toxicology annual meeting covered the topic of (Quantitative) Structure-Activity Relationships [(Q)SAR]. The (Q)SAR methodologies use predictive computer modeling based on predefined rules to describe the relationship between chemical structure and a chemical's associated biological activity or statistical tools to find correlations between biologic activity and the molecular structure or properties of a compound. The (Q)SAR has applications in risk assessment, drug discovery, and regulatory decision making. Pressure within industry to reduce the cost of drug development and societal pressure for government regulatory agencies to produce more accurate and timely risk assessment of drugs and chemicals have necessitated the use of (Q)SAR. Producing a high-quality (Q)SAR model depends on many factors including the choice of statistical methods and descriptors, but first and foremost the quality of the data input into the model. Understanding how a (Q)SAR model is developed and applied is critical to the successful use of such a tool. The CE session covered the basic principles of (Q)SAR, practical applications of these computational models in toxicology, how regulatory agencies use and interpret (Q)SAR models, and potential pitfalls of using them. PMID:25979517
Automated Structure-Activity Relationship Mining: Connecting Chemical Structure to Biological Profiles.
Wawer, Mathias J; Jaramillo, David E; Dančík, Vlado; Fass, Daniel M; Haggarty, Stephen J; Shamji, Alykhan F; Wagner, Bridget K; Schreiber, Stuart L; Clemons, Paul A
Understanding the structure-activity relationships (SARs) of small molecules is important for developing probes and novel therapeutic agents in chemical biology and drug discovery. Increasingly, multiplexed small-molecule profiling assays allow simultaneous measurement of many biological response parameters for the same compound (e.g., expression levels for many genes or binding constants against many proteins). Although such methods promise to capture SARs with high granularity, few computational methods are available to support SAR analyses of high-dimensional compound activity profiles. Many of these methods are not generally applicable or reduce the activity space to scalar summary statistics before establishing SARs. In this article, we present a versatile computational method that automatically extracts interpretable SAR rules from high-dimensional profiling data. The rules connect chemical structural features of compounds to patterns in their biological activity profiles. We applied our method to data from novel cell-based gene-expression and imaging assays collected on more than 30,000 small molecules. Based on the rules identified for this data set, we prioritized groups of compounds for further study, including a novel set of putative histone deacetylase inhibitors. PMID:24710340
Proteolytic activation of the SARS-coronavirus spike protein: Cutting enzymes at the cutting edge of antiviral research
Simmons, Graham; Zmora, Pawel; Gierer, Stefanie; Heurich, Adeline; Pöhlmann, Stefan
The severe acute respiratory syndrome (SARS) pandemic revealed that zoonotic transmission of animal coronaviruses (CoV) to humans poses a significant threat to public health and warrants surveillance and the development of countermeasures. The activity of host cell proteases, which cleave and activate the SARS-CoV spike (S) protein, is essential for viral infectivity and constitutes a target for intervention. However, the identities of the proteases involved have been unclear. Pioneer studies identified cathepsins and type II transmembrane serine proteases as cellular activators of SARS-CoV and demonstrated that several emerging viruses might exploit these enzymes to promote their spread. Here, we will review the proteolytic systems hijacked by SARS-CoV for S protein activation, we will discuss their contribution to viral spread in the host and we will outline antiviral strategies targeting these enzymes. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses." PMID:24121034
In vivo structure-activity relationship studies support allosteric targeting of a dual specificity phosphatase.
Korotchenko, Vasiliy N; Saydmohammed, Manush; Vollmer, Laura L; Bakan, Ahmet; Sheetz, Kyle; Debiec, Karl T; Greene, Kristina A; Agliori, Christine S; Bahar, Ivet; Day, Billy W; Vogt, Andreas; Tsang, Michael
Dual specificity phosphatase 6 (DUSP6) functions as a feedback attenuator of fibroblast growth factor signaling during development. In vitro high throughput chemical screening attempts to discover DUSP6 inhibitors have yielded limited success. However, in vivo whole-organism screens of zebrafish identified compound 1 (BCI) as an allosteric inhibitor of DUSP6. Here we designed and synthesized a panel of analogues to define the structure-activity relationship (SAR) of DUSP6 inhibition. In vivo high-content analysis in transgenic zebrafish, coupled with cell-based chemical complementation assays, identified structural features of the pharmacophore of 1 that were essential for biological activity. In vitro assays of DUSP hyperactivation corroborated the results from in vivo and cellular SAR. The results reinforce the notion that DUSPs are druggable through allosteric mechanisms and illustrate the utility of zebrafish as a model organism for in vivo SAR analyses. PMID:24909879
Syntheses, biological activities and SAR studies of novel carboxamide compounds containing piperazine and arylsulfonyl moieties.
Wang, Bao-Lei; Shi, Yan-Xia; Zhang, Shu-Jun; Ma, Yi; Wang, Hong-Xue; Zhang, Li-Yuan; Wei, Wei; Liu, Xing-Hai; Li, Yong-Hong; Li, Zheng-Ming; Li, Bao-Ju
A series of novel carboxamide compounds 19a-19j, 20a-20j and 22a-22d containing piperazine and arylsulfonyl moieties have been synthesized. The bioassay results showed that some compounds exhibited favorable herbicidal activities against dicotyledonous plants and many of them possessed excellent antifungal activities. Among 24 novel compounds, some showed superiority over the commercial fungicides Chlorothalonil, Dimethomorph, Thiophanate-methyl, Iprodione, and Zhongshengmycin at 500 mg/L concentration. Some compounds also exhibited high KARI inhibitory activity at 100 μg/mL concentration and could be used as new KARI lead inhibitors for further studies. Moreover, SAR of these new compounds were comprehensively investigated using different computational methods in which 3D-QSAR model obtained provided useful information for further structural optimization for the discovery of new fungicides. The results of this research will contribute to explore comprehensive biological activities of piperazine-containing compounds in different areas of chemistry. PMID:27092414
Structure-Activity Relationship of Azaindole-Based Glucokinase Activators.
Paczal, Attila; Bálint, Balázs; Wéber, Csaba; Szabó, Zoltán B; Ondi, Levente; Theret, Isabelle; De Ceuninck, Frédéric; Bernard, Catherine; Ktorza, Alain; Perron-Sierra, Francoise; Kotschy, András
7-Azaindole has been identified as a novel bidentate anchor point for allosteric glucokinase activators. A systematic investigation around three principal parts of the new small molecule glucokinase activators led to a robust SAR in agreement with structural data that also helped to assess the conformational flexibility of the allosteric activation site. The increase in glucose uptake resulting from glucokinase activation in hepatocytes in vitro translated into the efficient lowering of glucose levels in vivo with the best compounds. PMID:26685731
Active anthropogenic and surface salt deformation measured by InSAR, northwestern China
NASA Astrophysics Data System (ADS)
Colon, C.; Webb, A. G.; Lasserre, C.; Doin, M. P.
Despite the global occurrence of salt, very few salt bodies outcrop and are presently preserved at the surface. Because of this much of our knowledge on salt structures is sourced from subsurface imaging and modeling and less from field based studies. Using interferometry of synthetic aperture radar (InSAR) we monitor surface displacements across four surface salt outcrops in the western margin of the Kuqa fold-thrust belt of Xinjiang Province, China. An InSAR time series was constructed from 40 Envisat ASAR C-band images between June 2003 and October 2010. Interferometric processing was completed using the New Small Baseline Algorithm Subset (NSBAS). These poorly studied salt structures provide a fresh opportunity to study how salt behaves on the surface. The salt bodies outcrop along an active intracontinental thrust system between the Tian Shan and Tarim basin to the south. The four surface namakiers (salt glaciers) were analyzed in this study include: the Quele, Awate, Bozidun, and an unnamed structure referred to as the Western namakier. The ~35 km long Quele namakier is a line-sourced structure advancing along the Quele salt thrust. The other three namakiers range between ~1-3 km long and are point-sourced structures. The namakiers studied display non-steady deformation with rates of displacement varying between uplifts of up to +4 cm/yr and subsidence rates of -4 cm/yr. Additionally, the Kuqa fold-thrust belt hosts a number of hydrocarbon fields and InSAR measurements detect significant anthropogenic deformation associated with hydrocarbon extraction and fluid injection.
Out-of-Band 40 DB Bandwidth of EESS (Active) Spaceborne SARS
NASA Technical Reports Server (NTRS)
Huneycutt, Bryan L.
This document presents a study of out of band (OOB) 40 dB bandwidth requirements of spaceborne SARs in the Earth Exploration-Satellite Service (active) and Space Research Service (active). The purpose of the document is to study the OOB 40 dB bandwidth requirements and compare the 40 dB bandwidth B-40 as measured in simulations with that calculated using the ITU-R Rec SM.1541 equations. The spectra roll-off and resulting OOB 40 dB bandwidth of the linear FM signal is affected by the time-bandwidth product and the rise/fall times. Typical values of these waveform characteristics are given for existing EESS (active) sensors.
Monitoring the Progression of Structure-Activity Relationship Information during Lead Optimization.
Shanmugasundaram, Veerabahu; Zhang, Liying; Kayastha, Shilva; de la Vega de León, Antonio; Dimova, Dilyana; Bajorath, Jürgen
Lead optimization (LO) in medicinal chemistry is largely driven by hypotheses and depends on the ingenuity, experience, and intuition of medicinal chemists, focusing on the key question of which compound should be made next. It is essentially impossible to predict whether an LO project might ultimately be successful, and it is also very difficult to estimate when a sufficient number of compounds has been evaluated to judge the odds of a project. Given the subjective nature of LO decisions and the inherent optimism of project teams, very few attempts have been made to systematically evaluate project progression. Herein, we introduce a computational framework to follow the evolution of structure-activity relationship (SAR) information over a time course. The approach is based on the use of SAR matrix data structures as a diagnostic tool and enables graphical analysis of SAR redundancy and project progression. This framework should help the process of making decisions in close-in analogue work. PMID:26569348
Monitoring of Landslide Activity in Slovakia Territory Using Multi-Temporal InSAR Techniques
NASA Astrophysics Data System (ADS)
Bakon, M.; Papco, J.; Perissin, D.; Lazecky, M.; Sousa, J. J.; Hlavacova, I.; Batorova, K.; Ondrejka, P.; Liscak, P.; Paudits, P.; Real, N.
Slope deformations are the most important geohazards in Slovakia which annually cause an extensive economic damage of significant influence. About 22000 slope deformations have been registered so far, covering an area of almost 2600 km2 . Since 2010, 639 new slope failures have been witnessed and their activation was driven mainly by the climatic anomalies such as extraordinary rainfalls. Many of these landslides currently represent a direct threat to the lives, health and property of the residents in the affected areas. The landslide Nizna Mysla is considered to be the second most catastrophic landslide in the history of Slovakia. Damages to buildings and engineering networks had not been identified in the '90s of the last century when the first problems with the slope stability appeared. Up-to-now monitoring techniques has currently been reassessed to account for the results from satellite Synthetic Aperture Radar (SAR) techniques.
Understanding SARS with Wolfram approach.
Li, Da-Wei; Pan, Yu-Xi; Duan, Yun; Hung, Zhen-De; Xu, Ming-Qing; He, Lin
Stepping acquired immunodeficiency syndrome (AIDS), severe acute respiratory syndrome (SARS) as another type of disease has been threatening mankind since late last year. Many scientists worldwide are making great efforts to study the etiology of this disease with different approaches. 13 species of SARS virus have been sequenced. However, most people still largely rely on the traditional methods with some disadvantages. In this work, we used Wolfram approach to study the relationship among SARS viruses and between SARS viruses and other types of viruses, the effect of variations on the whole genome and the advantages in the analysis of SARS based on this novel approach. As a result, the similarities between SARS viruses and other coronaviruses are not really higher than those between SARS viruses and non-coronaviruses. PMID:14732867
Structure-Activity Relationships in Nitro-Aromatic Compounds
NASA Astrophysics Data System (ADS)
Vogt, R. A.; Rahman, S.; Crespo-Hernández, C. E.
Many nitro-aromatic compounds show mutagenic and carcinogenic properties, posing a potential human health risk. Despite this potential health hazard, nitro-aromatic compounds continue to be emitted into ambient air from municipal incinerators, motor vehicles, and industrial power plants. As a result, understanding the structural and electronic factors that influence mutagenicity in nitro-aromatic compounds has been a long standing objective. Progress toward this goal has accelerated over the years, in large part due to the synergistic efforts among toxicology, computational chemistry, and statistical modeling of toxicological data. The concerted influence of several structural and electronic factors in nitro-aromatic compounds makes the development of structure-activity relationships (SARs) a paramount challenge. Mathematical models that include a regression analysis show promise in predicting the mutagenic activity of nitro-aromatic compounds as well as in prioritizing compounds for which experimental data should be pursued. A major challenge of the structure-activity models developed thus far is their failure to apply beyond a subset of nitro-aromatic compounds. Most quantitative structure-activity relationship papers point to statistics as the most important confirmation of the validity of a model. However, the experimental evidence shows the importance of the chemical knowledge in the process of generating models with reasonable applicability. This chapter will concisely summarize the structural and electronic factors that influence the mutagenicity in nitro-aromatic compounds and the recent efforts to use quantitative structure-activity relationships to predict those physicochemical properties.
Railway deformation detected by DInSAR over active sinkholes in the Ebro Valley evaporite karst, Spain
NASA Astrophysics Data System (ADS)
Galve, J. P.; Castañeda, C.; Gutiérrez, F.
Previously not measured subsidence on railway tracks was detected using DInSAR displacement maps produced for the central sector of Ebro Valley (NE Spain). This area is affected by evaporite karst and the analyzed railway corridors traverse active sinkholes that produce deformations in these infrastructures. One of the railway tracks affected by slight settlements corresponds to the Madrid-Barcelona high-speed line, a transport infrastructure highly vulnerable to ground deformation processes. Our analysis based on DInSAR measurements and geomorphological surveys indicate that this line show dissolution-induced subsidence and compaction of anthropogenic deposits (infills and embankments). By using DInSAR techniques, it was also measured the significant subsidence related to the activity of sinkholes in the Castejón-Zaragoza conventional railway line. Thus, this study demonstrate that DInSAR velocity maps coupled with detailed geomorphological surveys may help in the identification of the sectors of railway tracks that may compromise the safety of travellers.
Structure-activity relationships of glutamate carboxypeptidase II (GCPII) inhibitors.
Ferraris, D V; Shukla, K; Tsukamoto, T
Glutamate carboxypeptidase II (GCPII, EC 184.108.40.206) is a zinc metallopeptidase that hydrolyzes N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate in the nervous system. Inhibition of GCPII has the potential to reduce extracellular glutamate and represents an opportune target for treating neurological disorders in which excess glutamate is considered pathogenic. Furthermore, GCPII was found to be identical to a tumor marker, prostate-specific membrane antigen (PSMA), and has drawn significant interest as a diagnostic and/or therapeutic target in oncology. Over the past 15 years, tremendous efforts have been made in the discovery of potent GCPII inhibitors, particularly those with phosphorus-, urea- and thiol-based zinc binding groups. In addition, significant progress has been made in understanding the three-dimensional structural characteristics of GCPII in complex with various ligands. The purpose of this review article is to analyze the structure-activity relationships (SAR) of GCPII inhibitors reported to date, which are classified on the basis of their zinc-binding group. SAR and crystallographic data are evaluated in detail for each of these series to highlight the future challenges and opportunities to identify clinically viable GCPII inhibitors. PMID:22304717
Characterization of sarR, a Modulator of sar Expression in Staphylococcus aureus
Manna, Adhar; Cheung, Ambrose L.
The expression of virulence determinants in Staphylococcus aureus is controlled by global regulatory loci (e.g., sar and agr). The sar locus is composed of three overlapping transcripts (sar P1, P3, and P2 transcripts from P1, P3, and P2 promoters, respectively), all encoding the 372-bp sarA gene. The level of SarA, the major regulatory protein, is partially controlled by the differential activation of sar promoters. We previously partially purified a ∼12 kDa protein with a DNA-specific column containing a sar P2 promoter fragment. In this study, the putative gene, designated sarR, was identified and found to encode a 13.6-kDa protein with homology to SarA. Transcriptional and immunoblot studies revealed the sarR gene to be expressed in other staphylococcal strains. Recombinant SarR protein bound sar P1, P2, and P3 promoter fragments in gel shift and footprinting assays. A sarR mutant expressed a higher level of P1 transcript than the parent, as confirmed by promoter green fluorescent protein fusion assays. As the P1 transcript is the predominant sar transcript, we confirmed that the sarR mutant expressed more SarA than the parental strain. We thus proposed that SarR is a regulatory protein that binds to the sar promoters to down-regulate P1 transcription and the ensuing SarA protein expression. PMID:11159982
In 2003, an International Life Sciences Institute (ILSI) Working Group examined the potential of statistically based structure-activity relationship (SAR) models for use in screening environmental contaminants for possible developmental toxicants.
A wide variety of artificial intelligence (AI) and structure-activity relationship (SAR approaches have been applied to tackling the general problem of predicting rodent chemical carcinogenicity. Given the diversity of chemical structures and mechanisms relative to this endpoin...
Riccardin C derivatives as anti-MRSA agents: structure-activity relationship of a series of hydroxylated bis(bibenzyl)s.
Sawada, Hiromi; Okazaki, Miki; Morita, Daichi; Kuroda, Teruo; Matsuno, Kenji; Hashimoto, Yuichi; Miyachi, Hiroyuki
Members of a series of macrocyclic bis(bibenzyl) riccardin-class derivatives were found to exhibit antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure-activity relationship (SAR) studies were conducted, focusing on the number and position of the hydroxyl groups. The minimum essential structure for anti-MRSA activity was also investigated. PMID:23122868
Semi-Automated Detection Of Terrain Activity In The Swiss Alpine Periglacial Environment From DInSAR Scenes
NASA Astrophysics Data System (ADS)
Barboux, Chloe; Dalaloye, Reynald; Lambiel, Christophe; Strozzi, Tazio; Raetzo, Hugo; Collet, Claude
This paper proposes a semi-automated method to update inventory of moving slopes. First a Map of Terrain Activity (MTA) is created by partitioning an interferogram, using segmentation and classification processes, into 3 regions: stable areas, coherently moving parts and decorrelated areas (due to motion or not). Then, a Combined-Map of Terrain Activity (C- MTA) is computed describing the general behavior of the terrain at a specific time-lapse. Finally, C-MTA is used to determine the potential change in the activity rate of moving slopes. Tests are performed in a small area using large set of TSX DInSAR scenes from summers 2008 to 2012 in order to update past moving slope inventories produced from ERS DInSAR data.
InSAR measurements around active faults: creeping Philippine Fault and un-creeping Alpine Fault
NASA Astrophysics Data System (ADS)
Fukushima, Y.
Recently, interferometric synthetic aperture radar (InSAR) time-series analyses have been frequently applied to measure the time-series of small and quasi-steady displacements in wide areas. Large efforts in the methodological developments have been made to pursue higher temporal and spatial resolutions by using frequently acquired SAR images and detecting more pixels that exhibit phase stability. While such a high resolution is indispensable for tracking displacements of man-made and other small-scale structures, it is not necessarily needed and can be unnecessarily computer-intensive for measuring the crustal deformation associated with active faults and volcanic activities. I apply a simple and efficient method to measure the deformation around the Alpine Fault in the South Island of New Zealand, and the Philippine Fault in the Leyte Island. I use a small-baseline subset (SBAS) analysis approach (Berardino, et al., 2002). Generally, the more we average the pixel values, the more coherent the signals are. Considering that, for the deformation around active faults, the spatial resolution can be as coarse as a few hundred meters, we can severely 'multi-look' the interferograms. The two applied cases in this study benefited from this approach; I could obtain the mean velocity maps on practically the entire area without discarding decorrelated areas. The signals could have been only partially obtained by standard persistent scatterer or single-look small-baseline approaches that are much more computer-intensive. In order to further increase the signal detection capability, it is sometimes effective to introduce a processing algorithm adapted to the signal of interest. In an InSAR time-series processing, one usually needs to set the reference point because interferograms are all relative measurements. It is difficult, however, to fix the reference point when one aims to measure long-wavelength deformation signals that span the whole analysis area. This problem can be
Broadening of neutralization activity to directly block a dominant antibody-driven SARS-coronavirus evolution pathway.
Sui, Jianhua; Aird, Daniel R; Tamin, Azaibi; Murakami, Akikazu; Yan, Meiying; Yammanuru, Anuradha; Jing, Huaiqi; Kan, Biao; Liu, Xin; Zhu, Quan; Yuan, Qing-An; Adams, Gregory P; Bellini, William J; Xu, Jianguo; Anderson, Larry J; Marasco, Wayne A
Phylogenetic analyses have provided strong evidence that amino acid changes in spike (S) protein of animal and human SARS coronaviruses (SARS-CoVs) during and between two zoonotic transfers (2002/03 and 2003/04) are the result of positive selection. While several studies support that some amino acid changes between animal and human viruses are the result of inter-species adaptation, the role of neutralizing antibodies (nAbs) in driving SARS-CoV evolution, particularly during intra-species transmission, is unknown. A detailed examination of SARS-CoV infected animal and human convalescent sera could provide evidence of nAb pressure which, if found, may lead to strategies to effectively block virus evolution pathways by broadening the activity of nAbs. Here we show, by focusing on a dominant neutralization epitope, that contemporaneous- and cross-strain nAb responses against SARS-CoV spike protein exist during natural infection. In vitro immune pressure on this epitope using 2002/03 strain-specific nAb 80R recapitulated a dominant escape mutation that was present in all 2003/04 animal and human viruses. Strategies to block this nAb escape/naturally occurring evolution pathway by generating broad nAbs (BnAbs) with activity against 80R escape mutants and both 2002/03 and 2003/04 strains were explored. Structure-based amino acid changes in an activation-induced cytidine deaminase (AID) "hot spot" in a light chain CDR (complementarity determining region) alone, introduced through shuffling of naturally occurring non-immune human VL chain repertoire or by targeted mutagenesis, were successful in generating these BnAbs. These results demonstrate that nAb-mediated immune pressure is likely a driving force for positive selection during intra-species transmission of SARS-CoV. Somatic hypermutation (SHM) of a single VL CDR can markedly broaden the activity of a strain-specific nAb. The strategies investigated in this study, in particular the use of structural information in
Preliminary results of ESA Category-1 Project 5834 "Application of DInSAR technique to areas of active ground deformations"
NASA Astrophysics Data System (ADS)
Massa, B.; D'Auria, L.
We have established a processing chain of Synthetic Aperture Radar (SAR) data for identification and parametrisation of deformation sources in areas of active ground deformation (e.g. seismogenic areas, volcanic districts). SAR data from European Space Agency (ESA) satellites ERS-2 and ENVISAT are used. SAR and InSAR data processing LEVEL 0 SAR data are focussed to Single Look Complex (SLC) through ROI_PAC (Copyright 2002-2008, Caltech/Jet Propulsion Laboratory). We perform an advanced data processing using Doris (Kampes and Usai, 1999) a single program that can do most common steps of the interferometric radar processing starting from SLC data to generation of interferometric products and geocoding. Unwrapping of interferometric phase is performed using the public domain software snaphu (Chen and Zebker, 2001). Modeling of deformation sources We propose a novel inversion approach base on non-linear inversion. The forward modeling is provided by the semi-analytic deformation model for point sources and finite faults. The parameters of the fault (center position, width, height, rake and seismic moment) are inverted using a combination of non-linear optimization algorithms (as Monte-Carlo, Nelder&Mead Simplex and Simulated Annealing). The misfit function defined for the optimization is based on the L2 norm of the error weighted by the coherence of the considered spatial point. Test datasets To test our modeling procedure we chose three different study areas, refer to mainly strike-slip seismogenic sources with different orientation to respect satellite Line Of Sight (LOS): December 26 2003 Iranian earthquake (Bam e.), data from both ascending and descending passes of ENVISAT ASAR narrow swath IS2 (RAW and SLCs); August 17 1999 Turkey earthquake (Izmit e.), data from both ascending and descending passes of ERS-2 AMI SAR (SLCs); June 17-21 2000 Iceland earthquakes, data from both ascending and descending passes of ERS-2 AMI SAR (SLCs). Tests carried over real
Development of structure-activity relationship rules for predicting carcinogenic potential of chemicals.
Woo, Y T; Lai, D Y; Argus, M F; Arcos, J C
Since the inception of Section 5 (Premanufacturing/Premarketing Notification, PMN) of the Toxic Substances Control Act (TSCA), structure-activity relationship (SAR) analysis has been effectively used by U.S. Environmental Protection Agency's (EPA) Structure Activity Team (SAT) in the assessment of potential carcinogenic hazard of new chemicals for which test data are not available. To capture, systematize and codify the Agency's predictive expertise in order to make it more widely available to assessors outside the TSCA program, a cooperative project was initiated to develop a knowledge rule-based expert system to mimic the thinking and reasoning of the SAT. In this communication, we describe the overall structure of this expert system, discuss the scientific bases and principles of SAR analysis of chemical carcinogens used in the development of SAR knowledge rules, and delineate the major factors/rules useful for assessing the carcinogenic potential of fibers, polymers, metals/metalloids and several major classes of organic chemicals. An integrative approach using available short-term predictive tests and non-cancer toxicological data to supplement SAR analysis has also been described. PMID:7570659
Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors.
Bouckaert, Charlotte; Serra, Silvia; Rondelet, Grégoire; Dolušić, Eduard; Wouters, Johan; Dogné, Jean-Michel; Frédérick, Raphaël; Pochet, Lionel
Inhibitors of the coagulation factor XIIa (FXIIa) are attractive to detail the roles of this protease in hemostasis and thrombosis, to suppress artifact due to contact pathway activation in blood coagulation assays, and they are promising as antithrombotic therapy. The 3-carboxamide coumarins have been previously described as small-molecular-weight FXIIa inhibitors. In this study, we report a structure-activity relationship (SAR) study around this scaffold with the aim to discover new selective FXIIa inhibitors with an improved physico-chemical profile. To better understand these SAR, docking experiments were undertaken. For this purpose, we built an original hybrid model of FXIIa. This model has the advantage to gather the best features from the recently published crystal structure of FXIIa in its zymogen form and a more classical homology model. Results with the hybrid model are encouraging as they help understanding the activity and selectivity of our best compounds. PMID:26827162
Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease.
Békés, Miklós; van der Heden van Noort, Gerbrand J; Ekkebus, Reggy; Ovaa, Huib; Huang, Tony T; Lima, Christopher D
Deubiquitinating enzymes (DUBs) recognize and cleave linkage-specific polyubiquitin (polyUb) chains, but mechanisms underlying specificity remain elusive in many cases. The severe acute respiratory syndrome (SARS) coronavirus papain-like protease (PLpro) is a DUB that cleaves ISG15, a two-domain Ub-like protein, and Lys48-linked polyUb chains, releasing diUb(Lys48) products. To elucidate this specificity, we report the 2.85 Å crystal structure of SARS PLpro bound to a diUb(Lys48) activity-based probe. SARS PLpro binds diUb(Lys48) in an extended conformation via two contact sites, S1 and S2, which are proximal and distal to the active site, respectively. We show that specificity for polyUb(Lys48) chains is predicated on contacts in the S2 site and enhanced by an S1-S1' preference for a Lys48 linkage across the active site. In contrast, ISG15 specificity is dominated by contacts in the S1 site. Determinants revealed for polyUb(Lys48) specificity should prove useful in understanding PLpro deubiquitinating activities in coronavirus infections. PMID:27203180
Design, structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives/analogues.
Sahu, Pramod K
New fourteen 3,4-dihydropyrimidine derivatives/analogues of curcumin (2a-2n) were designed, synthesized and biologically evaluated for their cytotoxicity and antioxidant activity. Cytotoxicity effect has been evaluated against three cell lines HeLa, HCT-116 and QG-56 by MTT assay method. From SAR study, it has been revealed that particularly, compound 2e and 2j (IC50 value 12.5 μM) have shown better cytotoxicity effect against three cell lines. According to results of SAR study, it was found that 3,4-dihydropyrimidines of curcumin, 2c, 2d, 2j and 2n exhibited better antioxidant activity than curcumin. A correlation of structure and activities relationship of these compounds with respect to drug score profiles and other physico-chemical properties of drugs are described and verified experimentally. Therefore, we conclude that physico-chemical analyses may prove structural features of curcumin analogues with their promising combined cytotoxicity/antioxidant activity and it is also concluded from virtual and practical screening that the compounds were varied to possess a broad range of lipophilic character, revealed by Log P values. PMID:27318975
New evidence for active tectonics at the boundary of the Kashi Depression, China, from time series InSAR observations
NASA Astrophysics Data System (ADS)
He, Ping; Wen, Yangmao; Xu, Caijun; Liu, Yang; Fok, H. S.
Kashi Depression is one of the most complex active tectonic areas in the southern flank of Tianshan, China. Due to the lack of ground observations, the boundary of basin mountain transition zone and the interseismic activity of the Tianshan have not been clearly determined. In this study, 48 Envisat Advanced Synthetic Aperture Radar (ASAR) imagery acquired from 2003 to 2010 are used to construct interferograms for measuring high-resolution interseismic deformation in the Kashi Depression area. A global atmospheric model ERA-Interim provided by the European Center for Medium Range Weather Forecast (ECMWF) and a global network orbital correction are applied to remove atmospheric effect, and the long-wavelength orbital errors, respectively, for the interferograms. Interferometric SAR time series with Atmospheric Estimation Model (InSAR TS + AEM) are then used to obtain a deformation rate map for the Kashi Depression area. The InSAR rate map indicates that the north part of South Atushi Fault has ~ 3 mm/year uplift relative to that of the south part. This result manifests the main tectonic deformation potentially occurs along the Southern Atushi Fault. Based on a simple edge dislocation model, the dip angle of 31 ± 0.6°, slip rate of 2.3 ± 0.1 mm/year, and locking depth of 10.6 ± 0.4 km for the Southern Atushi Fault between Tianshan Orogenic Belt and the Kashi Depression are obtained. This modeling result shows in good agreement with the InSAR derived rates. Our results show that the Southern Atushi Fault is the main active fault in block boundary region between the south of Tianshan and the Tarim Basin.
Remotely Sensed Active Layer Thickness (ReSALT) from InSAR data near Toolik Lake in Northern Alaska
NASA Astrophysics Data System (ADS)
Chen, A. C.; Liu, L.; Schaefer, K. M.; Parsekian, A.; Jafarov, E. E.; Zebker, H. A.; Zhang, T.
Toolik Field Station is built on spatially continuous permafrost on the north slope of Alaska. Seasonal surface subsidence and uplift occurs in permafrost regions due to thaw settlement and frost heave as the active layer thaws and refreezes. Using L-band (23.6 cm wavelength) InSAR data from ALOS-PALSAR acquired between 2006 and 2010, we use a small-baseline subset (SBAS) method to estimate seasonal surface subsidence and retrieve fine-resolution maps of active layer thickness (ALT) for a ~25x25 km area surrounding Toolik Field Station (located at 68.63°N, -149.60°E). We compare these remotely sensed ALT (ReSALT) results with in situ data from: 1) the Circumpolar Active Layer Monitoring (CALM) network showing mean ALT of ~40-50 cm in the region surrounding Toolik Field Station, corresponding to seasonal subsidence of 1 to 2 cm, and 2) mechanical probing measurements of ALT, obtained during field work in the study area in August 2014. We also solve for secular subsidence trends from the InSAR data. The trends are close to zero in most places, but larger subsidence trends in some isolated areas could be due to thermokarst processes (long-term thawing of ice-rich permafrost). We note, however, that downslope motion due to gelifluction cannot be separated from vertical thermokarst-related deformation without incorporating InSAR measurements from multiple look angles. Two key limitations to our method are the spatial variability of volumetric soil moisture content and the accuracy of the DEM needed to correct for topographic effects. We investigate the use of bulk volumetric water content inferred from ground-penetrating radar (GPR) data to improve the ReSALT retrieval algorithm. We also quantify the effect of DEM accuracy on ReSALT uncertainties, leads to requirements for DEM accuracy in InSAR-based ALT retrieval.
A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs
Cunningham, Albert R.; Carrasquer, C. Alex; Mattison, Donald R.
The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR) model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action. PMID:20111734
Observing ground surface change series at active volcanoes in Indonesia using backscattering intensity of SAR data
NASA Astrophysics Data System (ADS)
Saepuloh, Asep; Trianaputri, Mila Olivia
Indonesia contains 27 active volcanoes passing the West through the East part. Therefore, Indonesia is the most hazard front due to the volcanic activities. To obtain the new precursory signals leading to the eruptions, we applied remote sensing technique to observe ground surface change series at the summit of Sinabung and Kelud volcanoes. Sinabung volcano is located at Karo Region, North Sumatra Province. This volcano is a strato volcano type which is re-activated in August 2010. The eruption continues to the later years by ejecting volcanic products such as lava, pyroclastic flow, and ash fall deposits. This study is targeted to observe ground surface change series at the summit of Sinabung volcano since 2007 to 2011. In addition, we also compared the summit ground surface changes after the eruptions of Kelud volcano in 2007. Kelud volcano is also strato volcano type which is located at East Java, Indonesia. The Synthetic Aperture Radar (SAR) remotely sensed technology makes possible to observe rapidly a wide ground surface changes related to ground surface roughness. Detection series were performed by extracting the backscattering intensity of the Phased Array type L-band Synthetic Aperture Radar (PALSAR) onboard the Advanced Land Observing Satellite (ALOS). The intensity values were then calculated using a Normalized Radar Cross-Section (NRCS). Based on surface roughness criterion at the summit of Sinabung volcano, we could observe the ground surface changes prior to the early eruption in August 2010. The continuous increment of NRCS values showed clearly at window size 3×3 pixel of the summit of Sinabung volcano. The same phenomenon was also detected at the summit of Kelud volcano after the 2007 eruptions. The detected ground surface changes were validated using optical Landsat-8, backscattering intensity ratio for volcanic products detection, and radial component of a tilt-meter data.
The Grand Banks ERS-1 SAR wave spectra validation experiment
NASA Technical Reports Server (NTRS)
Vachon, P. W.; Dobson, F. W.; Smith, S. D.; Anderson, R. J.; Buckley, J. R.; Allingham, M.; Vandemark, D.; Walsh, E. J.; Khandekar, M.; Lalbeharry, R.
As part of the ERS-1 validation program, the ERS-1 Synthetic Aperture Radar (SAR) wave spectra validation experiment was carried out over the Grand Banks of Newfoundland (Canada) in Nov. 1991. The principal objective of the experiment was to obtain complete sets of wind and wave data from a variety of calibrated instruments to validate SAR measurements of ocean wave spectra. The field program activities are described and the rather complex wind and wave conditions which were observed are summarized. Spectral comparisons with ERS-1 SAR image spectra are provided. The ERS-1 SAR is shown to have measured swell and range traveling wind seas, but did not measure azimuth traveling wind seas at any time during the experiment. Results of velocity bunching forward mapping and new measurements of the relationship between wind stress and sea state are also shown.
Conformational Flexibility of a Short Loop near the Active Site of the SARS-3CLpro is Essential to Maintain Catalytic Activity
NASA Astrophysics Data System (ADS)
Li, Chunmei; Teng, Xin; Qi, Yifei; Tang, Bo; Shi, Hailing; Ma, Xiaomin; Lai, Luhua
The SARS 3C-like proteinase (SARS-3CLpro), which is the main proteinase of the SARS coronavirus, is essential to the virus life cycle. This enzyme has been shown to be active as a dimer in which only one protomer is active. However, it remains unknown how the dimer structure maintains an active monomer conformation. It has been observed that the Ser139-Leu141 loop forms a short 310-helix that disrupts the catalytic machinery in the inactive monomer structure. We have tried to disrupt this helical conformation by mutating L141 to T in the stable inactive monomer G11A/R298A/Q299A. The resulting tetra-mutant G11A/L141T/R298A/Q299A is indeed enzymatically active as a monomer. Molecular dynamics simulations revealed that the L141T mutation disrupts the 310-helix and helps to stabilize the active conformation. The coil-310-helix conformational transition of the Ser139-Leu141 loop serves as an enzyme activity switch. Our study therefore indicates that the dimer structure can stabilize the active conformation but is not a required structure in the evolution of the active enzyme, which can also arise through simple mutations.
Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354.
Wen, Wandong; Young, Summer E; Duvernay, Matthew T; Schulte, Michael L; Nance, Kellie D; Melancon, Bruce J; Engers, Julie; Locuson, Charles W; Wood, Michael R; Daniels, J Scott; Wu, Wenjun; Lindsley, Craig W; Hamm, Heidi E; Stauffer, Shaun R
Herein we report the discovery and SAR of an indole-based protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50=10μM). PMID:25176330
Strong Nonadditivity as a Key Structure–Activity Relationship Feature: Distinguishing Structural Changes from Assay Artifacts
Nonadditivity in protein–ligand affinity data represents highly instructive structure–activity relationship (SAR) features that indicate structural changes and have the potential to guide rational drug design. At the same time, nonadditivity is a challenge for both basic SAR analysis as well as many ligand-based data analysis techniques such as Free-Wilson Analysis and Matched Molecular Pair analysis, since linear substituent contribution models inherently assume additivity and thus do not work in such cases. While structural causes for nonadditivity have been analyzed anecdotally, no systematic approaches to interpret and use nonadditivity prospectively have been developed yet. In this contribution, we lay the statistical framework for systematic analysis of nonadditivity in a SAR series. First, we develop a general metric to quantify nonadditivity. Then, we demonstrate the non-negligible impact of experimental uncertainty that creates apparent nonadditivity, and we introduce techniques to handle experimental uncertainty. Finally, we analyze public SAR data sets for strong nonadditivity and use recourse to the original publications and available X-ray structures to find structural explanations for the nonadditivity observed. We find that all cases of strong nonadditivity (ΔΔpKi and ΔΔpIC50 > 2.0 log units) with sufficient structural information to generate reasonable hypothesis involve changes in binding mode. With the appropriate statistical basis, nonadditivity analysis offers a variety of new attempts for various areas in computer-aided drug design, including the validation of scoring functions and free energy perturbation approaches, binding pocket classification, and novel features in SAR analysis tools. PMID:25760829
Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT3 Receptor Ligands
The 5-HT3 receptor, a pentameric ligand-gated ion channel (pLGIC), is an important therapeutic target. During a recent fragment screen, 6-chloro-N-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine (1) was identified as a 5-HT3R hit fragment. Here we describe the synthesis and structure–activity relationships (SAR) of a series of (iso)quinoline and quinazoline compounds that were synthesized and screened for 5-HT3R affinity using a [3H]granisetron displacement assay. These studies resulted in the discovery of several high affinity ligands of which compound 22 showed the highest affinity (pKi > 10) for the 5-HT3 receptor. The observed SAR is in agreement with established pharmacophore models for 5-HT3 ligands and is used for ligand–receptor binding mode prediction using homology modeling and in silico docking approaches. PMID:23006041
Virulence Factor-activity Relationships: Workshop Summary
The concept or notion of virulence factor–activity relationships (VFAR) is an approach for identifying an analogous process to the use of qualitative structure–activity relationships (QSAR) for identifying new microbial contaminants. In QSAR, it is hypothesized that, for new chem...
Monceyron Jonassen, C
In the hunt for the aetiology of the SARS outbreak in 2003, a newly developed virus DNA micro-array was successfully used to hybridise PCR products obtained by random amplification of nucleic acids extracted from a cell culture infected with material from a SARS patient. The SARS agent was found to hybridise with micro-array probes from both coronaviruses and astroviruses, but one of the coronavirus probes and the four astrovirus probes contained redundant sequences, spanning a highly conserved motif, named s2m, found at the 3' end of the genomes of almost all astroviruses, one picornavirus, and the poultry coronaviruses. The three other coronavirus probes, that hybridised with the SARS agent, were located in the replicase gene, and it could be concluded that the SARS agent was a novel coronavirus, harbouring s2m. The presence of this motif in different virus families is probably the result of recombinations between unrelated viruses, but its presence in both poultry and SARS coronaviruses could suggest a bird involvement in the history of the SARS coronavirus. A recent screening of wild birds for the presence of coronaviruses, using a pan-coronavirus RT-PCR, led to the identification of novel coronaviruses in the three species studied. Phylogenetic analyses performed on both replicase gene and nucleocapsid protein could not add support to a close relationship between avian and SARS coronaviruses, but all the novel avian coronaviruses were found to harbour s2m. The motif is inserted at a homologous place in avian and SARS coronavirus genomes, but in a somewhat different context for the SARS coronavirus. If the presence of s2m in these viruses is a result of two separate recombination events, this suggests that its particular position in these genomes is the only one that would not be deleterious for coronaviral replication, or that it is the result of a copy-choice recombination between coronaviruses, following an ancestral introduction in the coronavirus family by
Synthesis and Structure-Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors.
Singh, Anamika; Kast, Johannes; Dirain, Marvin L S; Huang, Huisuo; Haskell-Luevano, Carrie
The melanocortin system is involved in the regulation of several complex physiological functions. In particular, the melanocortin-3 and -4 receptors (MC3R/MC4R) have been demonstrated to regulate body weight, energy homeostasis, and feeding behavior. Synthetic and endogenous melanocortin agonists have been shown to be anorexigenic in rodent models. Herein, we report synthesis and structure-activity relationship (SAR) studies of 27 nonpeptide small molecule ligands based on an unsymmetrical substituted urea core. Three templates containing key residues from the lead compounds, showing diversity at three positions (R(1), R(2), R(3)), were designed and synthesized. The syntheses were optimized for efficient microwave-assisted chemistry that significantly reduced total syntheses time compared to a previously reported room temperature method. The pharmacological characterization of the compounds on the mouse melanocortin receptors identified compounds 1 and 12 with full agonist activity at the mMC4R, but no activity was observed at the mMC3R when tested up to 100 μM concentrations. The SAR identified compounds possessing aliphatic or saturated cyclic amines at the R(1) position, bulky aromatic groups at the R(2) position, and benzyl group at the R(3) position resulted in mMC4R selectivity over the mMC3R. The small molecule template and SAR knowledge from this series may be helpful in further design of MC3R/MC4R selective small molecule ligands. PMID:26645732
... waiting room or office. Top of Page CDC's response to SARS during the 2003 outbreak CDC worked ... Center to provide round-the-clock coordination and response. Committed more than 800 medical experts and support ...
Synthesis, biological activities, and quantitative structure-activity relationship (QSAR) study of novel camptothecin analogues.
Wu, Dan; Zhang, Shao-Yong; Liu, Ying-Qian; Wu, Xiao-Bing; Zhu, Gao-Xiang; Zhang, Yan; Wei, Wei; Liu, Huan-Xiang; Chen, An-Liang
In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure-activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents. PMID:25985362
Nano(Q)SAR: Challenges, pitfalls and perspectives.
Tantra, Ratna; Oksel, Ceyda; Puzyn, Tomasz; Wang, Jian; Robinson, Kenneth N; Wang, Xue Z; Ma, Cai Y; Wilkins, Terry
Regulation for nanomaterials is urgently needed, and the drive to adopt an intelligent testing strategy is evident. Such a strategy will not only provide economic benefits but will also reduce moral and ethical concerns arising from animal testing. For regulatory purposes, such an approach is promoted by REACH, particularly the use of quantitative structure-activity relationships [(Q)SAR] as a tool for the categorisation of compounds according to their physicochemical and toxicological properties. In addition to compounds, (Q)SAR has also been applied to nanomaterials in the form of nano(Q)SAR. Although (Q)SAR in chemicals is well established, nano(Q)SAR is still in early stages of development and its successful uptake is far from reality. This article aims to identify some of the pitfalls and challenges associated with nano-(Q)SARs in relation to the categorisation of nanomaterials. Our findings show clear gaps in the research framework that must be addressed if we are to have reliable predictions from such models. Three major barriers were identified: the need to improve quality of experimental data in which the models are developed from, the need to have practical guidelines for the development of the nano(Q)SAR models and the need to standardise and harmonise activities for the purpose of regulation. Of these three, the first, i.e. the need to improve data quality requires immediate attention, as it underpins activities associated with the latter two. It should be noted that the usefulness of data in the context of nano-(Q)SAR modelling is not only about the quantity of data but also about the quality, consistency and accessibility of those data. PMID:25211549
Structure-activity relationship study between baicalein and wogonin by spectrometry, molecular docking and microcalorimetry.
Tu, Bao; Li, Rong-Rong; Liu, Zhi-Juan; Chen, Zhi-Feng; Ouyang, Yu; Hu, Yan-Jun
Flavones (e.g. baicalein and wogonin) extensively used worldwide in food preparation and traditional medicine. In this study, a systematically comparative study of their structure-activity relationships (SAR) on their interaction with BSA, antioxidant activity and antibacterial activity has been carried out by spectrometry, molecular docking and microcalorimetry. Our results show that the skeleton structure of flavones, the number of hydroxyl groups, the type of functional group, conjugated system and the steric hindrance may be responsible for their different biological activity. These findings not only would lay a scientific foundation for discovering and designing flavones-based food and drug, may also help us to understanding the structure-activity relationship between flavones at the molecular level. PMID:27132840
Whole structure-activity relationships of the fat-accumulation inhibitor (-)-ternatin: recognition of the importance of each amino acid residue.
Shimokawa, Kenichiro; Iwase, Yoshiaki; Miwa, Ryoka; Yamada, Kaoru; Uemura, Daisuke
A series of Ala and Aoc analogues of (-)-ternatin were prepared, and their bioactivities were assessed by a fat-accumulation inhibition assay using 3T3-L1 adipocytes, which led to the discovery of key structure-activity relationships (SAR). PMID:18798610
Insights into COPll Coat Nucleation from the Structure of Sec23 Sar1 Complexed with the Active Fragment of Sec31
Bi,X.; Mancias, J.; Goldberg, J.
The COPII vesicular coat forms on the endoplasmic reticulum from Sar1-GTP, Sec23/24 and Sec13/31 protein subunits. Here, we define the interaction between Sec23/24{center_dot}Sar1 and Sec13/31, involving a 40 residue Sec31 fragment. In the crystal structure of the ternary complex, Sec31 binds as an extended polypeptide across a composite surface of the Sec23 and Sar1-GTP molecules, explaining the stepwise character of Sec23/24{center_dot}Sar1 and Sec13/31 recruitment to the membrane. The Sec31 fragment stimulates GAP activity of Sec23/24, and a convergence of Sec31 and Sec23 residues at the Sar1 GTPase active site explains how GTP hydrolysis is triggered leading to COPII coat disassembly. The Sec31 active fragment is accommodated in a binding groove supported in part by Sec23 residue Phe380. Substitution of the corresponding residue F382L in human Sec23A causes cranio-lenticulo-sutural dysplasia, and we suggest that this mutation disrupts the nucleation of COPII coat proteins at endoplasmic reticulum exit sites.
Structure-Activity Relationship Studies and Biological Characterization of Human NAD+-dependent 15-Hydroxyprostaglandin Dehydrogenase Inhibitors
Duveau, Damien Y.; Yasgar, Adam; Wang, Yuhong; Hu, Xin; Kouznetsova, Jennifer; Brimacombe, Kyle R.; Jadhav, Ajit; Simeonov, Anton; Thomas, Craig J.; Maloney, David J.
The structure-activity relationship (SAR) study of two chemotypes identified as inhibitors of the human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (HPGD, 15-PGDH) was conducted. Top compounds from both series displayed potent inhibition (IC50 <50 nM), demonstrate excellent selectivity towards HPGD and potently induce PGE2 production in A549 lung cancer and LNCaP prostate cancer cells. PMID:24360556
The structure-activity relationship in herbicidal monosubstituted sulfonylureas
Li, Zheng-Ming; Ma, Yi; Guddat, Luke; Cheng, Pei-Quan; Wang, Jian-Guo; Pang, Siew S; Dong, Yu-Hui; Lai, Cheng-Ming; Wang, Ling-Xiu; Jia, Guo-Feng; Li, Yong-Hong; Wang, Su-Hua; Liu, Jie; Zhao, Wei-Guang; Wang, Bao-Lei
The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure-activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. After the analysis of scores of SU products by X-ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesized in the authors laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retain excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. Among the novel SU molecules, monosulfuron and monosulfuron-ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate-target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated.
Modeling chemical interaction profiles: I. Spectral data-activity relationship and structure-activity relationship models for inhibitors and non-inhibitors of cytochrome P450 CYP3A4 and CYP2D6 isozymes.
McPhail, Brooks; Tie, Yunfeng; Hong, Huixiao; Pearce, Bruce A; Schnackenberg, Laura K; Ge, Weigong; Valerio, Luis G; Fuscoe, James C; Tong, Weida; Buzatu, Dan A; Wilkes, Jon G; Fowler, Bruce A; Demchuk, Eugene; Beger, Richard D
An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals--drugs, pesticides, and environmental pollutants--interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure-activity relationship (SAR) approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV) test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR) spectral descriptors. In the present work, both 1D ¹³C and 1D ¹⁵N-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D ¹³C-NMR and ¹⁵N-NMR spectra caused an increase in the tenfold cross-validation (CV) performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold2 descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR
Often a compound's biological activity is determined by complex relationships between its structural components. Such a relationship often can only be adequately described and exploited by multivariate structure-activity relationship (SAR) studies that can deal with many variable...
Indolo[3,2-b]quinolines: Synthesis, Biological Evaluation and Structure Activity-Relationships
Kumar, Eyunni V.K. Suresh; Etukala, Jagan R.; Ablordeppey, Seth Y.
The tetracyclic indolo[3,2-b]quinoline ring system constitutes an important structural moiety in natural products exhibiting numerous biological activities. In particular, indolo [3, 2-b]quinoline, commonly known as linear quindo-line is of particular interest, because of its rigid structure and scope of derivatization. Although the core linear quindoline skeleton shows little or no activity in several biological systems, introduction of a methyl group on the N-5 atom leading to cryptolepine induces remarkable activity against a broad spectrum of biological targets. A number of analogs of quindoline and cryptolepine have been synthesized, incorporating various functional groups on the core quindoline skeleton leading to improved biological activities. In this review, we describe various synthetic methodologies leading to the quindoline scaffold, the biological activities and the structure activity relationships (SAR) of quindoline derivatives toward different disease states to give a better picture of the importance of this moiety in medicinal chemistry. PMID:18537709
Identification of New Nonsteroidal RORα Ligands; Related Structure–Activity Relationships and Docking Studies
A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key structure–activity relationships (SAR) were established, where benzyl and urea moieties were both identified as very important elements to maintain the activity. Most notably, the SAR were consistent with the binding mode of the compound 8 (S-isomer) in the RORα docking model that was developed in this program. As predicted by the model, the urea moiety is engaged in the formation of key hydrogen bonds with the backbone of Tyr380 and Asp382. The benzyl group is located in a wide hydrophobic pocket. The structural relationships reported in this letter will help in further optimization of this compound series and will provide novel synthetic probes helpful for elucidation of complex RORα physiopathology. PMID:24900700
The attempt to rationalize the connections between the molecular structures of organic compounds and their biological activities comprises the field of structure-activity relations (SAR) studies. Correlations between structure and activity are important for the understanding and ...
Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists.
Morin, Matthew D; Wang, Ying; Jones, Brian T; Su, Lijing; Surakattula, Murali M R P; Berger, Michael; Huang, Hua; Beutler, Elliot K; Zhang, Hong; Beutler, Bruce; Boger, Dale L
Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor. PMID:27050713
Crystal Structures of the Reduced, Sulfenic Acid, and Mixed Disulfide Forms of SarZ, a Redox Active Global Regulator in Staphylococcus aureus
Poor, Catherine B.; Chen, Peng R.; Duguid, Erica; Rice, Phoebe A.; He, Chuan
SarZ is a global transcriptional regulator that uses a single cysteine residue, Cys{sup 13}, to sense peroxide stress and control metabolic switching and virulence in Staphylococcus aureus. SarZ belongs to the single-cysteine class of OhrR-MgrA proteins that play key roles in oxidative resistance and virulence regulation in various bacteria. We present the crystal structures of the reduced form, sulfenic acid form, and mixed disulfide form of SarZ. Both the sulfenic acid and mixed disulfide forms are structurally characterized for the first time for this class of proteins. The Cys{sup 13} sulfenic acid modification is stabilized through two hydrogen bonds with surrounding residues, and the overall DNA-binding conformation is retained. A further reaction of the Cys{sup 13} sulfenic acid with an external thiol leads to formation of a mixed disulfide bond, which results in an allosteric change in the DNA-binding domains, disrupting DNA binding. Thus, the crystal structures of SarZ in three different states provide molecular level pictures delineating the mechanism by which this class of redox active regulators undergoes activation. These structures help to understand redox-mediated virulence regulation in S. aureus and activation of the MarR family proteins in general.
Design and synthesis of a series of serine derivatives as small molecule inhibitors of the SARS coronavirus 3CL protease.
Konno, Hiroyuki; Wakabayashi, Masaki; Takanuma, Daiki; Saito, Yota; Akaji, Kenichi
Synthesis of serine derivatives having the essential functional groups for the inhibitor of SARS 3CL protease and evaluation of their inhibitory activities using SARS 3CL R188I mutant protease are described. The lead compounds, functionalized serine derivatives, were designed based on the tetrapeptide aldehyde and Bai's cinnamoly inhibitor, and additionally performed with simulation on GOLD softwear. Structure activity relationship studies of the candidate compounds were given reasonable inhibitors ent-3 and ent-7k against SARS 3CL R188I mutant protease. These inhibitors showed protease selectivity and no cytotoxicity. PMID:26879854
Relationships between solar activity and climate change
NASA Technical Reports Server (NTRS)
Roberts, W. O.
The relationship between recurrent droughts in the High Plains of the United States and the double sunspot cycle is discussed in detail. It is suggested that high solar activity is generally related to an increase in meridional circulation and blocking patterns at high and intermediate latitudes, especially in winter, and the effect is related to the sudden formation of cirrus clouds during strong geomagnetic activity that originates in the solar corpuscular emission.
Applying PolSAR and PolInSAR to Forest Structure Information Extraction
NASA Astrophysics Data System (ADS)
Chen, E.; Li, Z.; Li, W.; Feng, Q.; Zhou, W.; Pottier, E.; Hong, W.
The key research activities and achievements in the field of applying PolSAR and PolInSAR to forest structure information extraction in DRAGON 2 are summarized in this paper. The limitation of the ALOS PolInSAR dataset acquired in the Culai test site for forest height extraction because of its long temporal baseline (46 days), and how the PolInSAR coherence optimization methods can help improve the topography inversion accuracy under forest canopy were presented. We have analyzed and evaluated the capability of multiple polarization parameters extracted from different frequency PolSAR data for forest scar mapping in the Shibazhan test site, and developed the land cover classification method based on SVM (Support Vector Machine) using PolSAR data. With the L-band E-SAR PolInSAR data acquired in the test site in Germany, we developed forest above ground biomass (AGB) estimation approach based on polarization coherence tomography (PCT).
High resolution SAR applications and instrument design
NASA Technical Reports Server (NTRS)
Dionisio, C.; Torre, A.
The Synthetic Aperture Radar (SAR) has viewed, in the last two years, a huge increment of interest from many preset and potential users. The good spatial resolution associated to the all weather capability lead to considering SAR not only a scientific instrument but a tool for verifying and controlling the daily human relationships with the Earth Environment. New missions were identified for SAR as spatial resolution became lower than three meters: disasters, pollution, ships traffic, volcanic eruptions, earthquake effect are only a few of the possible objects which can be effectively detected, controlled and monitored by SAR mounted on satellites. High resolution radar design constraints and dimensioning are discussed.
GPS and Satellite InSAR Observations of Landslide Activity at the Sinking Canyon in South Central Idaho
NASA Astrophysics Data System (ADS)
Aly, M. H.; Glenn, N. F.; Thackray, G. D.
Multiple rotational, transitional, and lateral spread landslides have occurred in south central Idaho where basalt lava flows overly unconsolidated lake and fluvial sediments at the Sinking Canyon. The canyon is about 0.1 km deep and 0.25-1 km wide along a 4-km segment of the Salmon Falls Creek (SFC). Local topography and hydrological conditions are most likely the major triggering factors that have initiated landslides by increasing the gravitational stresses and weakening the canyon wall materials. Landslide activity has created natural dams of SFC, which in turn has resulted in forming large lakes with a potential flooding hazard to life and property downstream. In this study, we use campaign Global Positioning System (GPS) measurements of 2003-2004 and Synthetic Aperture Radar Interferometric (InSAR) data acquired during 1992-2007 by the European radar satellites (ERS-1 and ERS-2) to identify, monitor, and analyze recent landslide activity at SFC. Results show that three main landslides have been active during the period of observation: the Salmon Falls landslide (SFL) that has been first reported in 1999, the historical 1937 landslide, and a third unnamed landslide to the north of the 1937 slide. InSAR measurements indicate that the SFL has been active during the period of our earliest interferogram (1992-1993) whereas the slide head has detached and has moved away from the eastern canyon wall about 3 cm. Over the years, the SFL body and toe have been pushed westward repetitively at rates of about 3-7 cm/yr. The toe is confined by the western canyon wall and thus is pushed upward in some years causing slight uplift (2-3 cm). Our field observations reveal many transverse and radial cracks associated with the deformation pattern caused by recurring motions. The historic 1937 slide is the largest mass wasting and is the least active landslide in the study area. The unnamed slide shows episodic activity with varying rates (0-4 cm/yr) of line-of-sight motions. This
SARS-coronavirus spike S2 domain flanked by cysteine residues C822 and C833 is important for activation of membrane fusion
Madu, Ikenna G.; Belouzard, Sandrine; Whittaker, Gary R.
The S2 domain of the coronavirus spike (S) protein is known to be responsible for mediating membrane fusion. In addition to a well-recognized cleavage site at the S1-S2 boundary, a second proteolytic cleavage site has been identified in the severe acute respiratory syndrome coronavirus (SARS-CoV) S2 domain (R797). C-terminal to this S2 cleavage site is a conserved region flanked by cysteine residues C822 and C833. Here, we investigated the importance of this well conserved region for SARS-CoV S-mediated fusion activation. We show that the residues between C822-C833 are well conserved across all coronaviruses. Mutagenic analysis of SARS-CoV S, combined with cell-cell fusion and pseudotyped virion infectivity assays, showed a critical role for the core-conserved residues C822, D830, L831, and C833. Based on available predictive models, we propose that the conserved domain flanked by cysteines 822 and 833 forms a loop structure that interacts with components of the SARS-CoV S trimer to control the activation of membrane fusion.
An active ring fault detected at Tendürek volcano by using InSAR
NASA Astrophysics Data System (ADS)
Bathke, H.; Sudhaus, H.; Holohan, E. P.; Walter, T. R.; Shirzaei, M.
ring faults are present at many ancient, deeply eroded volcanoes, they have been detected at only very few modern volcanic centers. At the so far little studied Tendürek volcano in eastern Turkey, we generated an ascending and a descending InSAR time series of its surface displacement field for the period from 2003 to 2010. We detected a large (~105 km2) region that underwent subsidence at the rate of ~1 cm/yr during this period. Source modeling results show that the observed signal fits best to simulations of a near-horizontal contracting sill located at around 4.5 km below the volcano summit. Intriguingly, the residual displacement velocity field contains a steep gradient that systematically follows a system of arcuate fractures visible on the volcano's midflanks. RapidEye satellite optical images show that this fracture system has deflected Holocene lava flows, thus indicating its presence for at least several millennia. We interpret the arcuate fracture system as the surface expression of an inherited ring fault that has been slowly reactivated during the detected recent subsidence. These results show that volcano ring faults may not only slip rapidly during eruptive or intrusive phases, but also slowly during dormant phases.
Structure—activity relationships for insecticidal carbamates*
Metcalf, Robert L.
Carbamate insecticides are biologically active because of their structural complementarity to the active site of acetylcholinesterase (AChE) and their consequent action as substrates with very low turnover numbers. Carbamates behave as synthetic neurohormones that produce their toxic action by interrupting the normal action of AChE so that acetylcholine accumulates at synaptic junctions. The necessary properties for a suitable insecticidal carbamate are lipid solubility, suitable structural complementarity to AChE, and sufficient stability to multifunction-oxidase detoxification. The relationships between the structure and the activity of a large number of synthetic carbamates are analysed in detail, with particular attention to the second of these properties. PMID:5315358
Synthesis, anticancer activity, and SAR analyses of compounds containing the 5:7-fused 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system.
Xie, Min; Lapidus, Rena G; Sadowska, Mariola; Edelman, Martin J; Hosmane, Ramachandra S
Described herein are our limited structure-activity relationship (SAR) studies on a 5:7-fused heterocycle (1), containing the 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N(6)-positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N(6)-position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N(6)-positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N(6) and no attachment at N-1, or a combined C-10 at N(6) and a CH2Ph at N-1. Any alkyl chain shorter or longer than C-10 at N(6) with a CH2Ph attached at N-1, would result in decrease of biological activity. PMID:27134120
Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity.
Martin, Matthew W; Newcomb, John; Nunes, Joseph J; McGowan, David C; Armistead, David M; Boucher, Christina; Buchanan, John L; Buckner, William; Chai, Lilly; Elbaum, Daniel; Epstein, Linda F; Faust, Theodore; Flynn, Shaun; Gallant, Paul; Gore, Anu; Gu, Yan; Hsieh, Faye; Huang, Xin; Lee, Josie H; Metz, Daniela; Middleton, Scot; Mohn, Deanna; Morgenstern, Kurt; Morrison, Michael J; Novak, Perry M; Oliveira-dos-Santos, Antonio; Powers, David; Rose, Paul; Schneider, Stephen; Sell, Stephanie; Tudor, Yanyan; Turci, Susan M; Welcher, Andrew A; White, Ryan D; Zack, Debra; Zhao, Huilin; Zhu, Li; Zhu, Xiaotian; Ghiron, Chiara; Amouzegh, Patricia; Ermann, Monika; Jenkins, James; Johnston, David; Napier, Spencer; Power, Eoin
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation. PMID:16884310
Structure-activity relationship of anthelmintic cyclooctadepsipeptides.
Ohyama, Makoto; Okada, Yumiko; Takahashi, Masaaki; Sakanaka, Osamu; Matsumoto, Maki; Atsumi, Kunio
The relationship between cyclooctadepsipeptides and their anthelmintic efficacy was examined by converting the natural products, PF1022A, PF1022E and PF1022H. Some analogues substituted at the para position of the phenyllactate moiety showed higher or equivalent activity against the parasitic nematode, Ascaridia galli in chicken when compared with the parent compounds. It is suggested that lipophilicity and the polar surface area, in addition to structural requirements of the derivatives, influenced the anthelmintic efficacy in vivo. PMID:21737929
The U.S. EPA has been mandated to screen industrial chemicals and pesticides for potential endocrine activity. Structure-activity relationships (SARs) to predict receptor binding are being developed as a first step to rank and prioritize chemicals for testing in bioassays. First ...
A mechanism-based structure-activity relationship (SAR) study attempts to determine a structural basis for activity by targeting a single or a few stages in a postulated mechanism of action.Computational chemistry approaches provide a valuable complement to experiment for probing...
Role of the staphylococcal accessory gene regulator (sar) in septic arthritis.
Nilsson, I M; Bremell, T; Rydén, C; Cheung, A L; Tarkowski, A
Staphylococcus aureus arthritis is a highly erosive disease in which both host and bacterial factors are of importance for its induction and progression. At the transcriptional level, three known loci act in regulating production of exoproteins and expression of cell wall structures. The aim of our study was to assess the role of the sar locus as a virulence determinant in the pathogenesis of septic arthritis. A recently established murine model of hematogenously spread S. aureus arthritis was employed. S. aureus strains, isogenic for the sar locus, were inoculated intravenously into NMRI mice, and the clinical, bacteriological, serological, and histopathological progression of the disease was studied. Within 1 week after inoculation of bacteria, the frequency of arthritis was 79% in the group of mice inoculated with the sar+ strain, whereas the corresponding frequency in sar mutants was 21% (P < 0.01). Mice inoculated with the sar+ staphylococcal strain exhibited a more pronounced T- and B-lymphocyte activation than those inoculated with the sar mutant, evidenced by splenomegaly, polyclonal B-cell activation, and high serum levels of interleukin 6 and gamma interferon. Also, infection with sar+ staphylococci induced a pronounced weight loss. To assess the relationship between clinical signs and spread of bacteria, we analyzed the homing pattern and persistence of S. aureus in host tissues. Kidneys and joints from sar+-inoculated subjects displayed a higher degree of bacterial persistence than other organs. Our results suggest that molecules controlled by the sar locus are important virulence determinants in the induction and progression of septic arthritis. PMID:8890189
Structure activity relationship studies of 3-arylsulfonyl-pyrido[1,2-a]pyrimidin-4-imines as potent 5-HT₆ antagonists.
Hu, Shuanghua; Huang, Yazhong; Wu, Yong-Jin; He, Huan; Grant-Young, Katherine A; Bertekap, Robert L; Whiterock, Valerie; Brassil, Patrick; Lentz, Kimberley; Sivaprakasam, Prasanna; Langley, David R; Westphal, Ryan S; Scola, Paul M
Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC50: 4.0 nM), as 5-HT6 selective antagonists. Activity was improved some 2-4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure-activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability. PMID:24495863
Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists.
Zheng, Guo Zhu; Bhatia, Pramila; Daanen, Jerome; Kolasa, Teodozyj; Patel, Meena; Latshaw, Steven; El Kouhen, Odile F; Chang, Renjie; Uchic, Marie E; Miller, Loan; Nakane, Masaki; Lehto, Sonya G; Honore, Marie P; Moreland, Robert B; Brioni, Jorge D; Stewart, Andrew O
SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models. PMID:16279797
Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part I: 2,5-dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators
Han, Changho; Chatterjee, Arindam; Noetzel, Meredith J.; Panarese, Joseph D.; Niswender, Colleen; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.
Results from a 2012 high-throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) against the human muscarinic receptor subtype 1 (M1) for positive allosteric modulators is reported. A content-rich screen utilizing an intracellular calcium mobilization triple-addition protocol allowed for assessment of all three modes of pharmacology at M1, including agonist, positive allosteric modulator, and antagonist activities in a single screening platform. We disclose a dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one hit (DBPQ, CID 915409) and examine N-benzyl pharmacophore/SAR relationships versus previously reported quinolin-3(5H)-ones and isatins, including ML137. SAR and consideration of recently reported crystal structures, homology modeling, and structure-function relationships using point mutations suggests a shared binding mode orientation at the putative common allosteric binding site directed by the pendant N-benzyl substructure. PMID:25435150
Synthesis, bioactivity and structure-activity relationships of new 2-aryl-8-OR-3,4-dihydroisoquinolin-2-iums salts as potential antifungal agents.
Zhu, Li-Fei; Hou, Zhe; Zhou, Kun; Tong, Zong-Bo; Kuang, Qian; Geng, Hui-Ling; Zhou, Le
As our continuing research on antifungal dihydroisoquinolin-2-ium salts, forty 2-aryl-8-OR-3,4-dihydroisoquinolin-2-ium bromides were synthesized and characterized by spectroscopic analysis. By using the mycelium growth rate method, the compounds were evaluated for antifungal activity against three plant pathogenic fungi and structure-activity relationships (SAR) were derived. The vast majority of the compounds displayed the medium to high activity with inhibition rates of 50-100% at 150μM. About half of the compounds were more active than their natural model compounds sanguinarine and chelerythrine for all the fungi, and part or most of them were more active than positive drugs thiabendazole and azoxystrobin. SAR analysis showed that both substitution patterns of the C-ring and the type of 8-OR group significantly influenced the activity. Thus, a series of new title compounds with excellent antifungal potency emerged. PMID:27072907
Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis.
Wu, Xiaoai; Fang, Zhen; Yang, Bo; Zhong, Lei; Yang, Qiuyuan; Zhang, Chunhui; Huang, Shenzhen; Xiang, Rong; Suzuki, Takayoshi; Li, Lin-Li; Yang, Sheng-Yong
Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against commercial chemical databases. A number of hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the most active hit compound, 9 (IC50: 2.3μM), which led to the discovery of several new KDM5A inhibitors. Among them, compound 15e is the most potent one with an IC50 value of 0.22μM against KDM5A. This compound showed good selectivity for KDM5A and considerable ability to suppress the demethylation of H3K4me3 in intact cells. Compound 15e could be taken as a good lead compound for further studies. PMID:27020306
Relationship between potential platelet activation and LCS
NASA Astrophysics Data System (ADS)
Shadden, Shawn
In the study of blood flow, emphasis is often directed at understanding shear stress at the vessel wall due to its potentially disruptive influence on the endothelium. However, it is also known that shear stress has a potent effect on platelet activation. Platelet activation is a precursor for blood clotting, which in turn is the cause of most forms of death. Since most platelets are contained in the flow domain, it is important to consider stresses acting on the platelet as they are convected. Locations of high stress can correspond to boundaries between different dynamic regions and locations of hyperbolic points in the Eulerian sense. In the computation of LCS, strain in typically considered in the Lagrangian sense. In this talk we discuss the relationship between locations of potential platelet activation due to increased stress and locations of LCS marking increase Lagrangian deformation.
Molecular characterization of the receptor binding structure-activity relationships of influenza B virus hemagglutinin.
Carbone, V; Kim, H; Huang, J X; Baker, M A; Ong, C; Cooper, M A; Li, J; Rockman, S; Velkov, T
Selectivity of α2,6-linked human-like receptors by B hemagglutinin (HA) is yet to be fully understood. This study integrates binding data with structure-recognition models to examine the impact of regional-specific sequence variations within the receptor-binding pocket on selectivity and structure activity relationships (SAR). The receptor-binding selectivity of influenza B HAs corresponding to either B/Victoria/2/1987 or the B/Yamagata/16/88 lineages was examined using surface plasmon resonance, solid-phase ELISA and gel-capture assays. Our SAR data showed that the presence of asialyl sugar units is the main determinant of receptor preference of α2,6 versus α2,3 receptor binding. Changes to the type of sialyl-glycan linkage present on receptors exhibit only a minor effect upon binding affinity. Homology-based structural models revealed that structural properties within the HA pocket, such as a glyco-conjugate at Asn194 on the 190-helix, sterically interfere with binding to avian receptor analogs by blocking the exit path of the asialyl sugars. Similarly, naturally occurring substitutions in the C-terminal region of the 190-helix and near the N-terminal end of the 140-loop narrows the horizontal borders of the binding pocket, which restricts access of the avian receptor analog LSTa. This study helps bridge the gap between ligand structure and receptor recognition for influenza B HA; and provides a consensus SAR model for the binding of human and avian receptor analogs to influenza B HA. PMID:24020757
NASA Astrophysics Data System (ADS)
Werninghaus, Rolf
The TerraSAR-X is a German national SAR- satellite system for scientific and commercial applications. It is the continuation of the scientifically and technologically successful radar missions X-SAR (1994) and SRTM (2000) and will bring the national technology developments DESA and TOPAS into operational use. The space segment of TerraSAR-X is an advanced high-resolution X-Band radar satellite. The system design is based on a sound market analysis performed by Infoterra. The TerraSAR-X features an advanced high-resolution X-Band Synthetic Aperture Radar based on the active phased array technology which allows the operation in Spotlight-, Stripmap- and ScanSAR Mode with various polarizations. It combines the ability to acquire high resolution images for detailed analysis as well as wide swath images for overview applications. In addition, experimental modes like the Dual Receive Antenna Mode allow for full-polarimetric imaging as well as along track interferometry, i.e. moving target identification. The Ground Segment is optimized for flexible response to (scientific and commercial) User requests and fast image product turn-around times. The TerraSAR-X mission will serve two main goals. The first goal is to provide the strongly supportive scientific community with multi-mode X-Band SAR data. The broad spectrum of scientific application areas include Hydrology, Geology, Climatology, Oceanography, Environmental Monitoring and Disaster Monitoring as well as Cartography (DEM Generation) and Interferometry. The second goal is the establishment of a commercial EO-market in Europe which is driven by Infoterra. The commercial goal is the development of a sustainable EO-business so that the e.g. follow-on systems can be completely financed by industry from the profit. Due to its commercial potential, the TerraSAR-X project will be implemented based on a public-private partnership with the Astrium GmbH. This paper will describe first the mission objectives as well as the
The 'SAR Matrix' method and its extensions for applications in medicinal chemistry and chemogenomics.
Gupta-Ostermann, Disha; Bajorath, Jürgen
We describe the 'Structure-Activity Relationship (SAR) Matrix' (SARM) methodology that is based upon a special two-step application of the matched molecular pair (MMP) formalism. The SARM method has originally been designed for the extraction, organization, and visualization of compound series and associated SAR information from compound data sets. It has been further developed and adapted for other applications including compound design, activity prediction, library extension, and the navigation of multi-target activity spaces. The SARM approach and its extensions are presented here in context to introduce different types of applications and provide an example for the evolution of a computational methodology in pharmaceutical research. PMID:25383183
Synthesis and structure–activity relationships of tyrosine-based inhibitors of autotaxin (ATX)
East, James E.; Kennedy, Andrew J.; Tomsig, Jose L.; De Leon, Alexandra R.; Lynch, Kevin R.; Macdonald, Timothy L.
Autotaxin (ATX) is a secreted soluble enzyme that generates lysophosphatidic acid (LPA) through its lysophospholipase D activity. Because of LPA's role in neoplastic diseases, ATX is an attractive therapeutic target due to its involvement in LPA biosynthesis. Here we describe the SAR of ATX inhibitor, VPC8a202, and apply this SAR knowledge towards developing a high potency inhibitor. We found that electron density in the pyridine region greatly influences activity of our inhibitors at ATX. PMID:20951039
The first Drinking Water Contaminant Candidate List (CCL), created in response to the Safe Drinking Water Act (SDWA) Amendments of 1996, consists of a list of chemicals or groups of chemicals that are known drinking water contaminants. The SDWA amendments of 1996 stipulated that...
Peptide Bacteriocins--Structure Activity Relationships.
Etayash, Hashem; Azmi, Sarfuddin; Dangeti, Ramana; Kaur, Kamaljit
With the growing concerns in the scientific and health communities over increasing levels of antibiotic resistance, antimicrobial peptide bacteriocins have emerged as promising alternatives to conventional small molecule antibiotics. A substantial attention has recently focused on the utilization of bacteriocins in food preservation and health safety. Despite the fact that a large number of bacteriocins have been reported, only a few have been fully characterized and structurally elucidated. Since knowledge of the molecular structure is a key for understanding the mechanism of action and therapeutic effects of peptide, we centered our focus in this review on the structure-activity relationships of bacteriocins with a particular focus in seven bacteriocins, namely, nisin, microcin J25, microcin B17, microcin C, leucocin A, sakacin P, and pediocin PA-1. Significant structural changes responsible for the altered activity of the recent bacteriocin analogues are discussed here. PMID:26265354
Representation of molecular structure using quantum topology with inductive logic programming in structure-activity relationships.
Buttingsrud, Bård; Ryeng, Einar; King, Ross D; Alsberg, Bjørn K
The requirement of aligning each individual molecule in a data set severely limits the type of molecules which can be analysed with traditional structure activity relationship (SAR) methods. A method which solves this problem by using relations between objects is inductive logic programming (ILP). Another advantage of this methodology is its ability to include background knowledge as 1st-order logic. However, previous molecular ILP representations have not been effective in describing the electronic structure of molecules. We present a more unified and comprehensive representation based on Richard Bader's quantum topological atoms in molecules (AIM) theory where critical points in the electron density are connected through a network. AIM theory provides a wealth of chemical information about individual atoms and their bond connections enabling a more flexible and chemically relevant representation. To obtain even more relevant rules with higher coverage, we apply manual postprocessing and interpretation of ILP rules. We have tested the usefulness of the new representation in SAR modelling on classifying compounds of low/high mutagenicity and on a set of factor Xa inhibitors of high and low affinity. PMID:17054018
SiSAR: advanced SAR simulation
NASA Astrophysics Data System (ADS)
Klaus, Ferdinand
SiSAR was planned as a realistic as possible, modular, user-friendly and fast SAR raw data simulator running on ordinary workstations. Interest in (interferometric) SAR products is growing on an international scale. There is a concentration of manpower and financial resources. Dead ends, respectively failures, have to be avoided during design and mission of every SAR project by simulating the system thoroughly before the experiment. Another reason to make use of extensive reproducible simulations during design and development is the reduction of time and manpower costs. As it comes down to verifying and comparing different processing algorithms we see that (interferometric) SAR simulation is an indispensable tool for testing individual processing steps. SiSAR is a modular SAR raw data simulator for realistic description of the functions of a SAR-system. It contains an implementation of diverse models to characterize radar targets, various approaches to describe the trajectory and the motion of the footprint on the target surface and different raw data formation algorithms. Beyond there is a wide supply of tools for manipulation, analysis and user-friendly simulation handling. Results obtained by SiSAR and some first simulated interferometric SAR raw data are shown in the paper.
NASA Technical Reports Server (NTRS)
Freeman, Anthony
Ambiguities are an aliasing effect caused by the periodic sampling of the scene backscatter inherent to pulsed radar systems such as Synthetic Aperture radar (SAR). In this paper we take a fresh look at the relationship between SAR range and azimuth ambiguity constraints on the allowable pulse repetition frequency (PRF) and the antenna length. We show that for high squint angles smaller antennas may be feasible in some cases. For some applications, the ability to form a synthetic aperture at high squint angles is desirable, but the size of the antenna causes problems in the design of systems capable of such operation. This is because the SAR system design is optimized for a side-looking geometry. In two examples design examples we take a suboptimum antenna size and examine the performance in terms of azimuth resolution and swath width as a function of squint angle. We show that for stripmap SARs, the swath width is usually worse for off-boresight squint angles, because it is severely limited by range walk, except in cases where we relax the spatial resolution. We consider the implications for the design of modest-resolution, narrow swath, scanning SAR scatterometers .
InSAR analysis of surface deformation over permafrost to estimate active layer thickness based on one-dimensional heat transfer model of soils
Li, Zhiwei; Zhao, Rong; Hu, Jun; Wen, Lianxing; Feng, Guangcai; Zhang, Zeyu; Wang, Qijie
This paper presents a novel method to estimate active layer thickness (ALT) over permafrost based on InSAR (Interferometric Synthetic Aperture Radar) observation and the heat transfer model of soils. The time lags between the periodic feature of InSAR-observed surface deformation over permafrost and the meteorologically recorded temperatures are assumed to be the time intervals that the temperature maximum to diffuse from the ground surface downward to the bottom of the active layer. By exploiting the time lags and the one-dimensional heat transfer model of soils, we estimate the ALTs. Using the frozen soil region in southern Qinghai-Tibet Plateau (QTP) as examples, we provided a conceptual demonstration of the estimation of the InSAR pixel-wise ALTs. In the case study, the ALTs are ranging from 1.02 to 3.14 m and with an average of 1.95 m. The results are compatible with those sparse ALT observations/estimations by traditional methods, while with extraordinary high spatial resolution at pixel level (~40 meter). The presented method is simple, and can potentially be used for deriving high-resolution ALTs in other remote areas similar to QTP, where only sparse observations are available now. PMID:26480892
InSAR analysis of surface deformation over permafrost to estimate active layer thickness based on one-dimensional heat transfer model of soils.
Li, Zhiwei; Zhao, Rong; Hu, Jun; Wen, Lianxing; Feng, Guangcai; Zhang, Zeyu; Wang, Qijie
This paper presents a novel method to estimate active layer thickness (ALT) over permafrost based on InSAR (Interferometric Synthetic Aperture Radar) observation and the heat transfer model of soils. The time lags between the periodic feature of InSAR-observed surface deformation over permafrost and the meteorologically recorded temperatures are assumed to be the time intervals that the temperature maximum to diffuse from the ground surface downward to the bottom of the active layer. By exploiting the time lags and the one-dimensional heat transfer model of soils, we estimate the ALTs. Using the frozen soil region in southern Qinghai-Tibet Plateau (QTP) as examples, we provided a conceptual demonstration of the estimation of the InSAR pixel-wise ALTs. In the case study, the ALTs are ranging from 1.02 to 3.14 m and with an average of 1.95 m. The results are compatible with those sparse ALT observations/estimations by traditional methods, while with extraordinary high spatial resolution at pixel level (~40 meter). The presented method is simple, and can potentially be used for deriving high-resolution ALTs in other remote areas similar to QTP, where only sparse observations are available now. PMID:26480892
Obstacles to activity pacing: assessment, relationship to activity and functioning.
Cane, Douglas; McCarthy, Mary; Mazmanian, Dwight
Activity pacing is frequently included among the strategies provided to individuals with chronic pain to manage pain and improve functioning. Individuals with chronic pain may, however, limit their use of activity pacing because they perceive significant obstacles to its use. This study describes the development of a measure to assess obstacles to activity pacing and examines the relationship of this measure to activity patterns and functioning. A sample of 637 individuals with chronic pain completed items describing potential obstacles to activity pacing as part of their pretreatment assessment. Item analyses were used to construct a 14-item measure of obstacles to activity pacing. A subset of these individuals completed the measure again after completion of a group treatment program. The resulting measure demonstrated excellent internal consistency and was minimally affected by social desirability. Correlations with measures of activity and psychosocial functioning provided initial construct validity for the measure. Sex differences were found with women initially identifying more obstacles to activity pacing. Fewer obstacles were identified by both men and women after treatment, and these changes were related to modest changes in activity patterns and functioning. The present results identify a number of obstacles that may limit the use of activity pacing by individuals with chronic pain. Treatment may result in a decrease in the number of obstacles identified, and this change is related to changes in the individual's activity pattern and psychosocial functioning. PMID:26963845
Structural relationships and vasorelaxant activity of monoterpenes
Background and purpose of the study The hypotensive activity of the essential oil of Mentha x villosa and its main constituent, the monoterpene rotundifolone, have been reported. Therefore, our objective was to evaluate the vasorelaxant effect of monoterpenes found in medicinal plants and establish the structure-activity relationship of rotundifolone and its structural analogues on the rat superior mesenteric artery. Methods Contractions of the vessels were induced with 10 μM of phenylephine (Phe) in rings with endothelium. During the tonic phase of the contraction, the monoterpenes (10-8 - 10-3, cumulatively) were added to the organ bath. The extent of relaxation was expressed as the percentage of Phe-induced contraction. Results The results from the present study showed that both oxygenated terpenes (rotundifolone, (+)-limonene epoxide, pulegone epoxide, carvone epoxide, and (+)-pulegone) and non-oxygenated terpene ((+)-limonene) exhibit relaxation activity. The absence of an oxygenated molecular structure was not a critical requirement for the molecule to be bioactive. Also it was found that the position of ketone and epoxide groups in the monoterpene structures influence the vasorelaxant potency and efficacy. Major conclusion The results suggest that the presence of functional groups in the chemical structure of rotundifolone is not essential for its vasorelaxant activity. PMID:23351149
Application of Satellite SAR Imagery in Mapping the Active Layer of Arctic Permafrost
NASA Technical Reports Server (NTRS)
Zhang, Ting-Jun; Li, Shu-Sun
The objective of this project is to map the spatial variation of the active layer over the arctic permafrost in terms of two parameters: (i) timing and duration of thaw period and (ii) differential frost heave and thaw settlement of the active layer. To achieve this goal, remote sensing, numerical modeling, and related field measurements are required. Tasks for the University of Colorado team are to: (i) determine the timing of snow disappearance in spring through changes in surface albedo (ii) simulate the freezing and thawing processes of the active layer and (iii) simulate the impact of snow cover on permafrost presence.
SAR/QSAR methods in public health practice
Demchuk, Eugene Ruiz, Patricia; Chou, Selene; Fowler, Bruce A.
Methods of (Quantitative) Structure-Activity Relationship ((Q)SAR) modeling play an important and active role in ATSDR programs in support of the Agency mission to protect human populations from exposure to environmental contaminants. They are used for cross-chemical extrapolation to complement the traditional toxicological approach when chemical-specific information is unavailable. SAR and QSAR methods are used to investigate adverse health effects and exposure levels, bioavailability, and pharmacokinetic properties of hazardous chemical compounds. They are applied as a part of an integrated systematic approach in the development of Health Guidance Values (HGVs), such as ATSDR Minimal Risk Levels, which are used to protect populations exposed to toxic chemicals at hazardous waste sites. (Q)SAR analyses are incorporated into ATSDR documents (such as the toxicological profiles and chemical-specific health consultations) to support environmental health assessments, prioritization of environmental chemical hazards, and to improve study design, when filling the priority data needs (PDNs) as mandated by Congress, in instances when experimental information is insufficient. These cases are illustrated by several examples, which explain how ATSDR applies (Q)SAR methods in public health practice.
Design, Synthesis and Structure-Activity Relationship Studies of Novel 4 (1-adamantyl) Phenyl Analogues as HIF-1α Inhibitors.
Xia, Yan; Duan, Qiong; Zhao, Bao-Hua; Li, Dong-Feng; Hou, Rui-Bin
Hypoxia inducible factor-1 (HIF-1) is a key mediator during cancer cells to adapt tumor hypoxic condition. In this study, a series of adamantane-based compounds were synthesized and evaluated as potential inhibitors of HIF-1α. Examination of their structure-activity relationship (SAR) identified the adamantane-containing indole derivative 20a as a potent inhibitor of HIF-1α in Hep3B cell lines under tumor hypoxia (IC50 = 0.02 µM). The study herein may provide valuable information for the development of novel therapeutics against cancer and tumor angiogenesis. PMID:26548744
Most toxicity data, particularly from whole animal bioassays, are generated without the needs or capabilities of structure-activity relationship (SAR) modeling in mind. Some toxicity endpoints have been of sufficient regulatory concern to warrant large scale testing efforts (e.g....
The relationship between computational SAR studies and relevant data gathering and generation activities is complex. irst, the chemical class to be studied is selected on the basis of information requirements for hazard identification and assessment. Membership in the class is de...
The structure-activity relationships of L3MBTL3 inhibitors: flexibility of the dimer interface
Camerino, Michelle A.; Zhong, Nan; Dong, Aiping; Dickson, Bradley M.; James, Lindsey I.; Baughman, Brandi M.; Norris, Jacqueline L.; Kireev, Dmitri B.; Janzen, William P.; Arrowsmith, Cheryl H.
We recently reported the discovery of UNC1215, a potent and selective chemical probe for the L3MBTL3 methyllysine reader domain. In this article, we describe the development of structure-activity relationships (SAR) of a second series of potent L3MBTL3 antagonists which evolved from the structure of the chemical probe UNC1215. These compounds are selective for L3MBTL3 against a panel of methyllysine reader proteins, particularly the related MBT family proteins, L3MBTL1 and MBTD1. A co-crystal structure of L3MBTL3 and one of the most potent compounds suggests that the L3MBTL3 dimer rotates about the dimer interface to accommodate ligand binding. PMID:24466405
Severe acute respiratory syndrome (SARS)
... when the virus spread from small mammals in China. When someone with SARS coughs or sneezes, infected ... causes SARS include: Antibody tests for SARS Direct isolation of the SARS virus Rapid polymerase chain reaction ( ...
Discretionary Time of Chinese College Students: Activities and Impact of SARS-Induced Constraints on Choices
ERIC Educational Resources Information Center
Yang, He; Hutchinson, Susan; Zinn, Harry; Watson, Alan
How people make choices about activity engagement during discretionary time is a topic of increasing interest to those studying quality of life issues. Assuming choices are made to maximize individual welfare, several factors are believed to influence these choices. Constraints theory from the leisure research literature suggests these choices are…
Satellite SAR imagery for site discovery, change detection and monitoring activities in cultural heritage sites: experiments on the Nasca region, Peru
NASA Astrophysics Data System (ADS)
Tapete, D.; Cigna, F.; Masini, N.; Lasaponara, R.
Besides their suitability for multi-temporal and spatial deformation analysis, the Synthetic Aperture Radar (SAR) image archives acquired by space-borne radar sensors can be exploited to support archaeological investigations over huge sites, even those partially or totally buried and still to be excavated. Amplitude information is one of the main properties of SAR data from which it is possible to retrieve evidences of buried structures, using feature extraction and texture analysis. Multi-temporality allows the reconstruction of past and recent evolution of both landscape and built-up environment, with the possibility to detect natural and/or anthropogenic changes, including human-induced damages to the conservation of cultural heritage. We present the methodology and first results of the experiments currently undertaken using SAR data in the Nasca region (Southern Peru), where two important civilizations such as Paracas and Nasca developed and flourished from 4th century BC to the 6th century AD. The study areas include a wide spectrum of archaeological and environmental elements to be preserved, among which: the archaeological site of Cahuachi and its surroundings, considered the largest adobe Ceremonial Centre in the World; the Nasca lines and geoglyphs in the areas of Palpa, Atarco and Nasca; the ancient networks of aqueducts and drainage galleries in the Puquios area, built by Nasca in the 1st-6th centuries AD. Archaeological prospection and multi-purpose remote sensing activities are currently carried out in the framework of the Italian mission of heritage Conservation and Archaeogeophysics (ITACA), with the direct involvement of researchers from the Institute for Archaeological and Monumental Heritage and the Institute of Methodologies for Environmental Analysis, Italian National Research Council. In this context, C- and L-band SAR images covering the Nasca region since 2001 were identified for the purposes of this research and, in particular, the following
Structure-Activity Relationship of Oligomeric Flavan-3-ols: Importance of the Upper-Unit B-ring Hydroxyl Groups in the Dimeric Structure for Strong Activities.
Hamada, Yoshitomo; Takano, Syota; Ayano, Yoshihiro; Tokunaga, Masahiro; Koashi, Takahiro; Okamoto, Syuhei; Doi, Syoma; Ishida, Masahiko; Kawasaki, Takashi; Hamada, Masahiro; Nakajima, Noriyuki; Saito, Akiko
Proanthocyanidins, which are composed of oligomeric flavan-3-ol units, are contained in various foodstuffs (e.g., fruits, vegetables, and drinks) and are strongly biologically active compounds. We investigated which element of the proanthocyanidin structure is primarily responsible for this functionality. In this study, we elucidate the importance of the upper-unit of 4-8 condensed dimeric flavan-3-ols for antimicrobial activity against Saccharomyces cerevisiae (S. cerevisiae) and cervical epithelioid carcinoma cell line HeLa S3 proliferation inhibitory activity. To clarify the important constituent unit of proanthocyanidin, we synthesized four dimeric compounds, (-)-epigallocatechin-[4,8]-(+)-catechin, (-)-epigallocatechin-[4,8]-(-)-epigallocatechin, (-)-epigallocatechin-[4,8]-(-)-epigallocatechin-3-O-gallate, and (+)-catechin-[4,8]-(-)-epigallocatechin and performed structure-activity relationship (SAR) studies. In addition to antimicrobial activity against S. cerevisiae and proliferation inhibitory activity on HeLa S3 cells, the correlation of 2,2-diphenyl-l-picrylhydrazyl radical scavenging activity with the number of phenolic hydroxyl groups was low. On the basis of the results of our SAR studies, we concluded that B-ring hydroxyl groups of the upper-unit of the dimer are crucially important for strong and effective activity. PMID:26501251
Surface Deformation Analysis of the Active Faults revealed by InSAR Observations and Geodetic Data in Southern Part of the Taitung Longitudinal Valley, Eastern Taiwan
NASA Astrophysics Data System (ADS)
Tung, H.; Chen, H. Y.; Hu, J. C.
The NNE-striking Longitudinal Valley Fault (LVF) in eastern Taiwan is an extremely active inverse fault, which is considered as a collision boundary between the Eurasian and the Philippine Sea plates. The fault segments of the LVF demonstrate different slip behaviors, especially in the southern segment of the LVF. The deformation is partitioned by the strike-slip (Lichi fault segment) and the reverse faulting (Luyeh segment). Thus we investigate crustal deformation pattern along the southern LVF by using SAR interferometry and precise leveling data. The SAR data of the Longitudinal Valley area were collected by ERS-1, ERS-2 and Envisat satellite of the European Space Agency in both descending (track: 232; frame: 3141) and ascending (track: 311; frame: 459) orbits. However, this area is so heavily vegetated that high coherence area is limited in the Taitung City and good interfergrams with better coherence are limited to short time span and small perpendicular baseline pairs. Therefore we made three stacking image from the higher coherence interferograms representing deformation interval from 1995-1996, 1996-1998 and 2006-2008 separately. These three results show a same relative subsidence between Luyeh fault and Lichi fault, which is consistent with leveling data measured that time. Besides, we also used the PSInSAR technique to trace the discrete points that were minimally affected by the decorrelation of radar signals through time. Finally we constrain the deformation map based on PSInSAR with leveling data for better understanding the deformation patterns in the southern Longitudinal Valley area.
NASA Astrophysics Data System (ADS)
Wdowinski, S.; Kim, S.; Amelung, F.; Dixon, T.
Wetlands are transition zones where the flow of water, the nutrient cycling, and the sun energy meet to produce a unique and very productive ecosystem. They provide critical habitat for a wide variety of plant and animal species, including the larval stages of many ocean fish. Wetlands also have a valuable economical importance, as they filter nutrients and pollutants from fresh water used by human and provide aquatic habitats for outdoor recreation, tourism, and fishing. Globally, many such regions are under severe environmental stress, mainly from urban development, pollution, and rising sea level. However, there is increasing recognition of the importance of these habitats, and mitigation and restoration activities have begun in a few regions. A key element in wetlands conservation, management, and restoration involves monitoring its hydrologic system, as the entire ecosystem depends on its water supply. Heretofore, hydrologic monitoring of wetlands are conducted by stage (water level) stations, which provide good temporal resolution, but suffer from poor spatial resolution, as stage station are typically distributed several, or even tens of kilometers, from one another. Wetland application of InSAR provides the needed high spatial resolution hydrological observations, complementing the high temporal resolution terrestrial observations. Although conventional wisdom suggests that interferometry does not work in vegetated areas, several studies have shown that both L- and C-band interferograms with short acquisition intervals (1-105 days) can maintain excellent coherence over wetlands. In this study we explore the usage of InSAR for detecting water level changes in various wetland environments around the world, including the Everglades (south Florida), Louisiana Coast (southern US), Chesapeake Bay (eastern US), Pantanal (Brazil), Okavango Delta (Botswana), and Lena Delta (Siberia). Our main study area is the Everglades wetland (south Florida), which is covered by
In Vitro Antioxidant Activity of Selected 4-Hydroxy-chromene-2-one Derivatives—SAR, QSAR and DFT Studies
Mladenović, Milan; Mihailović, Mirjana; Bogojević, Desanka; Matić, Sanja; Nićiforović, Neda; Mihailović, Vladimir; Vuković, Nenad; Sukdolak, Slobodan; Solujić, Slavica
The series of fifteen synthesized 4-hydroxycoumarin derivatives was subjected to antioxidant activity evaluation in vitro, through total antioxidant capacity, 1,1-diphenyl-2-picryl-hydrazyl (DPPH), hydroxyl radical, lipid peroxide scavenging and chelating activity. The highest activity was detected during the radicals scavenging, with 2b, 6b, 2c, and 4c noticed as the most active. The antioxidant activity was further quantified by the quantitative structure-activity relationships (QSAR) studies. For this purpose, the structures were optimized using Paramethric Method 6 (PM6) semi-empirical and Density Functional Theory (DFT) B3LYP methods. Bond dissociation enthalpies of coumarin 4-OH, Natural Bond Orbital (NBO) gained hybridization of the oxygen, acidity of the hydrogen atom and various molecular descriptors obtained, were correlated with biological activity, after which we designed 20 new antioxidant structures, using the most favorable structural motifs, with much improved predicted activity in vitro. PMID:21686153
The structure-AChE inhibitory activity relationships study in a series of pyridazine analogues.
Saracoglu, M; Kandemirli, F
The structure-activity relationships (SAR) are investigated by means of the Electronic-Topological Method (ETM) followed by the Neural Networks application (ETM-NN) for a class of anti-cholinesterase inhibitors (AChE, 53 molecules) being pyridazine derivatives. AChE activities of the series were measured in IC(50) units, and relative to the activity levels, the series was partitioned into classes of active and inactive compounds. Based on pharmacophores and antipharmacophores calculated by the ETM-software as sub-matrices containing important spatial and electronic characteristics, a system for the activity prognostication is developed. Input data for the ETM were taken as the results of conformational and quantum-mechanics calculations. To predict the activity, we used one of the most well known neural networks, namely, the feed-forward neural networks (FFNNs) trained with the back propagation algorithm. The supervised learning was performed using a variant of FFNN known as the Associative Neural Networks (ASNN). The result of the testing revealed that the high ETM's ability of predicting both activity and inactivity of potential AChE inhibitors. Analysis of HOMOs for the compounds containing Ph1 and APh1 has shown that atoms with the highest values of the atomic orbital coefficients are mainly those atoms that enter into the pharmacophores. Thus, the set of pharmacophores and antipharmacophores found as the result of this study forms a basis for a system of the anti-cholinesterase activity prediction. PMID:19689389
Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of sulphone-based CRTh2 antagonists.
Buil, Maria Antonia; Calbet, Marta; Castillo, Marcos; Castro, Jordi; Esteve, Cristina; Ferrer, Manel; Forns, Pilar; González, Jacob; López, Sara; Roberts, Richard S; Sevilla, Sara; Vidal, Bernat; Vidal, Laura; Vilaseca, Pere
Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times. PMID:26922232
Antipoliovirus structure-activity relationships of some aporphine alkaloids.
Boustie, J; Stigliani, J L; Montanha, J; Amoros, M; Payard, M; Girre, L
A series of 18 aporphinoids have been tested in vitro against human poliovirus. The aporphines (+)-glaucine fumarate (1), (+)-N-methyllaurotetanine (4), (+)-isoboldine (7), and (-)-nuciferine, HCl (10) were found to be active with selectivity indices > 14. The nature of the 1, 2-substituents of the isoquinoline moiety appeared to be critical for antipoliovirus activity. An SAR study demonstrated the importance of a methoxyl group at C-2 on the tetrahydroisoquinoline ring for the induction of antipoliovirus activity. Molecular modeling of some compounds in this series revealed the close similarities between the three-dimensional conformational features of the inactive 1,2-substituted derivatives (+)-boldine (6) and (+)-laurolitsine (5) with derivatives containing the 1,2-(methylenedioxy) moiety, which were generally found to be inactive as exemplified by (+)-cassythicine (9). PMID:9584402
Subsidence activity maps derived from DInSAR data: Orihuela case study
NASA Astrophysics Data System (ADS)
Sanabria, M. P.; Guardiola-Albert, C.; Tomás, R.; Herrera, G.; Prieto, A.; Sánchez, H.; Tessitore, S.
A new methodology is proposed to produce subsidence activity maps based on the geostatistical analysis of persistent scatterer interferometry (PSI) data. PSI displacement measurements are interpolated based on conditional Sequential Gaussian Simulation (SGS) to calculate multiple equiprobable realizations of subsidence. The result from this process is a series of interpolated subsidence values, with an estimation of the spatial variability and a confidence level on the interpolation. These maps complement the PSI displacement map, improving the identification of wide subsiding areas at a regional scale. At a local scale, they can be used to identify buildings susceptible to suffer subsidence related damages. In order to do so, it is necessary to calculate the maximum differential settlement and the maximum angular distortion for each building of the study area. Based on PSI-derived parameters those buildings in which the serviceability limit state has been exceeded, and where in situ forensic analysis should be made, can be automatically identified. This methodology has been tested in the city of Orihuela (SE Spain) for the study of historical buildings damaged during the last two decades by subsidence due to aquifer overexploitation. The qualitative evaluation of the results from the methodology carried out in buildings where damages have been reported shows a success rate of 100%.
Ground deformation associated with post-mining activity at the French-German border revealed by novel InSAR time series method
NASA Astrophysics Data System (ADS)
Samsonov, Sergey; d'Oreye, Nicolas; Smets, Benoît
We present a novel methodology for integration of multiple InSAR data sets for computation of two dimensional time series of ground deformation. The proposed approach allows combination of SAR data acquired with different acquisition parameters, temporal and spatial sampling and resolution, wavelength and polarization. Produced time series have combined coverage, improved temporal resolution and lower noise level. We apply this methodology for mapping coal mining related ground subsidence and uplift in the Greater Region of Luxembourg along the French-German border. For this we processed 167 Synthetic Aperture Radar ERS-1/2 and ENVISAT images acquired between 1995 and 2009 from one ascending (track 29) and one descending (track 337) tracks and created over five hundred interferograms that were used for time series analysis. Derived vertical and east-west linear deformation rates show with remarkable precision a region of localized ground deformation located above and caused by mining and post-mining activities. Time series of ground deformation display temporal variability: reversal from subsidence to uplift and acceleration of subsidence in the vertical component, and horizontal motion toward the center of the subsidence on the east-west component. InSAR results are validated by leveling measurements collected by the French Geological Survey (BRGM) during 2006-2008. We determined that deformation rate changes are mainly caused by water level variations in the mines. Due to higher temporal and spatial resolution the proposed space-borne method detected a larger number of subsidence and uplift areas in comparison to leveling measurements restricted to annual monitoring of benchmark points along roads. We also identified one deformation region that is not precisely located above the mining sites. Comparison of InSAR measurements with the water levels measured in the mining pits suggest that part of the water that filled the galleries after termination of the
Study of the relationship between mutagenicity and molecular structure for a data set of nitrogenous cyclic compounds is reported. A computerized SAR system (ADAPT) was utilized to classify a data set of 114 nitrogenous cyclic compounds with 19 molecular descriptors. All of the d...
Brief Report: Activities in Heterosexual Romantic Relationships--Grade Differences and Associations with Relationship Satisfaction
ERIC Educational Resources Information Center
Carlson, Wendy; Rose, Amanda J.
Whereas much research addresses relations of youths' heterosexual romantic relationships with sexual and/or delinquent activities, less attention has been paid to youths' more normative, day-to-day activities with romantic partners. This gap in the literature is problematic given that these activities define the substance of the relationships and…
Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G.
Costa, Eduarda C; Cassamale, Tatiana B; Carvalho, Diego B; Bosquiroli, Lauriane S S; Ojeda, Mariáh; Ximenes, Thalita V; Matos, Maria F C; Kadri, Mônica C T; Baroni, Adriano C M; Arruda, Carla C P
Sixteen 1,4-diaryl-1,2,3-triazole compounds 4-19 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania) amazonensis intracellular amastigotes. Triazole compounds 4-19 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP) ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR), compounds 14 and 19, containing a trimethoxy group, were the most active (IC50 values of 5.6 and 4.4 µM, respectively), with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6). These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities. PMID:27331807
Friend Flips: A Story Activity about Relationships
ERIC Educational Resources Information Center
Szucs, Leigh; Reyes, Jovanni V.; Farmer, Jennifer; Wilson, Kelly L.; McNeill, Elisa Beth
Adolescents are influenced by the type, length and quality of the connections shared with different people throughout their lifespan. Relationships with peers, friends, and adults help to shape knowledge, attitudes, and beliefs related to health. Recognizing healthy or unhealthy characteristics allow youth to strengthen relationships and…
NASA Astrophysics Data System (ADS)
Meadows, P. J.; Hounam, D.; Rye, A. J.; Rosich, B.; Börner, T.; Closa, J.; Schättler, B.; Smith, P. J.; Zink, M.
As SAR instruments and their operating modes become more complex, as new applications place more and more demands on image quality and as our understanding of their imperfections becomes more sophisticated, there is increasing recognition that SAR data quality has to be controlled more completely to keep pace. The SAR product CONtrol software (SARCON) is a comprehensive SAR product control software suite tailored to the latest generation of SAR sensors. SARCON profits from the most up-to-date thinking on SAR image performance derived from other spaceborne and airborne SAR projects and is based on the newest applications. This paper gives an overview of the structure and the features of this new software tool, which is a product of a co-operation between teams at BAE SYSTEMS Advanced Technology Centre and DLR under contract to ESA (ESRIN). Work on SARCON began in 1999 and is continuing.
NASA Astrophysics Data System (ADS)
Scarborough, Steven; Lemanski, Christopher; Nichols, Howard; Owirka, Gregory; Minardi, Michael; Hale, Todd
This paper examines the theory, application, and results of using single-channel synthetic aperture radar (SAR) data with Moving Reference Processing (MRP) to focus and geolocate moving targets. Moving targets within a standard SAR imaging scene are defocused, displaced, or completely missing in the final image. Building on previous research at AFRL, the SAR-MRP method focuses and geolocates moving targets by reprocessing the SAR data to focus the movers rather than the stationary clutter. SAR change detection is used so that target detection and focusing is performed more robustly. In the cases where moving target returns possess the same range versus slow-time histories, a geolocation ambiguity results. This ambiguity can be resolved in a number of ways. This paper concludes by applying the SAR-MRP method to high-frequency radar measurements from persistent continuous-dwell SAR observations of a moving target.
Application of an Integrated GPCR SAR-Modeling Platform To Explain the Activation Selectivity of Human 5-HT2C over 5-HT2B.
Heifetz, Alexander; Storer, R Ian; McMurray, Gordon; James, Tim; Morao, Inaki; Aldeghi, Matteo; Bodkin, Mike J; Biggin, Philip C
Agonism of the 5-HT2C serotonin receptor has been associated with the treatment of a number of diseases including obesity, psychiatric disorders, sexual health, and urology. However, the development of effective 5-HT2C agonists has been hampered by the difficulty in obtaining selectivity over the closely related 5-HT2B receptor, agonism of which is associated with irreversible cardiac valvulopathy. Understanding how to design selective agonists requires exploration of the structural features governing the functional uniqueness of the target receptor relative to related off targets. X-ray crystallography, the major experimental source of structural information, is a slow and challenging process for integral membrane proteins, and so is currently not feasible for every GPCR or GPCR-ligand complex. Therefore, the integration of existing ligand SAR data with GPCR modeling can be a practical alternative to provide this essential structural insight. To demonstrate this, we integrated SAR data from 39 azepine series 5-HT2C agonists, comprising both selective and unselective examples, with our hierarchical GPCR modeling protocol (HGMP). Through this work we have been able to demonstrate how relatively small differences in the amino acid sequences of GPCRs can lead to significant differences in secondary structure and function, as supported by experimental data. In particular, this study suggests that conformational differences in the tilt of TM7 between 5-HT2B and 5-HT2C, which result from differences in interhelical interactions, may be the major source of selectivity in G-protein activation between these two receptors. Our approach also demonstrates how the use of GPCR models in conjunction with SAR data can be used to explain activity cliffs. PMID:26900768
Space-Borne and Ground-Based Sar Interferometry for Landslide Activity Analysis and Monitoring in the Appennines of Emilia Romagna (Italy): Review of Methods and Preliminary Results
NASA Astrophysics Data System (ADS)
Barbieri, M.; Corsini, A.; Casagli, N.; Farina, P.; Coren, F.; Sterzai, P.; Leva, D.; Tarchi, D.
This work concerns the application of SAR interferometry for the assessment of the long-term analysis of the state of activity of deep seated mass movements affecting some urban areas in the northern Appennines of Emilia Romagna region (from 1994-2001 space-borne ERS data) and for the real-time monitoring of active flow-like landslides in year 2002 (from ground-based system). These activities are part of an ongoing research project supported by civil protection authorities of the Emilia-Romagna region that involves several research institutes with diverse expertises. A set of test sites characterized by a high landslide risk have been selected mainly taking into account phenomena characteristics such as deformation rates and vegetation coverage, with respect to the employed techniques. After a preliminary detailed geomorphologic characterization of the sites, the interferometric analyses, still in progress, have been implemented. In particular space-borne DInSAR has been applied for 10 unstable areas using a set of ERS1/ERS2 data acquired in the last 7 years. From 9 interferograms, the line-of-sight displacement maps have been calculated and, later on, post processed in GIS environment in order to have on-slope-direction displacement maps that could fully be integrated with geomorphologic and ancillary data and that could semi-quantitatively be compared with other traditional monitoring data. The results obtained have been rather satisfactory, especially in some test sites where entire villages are settled on the mass movement, as in the case of Berceto (Parma) presented in the paper, and post-processed products have proved a significant amelioration of basic interferometric ones. Moreover, in order to measure terrain displacements induced by landslide characterized by high deformation rates and little urbanisation, ground-based SAR interferometry (GBInSAR) has been used for the monitoring of a test site located in the province of Bologna. This application proved
NASA Astrophysics Data System (ADS)
Logan, T. A.; Arko, S. A.; Rosen, P. A.
To demonstrate the feasibility of orbital remote sensing for global ocean observations, NASA launched Seasat on June 27th, 1978. Being the first space borne SAR mission, Seasat produced the most detailed SAR images of Earth from space ever seen to that point in time. While much of the data collected in the USA was processed optically, a mere 150 scenes had been digitally processed by March 1980. In fact, only an estimated 3% of Seasat data was ever digitally processed. Thus, for over three decades, the majority of the SAR data from this historic mission has been dormant, virtually unavailable to scientists in the 21st century. Over the last year, researchers at the Alaska Satellite Facility (ASF) Distributed Active Archive Center (DAAC) have processed the Seasat SAR archives into imagery products. A telemetry decoding system was created and the data were filtered into readily processable signal files. Due to nearly 35 years of bit rot, the bit error rate (BER) for the ASF DAAC Seasat archives was on the order of 1 out of 100 to 1 out of 100,000. This extremely high BER initially seemed to make much of the data undecodable - because the minor frame numbers are just 7 bits and no range line numbers exist in the telemetry even the 'simple' tasks of tracking the minor frame number or locating the start of each range line proved difficult. Eventually, using 5 frame numbers in sequence and a handful of heuristics, the data were successfully decoded into full range lines. Concurrently, all metadata were stored into external files. Recovery of this metadata was also problematic, the BER making the information highly suspect and, initially at least, unusable in any sort of automated fashion. Because of the BER, all of the single bit metadata fields proved unreliable. Even fields that should be constant for a data take (e.g. receiving station, day of the year) showed high variability, each requiring a median filter to be usable. The most challenging, however, were the
Accurate and interpretable nanoSAR models from genetic programming-based decision tree construction approaches.
Oksel, Ceyda; Winkler, David A; Ma, Cai Y; Wilkins, Terry; Wang, Xue Z
The number of engineered nanomaterials (ENMs) being exploited commercially is growing rapidly, due to the novel properties they exhibit. Clearly, it is important to understand and minimize any risks to health or the environment posed by the presence of ENMs. Data-driven models that decode the relationships between the biological activities of ENMs and their physicochemical characteristics provide an attractive means of maximizing the value of scarce and expensive experimental data. Although such structure-activity relationship (SAR) methods have become very useful tools for modelling nanotoxicity endpoints (nanoSAR), they have limited robustness and predictivity and, most importantly, interpretation of the models they generate is often very difficult. New computational modelling tools or new ways of using existing tools are required to model the relatively sparse and sometimes lower quality data on the biological effects of ENMs. The most commonly used SAR modelling methods work best with large datasets, are not particularly good at feature selection, can be relatively opaque to interpretation, and may not account for nonlinearity in the structure-property relationships. To overcome these limitations, we describe the application of a novel algorithm, a genetic programming-based decision tree construction tool (GPTree) to nanoSAR modelling. We demonstrate the use of GPTree in the construction of accurate and interpretable nanoSAR models by applying it to four diverse literature datasets. We describe the algorithm and compare model results across the four studies. We show that GPTree generates models with accuracies equivalent to or superior to those of prior modelling studies on the same datasets. GPTree is a robust, automatic method for generation of accurate nanoSAR models with important advantages that it works with small datasets, automatically selects descriptors, and provides significantly improved interpretability of models. PMID:26956430
Synthesis, antitumor activity, and structure-activity relationship of some benzo[a]pyrano[2,3-c]phenazine derivatives.
Gao, Jing; Chen, Ming; Tong, Xue; Zhu, He; Yan, Hongbin; Liu, Daichun; Li, Wanjing; Qi, Shengyu; Xiao, Dake; Wang, Yongzhi; Lu, Yuanyuan; Jiang, Feng
A series of benzo[a]pyrano[2,3-c]phenazine derivatives with a wide range of substitutions at ring C of the benzophenazine were designed and synthesized using the one-pot, four-component domino reactions. The targeted compounds were evaluated for their antitumor activities against HCT116, MCF7, HepG2 and A549 cancer cell lines in vitro. The most active compound 6{1,2,1,9} featured the CN and p-dimethylamino phenyl substituents on γ-pyran structure on ring C. Significantly, compound 6{1,2,1,9} was found to have the highest growth inhibitory activity against the HepG2 cell line with IC50 values of 6.71 µM, which was 1.6-fold more potent than positive control anticancer drug Hydroxycamptothecine (HCPT). Furthermore, structure-activity relationship (SAR) studies on the substitutions at ring C were discussed in details. PMID:26369405
A Binding Site Model and Structure-Activity Relationships for the Rat A3 Adenosine Receptor
SUMMARY A novel adenosine receptor, the A3 receptor, has recently been cloned. We have systematically investigated the hitherto largely unexplored structure-activity relationships (SARs) for binding at A3 receptors, using 125I-N6-2-(4-aminophenyl)ethyladenosine as a radioligand and membranes from Chinese hamster ovary cells stably transfected with the rat A3-cDNA. As is the case for A1 and A2a, receptors, substitutions at the N6 and 5′ positions of adenosine, the prototypic agonist ligand, may yield fairly potent compounds. However, the highest affinity and A3 selectivity is found for N6,5′-disubstituted compounds, in contrast to A1 and A2a receptors. Thus, N6-benzyladenosine-5′-N-ethylcarboxamide is highly potent (Ki, 6.8 nM) and moderately selective (13- and 14-fold versus A1 and A2a). The N6 region of the A3 receptor also appears to tolerate hydrophilic substitutions, in sharp contrast to the other subtypes. Potencies of N6,5′-disubstituted compounds in inhibition of adenylate cyclase via A3 receptors parallel their high affinity in the binding assay. None of the typical xanthine or nonxanthine (A1/A2) antagonists tested show any appreciable affinity for rat A3 receptors. 1,3-Dialkylxanthines did not antagonize the A3 agonist-induced inhibition of adenylate cyclase. A His residue in helix 6 that is absent in A3 receptors but present in A1/A2 receptors may be causal in this respect. In a molecular model for the rat A3 receptor, this mutation, together with an increased bulkiness of residues surrounding the ligand, make antagonist binding unfavorable when compared with a previously developed A1 receptor model. Second, this A3 receptor model predicted similarities with A1 and A2 receptors in the binding requirements for the ribose moiety and that xanthine-7-ribosides would bind to rat A3 receptors. This hypothesis was supported experimentally by the moderate affinity (Ki 6 μM) of 7-riboside of 1,3-dibutylxanthine, which appears to be a partial agonist at
Synthesis and structure-activity relationship of α-keto amides as enterovirus 71 3C protease inhibitors.
Zeng, Debin; Ma, Yuying; Zhang, Rui; Nie, Quandeng; Cui, Zhengjie; Wang, Yaxin; Shang, Luqing; Yin, Zheng
α-Keto amide derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. structure-activity relationship (SAR) study indicated that small moieties were primarily tolerated at P1' and the introduction of para-fluoro benzyl at P2 notably improved the potency of inhibitor. Inhibitors 8v, 8w and 8x exhibited satisfactory activity (IC50=1.32±0.26μM, 1.88±0.35μM and 1.52±0.31μM, respectively) and favorable CC50 values (CC50>100μM). α-Keto amide may represent a good choice as a warhead for EV71 3C(pro) inhibitor. PMID:26916437
Synthesis and structure-activity relationship studies of O-biphenyl-3-yl carbamates as peripherally restricted fatty acid amide hydrolase inhibitors.
Moreno-Sanz, Guillermo; Duranti, Andrea; Melzig, Laurin; Fiorelli, Claudio; Ruda, Gian Filippo; Colombano, Giampiero; Mestichelli, Paola; Sanchini, Silvano; Tontini, Andrea; Mor, Marco; Bandiera, Tiziano; Scarpelli, Rita; Tarzia, Giorgio; Piomelli, Daniele
The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3'-carbamoyl-5-hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date. PMID:23822179
Use of Global Meteorological Model to Correct for Stratified Tropospheric Delays in SAR Data: Application to Active Mexican Stratovolcanoes.
NASA Astrophysics Data System (ADS)
Pinel, V. M.; Doin, M.; de La Cruz-Reyna, S.; Hooper, A.
Artefacts induced by temporal changes of water content within the tropospheric layer have long been recognised as the main limitation for the use of InSAR data in order to detect magma movement at depth beneath stratovolcanoes (Delacourt, 1998). Difficulty in discriminating between tropospheric artefacts and deformation induced by magma accumulation or withdrawal at depth is mainly due to the similarity of the expected signal centred on the volcanic edifice. However it is of prime importance to be able to detect magma storage which is the most reliable precursor for volcanic eruptions. We processed time series of InSAR data acquired by ENVISAT from December 2002 to August 2006 at Popocatépetl and Colima Volcano (Mexico) using both the Stanford method for persistent scatterers and a derived small baseline approach (Hooper, 2008). Tropospheric delays are estimated for each interferogram using temperature, pressure and water content profiles from the North American Regional Reanalysis (NARR), a global atmospheric model provided by the National Centers for Environmental Prediction. A strong seasonal effect is observed leading to maximum value for delays of 10 rad/km corresponding to 4 fringes on the volcano slopes. These delays are validated using the correlation between the wrapped phase and the elevation as well as spectrometer data acquired by the Medium Resolution Imaging System (MERIS) onboard on the ENVISAT platform. The tropospheric effect is removed from the wrapped phase which improves the unwrapping process. On Popocatépetl no significant deformations were observed. We could not detect any deep magma storage zone beneath Colima volcano, but its summit area exhibits a constant and almost linear subsidence of more than 1.5 cm/year mainly related to recent volcanic deposits loading. References: Delacourt, P. Briole and J. Achache, Tropospheric corrections of SAR interferograms with strong topography. Application to Etna. Geophys. Res. Lett., 25, 2849- 2852
Synergistic measurements of ocean winds and waves from SAR
NASA Astrophysics Data System (ADS)
Zhang, Biao; Li, Xiaofeng; Perrie, William; He, Yijun
In this study we present a synergistic method to retrieve both ocean surface wave and wind fields from spaceborne quad-polarization (QP) synthetic aperture radar (SAR) imaging mode data. This algorithm integrates QP-SAR wind vector retrieval model and the wave retrieval model, with consideration to the nonlinear mapping relationship between ocean wave spectra and SAR image spectra, in order to synergistically retrieve wind fields and wave directional spectra. The method does not require a priori information on the sea state. It combines the observed VV-polarized SAR image spectra with the retrieved wind vectors from the VH-polarized SAR image, to estimate the wind-generated wave directional spectra. The differences between the observed SAR spectra and optimal SAR image spectra associated with the wind waves are interpreted as the contributions from the swell waves. The retrieved ocean wave spectra are used to estimate the integrated spectral wave parameters such as significant wave heights, wavelengths, wave directions and wave periods. The wind and wave parameters retrieved by QP-SAR are validated against those measured by the National Data Buoy Center (NDBC) directional wave buoys under different sea states. The validation results show that the QP-SAR SAR has potential to simultaneously measure the ocean surface waves and wind fields from space.
Hybrid reduced graph for SAR studies.
Carrasco-Velar, R; Prieto-Entenza, J O; Antelo-Collado, A; Padrón-García, J A; Cerruela-García, G; Maceo-Pixa, Á L; Alcolea-Núñez, R; Silva-Rojas, L G
The purpose of this work is the definition and evaluation of both atomic and local new hybrid indices. Inspired by the Refractotopological State Index for Atoms, the new atomic indices are theoretically supported by graph theory principles. The local indices, named Descriptor Centres (DCs), are obtained from the sum of the atomic values of the atoms in the selected group. Different classifiers were used for structure-activity relationship (SAR) studies, including multilayer perceptron (MLP), support vector machines (SVM) and meta-classifiers. Prediction with SVM and MLP was around 60%, but the best result was obtained with the meta-classifiers, bagging, decorate and others, with more than 92% accurate prediction. These new hybrid descriptors derived from the Refractotopological State Index for Atoms show a low mutual correlation coefficient. The same behaviour is found in the analogously defined Descriptors Centres. The best results are obtained with the inclusion of the distance between DCs with the use of meta-classifiers. PMID:23439282
Nano-SAR development for bioactivity of nanoparticles with considerations of decision boundaries.
Liu, Rong; Rallo, Robert; Weissleder, Ralph; Tassa, Carlos; Shaw, Stanley; Cohen, Yoram
The development of classification nano-structure-activity Relationships (nano-SARs) of nanoparticle (NP) bioactivity is presented with the aim of demonstrating the integration of multiparametric toxicity/bioactivity assays to arrive at statistically meaningful class definitions (i.e., bioactivity/inactivity endpoints), as well as the implications of nano-SAR applicability domains and decision boundaries. Nano-SARs are constructed based on a dataset of 44 iron oxide core nanoparticles (NPs), used in molecular imaging and nano-sensing, containing bioactivity profiles for four cell types and four different assays. Class definitions are developed on the basis of 'hit' (i.e., significant bioactivity) identification analysis and self-organizing map based consensus clustering; these class definitions enable construction of nano-SARs of a high classification accuracy (>78%) with different NP descriptor combinations that include primary size, spin-lattice and spin-spin relaxivities, and zeta potentials. Analysis of the nano-SAR performance for different class definitions suggests that H4 (i.e., class with at least four hits) is a reasonable endpoint (from a 'regulatory' viewpoint) for keeping the level of false negatives (i.e., incorrect labeling of bioactive NPs as inactive) low. The establishment of a quantitative nano-SAR applicability domain is demonstrated, making use of a probability density with the H4 class definition and naive Bayesian classifier (NBC) model (with spin-lattice relaxivity and zeta potential as descriptors). Decision boundaries are determined for the above H4/NBC nano-SAR for different acceptance levels of false negative to false positive predictions, illustrating a practical approach that may assist in regulatory decision making with a consideration of reducing the likelihood of identifying bioactive NPs as being inactive. PMID:23423856
Crystal Structures and Structure–Activity Relationships of Imidazothiazole Derivatives as IDO1 Inhibitors
Indoleamine 2,3-dioxygenase 1 (IDO1) is considered as a promising target for the treatment of several diseases, including neurological disorders and cancer. We report here the crystal structures of two IDO1/IDO1 inhibitor complexes, one of which shows that Amg-1 is directly bound to the heme iron of IDO1 with a clear induced fit. We also describe the identification and preliminary optimization of imidazothiazole derivatives as novel IDO1 inhibitors. Using our crystal structure information and structure–activity relationships (SAR) at the pocket-B of IDO1, we found a series of urea derivatives as potent IDO1 inhibitors and revealed that generation of an induced fit and the resulting interaction with Phe226 and Arg231 are essential for potent IDO1 inhibitory activity. The results of this study are very valuable for understanding the mechanism of IDO1 activation, which is very important for structure-based drug design (SBDD) to discover potent IDO1 inhibitors. PMID:25313323
Natural and Synthetic Flavonoids: Structure-Activity Relationship and Chemotherapeutic Potential for the Treatment of Leukemia.
Menezes, José C J M D S; Orlikova, Barbora; Morceau, Franck; Diederich, Marc
Flavonoids and their derivatives are polyphenolic secondary metabolites with an extensive spectrum of pharmacological activities, including antioxidants, antitumor, anti-inflammatory, and antiviral activities. These flavonoids can also act as chemopreventive agents by their interaction with different proteins and can play a vital role in chemotherapy, suggesting a positive correlation between a lower risk of cancer and a flavonoid-rich diet. These agents interfere with the main hallmarks of cancer by various individual mechanisms, such as inhibition of cell growth and proliferation by arresting the cell cycle, induction of apoptosis and differentiation, or a combination of these mechanisms. This review is an effort to highlight the therapeutic potential of natural and synthetic flavonoids as anticancer agents in leukemia treatment with respect to the structure-activity relationship (SAR) and their molecular mechanisms. Induction of cell death mechanisms, production of reactive oxygen species, and drug resistance mechanisms, including p-glycoprotein efflux, are among the best-described effects triggered by the flavonoid polyphenol family. PMID:26463658
The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells
Background Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. Methods MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs' antitumor activity. Immunohistochemical analyses were carried out to study the Abs' inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo. Results MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27kip1. Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of
[Severe acute respiratory syndrome (SARS)].
Gillissen, Adrian; Ruf, Bernhard R
Severe acute respiratory syndrome (SARS) is a viral disease, observed primarily in Southern China in November 2002, with variable flu-like symptoms and pneumonia, in approx. 5% leading to death from respiratory distress syndrome (RDS). The disease was spread over more than 30 states all over the globe by SARS-virus-infected travelers. WHO and CDC received first information about a new syndrome by the end of February 2003, after the first cases outside the Republic of China had been observed. A case in Hanoi, Vietnam, led to the first precise information about the new disease entity to WHO, by Dr. Carlo Urbani, a co-worker of WHO/Doctors without Borders, who had been called by local colleagues to assist in the management of a patient with an unknown severe disease by the end of February 2003. Dr. Urbani died from SARS, as did many other health care workers. In the meantime, more than 7,000 cases have been observed worldwide, predominantly in China and Hong Kong, but also in Taiwan, Canada, Singapore, and the USA, and many other countries, and more than 600 of these patients died from RDS. Since the beginning of March 2003, when WHO and CDC started their activities, in close collaboration with a group of international experts, including the Bernhard-Nocht-Institute in Hamburg and the Department of Virology in Frankfurt/Main, a previously impossible success in the disclosure of the disease was achieved. Within only 8 weeks of research it was possible to describe the infectious agent, a genetically modified coronavirus, including the genetic sequence, to establish specific diagnostic PCR methods and to find possible mechanisms for promising therapeutic approaches. In addition, intensifying classical quarantine and hospital hygiene measures, it was possible to limit SARS in many countries to sporadic cases, and to reduce the disease in countries such as Canada and Vietnam. This review article summarizes important information about many issues of SARS (May 15th, 2003
1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies.
La Regina, Giuseppe; D'Auria, Felicia Diodata; Tafi, Andrea; Piscitelli, Francesco; Olla, Stefania; Caporuscio, Fabiana; Nencioni, Lucia; Cirilli, Roberto; La Torre, Francesco; De Melo, Nadja Rodrigues; Kelly, Steven L; Lamb, David C; Artico, Marino; Botta, Maurizio; Palamara, Anna Teresa; Silvestri, Romano
New 1-[(3-aryloxy-3-aryl)propyl]-1 H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives ( 10, 12, 14, 18- 20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 microg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC
Ongoing Active Deformation Processes at Fernandina Volcano (Galapagos) Detected via Multi-Orbit COSMO-SkyMed SAR Data Analysis
NASA Astrophysics Data System (ADS)
Pepe, Susi; Castaldo, Raffaele; De Luca, Claudio; Casu, Francesco; Tizzani, Pietro; Sansosti, Eugenio
Fernandina Volcano, Galápagos (Ecuador), has experienced several uplift and eruption episodes over the last twenty-two years. The ground deformation between 2002 and 2006 was interpreted as the effect of an inflation phenomenon of two separate magma reservoirs beneath the caldera. Moreover, the uplift deformation occurred during the 2005 eruption was concentrated near the circumferential eruptive fissures, while being superimposed on a broad subsidence centred on the caldera. The geodetic studies emphasized the presence of two sub volcanic lateral intrusions from the central storage system in December 2006 and August 2007. The latest eruption in 2009 was characterized by lava flows emitted from the SW radial fissures. We analyze the spatial and temporal ground deformation between March 2012 and July 2013, by using data acquired by COSMO-SkyMed X-band constellation along both ascending and descending orbits and by applying advanced InSAR techniques. In particular, we use the SBAS InSAR approach and combine ascending and descending time series to produce vertical and East-West components of the mean deformation velocity and deformation time series. Our analysis revealed a new uplift phenomenon due to the stress concentration inside the shallow magmatic system of the volcano. In particular, the vertical mean velocity map shows that the deformation pattern is concentrated inside caldera region and is characterized by strongly radial symmetry with a maximum displacement of about 20 cm in uplift; an axial symmetry is also observed in the EW horizontal mean velocity map, showing a maximum displacement of about +12 cm towards East for the SE flank, and -12 cm towards West for the NW flank of the volcano. Moreover, the deformation time series show a rather linear uplift trend from March to September 2012, interrupted by a low deformation rate interval lasting until January 2013. After this stage, the deformation shows again a linear behaviour with an increased uplift rate
Ethyl cinnamate derivatives as promising high-efficient acaricides against Psoroptes cuniculi: synthesis, bioactivity and structure-activity relationship.
Zhang, Bingyu; Lv, Chao; Li, Weibo; Cui, Zhiming; Chen, Dongdong; Cao, Fangjun; Miao, Fang; Zhou, Le
This paper reported the synthesis, structure-activity relationship (SAR) and acaricidal activity in vitro against Psoroptes cuniculi, a mange mite, of 25 ethyl cinnamate derivatives. All target compounds were synthesized and elucidated by means of MS, (1)H- and (13)C-NMR analysis. The results showed that 24 out of 25 tested compounds at 1.0 mg/mL demonstrated acaricidal activity in varying degrees. Among them, 6, 15, 26, 27 and 30 showed significant activity with median lethal concentration values (LC50) of 89.3, 119.0, 39.2, 29.8 and 41.2 µg/mL, respectively, which were 2.1- to 8.3-fold the activity of ivermectin (LC50=247.4 µg/mL), a standard drug in the treatment of Psoroptes cuniculi. Compared with ivermectin, with a median lethal time value (LT50) of 8.9 h, 27 and 30 showed smaller LT50 values of 7.9 and 1.3 h, respectively, whereas 6, 15 and 26 showed slightly larger LT50 values of 10.6, 11.0 and 10.4 h at 4.5 µmol/mL. SARs showed that the presence of o-NO2 or m-NO2 on the benzene ring significantly improved the activity, whereas the introduction of a hydroxy, methoxy, acetoxy, methylenedioxy, bromo or chloro group reduced the activity. (E)-Cinnamates were more effective than their (Z)-isomer. Nevertheless, the carbon-carbon double bond in the acrylic ester moiety was proven not to be essential to improve the activity of cinnamic acid esters. Thus, the results strongly indicate that cinnamate derivatives, especially their dihydro derivatives, should be promising candidates or lead compounds for the development of novel acaricides for the effective control of animal or human acariasis. PMID:25739666
Characterizing hydrologic changes of Great Dismal Swamp using SAR/InSAR technology
NASA Astrophysics Data System (ADS)
Kim, J. W.; Lu, Z.; Zhu, Z.
Great Dismal Swamp is one of the largest, northernmost peatlands on the Atlantic Coastal Plain, and the swamp is underlain by a thick water-logged organic soil layer (peat) made up of dead and decaying plant material. The peatlands play a role as the sink of large amount of soil organic carbon and methane. However, the disturbance of the peatland negatively impacted the ecosystem and contributed to the climate change caused by the released greenhouse gas. Our SAR/InSAR methods observed the hydrologic changes in the peatlands, which is a key factor to conserve the wetland, through several methods. First, we compared averaged SAR intensity from C- and L-band SAR sensors with groundwater level changes, and deduced a linear relationship between the SAR backscattering intensity and the groundwater level change. Second, we extracted the inundated area during wet season from InSAR coherence. Third, we measured the relative water level changes in the inundated area using the interferometric phases. Finally, we estimated the groundwater level changes corresponding to the soil moisture changes from time-series InSAR method. Our results can provide the unique opportunity to understand the occurring hydrologic and vegetation changes in the Great Dismal Swamp.
The relationship between chitotriosidase activity and tuberculosis.
Chen, M; Deng, J; Li, W; Su, C; Xia, Y; Wang, M; Li, X; Abuaku, B K; Tan, H; Wen, S W
Chitotriosidase, secreted by activated macrophages, is a biomarker of activated macrophages. In this study, we explored whether chitotriosidase could be adopted as a biomarker to evaluate the curative effect on tuberculosis (TB). Five counties were randomly selected out of 122 counties/cities/districts in Hunan Province, China. Our cases were all TB patients who were newly diagnosed or had been receiving treatment at the Centers for Disease Control (CDCs) of these five counties between April and August in 2009. Healthy controls were selected from a community health facility in the Kaifu district of Changsha City after frequency-matching of gender and age with the cases. Chitotriosidase activity was evaluated by a fluorometric assay. Categorical variables were analysed with the χ 2 test. Measurement data in multiple groups were tested with analysis of variance and least significant difference (LSD). Correlation between chitotriosidase activity and the degree of radiological extent (DRE) was examined by Spearman's rank correlation test. The average chitotriosidase activity levels of new TB cases, TB cases with different periods of treatment (6 months) and the control group were 54·47, 34·77, 21·54, 12·73 and 10·53 nmol/h.ml, respectively. Chitotriosidase activity in TB patients declined along with the continuity of treatment. The chitotriosidase activity of both smear-positive and the smear-negative pulmonary TB patients decreased after 6 months' treatment to normal levels (P < 0·05). Moreover, chitotriosidase activity was positively correlated with DRE (r = 0·607, P < 0·001). Our results indicate that chitotriosidase might be a marker of TB treatment effects. However, further follow-up study of TB patients is needed in the future. PMID:26418349
Possible relationships between solar activity and meteorological phenomena
NASA Technical Reports Server (NTRS)
Bandeen, W. R. (Editor); Maran, S. P. (Editor)
A symposium was conducted in which the following questions were discussed: (1) the evidence concerning possible relationships between solar activity and meteorological phenomena; (2) plausible physical mechanisms to explain these relationships; and (3) kinds of critical measurements needed to determine the nature of solar/meteorological relationships and/or the mechanisms to explain them, and which of these measurements can be accomplished best from space.
Synthesis and SAR requirements of adamantane-colchicine conjugates with both microtubule depolymerizing and tubulin clustering activities.
Zefirova, Olga N; Nurieva, Evgeniya V; Shishov, Dmitrii V; Baskin, Igor I; Fuchs, Fabian; Lemcke, Heiko; Schröder, Fabian; Weiss, Dieter G; Zefirov, Nikolay S; Kuznetsov, Sergei A
A series of analogues of conjugate 1, combining an adamantane-based paclitaxel (taxol) mimetic with colchicine was synthesized and tested for cytotoxicity in a cell-based assay with the human lung carcinoma cell line A549. The most active compounds (10 EC(50) 2 ± 1.0 nM, 23 EC(50) 6 ± 1.4 nM, 26 EC(50) 5 ± 1.8 nM, 28 EC(50) 11 ± 1.7 nM, 30 EC(50) 4.8 ± 0.5 nM) were found to interfere with the microtubule dynamics in an interesting manner. Treatment of the cells with these compounds promoted disassembly of microtubules followed by the formation of stable tubulin clusters. Structure-activity relationships for the analogues of 23 revealed the sensitivity of both cytotoxicity and tubulin clustering ability to the linker length. The presence of adamantane (or another bulky hydrophobic and non-aromatic moiety) in 23 was found to play an important role in the formation of tubulin clusters. Structural requirements for optimal activity have been partially explained by molecular modeling. PMID:21873068
Volcano Deformation and Modeling on Active Volcanoes in the Philippines from ALOS InSAR Time Series
NASA Astrophysics Data System (ADS)
Morales Rivera, Anieri M.; Amelung, Falk; Eco, Rodrigo
Bulusan, Kanlaon, and Mayon volcanoes have erupted over the last decade, and Taal caldera showed signs of volcanic unrest within the same time range. Eruptions at these volcanoes are a threat to human life and infrastructure, having over 1,000,000 people living within 10 km from just these 4 volcanic centers. For this reason, volcano monitoring in the Philippines is of extreme importance. We use the ALOS-1 satellite from the Japanese Aerospace Exploration Agency (JAXA) to make an InSAR time series analysis over Bulusan, Kanlaon, Mayon, and Taal volcanoes for the 2007-2011 period. Time-dependent deformation was detected at all of the volcanoes. Deformation related to changes in pressurization of the volcanic systems was found on Taal caldera and Bulusan volcanoes, with best fitting Mogi sources located at half-space depths of 3.07 km and 0.5 km respectively.
Building detection in SAR imagery
Steinbach, Ryan Matthew
Current techniques for building detection in Synthetic Aperture Radar (SAR) imagery can be computationally expensive and/or enforce stringent requirements for data acquisition. I present two techniques that are effective and efficient at determining an approximate building location. This approximate location can be used to extract a portion of the SAR image to then perform a more robust detection. The proposed techniques assume that for the desired image, bright lines and shadows, SAR artifact effects, are approximately labeled. These labels are enhanced and utilized to locate buildings, only if the related bright lines and shadows can be grouped. In order to find which of the bright lines and shadows are related, all of the bright lines are connected to all of the shadows. This allows the problem to be solved from a connected graph viewpoint, where the nodes are the bright lines and shadows and the arcs are the connections between bright lines and shadows. For the first technique, constraints based on angle of depression and the relationship between connected bright lines and shadows are applied to remove unrelated arcs. The second technique calculates weights for the connections and then performs a series of increasingly relaxed hard and soft thresholds. This results in groups of various levels on their validity. Once the related bright lines and shadows are grouped, their locations are combined to provide an approximate building location. Experimental results demonstrate the outcome of the two techniques. The two techniques are compared and discussed.
On the number of EINECS compounds that can be covered by (Q)SAR models for acute toxicity.
Zvinavashe, Elton; Murk, Albertinka J; Rietjens, Ivonne M C M
The new EU legislation for managing chemicals called REACH aims to fill in gaps in toxicity information that exist for the chemicals listed on the European Inventory of Existing Chemical Substances (EINECS). REACH advocates the use of alternatives to animal experimentation including, amongst others, (quantitative) structure-activity relationship models [(Q)SARs] to help fill in the toxicity data gaps. The aim of the present study was to provide a science-based estimate of the number of EINECS compounds that can be covered by (Q)SAR models for acute toxicity. Using the ECOSAR software, 54% of the 100196 EINECS chemicals were classified into 49 classes that can be potentially covered by (Q)SAR models. The largest proportion of the classified compounds (40% of the EINECS list) falls into the classes of non-polar and polar narcotics. Compounds that were not classified include, for example, fish oils, botanical and animal extracts, and crude oil distillates. With rapid improvements in analytical tools, the number of EINECS compounds for which toxicity evaluations may be based on (Q)SAR approaches may be extended by further developing the method recently developed for the safety assessment of natural flavor complexes used as ingredients in food. This method is based on identification of the individual components in a mixture, and judgment of the safety of these identified individual compounds using toxicity information on structurally similar congeners in the respective classes. Such (Q)SAR approaches may be applied to an additional 2938 EINECS compounds, representing botanical and animal extracts, leading to a total estimate of 57% of the EINECS compounds for which (Q)SAR-based approaches may assist in their safety assessment. It is concluded that, despite the fact that individual (Q)SARs may often each cover only a limited number, i.e. less than 1%, of the EINECS compounds, the potential for applying (Q)SAR approaches for safety assessment of EINECS compounds may prove
Young Adolescents' Perceptions of Romantic Relationships and Sexual Activity
ERIC Educational Resources Information Center
Royer, Heather R.; Keller, Mary L.; Heidrich, Susan M.
The purpose of this article is to describe young adolescents' perceptions of romantic relationships, ratings of important romantic partner characteristics, and acceptability of sexual activity with romantic relationships. Fifty-seven eighth-grade participants (average age = 13.8 years) from one urban US public middle school completed an anonymous…
Synthesis, SAR, and series evolution of novel oxadiazole-containing 5-lipoxygenase activating protein inhibitors: discovery of 2-[4-(3-{(r)-1-[4-(2-amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide (BI 665915).
Takahashi, Hidenori; Riether, Doris; Bartolozzi, Alessandra; Bosanac, Todd; Berger, Valentina; Binetti, Ralph; Broadwater, John; Chen, Zhidong; Crux, Rebecca; De Lombaert, Stéphane; Dave, Rajvee; Dines, Jonathon A; Fadra-Khan, Tazmeen; Flegg, Adam; Garrigou, Michael; Hao, Ming-Hong; Huber, John; Hutzler, J Matthew; Kerr, Steven; Kotey, Adrian; Liu, Weimin; Lo, Ho Yin; Loke, Pui Leng; Mahaney, Paige E; Morwick, Tina M; Napier, Spencer; Olague, Alan; Pack, Edward; Padyana, Anil K; Thomson, David S; Tye, Heather; Wu, Lifen; Zindell, Renee M; Abeywardane, Asitha; Simpson, Thomas
The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production. PMID:25671290
Social Relationships, Leisure Activity, and Health in Older Adults
Chang, Po-Ju; Wray, Linda; Lin, Yeqiang
Objective Although the link between enhanced social relationships and better health has generally been well established, few studies have examined the role of leisure activity in this link. This study examined how leisure influences the link between social relationships and health in older age. Methods Using data from the 2006 and 2010 waves of the nationally representative U.S. Health and Retirement Study and structural equation modelling analyses, we examined data on 2,965 older participants to determine if leisure activities mediated the link between social relationships and health in 2010, controlling for race, education level, and health in 2006. Results The results demonstrated that leisure activities mediate the link between social relationships and health in these age groups. Perceptions of positive social relationships were associated with greater involvement in leisure activities, and greater involvement in leisure activities was associated with better health in older age. Discussion & Conclusions The contribution of leisure to health in these age groups is receiving increasing attention, and the results of this study add to the literature on this topic, by identifying the mediating effect of leisure activity on the link between social relationships and health. Future studies aimed at increasing leisure activity may contribute to improved health outcomes in older adults. PMID:24884905
Relationships between Interlibrary Loan and Research Activity in Canada
ERIC Educational Resources Information Center
Duy, Joanna; Larivière, Vincent
Interlibrary Loan borrowing rates in academic libraries are influenced by an array of factors. This article explores the relationship between interlibrary loan borrowing activity and research activity at 42 Canadian academic institutions. A significant positive correlation was found between interlibrary loan borrowing activity and measures of…
Relationships between Reading Activities and Language Use.
ERIC Educational Resources Information Center
Gordon, Sandra L.; Van Dongen, Richard
Noting that the ways children encounter and use print in the classroom can be examined as surface and organizing content of curriculum, this article provides descriptions of innovative uses of print in the kindergarten and elementary school classroom. Curriculum "surface content" includes activities, use of classroom space, display, and materials…
Distributed Anelastic Strain and its Relationship to Compliant Zones Surrounding Active Faults of the Eastern California Shear Zone
NASA Astrophysics Data System (ADS)
Shelef, E.; Oskin, M.; Fialko, Y.
Geologic measurements of distributed anelastic strain (DAS) adjacent to active strike slip faults of the Mojave Desert portion of the Eastern California shear zone quantify the magnitude, mechanism, temporal evolution, and relationship of DAS to fault compliant zones imaged via InSAR. Prefaulting markers (mylonitic lineation, dikes, and faults assumed linear prior to dextral faulting) in crystalline rocks next to the Harper Lake fault and Calico fault indicate that DAS accounts for 6 to 23 percent of total displacement and that this displacement scales with fault slip. We conclude that DAS is a significant, active process that is not restricted to the initial fault propagation stage. We find that the width of the zone of DAS is 400-700 m on each side of the faults studied, irrespective of total fault slip. 60 percent of the displacement due to DAS occurs within 100 m of the Calico fault. A similar zone of more intense deformation occurs adjacent to the Harper Lake fault. These 100m- wide-zones are of the same extent but much less intensely deformed compared to the damage zones surrounding the San Andreas fault. Based on these relationships, we hypothesize that damage feedback progressively focuses DAS into a stable, approximately 100-m-wide-zone where its intensity can increase proportionally to fault slip. Disruption of linear markers supports that DAS in crystalline rocks occurs via slip along secondary faults and small-scale block rotation with block sizes decreasing with proximity to faults. The widths of the geologically documented zones of DAS in the Eastern California shear zone are similar to the approximately 1 km width of compliant zones modeled from InSAR observations of surface deformation due to stress changes caused by nearby earthquakes. This correlation suggests a relationship between damage- reduction of shear modulus and displacement via DAS. Paleomagnetic measurements of prefaulting and syntectonically emplaced volcanic rocks in sedimentary
Quantitative Structure-Activity Relationships (QSARs) - Applications and Methodology
NASA Astrophysics Data System (ADS)
Cronin, Mark T. D.
The aim of this introduction is to describe briefly the applications and methodologies involved in (Q)SAR and relate these to the various chapters in this volume. This chapter gives the reader an overview of how, why and where in silico methods, including (Q)SAR, have been utilized to predict endpoints as diverse as those from pharmacology and toxicology. It provides an illustration of how all the various topics in this book interweave to form a single coherent area of science.
Synthetic retinoids: structure-activity relationships.
Barnard, Jonathan H; Collings, Jonathan C; Whiting, Andrew; Przyborski, Stefan A; Marder, Todd B
Retinoid signalling pathways are involved in numerous processes in cells, particularly those mediating differentiation and apoptosis. The endogenous ligands that bind to the retinoid receptors, namely all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, are prone to double-bond isomerisation and to oxidation by metabolic enzymes, which can have significant and deleterious effects on their activities and selectivities. Many of these problems can be overcome through the use of synthetic retinoids, which are often much more stable, as well as being more active. Modification of their molecular structures can result in retinoids that act as antagonists, rather than agonists, or exhibit a large degree of selectivity for particular retinoid-receptor isotypes. Several such selective retinoids are likely to be of value as pharmaceutical agents with reduced toxicities, particularly in cancer therapy, as reagents for controlling cell differentiation, and as tools for elucidating the precise roles that specific retinoid signalling pathways play within cells. PMID:19821467
Ground Deformation Associated With Post-Mining Activity at the French-German Border Revealed by Multidimensional Time Series Analysis of SAR Data Acquired in Various Orbital Geometries
NASA Astrophysics Data System (ADS)
Smets, B.; Samsonov, S. V.; d'Oreye, N.
We present the application of an innovative methodology for producing multidimensional time series of ground deformation from satellite radar data acquired by sensors with various acquisition geometry, ground resolution, and wave band (Samsonov and d'Oreye, Resubmitted). This technique is based on the Small Baseline Subset (SBAS) method that is modified to produce horizontal and vertical time series of ground deformation. Produced time series have combined coverage, improved temporal resolution and lower noise level. We apply this methodology for mapping coal mining related ground subsidence and heave in the Greater Region of Luxembourg along the French-German border. For this we processed 167 Synthetic Aperture Radar ERS-1/2 and ENVISAT images acquired between 1995 and 2009 from one ascending (track 29) and one descending (track 337) tracks and created over five hundred interferograms that were used for time series analysis. Produced vertical and east-west linear deformation rates show with remarkable precision region of localized ground deformation located above and caused by mining and post-mining activities. Time series of ground de- formation display temporal variability: reversal from subsidence to uplift and acceleration of subsidence on the vertical component and horizontal motion towards the center of the subsidence on the east-west component. InSAR results are successfully validated by leveling measurements performed by the French Geological Survey (BRGM) during 2006-2008. We determined that deformation rate changes are mainly caused by water level variations in the mines. Due to higher temporal and spatial resolution the proposed space-born method detected a larger number of subsidence and uplift areas in comparison to leveling measurements restricted to annual monitoring of benchmark points along roads. We also identified deformation regions that are not precisely located above the mining sites. Comparison of InSAR measurements with the water levels
Orally Active Metabotropic Glutamate Subtype 2 Receptor Positive Allosteric Modulators: Structure-Activity Relationships and Assessment in a Rat Model of Nicotine Dependence
Sidique, Shyama; Dhanya, Raveendra-Panickar; Sheffler, Douglas J.; Nickols, Hilary Highfield; Yang, Li; Dahl, Russell; Mangravita-Novo, Arianna; Smith, Layton H.; D'Souza, Manoranjan S.; Semenova, Svetlana; Conn, P. Jeffrey; Markou, Athina; Cosford, Nicholas D. P.
Compounds that modulate metabotropic glutamate subtype 2 (mGlu2) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu2 receptor positive allosteric modulators (PAMs). The effects of N-substitution (R1) and substitutions on the aryl ring (R2) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu2 receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans. PMID:23009245
Knowledge based SAR images exploitations
NASA Astrophysics Data System (ADS)
Wang, David L.
One of the basic functions of SAR images exploitation system is the detection of man-made objects. The performance of object detection is strongly limited by performance of segmentation modules. This paper presents a detection paradigm composed of an adaptive segmentation algorithm based on a priori knowledge of objects followed by a top-down hierarchical detection process that generates and evaluates object hypotheses. Shadow information and inter-object relationships can be added to the knowledge base to improve performance over that of a statistical detector based only on the attributes of individual objects.
Derivation of terrain slope from SAR interferometric phase gradient
NASA Technical Reports Server (NTRS)
Wegmueller, Urs; Werner, Charles L.; Rosen, Paul A.
The relationship between the gradient of the interferometric phase and the terrain slope, which, it is thought, would allow a derivation of the terrain slopes without phase unwrapping, is presented. A linear relationship between the interferometric phase gradient and the terrain slopes was found. A quantitative error analysis showed that only very small errors are introduced by these approximations for orbital Synthetic Aperture Radar (SAR) geometries. An example of a slope map for repeat pass interferometry from ERS-1 SAR data is given. A number of direct and indirect applications of the terrain slope are indicated: erosion and avalanche hazard studies, radiometric calibration of SAR data, and normalization of the interferometric correlation coefficient.
Web-GIS-based SARS epidemic situation visualization
NASA Astrophysics Data System (ADS)
Lu, Xiaolin
In order to research, perform statistical analysis and broadcast the information of SARS epidemic situation according to the relevant spatial position, this paper proposed a unified global visualization information platform for SARS epidemic situation based on Web-GIS and scientific virtualization technology. To setup the unified global visual information platform, the architecture of Web-GIS based interoperable information system is adopted to enable public report SARS virus information to health cure center visually by using the web visualization technology. A GIS java applet is used to visualize the relationship between spatial graphical data and virus distribution, and other web based graphics figures such as curves, bars, maps and multi-dimensional figures are used to visualize the relationship between SARS virus tendency with time, patient number or locations. The platform is designed to display the SARS information in real time, simulate visually for real epidemic situation and offer an analyzing tools for health department and the policy-making government department to support the decision-making for preventing against the SARS epidemic virus. It could be used to analyze the virus condition through visualized graphics interface, isolate the areas of virus source, and control the virus condition within shortest time. It could be applied to the visualization field of SARS preventing systems for SARS information broadcasting, data management, statistical analysis, and decision supporting.
Interaction between photoperiod and an endogenous seasonal factor in influencing the diel locomotor activity of the benthic polychaete Nereis virens Sars.
Last, Kim S; Olive, Peter J W
The locomotor activity of Nereis virens Sars associated with food prospecting was investigated in response to photoperiod and season using an actograph. Experimental animals which had been reared under natural photoperiods were exposed to two constant photoperiodic treatments, LD 16:8 and LD 8:16, in both the autumn and winter and in the absence of tidal entrainment. Autocorrelation analysis of rhythmicity showed that during the autumn, animals under the LD 16:8 photoperiod displayed a strong nocturnal rhythm of activity, whereas animals under the LD 8:16 photoperiod showed only a weak nocturnal activity rhythm. This is believed to represent an autumn feeding cessation that is triggered when the animals pass through a critical photoperiod LD(crit) <12:>12. Later in the winter, however, animals exposed to both photoperiodic treatments showed strong rhythms of foraging activity irrespective of the imposed photoperiod. It is suggested that the autumn cessation may maximize the fitness of N. virens, a spring-breeding semelparous organism, by reducing risk during gamete maturation, while spontaneous resurgence of activity after the winter solstice permits animals that are not physiologically competent to spawn to accrue further metabolic reserves. This response is believed to be initiated by a seasonal (possibly circannual) endogenous oscillator or interval timer. PMID:15111365
SAR antenna calibration techniques
NASA Technical Reports Server (NTRS)
Carver, K. R.; Newell, A. C.
Calibration of SAR antennas requires a measurement of gain, elevation and azimuth pattern shape, boresight error, cross-polarization levels, and phase vs. angle and frequency. For spaceborne SAR antennas of SEASAT size operating at C-band or higher, some of these measurements can become extremely difficult using conventional far-field antenna test ranges. Near-field scanning techniques offer an alternative approach and for C-band or X-band SARs, give much improved accuracy and precision as compared to that obtainable with a far-field approach.
Structure–Activity Relationships of α-Keto Oxazole Inhibitors of Fatty Acid Amide Hydrolase
Hardouin, Christophe; Kelso, Michael J.; Romero, F. Anthony; Rayl, Thomas J.; Leung, Donmienne; Hwang, Inkyu; Cravatt, Benjamin F.; Boger, Dale L.
A systematic study of the structure–activity relationships (SAR) of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, Ki = 2.6 nM) with 5hh (aryl = 3-Cl-Ph, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally-restricted C2 side chains were examined and many provided exceptionally potent inhibitors of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteomic-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases. PMID:17559203
Input of UAV, DTM photo-interpretation and SAR interferometry on active tectonics applied on the Southern Coastal Range (SE Taiwan)
NASA Astrophysics Data System (ADS)
Deffontaines, Benoit; Chang, Kuo-Jen; Champenois, Johann; Magalhaes, Samuel; Serries, Gregory
Taiwan is an excellent geomorphic laboratory where both extreme climatic events and high active tectonics compete. Moreover many Earth Sciences and Environmental data bases exist nowadays that help to better constrain both structural geology and active deformations. The latter unfortunately is still poorly known in the Cosatal Range of E.Taiwan in terms of geology due to access difficulties, high relief, paucity of roads, tropical vegetation and high climatic events (typhoons and heavy rainfall) and so on. Indirect methods such as photogrammetric survey using UAV's helps a lot to get high resolution topographic DEM and DTM, better than 10cm in planimetry, that helps a lot to get through careful photo-interpretation, a bird's eye view of the geology. Therefore we were able to much update the famous pre-existing geological maps (Wang and Chen, 1993). Moreover, by combining our high resolution topographic results with those of SAR interferometry (database of Champenois et al, EPSL, 2012), we were able to identify, characterise and quantify the differential active features toward the LOS of the Coastal Range (eastern Taiwan). In order to synthetise and to model the deformation of that famous place, we herein constructed more than 500 parallel projected profiles in order to locate, characterize and quantify the active tectonic features and compare them to the topography and the updated photo-interpreted geology (this work). We then were able to reconstruct the structural geometry of the Coastal Range and the Longitudinal Valley in SE Taiwan. Among our results, we reveal and prove : 1. the whole 2cm differential surrection of the Coastal Range ; 2. the differential displacement between both Central and Coastal Ranges ; 3. we explain the location of the Pinantashi river situated within the Lichi melange that correspond to the maximum surrection of the Coastal Range ; 4. we reveal the different units and their relative displacement within the Coastal Range itself ; 5. we
Quantum-SAR extension of the spectral-SAR algorithm: application to polyphenolic anticancer bioactivity.
Putz, Mihai V; Putz, Ana-Maria; Lazea, Marius; Ienciu, Luciana; Chiriac, Adrian
Aiming to assess the role of individual molecular structures in the molecular mechanism of ligand-receptor interaction correlation analysis, the recent Spectral-SAR approach is employed to introduce the Quantum-SAR (QuaSAR) "wave" and "conversion factor" in terms of difference between inter-endpoint inter-molecular activities for a given set of compounds; this may account for inter-conversion (metabolization) of molecular (concentration) effects while indicating the structural (quantum) based influential/detrimental role on bio-/eco- effect in a causal manner rather than by simple inspection of measured values; the introduced QuaSAR method is then illustrated for a study of the activity of a series of flavonoids on breast cancer resistance protein. PMID:19399244
SAR calibration technology review
NASA Technical Reports Server (NTRS)
Walker, J. L.; Larson, R. W.
Synthetic Aperture Radar (SAR) calibration technology including a general description of the primary calibration techniques and some of the factors which affect the performance of calibrated SAR systems are reviewed. The use of reference reflectors for measurement of the total system transfer function along with an on-board calibration signal generator for monitoring the temporal variations of the receiver to processor output is a practical approach for SAR calibration. However, preliminary error analysis and previous experimental measurements indicate that reflectivity measurement accuracies of better than 3 dB will be difficult to achieve. This is not adequate for many applications and, therefore, improved end-to-end SAR calibration techniques are required.
Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3
Ojo, Kayode K; Arakaki, Tracy L; Napuli, Alberto J; Inampudi, Krishna K; Keyloun, Katelyn R; Zhang, Li; Hol, Wim G.J.; Verlind, Christophe L.M.J.; Merritt, Ethan A; Van Voorhis, Wesley C
Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 Å resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3β (HsGSK-3β) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found.
Design, Synthesis, and Structure--Activity Relationship of New 2-Aryl-3,4-dihydro-β-carbolin-2-ium Salts as Antifungal Agents.
Hou, Zhe; Zhu, Li-Fei; Yu, Xin-chi; Sun, Ma-Qiang; Miao, Fang; Zhou, Le
Twenty-two 2-aryl-9-methyl-3,4-dihydro-β-carbolin-2-ium bromides along with four 9-demethylated derivatives were synthesized and characterized by spectroscopic analysis. By using the mycelium growth rate method, the compounds were evaluated for antifungal activities in vitro against six plant pathogenic fungi, and structure-activity relationships (SAR) were derived. Almost all of the compounds showed obvious inhibition activity on each of the fungi at 150 μM. For all of the fungi, 10 of the compounds showed average inhibition rates of >80% at 150 μM, and most of their EC50 values were in the range of 2.0-30.0 μM. SAR analysis showed that the substitution pattern of the N-aryl ring significantly influences the activity; N9-alkylation improves the activity, whereas aromatization of ring-C reduces the activity. It was concluded that the present research provided a series of new 2-aryl-9-alkyl-3,4-dihydro-β-carbolin-2-iums with excellent antifungal potency and structure optimization design for the development of new carboline antifungal agents. PMID:27004437
Antioxidant activity of taxifolin: an activity-structure relationship.
Topal, Fevzi; Nar, Meryem; Gocer, Hulya; Kalin, Pınar; Kocyigit, Umit M; Gülçin, İlhami; Alwasel, Saleh H
Taxifolin is a kind of flavanonol, whose biological ability. The objectives of this study were to investigate the antioxidants and antiradical activities of taxifolin by using different in vitro bioanalytical antioxidant methods including DMPD√(+), ABTS√(+), [Formula: see text], and DPPH√-scavenging effects, the total antioxidant influence, reducing capabilities, and Fe(2+)-chelating activities. Taxifolin demonstrated 81.02% inhibition of linoleic acid emulsion peroxidation at 30 µg/mL concentration. At the same concentration, standard antioxidants including trolox, α-tocopherol, BHT, and BHA exhibited inhibitions of linoleic acid emulsion as 88.57, 73.88, 94.29, and 90.12%, respectively. Also, taxifolin exhibited effective DMPD√(+), ABTS√(+), [Formula: see text], and DPPH√-scavenging effects, reducing capabilities, and Fe(2+)-chelating effects. The results obtained from this study clearly showed that taxifolin had marked antioxidant, reducing ability, radical scavenging and metal-chelating activities. Also, this study exhibits a scientific shore for the significant antioxidant activity of taxifolin and its structure-activity insight. PMID:26147349
Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold.
Gladysz, Rafaela; Adriaenssens, Yves; De Winter, Hans; Joossens, Jurgen; Lambeir, Anne-Marie; Augustyns, Koen; Van der Veken, Pieter
Urokinase plasminogen activator (uPA) is a biomarker and therapeutic target for several cancer types. Its inhibition is regarded as a promising, noncytotoxic approach in cancer therapy by blocking growth and/or metastasis of solid tumors. Earlier, we reported the modified substrate activity screening (MSAS) approach and applied it for the identification of fragments with affinity for uPA's S1 pocket. Here, these fragments are transformed into a novel class of uPA inhibitors with an imidazo[1,2-a]pyridine scaffold. The SAR for uPA inhibition around this scaffold is explored, and the best compounds in the series have nanomolar uPA affinity and selectivity with respect to the related trypsin-like serine proteases (thrombin, tPA, FXa, plasmin, plasma kallikrein, trypsin, FVIIa). Finally, the approach followed for translating fragments into small molecules with a decorated scaffold architecture is conceptually straightforward and can be expected to be broadly applicable in fragment-based drug design. PMID:26575094
Interplay Between Tectonics And Volcanic Processes Active In The Yellowstone Caldera Detected Via DInSAR And GPS Time-Series
NASA Astrophysics Data System (ADS)
Tizzani, Pietro; Battaglia, Maurizio; Castaldo, Raffaele; Pepe, Antonio; Zeni, Giovanni; Lanari, Riccardo
We discriminate and quantify the effects of different stress sources that are active in the Yellowstone volcanic region. In particular, the use of long-term deformation time series allows us to separate the spatial and temporal contributions of the regional tectonic field due to North American (NA) plate motion from the dynamic of magmatic/hydrothermal sources beneath the caldera area. Yellowstone volcano was formed by three major caldera forming eruptions that occurred around 2.0, 1.3 and 0.64 Ma, the most recent one responsible for the 60 km-wide and 40 km-long Yellowstone caldera. Two structural resurgent domes emerged after the last caldera forming eruption: the Mallard Lake (ML) resurgent dome in the southwestern region of Yellowstone caldera, and the Sour Creek (SC) resurgent dome in the northeast part of the caldera. In this work, we extensively exploit DInSAR and GPS measurements to investigate surface deformation at Yellowstone caldera over the last 18 years. We start by analyzing the 1992-2010 deformation time series retrieved by applying the Small BAseline Subset (SBAS) DInSAR technique. This allows us identifying three macro-areas: i) Norris Geyser Basin (NGB), ii) ML and SC resurgent domes and iii) Snake River Plain (SRP), characterized by unique deformation behaviors. In particular, SRP shows a signal related to tectonic deformation, while the other two regions are influenced by the caldera unrest. To isolate the deformation signals related to different stress sources in the Yellowstone caldera, we also remove from the retrieved mean deformation velocity maps the mean displacement rate associated to the northern sector of the Snake River Plain. This latter is the result of tectonic processes controlled by complex interactions between the NA plate, moving in the ENE - WSW direction with a rate of about 2 cm/yr, and the flow of the asthenosphere plume beneath the Yellowstone volcanic region. These de-trended data allow recognizing four major deformation
Partitioning and lipophilicity in quantitative structure-activity relationships.
Dearden, J C
The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated. Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structure-activity relationships (QSARs) well on the whole, confirming that partitioning is of key importance in in vivo behavior of a xenobiotic. The partition coefficient is shown to correlate with numerous other parameters representing bulk, such as molecular weight, volume and surface area, parachor and calculated indices such as molecular connectivity; this is especially so for apolar molecules, because for polar molecules lipophilicity factors into both bulk and polar or hydrogen bonding components. The relationship of partition coefficient to chromatographic parameters is discussed, and it is shown that such parameters, which are often readily obtainable experimentally, can successfully supplant partition coefficient in QSARs. The relationship of aqueous solubility with partition coefficient is examined in detail. Correlations are observed, even with solid compounds, and these can be used to predict solubility. The additive/constitutive nature of partition coefficient is discussed extensively, as are the available schemes for the calculation of partition coefficient. Finally the use of partition coefficient to provide structural information is considered. It is shown that partition coefficient can be a valuable structural tool, especially if the enthalpy and entropy of partitioning are available. PMID:3905374
The Relationship Between Neck Pain and Physical Activity
Cheung, Janice; Kajaks, Tara; MacDermid, Joy C.
Neck pain is a significant societal burden due to its high prevalence and healthcare costs. While physical activity can help to manage other forms of chronic musculoskeletal pain, little data exists on the relationship between physical activity and neck pain. The purpose of this study was to compare physical activity levels between individuals with neck pain and healthy controls, and then to relate disability, fear of movement, and pain sensitivity measures to physical activity levels in each of the two participant groups. 21 participants were recruited for each of the two participant groups (n = 42). Data collection included the use of the Neck Disability Index, the Tampa Scale for Kinesiophobia, electrocutaneous (Neurometer® CPT) and pressure stimulation (JTech algometer) for quantitative sensory testing, and 5 days of subjective (Rapid Assessment of Physical Activity) and objective (BioTrainer II) measurements of physical activity. Analysis of Variance and Pearson's Correlation were used to determine if differences and relationships exist between dependent variables both within and between groups. The results show that individuals with mild neck pain and healthy controls do not differ in subjectively and objectively measured physical activity. While participants with neck pain reported higher neck disability and fear of movement, these factors did not significantly relate to physical activity levels. Perceived activity level was related to pain threshold and tolerance at local neck muscles sites (C2 paraspinal muscle and upper trapezius muscle), whereas measured activity was related to generalized pain sensitivity, as measured at the tibialis anterior muscle site. PMID:24133553
Structure-activity relationship of indoloquinoline analogs anti-MRSA.
Zhao, Min; Kamada, Tomonori; Takeuchi, Aya; Nishioka, Hiromi; Kuroda, Teruo; Takeuchi, Yasuo
Indolo[3,2-b]quinoline analogs (3a-3s), 4-(acridin-9-ylamino) phenol hydrochloride (4), benzofuro[3,2-b]quinoline (3t), indeno[1,2-b]quinolines (3u and 3v) have been synthesized. Those compounds were found to exhibit anti-bacterial activity towards Methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure-activity relationship studies were conducted that indoloquinoline ring, benzofuroquinoline ring and 4-aminophenol group are essential structure for anti-MRSA activity. PMID:26522949
Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG)
Steffen, Jamin D.; Coyle, Donna L.; Damodaran, Komath; Beroza, Paul; Jacobson, Myron K.
The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials due to their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, Target-related Affinity Profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of drug-like compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogs of one of the most active chemotypes were synthesized to explore structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1, and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development. PMID:21692479
Quantitative structure-activity relationships for fluoroelastomer/chlorofluorocarbon systems
Paciorek, K.J.L.; Masuda, S.R.; Nakahara, J.H. ); Snyder, C.E. Jr.; Warner, W.M. )
This paper reports on swell, tensile, and modulus data that were determined for a fluoroelastomer after exposure to a series of chlorofluorocarbon model fluids. Quantitative structure-activity relationships (QSAR) were developed for the swell as a function of the number of carbons and chlorines and for tensile strength as a function of carbon number and chlorine positions in the chlorofluorocarbons.
SAR calibration: A technology review
NASA Technical Reports Server (NTRS)
Larson, R. W.; Politis, D. T.; Shuchman, R. A.
Various potential applications of amplitude-calibrated SAR systems are briefly described, along with an estimate of calibration performance requirements. A review of the basic SAR calibration problem is given. For background purposes and to establish consistent definition of terms, various conventional SAR performance parameters are reviewed along with three additional parameters which are directly related to calibrated SAR systems. Techniques for calibrating a SAR are described. Included in the results presented are: calibration philosophy and procedures; review of the calibration signal generator technology development with results describing both the development of instrumentation and internal calibration measurements for two SAR systems; summary of analysis and measurements required to determine optimum retroreflector design and configuration for use as a reference for the absolute calibration of a SAR system; and summary of techniques for in-flight measurements of SAR antenna response.
Segmentation Of Polarimetric SAR Data
NASA Technical Reports Server (NTRS)
Rignot, Eric J. M.; Chellappa, Rama
Report presents one in continuing series of studies of segmentation of polarimetric synthetic-aperture-radar, SAR, image data into regions. Studies directed toward refinement of method of automated analysis of SAR data.
Design, Synthesis, and Structure–Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents
Cycloxygenase-2 (COX-2) is an attractive target for molecular imaging because it is an inducible enzyme that is expressed in response to inflammatory and proliferative stimuli. Recently, we reported that conjugation of indomethacin with carboxy-X-rhodamine dyes results in the formation of effective, targeted, optical imaging agents able to detect COX-2 in inflammatory tissues and premalignant and malignant tumors (Uddin et al. Cancer Res. 2010, 70, 3618–3627). The present paper summarizes the details of the structure–activity relationship (SAR) studies performed for lead optimization of these dyes. A wide range of fluorescent conjugates were designed and synthesized, and each of them was tested for the ability to selectively inhibit COX-2 as the purified protein and in human cancer cells. The SAR study revealed that indomethacin conjugates are the best COX-2-targeted agents compared to the other carboxylic acid-containing nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors (COXIBs). An n-butyldiamide linker is optimal for tethering bulky fluorescent functionalities onto the NSAID or COXIB cores. The activity of conjugates also depends on the size, shape, and electronic properties of the organic fluorophores. These reagents are taken up by COX-2-expressing cells in culture, and the uptake is blocked by pretreatment with a COX inhibitor. In in vivo settings, these reagents become highly enriched in COX-2-expressing tumors compared to surrounding normal tissue, and they accumulate selectively in COX-2-expressing tumors as compared with COX-2-negative tumors grown in mice. Thus, COX-2-targeted fluorescent inhibitors are useful for preclinical and clinical detection of lesions containing elevated levels of COX-2. PMID:23488616
The potential of SAR directional spectra in operational wave forecasting
NASA Technical Reports Server (NTRS)
Beal, R. C.; Gerling, T. W.; Irvine, D. E.
Digitally processed Seasat SAR ocean wave imagery, when digitally transformed, smoothed, and corrected for known instrument biases, can accurately track multiple (at least three) wave systems in the open ocean, across major currents, and into shallow water. Furthermore, the relative backscatterer of the digitally processed SAR image, when sampled within a single pass and along a constant range, responds to the local wind through a simple power law relationship. The results indicate that SAR spectra, if obtained from a low altitude satellite, could be an important supplement to global winds and non-directional wave heights obtained through other methods.
In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii
Le Calve, Benjamin; Lallemand, Benjamin; Perrone, Carmen; Lenglet, Gaelle; Depauw, Sabine; Van Goietsenoven, Gwendoline; Bury, Marina; Vurro, Maurizio; Herphelin, Francoise; Andolfi, Anna; Zonno, Maria Chiara; Mathieu, Veronique; Dufrasne, Francois; Van Antwerpen, Pierre; Poumay, Yves
The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro.
In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii.
Le Calvé, Benjamin; Lallemand, Benjamin; Perrone, Carmen; Lenglet, Gaëlle; Depauw, Sabine; Van Goietsenoven, Gwendoline; Bury, Marina; Vurro, Maurizio; Herphelin, Françoise; Andolfi, Anna; Zonno, Maria Chiara; Mathieu, Véronique; Dufrasne, François; Van Antwerpen, Pierre; Poumay, Yves; David-Cordonnier, Marie-Hélène; Evidente, Antonio; Kiss, Robert
The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro. PMID:21504755
The Structure-Activity Relationship of the 3-Oxy Site in the Anticonvulsant (R)-N-Benzyl 2-Acetamido-3-methoxypropionamide
Morieux, Pierre; Salomé, Christophe; Park, Ki Duk; Stables, James P.; Kohn, Harold
Lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-1) is a low molecular weight anticonvulsant recently introduced in the United States and Europe for adjuvant treatment of partial-onset seizures in adults. In this study, we define the structure-activity relationship (SAR) for the compound's 3-oxy site. Placement of small non-polar, non-bulky substituents at the 3-oxy site provided compounds with pronounced seizure protection in the maximal electroshock (MES) seizure test with activities similar to (R)-1. The anticonvulsant activity loss that accompanied introduction of larger moieties at the 3-oxy site in (R)-1 was offset, in part, by including unsaturated groups at this position. Our findings were similar to a recently reported SAR study of the 4′-benzylamide site in (R)-1 (J. Med. Chem.2010, 53, 1288–1305). Together, these results indicate that both the 3-oxy and 4′-benzylamide positions in (R)-1 can accommodate non-bulky, hydrophobic groups and still retain pronounced anticonvulsant activities in rodents in the MES seizure model. PMID:20614888
NASA Astrophysics Data System (ADS)
Snoeij, Paul; Pouwels, Henk; Koomen, Peter J.; Hoogeboom, Peter
PHARUS (phased array universal SAR) is an airborne SAR concept which is being developed in the Netherlands. The PHARUS system differs from other airborne SARs by the use of a phased array antenna, which provides both for the flexibility in the design as well as for a compact, light-weight instrument that can be carried on small aircraft. The concept allows for the construction of airborne SAR systems on a common generic basis but tailored to specific user needs and can be seen as a preparation for future spaceborne SAR systems using solid state transmitters with electronically steerable phased array antenna. The whole approach is aimed at providing an economic and yet technically sophisticated solution to remote sensing or surveying needs of a specific user. The solid state phased array antenna consists of a collection of radiating patches; the design flexibility for a large part resides in the freedom to choose the number of patches, and thereby the essential radar performance parameters such as resolution and swath width. Another consequence of the use of the phased array antenna is the system's compactness and the possibility to rigidly mount it on a small aircraft. The use of small aircraft of course considerably improves the cost/benefit ratio of the use of airborne SAR. Flight altitude of the system is flexible between about 7,000 and 40,000 feet, giving much operational freedom within the meteo and airspace control limits. In the PHARUS concept the airborne segment is complemented by a ground segment, which consists of a SAR processor, possibly extended by a matching image processing package. (A quick look image is available in real-time on board the aircraft.) The SAR processor is UNIX based and runs on easily available hardware (SUN station). Although the additional image processing software is available, the SAR processing software is nevertheless designed to be able to interface with commercially available image processing software, as well as being able
Discovery and preliminary structure-activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors.
Cadelis, Melissa M; Bourguet-Kondracki, Marie-Lise; Dubois, Joëlle; Valentin, Alexis; Barker, David; Copp, Brent R
Biological screening of a library of synthesized benzo[c]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065±0.004μM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44±0.20μM. Two novel series of analogues, based on the benzo[c]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure-activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed. PMID:27240468
Structure-cardiac activity relationship of C19-diterpenoid alkaloids.
Jian, Xi-Xian; Tang, Pei; Liu, Xiu-Xiu; Chao, Ruo-Bing; Chen, Qiao-Hong; She, Xue-Ke; Chen, Dong-Lin; Wang, Feng-Peng
Thirty three C19-diterpenoid alkaloids, twenty-two prepared from known C19-diterpenoid alkaloids and eleven isolated from Aconitum and Delphinium spp. were evaluated for their cardiac activity in the isolated bullfrog heart assay. Among them, eleven compounds exhibited cardiac activity, with average rate of amplitude increase in the range of 16-118%. Compound 7, mesaconine (17), hypaconine (25), and beiwutinine (26) exhibited strong cardiac activities relative to the reference drug. The structure-activity relationship data acquired indicated that an alpha-hydroxyl group at C-15, a hydroxyl group at C-8, an alpha-methoxyl or hydroxyl group at C-1, and a secondary amine or N-methyl group in ring A are important structure features necessary for the cardiac activities of the aconitine-type C19-diterpenoid alkaloids without any ester groups. In addition, an alpha-hydroxyl group at C-3 is also helpful for the cardiac activity of these alkaloids. PMID:22816290
Structure-Activity Relationship of Fluoroquinolones Against K. pneumoniae
NASA Astrophysics Data System (ADS)
Li, Xiao-hong; Zhang, Rui-zhou; Cheng, Xin-lu; Yang, Xiang-dong
The structure-activity relationship of fluoroquinolones, which show anti-K. pneumoniae activity, was studied by using principal component analysis (PCA) and hierarchical cluster analysis (HCA). The PCA results showed that the lowest unoccupied molecular orbital energy, energy difference between the highest occupied and the lowest unoccupied molecular orbital, dipole moment, net atomic charge on atom I, molecular polarizability, partition coefficient and molecular refractivity of these compounds are responsible for the separation between high-activity and low-activity groups. The HCA results were similar to those obtained with PCA. By using the chemometric results, four synthetic compounds were analyzed through PCA and HCA, and three of them are proposed as active molecules against K. pneumoniae which is consistent with the results of clinical experiments. The methodologies of PCA and HCA provide a reliable rule for classifying new fluoroquinolones with anti-K. pneumoniae activity.
Therapeutic targeting of erbB3 with MM-121/SAR256212 enhances antitumor activity of paclitaxel against erbB2-overexpressing breast cancer
Introduction Elevated expression of erbB3 rendered erbB2-overexpressing breast cancer cells resistant to paclitaxel via PI-3 K/Akt-dependent upregulation of Survivin. It is unclear whether an erbB3-targeted therapy may abrogate erbB2-mediated paclitaxel resistance in breast cancer. Here, we study the antitumor activity of an anti-erbB3 antibody MM-121/SAR256212 in combination with paclitaxel against erbB2-overexpressing breast cancer. Methods Cell growth assays were used to determine cell viability. Cells undergoing apoptosis were quantified by a specific apoptotic ELISA. Western blot analyses were performed to assess the protein expression and activation. Lentiviral vector containing shRNA was used to specifically knockdown Survivin. Tumor xenografts were established by inoculation of BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with paclitaxel and/or MM-121/SAR256212 to determine whether the antibody (Ab) enhances paclitaxel's antitumor activity. Immunohistochemistry was carried out to study the combinatorial effects on tumor cell proliferation and induction of apoptosis in vivo. Results MM-121 significantly facilitated paclitaxel-mediated anti-proliferative/anti-survival effects on SKBR3 cells transfected with a control vector or erbB3 cDNA. It specifically downregulated Survivin associated with inactivation of erbB2, erbB3, and Akt. MM-121 enhances paclitaxel-induced poly(ADP-ribose) polymerase (PARP) cleavage, activation of caspase-8 and -3, and apoptosis in both paclitaxel-sensitive and -resistant cells. Specific knockdown of Survivin in the trastuzumab-resistant BT474-HR20 cells dramatically enhanced paclitaxel-induced apoptosis, suggesting that increased Survivin caused a cross-resistance to paclitaxel. Furthermore, the studies using a tumor xenograft model-established from BT474-HR20 cells revealed that either MM-121 (10 mg/kg) or low-dose (7.5 mg/kg) paclitaxel had no effect on tumor growth, their combinations significantly
BioSAR Airborne Biomass Sensing System
Graham, R.L.; Johnson, P.
This CRADA was developed to enable ORNL to assist American Electronics, Inc. test a new technology--BioSAR. BioSAR is a an airborne, low frequency (80-120 MHz {approx} FM radio frequencies) synthetic aperture radar (SAR) technology which was designed and built for NASA by ZAI-Amelex under Patrick Johnson's direction. At these frequencies, leaves and small branches are nearly transparent and the majority of the energy reflected from the forest and returned to the radar is from the tree trunks. By measuring the magnitude of the back scatter, the volume of the tree trunk and therefore the biomass of the trunks can be inferred. The instrument was successfully tested on tropical rain forests in Panama. Patrick Johnson, with American Electronics, Inc received a Phase II SBIR grant from DOE Office of Climate Change to further test and refine the instrument. Mr Johnson sought ORNL expertise in measuring forest biomass in order for him to further validate his instrument. ORNL provided ground truth measurements of forest biomass at three locations--the Oak Ridge Reservation, Weyerhaeuser Co. commercial pine plantations in North Carolina, and American Energy and Power (AEP) Co. hardwood forests in southern Ohio, and facilitated flights over these forests. After Mr. Johnson processed the signal data from BioSAR instrument, the processed data were given to ORNL and we attempted to derive empirical relationships between the radar signals and the ground truth forest biomass measurements using standard statistical techniques. We were unsuccessful in deriving such relationships. Shortly before the CRADA ended, Mr Johnson discovered that FM signal from local radio station broadcasts had interfered with the back scatter measurements such that the bulk of the signal received by the BioSAR instrument was not backscatter from the radar but rather was local radio station signals.
Polychlorinated dibenzofurans (PCDFs) and dibenzo-p-dioxins (PCDDs) elicit a number of common biologic and toxic responses which are triggered by their initial binding to a cytosolic receptor protein. hese effects include the induction of several cytochrome P-448 dependent monoox...