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Total Synthesis of Piericidin A1 and B1 and Key Analogues  

PubMed Central

Full details of the total synthesis of piericidin A1 and B1 and its extension to the preparation of a series of key analogues are described including ent-piericidin A1 (ent-1), 4'-deshydroxypiericidin A1 (58), 5'-desmethylpiericidin A1 (73), 4'-deshydroxy-5'-desmethylpiericidin A1 (75), and the corresponding analogues 51, 59, 76, and 77 bearing a simplified farnesyl side chain. The evaluation of these key analogues, along with those derived from their further functionalizations, permitted a scan of the key structural features providing new insights into the role of the substituents found in both the pyridyl core as well as the side chain. A strategic late stage heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain permitted ready access to the analogues in which each half of the molecule could be systematically and divergently modified. The pyridyl cores were assembled enlisting inverse electron demand Diels–Alder reactions of N-sulfonyl-1-azabutadienes while key elements of side chain syntheses include an anti selective asymmetric aldol to install the C9 and C10 relative and absolute stereochemistry (for natural and ent-1) and a modified Julia olefination for formation of the C5–C6 trans double bond with convergent assemblage of the side chains. PMID:16953619

Schnermann, Martin J.; Romero, F. Anthony; Hwang, Inkyu; Nakamaru-Ogiso, Eiko; Yagi, Takao; Boger, Dale L.



Structured Key-Word Analysis.  

ERIC Educational Resources Information Center

Structured Key-word Analysis is a computerizable technique for objectively analyzing the natural language responses to open-end questions. Key-words are frequently used content words. Pairs of key-words that appear together in protocols either extremely often or extremely seldom (compared with the probability of co-appearance) are termed conjoint…

Dirlam, David K.; Manganal, Richard A.


Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues  

NASA Astrophysics Data System (ADS)

The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1 and structural analogues by late-stage stereoselective glycosylation reactions of fully functionalized, differentially protected aglycon substrates. Key issues addressed in this work include the identification of an appropriate means to activate and protect each of the two 2-deoxysugar components, trioxacarcinose A and trioxacarcinose B, as well as a viable sequencing of the glycosidic couplings. The convergent, component-based sequence we present allows for rapid construction of structurally diverse, synthetic analogues that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogues that arise from the modification of four of five modular components are assembled in 11 steps or fewer. The majority of these are found to be active in antiproliferative assays using cultured human cancer cells.

Magauer, Thomas; Smaltz, Daniel J.; Myers, Andrew G.



The Packing Analogues of Sodalite, Tetrahedrite and Related Structures  

Microsoft Academic Search

Sodalite and tetrahedrite are normally treated separately because they are chemically very different and do not appear to be related. However, if appropriate representations (packing analogues) are used, one can realise how similar they are in crystal structure. Other interesting relationships, though not so close, may also be found with cristobalite and MgCu2 (Friauf-Laves phase).

José Lima-de-Faria


The International Space Analogue Rock Store (ISAR): A key tool for future planetary exploration.  

NASA Astrophysics Data System (ADS)

In order to prepare the next in situ space missions we have created a « lithothèque » of analogue rocks for calibrating and testing future (and existing) space flight instruments. This rock collection is called the International Space Analogue Rockstore (ISAR) and is hosted in the CNRS and the Observatoire des Sciences de l'Univers en Region Centre (OSUC) in Orléans. For maximum science return, all instruments on a single mission should ideally be tested with the same suite of relevant analogue materials. The ISAR lithothéque aims to fulfill this role by providing suitable materials to instrument teams [1]. The lithothèque is accompanied by an online database of all relevant structural, textural, and geochemical data ( data base will also be available during missions to aid interpretation of data obtained in situ. Mars is the immediate goal for MSL-2011 and the new international Mars 2018 mission. The lithothèque thus presently contains relevant Mars-analogue rock and mineral samples, a preliminary range of which is now available to the scientific community for instrument testing [2]. The preliminary group of samples covers a range of lithologies to be found on Mars, especially those in Noachain/Hesperian terrains where MSL will land (Gale Crater) and where the 2018 landing site will most likely be located. It includes a variety of basalts (tephrite, primitive basalt, silicified basalt; plus cumulates), komatiites, artificially synthesized martian basalts [3], volcanic sands, a banded iron formation, carbonates associated with volcanic lithologies and hydrothermalism, the clay Nontronite, and hydrothermal cherts. Some of the silicified volcanic sands contain traces of early life that are good analogues for potential martian life [4]. [1] Westall F. et al., LPI contribution 1608, 1346, 42nd LPSC, 2011; [2] Bost N. et al., in review (Icarus); [3] Bost N. et al., in review (Meteoritics); [4] Westall et al., 2011, Planetary and Space Science 59. ISAR Team: N. Bost, F. Westall, C; Ramboz, F. Foucher, D. Pullan, T. Zegers, B. Hoffman, F. Rull, J. Bridges, A; Steele, H. Amundsen, R. Barbieri, A. Hubert, B. Cavalazzi, J. Bridges, M. Viso, J. Vago, S. Petit, A. Meunier, I. Fleischer, G. Klingelhöfer, N. Arndt…

Bost, N.; Westall, F.; Ramboz, C.; Foucher, F.



The crystal structure of faustite and its copper analogue turquoise  

Microsoft Academic Search

The crystal structure of faustite, ZnAI6(P04MOHhAH20, was determined using single-crystal data (Mo-KIX X-radiation, CCD area detector, 1624 unique reflections, RI = 4.91 %, wR2 = 9.23%), and compared with results of a reinvestigation of the structure of its copper analogue turquoise, CuAI6(P04MOH)gAH20 (2737 unique reflections, RI = 2.81%, wR2 = 6.90%). Both are isostructural and crystallize in space group PI,

U. Kolitsch; G. Giester



A Structurally Simplified Analogue of Geldanamycin Exhibits Neuroprotective Activity  

PubMed Central

The syntheses of a structurally simplified geldanamycin analogue 2 and two related compounds are described. Compound 2 conferred cytoprotection and quenched ROS and lipid peroxidation in a dose-dependent manner in Friedreich’s ataxia (FRDA) lymphocytes at low micromolar concentrations. It also prevented ROS-induced damage of cellular lipid membranes and maintained the mitochondrial membrane potential of FRDA lymphocytes. In addition, 2 did not inhibit Hsp90 when tested at micromolar concentrations, exhibited no cytotoxicity, and afforded neuroprotection to differentiated SH-SY5Y cells under conditions of A?-induced cell toxicity. PMID:24900591



Improved synthesis of structural analogues of (?)-epicatechin gallate for modulation of staphylococcal ?-lactam resistance?  

PubMed Central

The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin stereochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereochemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric dihydroxylation. PMID:24876661

Anderson, James C.; Grounds, Helen; Reeves, Suzanna; Taylor, Peter W.



Structure elucidation of sildenafil analogues in herbal products.  


The structure of unknown compounds present in herbal products was elucidated using liquid chromatography-electrospray ionization-mass spectrometry, direct-infusion electrospray ionization-mass spectrometry, and nuclear magnetic resonance. Compounds 1-3 were identified as sildenafil analogues, 1 bearing an N-ethylpiperazine moiety instead of an N-methylpiperazine, and an acetyl group instead of the sulfonyl group, named acetildenafil, 2 bearing an N-ethylpiperazine moiety instead of an N-methylpiperazine (homosildenafil), and 3 bearing an N-hydroxylethylpiperazine moiety instead of an N-methylpiperazine, named hydroxyhomosildenafil. When analysing products marketed for penile erectile dysfunction or marketed as aphrodisiacs, attention should be given to the possible presence of these components. PMID:15370823

Blok-Tip, L; Zomer, B; Bakker, F; Hartog, K D; Hamzink, M; Ten Hove, J; Vredenbregt, M; De Kaste, D



Modern freshwater microbialite analogues for ancient dendritic reef structures  

NASA Technical Reports Server (NTRS)

Microbialites are organosedimentary structures that can be constructed by a variety of metabolically distinct taxa. Consequently, microbialite structures abound in the fossil record, although the exact nature of the biogeochemical processes that produced them is often unknown. One such class of ancient calcareous structures, Epiphyton and Girvanella, appear in great abundance during the Early Cambrian. Together with Archeocyathids, stromatolites and thrombolites, they formed major Cambrian reef belts. To a large extent, Middle to Late Cambrian reefs are similar to Precambrian reefs, with the exception that the latter, including terminal Proterozoic reefs, do not contain Epiphyton or Girvanella. Here we report the discovery in Pavilion Lake, British Columbia, Canada, of a distinctive assemblage of freshwater calcite microbialites, some of which display microstructures similar to the fabrics displayed by Epiphyton and Girvanella. The morphologies of the modern microbialites vary with depth, and dendritic microstructures of the deep water (> 30 m) mounds indicate that they may be modern analogues for the ancient calcareous structures. These microbialites thus provide an opportunity to study the biogeochemical interactions that produce fabrics similar to those of some enigmatic Early Cambrian reef structures.

Laval, B.; Cady, S. L.; Pollack, J. C.; McKay, C. P.; Bird, J. S.; Grotzinger, J. P.; Ford, D. C.; Bohm, H. R.



In Vitro Structure-Activity Relationship of Re-cyclized Octreotide Analogues  

PubMed Central

Introduction Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods Various octreotide analogue sequences and coordination systems (e.g., S2N2 and S3N) were synthesized and cyclized with non-radioactive Re. In vitro competitive binding assays with 111In-DOTA-Tyr3-octreotide in AR42J rat pancreatic tumor cells yielded IC50 values as a measure of somatostatin receptor affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr3-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue’s pharmacophore. Results Only two of the eleven Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr3-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal-cyclization of octreotide analogues via NS3 and N2S2 coordination forming 5- and 6- membered chelate rings. In vivo biodistribution studies are underway of 99m Tc- cyclized analogue 4. PMID:20610157

Dannoon, Shorouk F.; Bigott-Hennkens, Heather M.; Ma, Lixin; Gallazzi, Fabio; Lewis, Michael R.; Jurisson, Silvia S.



Structural Basis of Thiamine Pyrophosphate Analogues Binding to the Eukaryotic Riboswitch  

E-print Network

Structural Basis of Thiamine Pyrophosphate Analogues Binding to the Eukaryotic Riboswitch Ste the bacterial and the eukaryotic thiamine pyrophosphate (TPP)-specific riboswitches,10­15 uncovered in a broad range of enzymatic reactions.19 Two thiamine analogues, oxythiamine and pyrithiamine, have been

Halazonetis, Thanos


Synthesis and structure/antioxidant activity relationship of novel catecholic antioxidant structural analogues to hydroxytyrosol and its lipophilic esters.  


A large panel of novel catecholic antioxidants and their fatty acid or methyl carbonate esters has been synthesized in satisfactory to good yields through a 2-iodoxybenzoic acid (IBX)-mediated aromatic hydroxylation as the key step. The new catechols are structural analogues of naturally occurring hydroxytyrosol (3,4-DHE). To evaluate structure/activity relationships, the antioxidant properties of all catecholic compounds were evaluated in vitro by ABTS assay and on whole cells by DCF fluorometric assay and compared with that of the corresponding already known hydroxytyrosyl derivatives. Results outline that all of the new catechols show antioxidant capacity in vitro higher than that of the corresponding hydroxytyrosyl derivatives. Less evident positive effects have been detected in whole cells experiments. Cytotoxicity experiments, using MTT assay, on a representative set of compounds evidenced no influence in cell survival. PMID:22780104

Bernini, Roberta; Crisante, Fernanda; Barontini, Maurizio; Tofani, Daniela; Balducci, Valentina; Gambacorta, Augusto



Structural Basis of Ligand Binding to UDP-Galactopyranose Mutase from Mycobacterium tuberculosis Using Substrate and Tetrafluorinated Substrate Analogues.  


UDP-Galactopyranose mutase (UGM) is a flavin-containing enzyme that catalyzes the reversible conversion of UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf) and plays a key role in the biosynthesis of the mycobacterial cell wall galactofuran. A soluble, active form of UGM from Mycobacterium tuberculosis (MtUGM) was obtained from a dual His6-MBP-tagged MtUGM construct. We present the first complex structures of MtUGM with bound substrate UDP-Galp (both oxidized flavin and reduced flavin). In addition, we have determined the complex structures of MtUGM with inhibitors (UDP and the dideoxy-tetrafluorinated analogues of both UDP-Galp (UDP-F4-Galp) and UDP-Galf (UDP-F4-Galf)), which represent the first complex structures of UGM with an analogue in the furanose form, as well as the first structures of dideoxy-tetrafluorinated sugar analogues bound to a protein. These structures provide detailed insight into ligand recognition by MtUGM and show an overall binding mode similar to those reported for other prokaryotic UGMs. The binding of the ligand induces conformational changes in the enzyme, allowing ligand binding and active-site closure. In addition, the complex structure of MtUGM with UDP-F4-Galf reveals the first detailed insight into how the furanose moiety binds to UGM. In particular, this study confirmed that the furanoside adopts a high-energy conformation ((4)E) within the catalytic pocket. Moreover, these investigations provide structural insights into the enhanced binding of the dideoxy-tetrafluorinated sugars compared to unmodified analogues. These results will help in the design of carbohydrate mimetics and drug development, and show the enormous possibilities for the use of polyfluorination in the design of carbohydrate mimetics. PMID:25562380

van Straaten, Karin E; Kuttiyatveetil, Jijin R A; Sevrain, Charlotte M; Villaume, Sydney A; Jiménez-Barbero, Jesús; Linclau, Bruno; Vincent, Stéphane P; Sanders, David A R



Preparing to return to the Moon: Lessons from science-driven analogue missions to the Mistastin Lake impact structure, Canada, a unique lunar analogue site  

NASA Astrophysics Data System (ADS)

Impact cratering is the dominant geological process on the Moon, Near Earth Asteroids (NEAs) and the moons of Mars - the objectives for the new Solar System Exploration Research Virtual Institute (SSERVI). Led by members of the Canadian Lunar Research Network (CLRN), funded by the Canadian Space Agency, and with participants from the U.S., we carried out a series of analogue missions on Earth in order to prepare and train for future potential robotic and human sample return missions. Critically, these analogue missions were driven by the paradigm that operational and technical objectives are conducted while conducting new science and addressing real overarching scientific objectives. An overarching operational goal was to assess the utility of a robotic field reconnaissance mission as a precursor to a human sortie sample return mission. Here, we focus on the results and lessons learned from a robotic precursor mission and follow on human-robotic mission to the Mistastin Lake impact structure in Labrador, northern Canada (55°53'N; 63°18'W). The Mistastin structure was chosen because it represents an exceptional analogue for lunar craters. This site includes both an anorthositic target, a central uplift, well-preserved impact melt rocks - mostly derived from melting anorthosite - and is (or was) relatively unexplored. This crater formed ~36 million years ago and has a diameter of ~28 km. The scientific goals for these analogue missions were to further our understanding of impact chronology, shock processes, impact ejecta and potential resources within impact craters. By combining these goals in an analogue mission campaign key scientific requirements for a robotic precursor were determined. From the outset, these analogue missions were formulated and executed like an actual space mission. Sites of interest were chosen using remote sensing imagery without a priori knowledge of the site through a rigorous site selection process. The first deployment occurred in August and September 2010 and involved simulated robotic surveying of selected 'landing sites' at the Mistastin structure. The second deployment took place at the same location in 2011, which included simulated astronaut surface operations with, and without, the aid of a robotic assistant. A mission control team, based at the University of Western Ontario, London, Ontario, 1,900 km from the field site, oversaw operations. Our study showed the value of precursor reconnaissance missions in providing surface geology visualization at resolutions and from viewpoints not achievable from orbit, including high-resolution surface imagery on the scale of 10s of metres to kilometres. Indeed, data collected during the robotic precursor mission led to the formulation of a hypothesis that a large impact melt outcrop - named Discovery Hill - represents an impact melt pond in the terraced region of the crater, analogous to similar ponds of melt documented around the rim of well-preserved lunar craters such as Tycho. Further discoveries, that will be highlight here, include documentation of ejecta deposits for the first time at Mistastin, quantification of shock in anorthosites, and refined age estimates for the Mistastin impact event.

Osinski, G. R.; Barfoot, T.; Chanou, A.; Daly, M. G.; Francis, R.; Hodges, K. V.; Jolliff, B. L.; Mader, M. M.; McCullough, E. M.; Moores, J. E.; Pickersgill, A.; Pontefract, A.; Preston, L.; Shankar, B.; Singleton, A.; Sylvester, P.; Tornabene, L. L.; Young, K. E.



Structure elucidation of a novel synthetic thiono analogue of sildenafil detected in an alleged herbal aphrodisiac.  


A new analogue of sildenafil was detected in a herbal aphrodisiac. The structure of the compound was established using LC-MS, UV and IR spectroscopy, MS-MS, and NMR. The compound, named thio-homosildenafil is a synthetic N-ethylpiperazine analogue of sildenafil in which also the CO moiety has been converted into a CS group. This is the first time a sildenafil analogue modified at the chromophore was identified as an adulterant of a herbal aphrodisiac. Preliminary pharmacological analysis confirmed the erectogenic potency of thio-homosildenafil. PMID:18207347

Venhuis, B J; Zomer, G; de Kaste, D



Similarities and differences in the structure-activity relationships of capsaicin and resiniferatoxin analogues.  


Structure-activity relationships in analogues of the irritant natural product capsaicin have previously been rationalized by subdivision of the molecule into three structural regions (A,B, and C). The hypothesis that resiniferatoxin (RTX), which is a high-potency ligand for the same receptor and which has superficial structural similarities with capsaicin, could be analogously subdivided has been investigated. The effects of making parallel changes in the two structural series have been studied in a cellular functional assay which is predictive of analgesic activity. Parallel structural changes in the two series lead to markedly different consequences on biological activity; the 3- and 4-position aryl substituents (corresponding to the capsaicin 'A-region') which are strictly required for activity in capsaicin analogues are not important in RTX analogues. The homovanillyl C-20 ester group in RTX (corresponding to the capsaicin 'B-region') is more potent than the corresponding amide, in contrast to the capsaicin analogues. Structural variations to the diterpene moiety suggest that the functionalized 5-membered diterpene ring of RTX is an important structural determinant for high potency. Modeling studies indicate that the 3D position of the alpha-hydroxy ketone moiety in the 5-membered ring is markedly different in the phorbol (inactive) analogues and RTX (active) series. This difference appears to be due to the influence of the strained ortho ester group in RTX, which acts as a local conformational constraint. The reduced activity of an analogue substituted in this region and the inactivity of a simplified analogue in which this unit is entirely removed support this conclusion. PMID:8709128

Walpole, C S; Bevan, S; Bloomfield, G; Breckenridge, R; James, I F; Ritchie, T; Szallasi, A; Winter, J; Wrigglesworth, R



Optimizing the tree structure in secure multicast key management  

Microsoft Academic Search

We study the issue of distributing cryptographic keys to a secure multicast group. The key management is focused on virtual tree-based schemes represented by the logical key hierarchy (LKH). We present the optimal key tree structure problem. Specifically, we address minimizing the computational overhead of the key server with analytical formulation and propose two new variations of LKH. The first

Wen Tao Zhu



Lead structures for new antibacterials: stereocontrolled synthesis of a bioactive muraymycin analogue.  


Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antibacterial agents. The structural complexity suggests the investigation of simplified analogues as potential lead structures, which can then be further optimized towards highly potent antimicrobials. Herein we report studies on muraymycin-derived potential lead structures lacking an aminoribose motif found in most naturally occurring muraymycins. We have identified a 5'-defunctionalized motif to be ideal in terms of stability and chemical accessibility and have synthesized a full-length muraymycin analogue based on this structure using a novel fully stereocontrolled route. The obtained 5'-deoxy analogue of the natural product muraymycin C4 showed good inhibitory properties towards the bacterial target protein MraY, sufficient pharmacokinetic stability and no cytotoxicity against human cells, thus making it a promising lead for antibacterial drug development. PMID:25318977

Spork, Anatol P; Büschleb, Martin; Ries, Oliver; Wiegmann, Daniel; Boettcher, Stefan; Mihalyi, Agnes; Bugg, Timothy D H; Ducho, Christian



Analogue Modeling of Resurgent Calderas: The Role of Prehexisting Tectonic and Volcano-tectonic Structures  

Microsoft Academic Search

Analogue models of block resurgence have been carried out on samples previously de- formed in an extensional setting, in order to better understand the role of pre-existing structures. Two lines of experiments were performed by superposition of two different equipments to simulate: a) resurgence in an area with a simple graben-like structure; b) ersurgence in an area with a caldera

S. de Vita; E. Marotta; G. Orsi; V. Acocella; R. Funiciello; F. Cifelli



Natural and Semisynthetic Analogues of Manadoperoxide B Reveal New Structural Requirements for Trypanocidal Activity  

PubMed Central

Chemical analysis of the Indonesian sponge Plakortis cfr. lita afforded two new analogues of the potent trypanocidal agent manadoperoxide B (1), namely 12-isomanadoperoxide B (2) and manadoperoxidic acid B (3). These compounds were isolated along with a new short chain dicarboxylate monoester (4), bearing some interesting relationships with the polyketide endoperoxides found in this sponge. Some semi-synthetic analogues of manadoperoxide B (6–8) were prepared and evaluated for antitrypanosomal activity and cytotoxicity. These studies revealed crucial structure–activity relationships that should be taken into account in the design of optimized and simplified endoperoxyketal trypanocidal agents. PMID:23989650

Chianese, Giuseppina; Scala, Fernando; Calcinai, Barbara; Cerrano, Carlo; Dien, Henny A.; Kaiser, Marcel; Tasdemir, Deniz; Taglialatela-Scafati, Orazio



Novel biological effects of alloferon and its selected analogues: structure-activity study.  


The subject of this paper is a search for new biological properties of alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH) and a series of its analogues. The studies on structure/activity relationship in alloferon, the synthesis of a series of 28 analogues were performed. The analogues were modified at position 1 or 6, and other were oligopeptides with a shortened peptide sequence. Biological effects of the peptides were evaluated by the pro-apoptotic action in vivo on haemocytes of Tenebrio molitor and in the cardiotropic test in vitro on the heart of T. molitor and Zophobas atratus. In the in vivo bioassays, new biological activities of alloferon and its analogues were discovered. In haemocytotoxic bioassay, alloferon strongly induces T. molitor haemocytes to undergo apoptosis at a dose of 10 nM. Moreover, [Phe(p-NH2)(1)]-, [Tyr(6)]- and [1-10]-alloferon exhibit a two-fold increase of caspases activation in comparison with the alloferon. However, alloferon and its analogues show a weak cardiostimulatory activity in Z. atratus but the heart of T. molitor is not sensitive to these peptides. The results obtained here suggest that alloferon plays pleiotropic functions in insects. PMID:23499798

Kuczer, Mariola; Czarniewska, El?bieta; Rosi?ski, Grzegorz



Synthesis, biological activity, and hologram quantitative structure-activity relationships of novel allatostatin analogues.  


Cockroach-type allatostatins (FGLamides) (ASTs) can inhibit the production of juvenile hormone in vitro, and they therefore are regarded as possible insect growth regulator (IGR) candidates for pest control. However, several shortcomings, such as the absence of in vivo effects, rapid degradation, and high production costs, preclude their practical use in pest management. To discover new IGRs, 25 novel analogues of pentapeptide (Y/FXFGLa) were designed and synthesized with different aromatic acids, fatty acids, and dicarboxylic acids as the Y/FX region replacements on the basis of previous results. Their bioactivities in vitro were determined, and the results showed that eight analogues (K14, K15, K17, K18, K19, K23, K24, and K25) were more active than the lead, core region pentapeptide. The IC(50) values of K15 and K24 (IC(50) = 1.79 and 5.32 nM, respectively) were even lower than that of the natural AST, Dippu-AST 1(IC(50) = 8 nM), which indicated both analogues have better activity than Dippu-AST 1; particularly, K15 has better activity than most natural Dippu-ASTs. A predictable and statistically meaningful hologram quantitative structure-activity relationship (HQSAR) model of 32 AST analogues (28 as training sets and 4 as test sets) was obtained. The final model suggested that a potent AST analogue should contain an aromatic group, a linker of appropriate length, and the FGLa portion. These results will be useful in the design of new AST analogues that are structurally related to the training set compounds. PMID:19950981

Kai, Zhen-Peng; Huang, Juan; Xie, Yong; Tobe, Stephen S; Ling, Yun; Zhang, Li; Zhao, Yi-Chen; Yang, Xin-Ling



Isolation and structural characterisation of a propoxyphenyl-linked thiohomosildenafil analogue found in a herbal product.  


A propoxyphenyl-linked thiohomosildenafil analogue, one of the sildenafil analogues, was found in an herbal product. It was isolated by semi-preparative high-performance liquid chromatography (HPLC). The structure was established based on a comparison of chromatographic and spectroscopic behaviour with other sildenafil analogues using HPLC with diode array detection, quadrupole time-of-flight mass spectrometry (Q-TOF/MS), and nuclear magnetic resonance (NMR) spectroscopy. The HPLC analysis showed separation from known sildenafil analogues with a similar chromatographic retention time. An [M + H](+) ion at m/z 519.22 was detected by mass spectrometry corresponding to an empirical formula of C24H34N6O3S2. The structure was similar to that of thiohomosildenafil, except that the ethoxy group attached to the phenyl ring was substituted for a propoxy group. It was assigned as 5-[2-propoxy-5-(4-ethylpiperazin-4-ylsulfonyl)phenyl]-3-methyl-1-n-propyl-4,5,dihydro-1H-pyrazole[7,1,d]pyrimidin-4-thione and named as propoxyphenyl-thiohomosildenafil because the structure was considerably similar to thiohomosildenafil. PMID:23984909

Kim, Nam Sook; Lee, Ji Hyune; Han, Kyoung Moon; Kim, Hyung Joo; Cho, Sooyeul; Han, Soon Young; Kim, Woo Seong



Synthesis and structure-activity relationship of antifungal coniothyriomycin analogues.  


The structure of the antifungal metabolite coniothyriomycin was systematically modified by changing the acids of the open chain imide, modification of the hydrophobicity, variation in the degree of saturation, replacement of carbons by nitrogen or oxygen, and incorporation of the open chain molecule into cyclic arrangements. Structure-activity studies showed that antifungal activity was retained by replacement of phenylacetic acids by benzoic acids in the imide structure but diminished by hydrogenation of the fumaric ester part. PMID:12760686

Krohn, Karsten; Elsässer, Brigitta; Antus, Sándor; Kónya, Krisztina; Ammermann, Eberhard



Structure–activity relationship of indomethacin analogues for MRP-1, COX1 and COX2 inhibition  

Microsoft Academic Search

We report the screening of analogues of indomethacin to investigate the structure–activity relationship (SAR) of indomethacin-mediated multidrug resistance associated protein-1 (MRP-1) inhibition. By examining the activities of compounds with minor variations of the parent structure, we were able to separate MRP-1, glutathione-S-transferase (GST), cyclooxygenase (COX)-1 and COX-2 inhibitory activities. Combination cytotoxicity assays were utilised to identify agents which possess synergistic

S Touhey; R O'Connor; S Plunkett; A Maguire; M Clynes



Design, synthesis, antiviral activity, and structure-activity relationships (SARs) of two types of structurally novel phenanthroindo/quinolizidine analogues.  


To investigate the influence of the variation of the original skeletons of natural phenanthroindo/quinolizidine alkaloids on antiviral activities, two types of structurally totally novel analogues 7a, 7b, 16a, and 16b were designed, synthesized, and evaluated against tobacco mosaic virus (TMV) for the first time. Bioassay results indicated that all four of the newly designed analogues showed good to excellent antiviral activities, among which analogue 16a dispalyed comparable activity with that of ningnanmycin, perhaps one of the most successful commercial antiviral agents, thus emerging as a potential inhibitor of plant virus and serving as a new lead for further optimization. Further structure-activity relationships are also discussed, demonstrating for the first time that the same changes of the original skeletons of phenanthroindolizidine and phenanthroquinolizidine exihibted totally different antiviral activities results, providing some original and useful information about the preferential conformation for maintaining high activities. PMID:24467600

Su, Bo; Chen, Fazhong; Wang, Lizhong; Wang, Qingmin



Structure-activity relationship analysis of curcumin analogues on anti-influenza virus activity.  


Curcumin (Cur) is a commonly used colouring agent and spice in food. Previously, we reported that Cur inhibits type A influenza virus (IAV) infection by interfering with viral haemagglutination (HA) activity. To search for a stable Cur analogue with potent anti-IAV activity and to investigate the structure contributing to its anti-IAV activity, a comparative analysis of structural and functional analogues of Cur, such as tetrahydrocurcumin (THC) and petasiphenol (Pet), was performed. The result of time-of-drug addition tests indicated that these curcuminoids were able to inhibit IAV production in cell cultures. Noticeably, Pet and THC inhibit IAV to a lesser extent than Cur, which is in line with their effect on reducing plaque formation when IAV was treated with Cur analogues before infection. Unexpectedly, both THC and Pet did not harbour any HA inhibitory effect. It should be noted that the structure of Pet and THC differs from Cur with respect to the number of double bonds present in the central seven-carbon chain, and structure modelling of Cur analogues indicates that the conformations of THC and Pet are distinct from that of Cur. Moreover, simulation docking of Cur with the HA structure revealed that Cur binds to the region constituting sialic acid anchoring residues, supporting the results obtained by the inhibition of HA activity assay. Collectively, structure-activity relationship analyses indicate that the presence of the double bonds in the central seven-carbon chain enhanced the Cur -dependent anti-IAV activity and also that Cur might interfere with IAV entry by its interaction with the receptor binding region of viral HA protein. PMID:24034558

Ou, Jun-Lin; Mizushina, Yoshiyuki; Wang, Sheng-Yang; Chuang, Duen-Yau; Nadar, Muthukumar; Hsu, Wei-Li



Characterization and use of an unprecedentedly bright and structurally non-perturbing fluorescent DNA base analogue  

PubMed Central

This article presents the first evidence that the DNA base analogue 1,3-diaza-2-oxophenoxazine, tCO, is highly fluorescent, both as free nucleoside and incorporated in an arbitrary DNA structure. tCO is thoroughly characterized with respect to its photophysical properties and structural performance in single- and double-stranded oligonucleotides. The lowest energy absorption band at 360 nm (? = 9000 M?1 cm?1) is dominated by a single in-plane polarized electronic transition and the fluorescence, centred at 465 nm, has a quantum yield of 0.3. When incorporated into double-stranded DNA, tCO shows only minor variations in fluorescence intensity and lifetime with neighbouring bases, and the average quantum yield is 0.22. These features make tCO, on average, the brightest DNA-incorporated base analogue so far reported. Furthermore, it base pairs exclusively with guanine and causes minimal perturbations to the native structure of DNA. These properties make tCO a promising base analogue that is perfectly suited for e.g. photophysical studies of DNA interacting with macromolecules (proteins) or for determining size and shape of DNA tertiary structures using techniques such as fluorescence anisotropy and fluorescence resonance energy transfer (FRET). PMID:18003656

Sandin, Peter; Börjesson, Karl; Li, Hong; Mårtensson, Jerker; Brown, Tom; Wilhelmsson, L. Marcus; Albinsson, Bo



The solution structure of a superpotent B-chain-shortened single-replacement insulin analogue.  

PubMed Central

This paper reports on an insulin analogue with 12.5-fold receptor affinity, the highest increase observed for a single replacement, and on its solution structure, determined by NMR spectroscopy. The analogue is [D-AlaB26]des-(B27-B30)-tetrapeptide-insulin-B26-amide. C-terminal truncation of the B-chain by four (or five) residues is known not to affect the functional properties of insulin, provided the new carboxylate charge is neutralized. As opposed to the dramatic increase in receptor affinity caused by the substitution of D-Ala for the wild-type residue TyrB26 in the truncated molecule, this very substitution reduces it to only 18% of that of the wild-type hormone when the B-chain is present in full length. The insulin molecule in solution is visualized as an ensemble of conformers interrelated by a dynamic equilibrium. The question is whether the "active" conformation of the hormone, sought after in innumerable structure/function studies, is or is not included in the accessible conformational space, so that it could be adopted also in the absence of the receptor. If there were any chance for the active conformation, or at least a predisposed state to be populated to a detectable extent, this chance should be best in the case of a superpotent analogue. This was the motivation for the determination of the three-dimensional structure of [D-AlaB26]des-(B27-B30)-tetrapeptide-insulin-B26-amide. However, neither the NMR data nor CD spectroscopic comparison of a number of related analogues provided a clue concerning structural features predisposing insulin to high receptor affinity. After the present study it seems more likely than before that insulin will adopt its active conformation only when exposed to the force field of the receptor surface. PMID:10091652

Kurapkat, G.; Siedentop, M.; Gattner, H. G.; Hagelstein, M.; Brandenburg, D.; Grötzinger, J.; Wollmer, A.



Structure of Mandelate Racemase with Bound Intermediate Analogues Benzohydroxamate and Cupferron  

SciTech Connect

Mandelate racemase (MR, EC from Pseudomonas putida catalyzes the Mg{sup 2+}-dependent interconversion of the enantiomers of mandelate, stabilizing the altered substrate in the transition state by 26 kcal/mol relative to the substrate in the ground state. To understand the origins of this binding discrimination, we determined the X-ray crystal structures of wild-type MR complexed with two analogues of the putative aci-carboxylate intermediate, benzohydroxamate and Cupferron, to 2.2-{angstrom} resolution. Benzohydroxamate is shown to be a reasonable mimic of the transition state and/or intermediate because its binding affinity for 21 MR variants correlates well with changes in the free energy of transition state stabilization afforded by these variants. Both benzohydroxamate and Cupferron chelate the active site divalent metal ion and are bound in a conformation with the phenyl ring coplanar with the hydroxamate and diazeniumdiolate moieties, respectively. Structural overlays of MR complexed with benzohydroxamate, Cupferron, and the ground state analogue (S)-atrolactate reveal that the para carbon of the substrate phenyl ring moves by 0.8-1.2 {angstrom} between the ground state and intermediate state, consistent with the proposal that the phenyl ring moves during MR catalysis while the polar groups remain relatively fixed. Although the overall protein structure of MR with bound intermediate analogues is very similar to that of MR with bound (S)-atrolactate, the intermediate-Mg{sup 2+} distance becomes shorter, suggesting a tighter complex with the catalytic Mg{sup 2+}. In addition, Tyr 54 moves closer to the phenyl ring of the bound intermediate analogues, contributing to an overall constriction of the active site cavity. However, site-directed mutagenesis experiments revealed that the role of Tyr 54 in MR catalysis is relatively minor, suggesting that alterations in enzyme structure that contribute to discrimination between the altered substrate in the transition state and the ground state by this proficient enzyme are extremely subtle.

Lietzan, Adam D.; Nagar, Mitesh; Pellmann, Elise A.; Bourque, Jennifer R.; Bearne, Stephen L.; Maurice, Martin St. (Dalhousie U.); (Marquette)



Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs.  


Two analogues of sildenafil were detected in herbal dietary supplements marketed as aphrodisiacs. Both compounds were identified as thioketone analogues of sildenafil in which the carbonyl group in the pyrimidine ring of sildenafil was substituted with a thiocarbonyl group. The first compound was identified as thiosildenafil, a compound that has recently been reported as an adulterant in health supplements. The structure of the second compound was established using LC-MS, UV spectroscopy, ESI-MS(n), NMR and a hydrolytic process. A detailed study of the hydrolysis products of sildenafil, thiosildenafil, and the second unknown compound proved that the second compound, named thiomethisosildenafil, had a structure analogous to sildenafil in which the N-methylpiperazine moiety had been replaced with 2,6-dimethylpiperazine and the oxygen atom of the carbonyl group in the heterocyclic ring had been replaced with a sulfur atom. Under the hydrolytic reaction conditions employed in this study, thioketones hydrolyze to ketones (e.g., thiosildenafil-->sildenafil), making this a valuable technique for the structure elucidation of thiosildenafil analogues. Ten herbal dietary supplements, each as a capsule dosage form, were found to contain 8-151 mg of thiomethisosildenafil per capsule, and one herbal dietary supplement was found to contain 35 mg of thiosildenafil per capsule. PMID:19042103

Reepmeyer, John C; d'Avignon, D André



Characterization of electronic structure and physicochemical properties of antiparasitic nifurtimox analogues: A theoretical study  

NASA Astrophysics Data System (ADS)

American trypanosomiasis, also known as Chagas' disease, is caused by Trypanosoma cruzi (T. cruzi). It is well known that trypanosomes, and particularly T. cruzi, are highly sensitive towards oxidative stress, i.e., to compounds than are able to produce free radicals. Generally, nifurtimox (NFX) and benznidazol are most effective in the acute phase of the disease; therefore, nitroheterocycles constitute good models to design other nitrocompounds with specific biological characteristics. Thus, we have performed an ab initio study at the Hartree-Fock and Density Functional Theory levels of theory of several NFX analogues recently synthesized, to characterize them by obtaining their electronic, structural, and physicochemical properties, which might be linked to the observed antichagasic activity. The antitrypanosomal activity scale previously reported for the NFX analogues studied in this work is in good agreement with our theoretical results, from which we can conclude that the activity seems to be related to the reactivity along with the acidity observed for the most active molecules.

Soriano-Correa, Catalina; Raya, A.; Esquivel, Rodolfo O.


Structure-antitumor activity relationship of semi-synthetic spicamycin analogues.  


Spicamycin, a nucleoside antibiotic containing fatty acids with a variety of chain lengths (C12-C18), showed potent antitumor activity against human gastric cancer SC-9 and human breast cancer MX-1 in a xenograft model. We have made several semi-synthetic spicamycin analogues (SPMs) which differed in the chain length of the fatty acid moiety, and examined their structure-antitumor activity relationship. The cytotoxic activities of SPMs depended on the chain length of the fatty acid moiety, with dodecanoyl, tetradecanoyl, hexadecanoyl and icosanoyl analogues (SPM VIII, SPM X, SPM XII and SPM XVI) exhibiting the most potent cytotoxic activity against P388 murine leukemia cells. SPM VIII showed the most activity against SC-9 in the human tumor xenograft model with the highest therapeutic index among SPMs. The antitumor activity of SPM VIII was superior to that of mitomycin C. PMID:8226322

Kamishohara, M; Kawai, H; Odagawa, A; Isoe, T; Mochizuki, J; Uchida, T; Hayakawa, Y; Seto, H; Tsuruo, T; Otake, N



Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2  

PubMed Central

Resveratrol (3,5,4?-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation. PMID:23953689

St. John, Sarah E.; Jensen, Katherine C.; Kang, SooSung; Chen, Yafang; Calamini, Barbara; Mesecar, Andrew D.; Lipton, Mark A.



Inhibition of fatty acid amide hydrolase, a key endocannabinoid metabolizing enzyme, by analogues of ibuprofen and indomethacin.  


There is evidence in the literature that the nonsteroidal anti-inflammatory drugs indomethacin and ibuprofen can interact with the cannabinoid system both in vitro and in vivo. In the present study, a series of analogues of ibuprofen and indomethacin have been investigated with respect to their ability to inhibit fatty acid amide hydrolase, the enzyme responsible for the hydrolysis of the endogenous cannabinoid anandamide. Of the fourteen compounds tested, the 6-methyl-pyridin-2-yl analogue of ibuprofen ("ibu-am5") was selected for further study. This compound inhibited rat brain anandamide hydrolysis in a non-competitive manner, with IC50 values of 4.7 and 2.5 microM being found at pH 6 and 8, respectively. By comparison, the IC50 values for ibuprofen were 130 and 750 microM at pH 6 and 8, respectively. There was no measurable N-acylethanolamine hydrolyzing acid amidase activity in rat brain membrane preparations. In intact C6 glioma cells, ibu-am5 inhibited the hydrolysis of anandamide with an IC50 value of 1.2 microM. There was little difference in the potencies of ibu-am5 and ibuprofen towards cyclooxygenase-1 and -2 enzymes, and neither compound inhibited the activity of monoacylglycerol lipase. Ibu-am5 inhibited the binding of [3H]-CP55,940 to rat brain CB1 and human CB2 cannabinoid receptors more potently than ibuprofen, but the increase in potency was less than the corresponding increase in potency seen for inhibition of FAAH activity. It is concluded that ibu-am5 is an analogue of ibuprofen with a greater potency towards fatty acid amide hydrolase but with a similar cyclooxygenase inhibitory profile, and may be useful for the study of the therapeutic potential of combined fatty acid amide hydrolase-cyclooxygenase inhibitors. PMID:17397826

Holt, Sandra; Paylor, Ben; Boldrup, Linda; Alajakku, Kirsi; Vandevoorde, Séverine; Sundström, Anna; Cocco, Maria Teresa; Onnis, Valentina; Fowler, Christopher J



Study of IspH, A Key Enzyme in the Methylerythritol Phosphate Pathway Using Fluoro-substituted Substrate Analogues  

PubMed Central

IspH, a [4Fe-4S]-cluster-containing enzyme, catalyzes the reductive dehydroxylation of 4-hydroxy-3-methyl-butenyl diphosphate (HMBPP) to isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) in the methylerythritol phosphate pathway. Studies of IspH using fluoro-substituted substrate analogues to dissect the contributions of several factors to IspH catalysis, including the coordination of the HMBPP C4-OH group to the iron-sulfur cluster, the H-bonding network in the active site, and the electronic properties of the substrates are reported. PMID:21981393

Xiao, Youli; Chang, Wei-chen; Liu, Hung-wen; Liu, Pinghua



Structure optimization of Prussian blue analogue cathode materials for advanced sodium ion batteries.  


A structure optimized Prussian blue analogue Na1.76Ni0.12Mn0.88[Fe(CN)6]0.98 (PBMN) is synthesized and investigated. Coexistence of inactive Ni(2+) (Fe-C?N-Ni group) with active Mn(2+/3+) (Fe-C?N-Mn group) balances the structural disturbances caused by the redox reactions. This cathode material exhibits particularly excellent cycle life with high capacity (118.2 mA h g(-1)). PMID:25233263

Yang, Dezhi; Xu, Jing; Liao, Xiao-Zhen; He, Yu-Shi; Liu, Haimei; Ma, Zi-Feng



Synthesis of reactive nucleic acid analogues and their application for the study of structure and functions of biopolymers  

NASA Astrophysics Data System (ADS)

Data on the synthesis of reactive derivatives of nucleic acid analogues and their application for the study of structure and functions of biopolymers are generalised. The main types of such analogues including photoactivated reagents containing azidoaryl, halogeno, and thiol groups, psoralen and its derivatives, platinum-based reagents, and nucleic acid analogues containing substituted pyrophosphate or acyl phosphate internucleotide groups are presented. The mechanisms of interaction of these compounds with proteins and nucleic acids are considered. The prospects for the in vivo application of reactive nucleic acids in various systems are discussed. The bibliography includes 76 references.

Kanevskii, Igor'E.; Kuznetsova, Svetlana A.



Quad Trees: A Data Structure for Retrieval on Composite Keys  

Microsoft Academic Search

The quad tree is a data structure appropriate for storing information to be retrieved on composite keys. We discuss the specific case of two-dimensional retrieval, although the structure is easily generalised to arbitrary dimensions. Algorithms are given both for staightforward insertion and for a type of balanced insertion into quad trees. Empirical analyses show that the average time for insertion

Raphael A. Finkel; Jon Louis Bentley



Dissecting the chemical interactions and substrate structural signatures governing RNA polymerase II trigger loop closure by synthetic nucleic acid analogues  

PubMed Central

The trigger loop (TL) of RNA polymerase II (Pol II) is a conserved structural motif that is crucial for Pol II catalytic activity and transcriptional fidelity. The TL remains in an inactive open conformation when the mismatched substrate is bound. In contrast, TL switches from an inactive open state to a closed active state to facilitate nucleotide addition upon the binding of the cognate substrate to the Pol II active site. However, a comprehensive understanding of the specific chemical interactions and substrate structural signatures that are essential to this TL conformational change remains elusive. Here we employed synthetic nucleotide analogues as ‘chemical mutation’ tools coupling with ?-amanitin transcription inhibition assay to systematically dissect the key chemical interactions and structural signatures governing the substrate-coupled TL closure in Saccharomyces cerevisiae Pol II. This study reveals novel insights into understanding the molecular basis of TL conformational transition upon substrate binding during Pol II transcription. This synthetic chemical biology approach may be extended to understand the mechanisms of other RNA polymerases as well as other nucleic acid enzymes in future studies. PMID:24692664

Xu, Liang; Butler, Kyle Vincent; Chong, Jenny; Wengel, Jesper; Kool, Eric T.; Wang, Dong



Structure-activity relationship of gramicidin S analogues on membrane permeability.  


The previous study of the action of gramicidin S on bacteria (Katsu, T., Kobayashi, H. and Fujita, Y. (1986) Biochim. Biophys. Acta 860, 608-619) prompted us to investigate further the structure-activity relationship of the gramicidin S analogues on membrane permeability. Two types of the gramicidin S analogues were used in the present study: (1) cyclo(-X-D-Leu-D-Lys-D-Leu-L-Pro-)2, where X = Gly, D-Leu and D-cyclohexylalanine (D-cHxAla); (2) N,N'-diacetyl derivative of gramicidin S (diacetyl-gramicidin S) which lacks a cationic moiety of gramicidin S. All the analogues have a beta-sheet conformation as gramicidin S. The following cellular systems were used: Staphylococcus aureus as Gram-positive bacteria, Escherichia coli as Gram-negative bacteria, human erythrocytes, rat liver mitochondria and artificial liposomal membranes. It was found that gramicidin S and one of the type 1 analogues having X = D-cHxAla induced the efflux of K+ through the cytoplasmic membrane of all types of the cells. In addition, these two peptides had the ability to lower the phase transition temperature of dipalmitoylphosphatidylcholine. Accordingly, it was concluded that, if peptides can expand greatly the membrane structure of neutral lipids which constitute main parts of the biological membrane, they can stimulate the permeability of cells without any selectivity. The action of the type 2 peptide, diacetyl-gramicidin S, was strongly cell dependent. Although this peptide stimulated the efflux of K+ from mitochondria, it did not do so efficiently, if at all, from S. aureus, E. coli and erythrocytes. In experiments using liposomes, diacetyl-gramicidin S increased markedly the permeability of liposomes composed of egg phosphatidylcholine. The presence of egg phosphatidylethanolamine or cholesterol reduced its activity. These results on liposomes explained well the low sensitivity of diacetyl-gramicidin S against E. coli and erythrocytes in terms of lipid constituents of the membranes. The mechanism of action of diacetyl-gramicidin S was discussed from the formation of a boundary lipid induced by this peptide. PMID:2437956

Katsu, T; Kobayashi, H; Hirota, T; Fujita, Y; Sato, K; Nagai, U



Inhibitory effects of caffeine analogues on neoplastic transformation: structure–activity relationship  

PubMed Central

Some xanthine analogues, including 1,3,7-trimethylxanthine (caffeine) and 1,3-dimethylxanthine (theophylline), have been shown to exert anticancer activities in both cell culture and animal models. The present study focused on the relationship of structure and activity of 50 different caffeine analogues in preventing epidermal growth factor (EGF)-induced malignant transformation of mouse epidermal JB6 promotion-sensitive (P+) Cl41 (JB6 P+) cells. Results indicated that the inhibition of cell transformation by the 1,3,7-trialkylxanthines depends on the number of carbons at the alkyl groups R1 and R3, but not R7. Notably, 1-ethyl-3-hexylxanthine (xanthine 70) was the most effective compound for inhibiting EGF-induced neoplastic transformation among the 50 xanthine analogues tested. The 50% inhibition of cell transformation (ICT50) value for xanthine 70 was 48- or 75-fold less than the ICT50 value of caffeine or theophylline, respectively. Further study revealed that xanthine 70 (5–40 ?M) dose dependently inhibited EGF-induced transactivation of activator protein 1 (AP-1), whereas theophylline or caffeine (up to 500 ?M) had no effect on AP-1 activity. In addition, xanthine 70 (10 ?M) inhibited 12-O-tetradecanoylphorbol-13-acetate- or H-Ras-induced neoplastic transformation in JB6 P+ cells by 78.2 or 62.0%, respectively. Collectively, these results indicated that the number of carbons at R1 and R3 is important for the antitumor-promoting activity of the trialkylxanthines and xanthine 70 might be a promising anticancer agent. PMID:18195054

Rogozin, Evgeny A.; Lee, Ki Won; Kang, Nam Joo; Yu, Haoyu; Nomura, Masaaki; Miyamoto, Ken-Ichi; Conney, Allan H.; Bode, Ann M.; Dong, Zigang



Adherence to RIASEC Structure as a Key Career Decision Construct  

ERIC Educational Resources Information Center

The present study examined the relation between individual cognitive structure and several key career decision variables. Specifically, in a sample of college students enrolled in a career development class, the usage of the RIASEC (Realistic, Investigative, Artistic, Social, Enterprising, and Conventional) circumplex (adherence) was examined as…

Tracey, Terence J. G.



Structural correlation of some heterocyclic chalcone analogues and evaluation of their antioxidant potential.  


A series of six novel heterocyclic chalcone analogues 4(a-f) has been synthesized by condensing 2-acetyl-5-chlorothiophene with benzaldehyde derivatives in methanol at room temperature using a catalytic amount of sodium hydroxide. The newly synthesized compounds are characterized by IR, mass spectra, elemental analysis and melting point. Subsequently; the structures of these compounds were determined using single crystal X-ray diffraction. All the synthesized compounds were screened for their antioxidant potential by employing various in vitro models such as DPPH free radical scavenging assay, ABTS radical scavenging assay, ferric reducing antioxidant power and cupric ion reducing antioxidant capacity. Results reflect the structural impact on the antioxidant ability of the compounds. The IC? values illustrate the mild to good antioxidant activities of the reported compounds. Among them, 4f with a p-methoxy substituent was found to be more potent as antioxidant agent. PMID:24077177

Kumar, C S Chidan; Loh, Wan-Sin; Ooi, Chin Wei; Quah, Ching Kheng; Fun, Hoong-Kun



Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins  

PubMed Central

Ricin A-chain (RTA) and saporin-L1 (SAP) catalyze adenosine depurination of 28S rRNA to inhibit protein synthesis and cause cell death. We present the crystal structures of RTA and SAP in complex with transition state analogue inhibitors. These tight-binding inhibitors mimic the sarcin–ricin recognition loop of 28S rRNA and the dissociative ribocation transition state established for RTA catalysis. RTA and SAP share unique purine-binding geometry with quadruple ?-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the ?-stack provides cationic polarization and enhanced leaving group ability to the susceptible adenine. Common features of these ribosome-inactivating proteins include adenine leaving group activation, a remarkable lack of ribocation stabilization, and conserved glutamates as general bases for activation of the H2O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues. PMID:19920175

Ho, Meng-Chiao; Sturm, Matthew B.; Almo, Steven C.; Schramm, Vern L.



Structural influences on preferential oxazolone versus diketopiperazine b(2+) ion formation for histidine analogue-containing peptides.  


Studies of peptide fragment ion structures are important to aid in the accurate kinetic modeling and prediction of peptide fragmentation pathways for a given sequence. Peptide b(2)(+) ion structures have been of recent interest. While previously studied b(2)(+) ions that contain only aliphatic or simple aromatic residues are oxazolone structures, the HA b(2)(+) ion consists of both oxazolone and diketopiperazine structures. The structures of a series of histidine-analogue-containing Xxx-Ala b(2)(+) ions were studied by using action infrared multiphoton dissociation (IRMPD) spectroscopy, fragment ion hydrogen-deuterium exchange (HDX), and density functional theory (DFT) calculations to systematically probe the influence of different side chain structural elements on the resulting b(2)(+) ion structures formed. The b(2)(+) ions studied include His-Ala (HA), methylated histidine analogues, including ?-methyl-HA and ?-methyl-HA, pyridylalanine (pa) analogues, including 2-(pa)A, 3-(pa)A, and 4-(pa)A, and linear analogues, including diaminobutanoic acid-Ala (DabA) and Lys-Ala (KA). The location and accessibility of the histidine ?-nitrogen, or an amino nitrogen on an aliphatic side chain, were seen to be essential for diketopiperazine formation in addition to the more typical oxazolone structure formation, while blocking or removal of the ?-nitrogen did not change the b(2)(+) ion structures formed. Linear histidine analogues, DabA and KA, formed only diketopiperazine structures, suggesting that a steric interaction in the HisAla case may interfere with the complete trans-cis isomerization of the first amide bond that is necessary for diketopiperazine formation. PMID:22448972

Gucinski, Ashley C; Chamot-Rooke, Julia; Nicol, Edith; Somogyi, Árpád; Wysocki, Vicki H



Structural Influences on Preferential Oxazolone versus Diketopiperazine b2+ Ion Formation for Histidine Analogue-containing Peptides  

PubMed Central

Studies of peptide fragment ion structures are important to aid in the accurate kinetic modeling and prediction of peptide fragmentation pathways for a given sequence. Peptide b2+ ion structures have been of recent interest. While previously studied b2+ ions that contain only aliphatic or simple aromatic residues are oxazolone structures, the HA b2+ ion consists of both oxazolone and diketopiperazine structures. The structures of a series of histidine-analogue-containing Xxx-Ala b2+ ions were studied by using action infrared multiphoton dissociation (IRMPD) spectroscopy, fragment ion hydrogen-deuterium exchange (HDX), and density functional theory (DFT) calculations to systematically probe the influence of different side chain structural elements on the resulting b2+ ion structures formed. The b2+ ions studied include His-Ala (HA), methylated histidine analogues, including pi-methyl-HA and tau-methyl-HA, pyridylalanine (pa) analogues, including 2-(pa)A, 3-(pa)A, and 4-(pa)A, and linear analogues, including diaminobutanoic acid (DabA) and Lys-Ala (KA). The location and accessibility of the histidine pi nitrogen, or an amino nitrogen on an aliphatic side chain, were seen to be essential for diketopiperazine formation in addition to the more typical oxazolone structure formation, while blocking or removal of the tau nitrogen did not change the b2+ ion structures formed. Linear histidine analogues, DabA and KA, formed only diketopiperazine structures, suggesting that a steric interaction in the HisAla case may interfere with the complete trans-cis isomerization of the first amide bond that is necessary for diketopiperazine formation. PMID:22448972

Gucinski, Ashley C.; Chamot-Rooke, Julia; Nicol, Edith; Somogyi, Árpád; Wysocki, Vicki H.



Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationship.  


Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is found in grapes and various medical plants. Among cytotoxic, antifungal, antibacterial cardioprotective activity resveratrol also demonstrates non-selective cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition. In order to find more selective COX-2 inhibitors a series of methoxylated and hydroxylated resveratrol derivatives were synthesized and evaluated for their ability to inhibit both enzymes using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production. Hydroxylated but not methoxylated resveratrol derivatives showed a high rate of inhibition. The most potent resveratrol compounds were 3,3',4',5-tetra-trans-hydroxystilbene (COX-1: IC(50)=4.713, COX-2: IC(50)=0.0113 microM, selectivity index=417.08) and 3,3',4,4',5,5'-hexa-hydroxy-trans-stilbene (COX-1: IC(50)=0.748, COX-2: IC(50)=0.00104 microM, selectivity index=719.23). Their selectivity index was in part higher than celecoxib, a selective COX-2 inhibitor already established on the market (COX-1: IC(50)=19.026, COX-2: IC(50)=0.03482 microM, selectivity index=546.41). Effect of structural parameters on COX-2 inhibition was evaluated by quantitative structure-activity relationship (QSAR) analysis and a high correlation was found with the topological surface area TPSA (r=0.93). Docking studies on both COX-1 and COX-2 protein structures also revealed that hydroxylated but not methoxylated resveratrol analogues are able to bind to the previously identified binding sites of the enzymes. Hydroxylated resveratrol analogues therefore represent a novel class of highly selective COX-2 inhibitors and promising candidates for in vivo studies. PMID:15465334

Murias, Marek; Handler, Norbert; Erker, Thomas; Pleban, Karin; Ecker, Gerhard; Saiko, Philipp; Szekeres, Thomas; Jäger, Walter



Verbenone structural analogues isolated from Artemesia aucheri as natural acaricides against Dermatophagoides spp. and Tyrophagus putrescentiae.  


The acaricidal activities of Artemisia aucheri oil and (1S)-(-)-verbenone structural analogues were evaluated using a fumigant method against Dermatophagoides farinae , Dermatophagoides pteronyssinus , and Tyrophagus putrescentiae and then compared to those of benzyl benzoate. On the basis of the LD50 values against D. farinae , (1S)-(-)-verbenone (1.38 ?g/cm(2)) was about 7.4 times more active than benzyl benzoate (10.15 ?g/cm(2)), followed by (+)-trans-myrtanol (2.27 ?g/cm(2)), (-)-trans-myrtanol (2.30 ?g/cm(2)), and A. aucheri oil (8.75 ?g/cm(2)). (1S)-(-)-Verbenone (1.25 ?g/cm(2)) was approximately 7.8 times more effective against D. pteronyssinus than benzyl benzoate (9.80 ?g/cm(2)), followed by (+)-trans-myrtanol (2.18 ?g/cm(2)), (-)-trans-myrtanol (2.22 ?g/cm(2)), and A. aucheri oil (8.46 ?g/cm(2)). In the case of T. putrescentiae , (1S)-(-)-verbenone (3.75 ?g/cm(2)) was roughly 3.5 times more toxic than benzyl benzoate (13.25 ?g/cm(2)), followed by (+)-trans-myrtanol (12.57 ?g/cm(2)), (-)-trans-myrtanol (12.95 ?g/cm(2)), and A. aucheri oil (11.55 ?g/cm(2)). These results indicate that A. aucheri oil and (1S)-(-)-verbenone structural analogues may be effective natural agents to control house dust and storage mites. PMID:24295367

Yang, Ji-Yeon; Lee, Hoi-Seon



Structure elucidation of a novel analogue of sildenafil detected as an adulterant in an herbal dietary supplement.  


A new analogue of sildenafil was detected in an herbal dietary supplement, which was sold over the internet and promoted as a product for the enhancement of sexual performance. The structure of the compound was established using LC-MS, UV spectroscopy, MS-MS, and NMR. In addition, the compound was cleaved at its sulfonamide S-N bond yielding a sulfonic acid and an amine, which were independently characterized using LC-MS, GC-MS, and derivatization. The compound, named methisosildenafil, is a novel synthetic analogue of sildenafil in which the N-methylpiperazine moiety has been replaced with 2,6-dimethylpiperazine. PMID:17207601

Reepmeyer, John C; Woodruff, Jeffrey T; d'Avignon, D André



Morpho-structural criteria for the identification of volcano deformation processes from analogue modeling  

NASA Astrophysics Data System (ADS)

The morphology of volcanoes provides important information about edifice evolution. Volcanoes can deform by gravitational instability and intrusions. This deformation can compromise volcano structural stability, promoting flank collapse even at dormant edifices. Identification of past/active deformation processes is therefore important not only for the understanding of volcano evolution but also for volcanic hazards. Both deformation due to the flank spreading of a volcano over its weak core and due to the intrusion of a cryptodome in the volcano edifice can produce faulting and changes in the morphology of volcano flanks. These morpho-structural changes in the volcano open the possibility to identify potential deformed and unstable volcanoes using remote sensing techniques and DEMs. We have used analogue models of flank spreading and intrusion processes to make progress in the morpho-structural identification of deformation features which can provide criteria for distinguishing processes. We have geometrically and mechanically scaled two different sets of experiments using a sand-plaster mixture for volcano materials, silicone putty for weak core rocks and Golden Syrup for magma intrusions. For monitoring changes in the volcano morphology we have used a Kinect sensor (Microsoft), which provides us vertical displacements of volcano flanks several times per second with a 1 mm precision. We have synchronized the Kinect sensor with a digital camera for monitoring the spatio-temporal evolution of tectonic structures together with morphology. All experiments produce asymmetrical changes in volcano morphology, developing convex-concave geometries in the deformed flank. However, the spatial relationships of structures with changes in volcano flank curvature are different for the two processes, as noted by previous authors. The morphometric tools developed for analyzing volcano topography allow us to identify intrusion processes due to volcano volume increase. We have compared the results of our experiments with known examples of deformed volcanoes due to intrusions (eg., St Helens) and flank spreading (eg. Casita) and we confirmed that the criteria developed from modeling works well in the natural cases. We consider that further experiments are necessary to fully explore the capacity of application of morphometric tools to analogue modeling of volcano deformation processes, since our first results show a promising research avenue for the remote identification and evaluation of volcano deformation processes in remote volcanoes worldwide.

Rincon, Marta; Marquez, Alvaro; van Wyk de Vries, Benjamin; Herrera, Raquel; Granja Bruña, Jose Luis; Llanes, Pilar



Bispidine analogues of cisplatin, carboplatin, and oxaliplatin. synthesis, structures, and cytotoxicity.  


Bispidine (3,7-diazabicyclo[3.3.1]nonane, C7H14N2) analogues of cisplatin, carboplatin, and oxaliplatin have been prepared. (C7H14N2)PtCl2·DMF (1b), obtained from (1,5-hexadiene)PtCl2 and bispidine in DMF, is dimeric in the solid state. Dissolving 1b in hot N-methylformamide allows crystallization of the solvent-free polymeric (C7H14N2)PtCl2 (1a). Recrystallization of 1a,b from hot water yields the trihydrate (C7H14N2)PtCl2·3H2O (1c). Reaction of 1 with Ag2(cbdca) (cbdca = 1,1-cyclobutanedicarboxylate) in water affords the pentahydrate (C7H14N2)Pt{C4H6(CO2)2}·5H2O (2b), which loses water in vacuo to give (C7H14N2)Pt{C4H6(CO2)2} (2a). Reaction of 1 with AgNO3 in water, followed by addition of Na2C2O4, affords the water-free polymeric (C7H14N2)Pt(C2O4) (3). All complexes have been structurally characterized, revealing various patterns of N-H···Cl and N-H···O hydrogen bonds. In the hydrates 1c and 2b the complexes are embedded in intricate three-dimensional water networks. Complexes 1a, 2a, and 3 have been tested for their cytotoxicity against human cancer cell lines K562 (chronic myeloid leukemia), A2780 (ovarian cancer), and its platinum-resistant subline A2780 CisR and are compared to their parent analogues. The new complexes show significant cytotoxic activity along with a low platinum resistance factor. PMID:24665859

Cui, Huiling; Goddard, Richard; Pörschke, Klaus-Richard; Hamacher, Alexandra; Kassack, Matthias U



Structure of a pancreatic alpha-amylase bound to a substrate analogue at 2.03 A resolution.  

PubMed Central

The structure of pig pancreatic alpha-amylase in complex with carbohydrate inhibitor and proteinaceous inhibitors is known but the successive events occurring at the catalytic center still remain to be elucidated. The X-ray structure analysis of a crystal of pig pancreatic alpha-amylase (PPA, EC soaked with an enzyme-resistant substrate analogue, methyl 4,4'-dithio-alpha-maltotrioside, showed electron density corresponding to the binding of substrate analogue molecules at the active site and at the "second binding site." The electron density observed at the active site was interpreted in terms of overlapping networks of oligosaccharides, which show binding of substrate analogue molecules at subsites prior to and subsequent to the cleavage site. A weaker patch of density observed at subsite -1 (using a nomenclature where the site of hydrolysis is taken to be between subsites -1 and +1) was modeled with water molecules. Conformational changes take place upon substrate analogue binding and the "flexible loop" that constitutes the surface edge of the active site is observed in a specific conformation. This confirms that this loop plays an important role in the recognition and binding of the ligand. The crystal structure was refined at 2.03 A resolution, to an R-factor of 16.0 (Rfree, 18.5). PMID:9385631

Qian, M.; Spinelli, S.; Driguez, H.; Payan, F.



Synthesis of boroxifen, a nido-carborane analogue of tamoxifen.  


A nido-carborane analogue of tamoxifen, the widely employed breast cancer therapy agent, was prepared as an archetype of a potential new class of antiestrogen and boron neutron capture therapy agent in which the carborane is incorporated within the framework of the parent compound. The carborane was introduced through the reaction of 6,9-bis(acetonitrile)decaborane with a unique and highly conjugated ene-yne, which was prepared stereoselectively. NMR spectroscopy and a crystal structure of a key intermediate, the carborane analogue of chloro-tamoxifen, demonstrated the structural similarities between the tamoxifen carboranes and their corresponding phenyl analogues. PMID:11798307

Valliant, John F; Schaffer, Paul; Stephenson, Karin A; Britten, James F



Phenyl-imidazolo-cytidine analogues: structure-photophysical activity relationship and ability to detect single DNA mismatch.  


To expand the arsenal of fluorescent cytidine analogues for the detection of genetic material, we synthesized para-substituted phenyl-imidazolo-cytidine ((Ph)ImC) analogues 5a-g and established a relationship between their structure and fluorescence properties. These analogues were more emissive than cytidine (?em 398-420 nm, ? 0.009-0.687), and excellent correlation was found between ? of 5a-g and ?p(-) of the substituent on the phenyl-imidazolo moiety (R(2) = 0.94). Calculations suggested that the dominant tautomer of (Ph)ImC in methanol solution is identical to that of cytidine. DFT calculations of the stable tautomer of selected (Ph)ImC analogues suggested a relationship between the HOMO-LUMO gap and ? and explained the loss of fluorescence in the nitro analogue. Incorporation of the CF3-(Ph)ImdC analogue into a DNA probe resulted in 6-fold fluorescence quenching of the former. A 17-fold reduction of fluorescence was observed for the G-matched duplex vs ODN(CF3-(Ph)ImdC), while for A-mismatched duplex, only a 2-fold decrease was observed. Furthermore, since the quantum yield of ODN(CF3-(Ph)ImdC):ODN(G) was reduced 17-fold vs that of a single strand, whereas that of ODN(CF3-(Ph)ImdC):ORN(G) was reduced only 3.8-fold, ODN(CF3-(Ph)ImdC) appears to be a DNA-selective probe. We conclude that the ODN(CF3-(Ph)ImdC) probe, exhibiting emission sensitivity upon single nucleotide replacement, may be potentially useful for DNA single nucleotide polymorphism (SNP) typing. PMID:24992467

Kovaliov, Marina; Weitman, Michal; Major, Dan Thomas; Fischer, Bilha



The Grid File: An Adaptable, Symmetric Multi-Key File Structure  

Microsoft Academic Search

Traditional file structures that provide multi-key access to records, for example inverted files, are extensions of file structures originally designed for single-key access. They manifest various deficiencies, in particular for multi-key access to highly dynamic files. We study the dynamic aspects of file structures that treat all keys symmetrically, that is, avoid the distinction between primary key and secondary keys.

Jürg Nievergelt; Hans Hinterberger; Kenneth C. Sevcik



Carbocyclic nucleoside analogues: classification, target enzymes, mechanisms of action and synthesis  

NASA Astrophysics Data System (ADS)

Key biological targets (S-adenosyl-L-homocysteine hydrolase, telomerase, human immunodeficiency virus reverse transcriptase, herpes virus DNA polymerase and hepatitis B virus DNA polymerase) and the mechanisms of action of carbocyclic nucleoside analogues are considered. Structural types of analogues are discussed. Methods of synthesis for the most promising compounds and the spectrum of their biological activities are described. The bibliography includes 126 references.

Matyugina, E. S.; Khandazhinskaya, A. P.; Kochetkov, Sergei N.



Analogue Modeling of Resurgent Calderas: The Role of Prehexisting Tectonic and Volcano-tectonic Structures.  

NASA Astrophysics Data System (ADS)

Analogue models of block resurgence have been carried out on samples previously de- formed in an extensional setting, in order to better understand the role of pre-existing structures. Two lines of experiments were performed by superposition of two different equipments to simulate: a) resurgence in an area with a simple graben-like structure; b) ersurgence in an area with a caldera collapsed within the previously generated graben- like structure. We used dry sand to simulate the brittle crust and silicone to simulate the intruding magma. It has been observed that in the sample in which no caldera col- lapses were simulated, resurgence occurs through the formation of a discrete number of differentially displaced blocks. The most uplifted block is bordered, along one side, by a newly formed, high-angle, inward dipping reverse fault, that causes horizon- tal shortening of the sample. To accomodate the resulting shortening, normal faults with similar orientations forms in the opposite side together with the reactivation of the pre-existent graben faults. This asymmetric block resurgence that determine the generation of a compressional stress regime along one side and an extensional stress regime along the opposite side has been also observed in the experiments performed with a previous caldera collapse. In this case the reverse ring fault that accommodate the caldera collapse is completely erased along the shortened side, and enhance the effect of the extensional faults on the opposite side, facilitating the intrusion of the silicone. In nature this kind of behaviour has been widely described for the resurgent calderas of Campi Flegrei, Ischia and Pantelleria.

de Vita, S.; Marotta, E.; Orsi, G.; Acocella, V.; Funiciello, R.; Cifelli, F.


Structural analogues of homoeriodictyol as flavor modifiers. Part III: short chain gingerdione derivatives.  


In order to find new flavor modifiers, various short chain gingerdione derivatives were synthesized as structural analogues of the known bitter masker homoeriodictyol and evaluated by a sensory panel for masking and sweetness enhancing activities. 1-(4-Hydroxy-3-methoxyphenyl)hexa-3,5-dione ([2]-gingerdione) and the homologue 1-(4-hydroxy-3-methoxyphenyl)hepta-3,5-dione ([3]-gingerdione) at concentration ranges 50-500 mg kg (-1) showed the most promising masking activity of 20-30% against bitterness of a 500 mg kg (-1) aqueous caffeine solution. Additionally, both compounds were able to reduce the bitterness of a 5 mg kg (-1) quinine solution by about 20%; however, the bitter tastes of salicine, the model peptide H-Leu-Trp-OH, and KCl solutions were not reduced. Whereas for bitter masking activity a vanillyl moiety seems to be important, some of the tested isovanillyl isomers showed an interesting sweet enhancing effect without exhibiting a significant intrinsic sweetness. The isomer 1-(3-hydroxy-4-methoxyphenyl)hexa-3,5-dione ([2]-isogingerdione) at 100 mg kg (-1) caused a significant and synergistic increase of 27% of sweet taste of a 5% sucrose solution. PMID:18598048

Ley, Jakob P; Paetz, Susanne; Blings, Maria; Hoffmann-Lücke, Petra; Bertram, Heinz-Jürgen; Krammer, Gerhard E



The Manicouagan impact structure as a terrestrial analogue site for lunar and martian planetary science  

NASA Astrophysics Data System (ADS)

The 90 km diameter, late Triassic Manicouagan impact structure of Québec, Canada, is a well-preserved, undeformed complex crater possessing an anorthositic central uplift and a 55 km diameter melt sheet. As such, it provides a valuable terrestrial analogue for impact structures developed on other planetary bodies, especially the Moon and Mars, which are currently the focus of exploration initiatives. The scientific value of Manicouagan has recently been enhanced due to the production, between 1994 and 2006, of ˜18 km of drill core from 38 holes by the mineral exploration industry. Three of these holes are in excess of 1.5 km deep, with the deepest reaching 1.8 km. Here we combine recent field work, sampling and the drill core data with previous knowledge to provide insight into processes occurring at Manicouagan and, by inference, within extraterrestrial impact structures. Four areas of comparative planetology are discussed: impact melt sheets, central uplifts, impact-generated hydrothermal regimes and footwall breccias. Human training and instrument testing opportunities are also considered. The drill core reveals that the impact melt and clast-bearing impact melts in the centre of the structure reach thicknesses of 1.4 km. The 1.1 km thick impact melt has undergone differentiation to yield a lower monzodiorite, a transitional quartz monzodiorite and an upper quartz monzonite sequence. This calls into question the previous citing of Manicouagan as an exemplar of a relatively large crater possessing an undifferentiated melt sheet, which was used as a rationale for assigning different composition lunar impact melts and clast-bearing impact melts to separate cratering events. The predominantly anorthositic central uplift at Manicouagan is comparable to certain lunar highlands material, with morphometric analogies to the King, Tycho, Pythagoras, Jackson, and Copernicus impact structures, which have similar diameters and uplift structure. Excellent exposure of the Manicouagan uplift facilitates mapping and an appraisal of its formation and collapse mechanisms, enhanced by drill core data from the centre of the structure. Recent field studies at the edge of the central island at Manicouagan, and multiple drill core sections through footwall lithologies, provide insight into allochthonous (clastic and suevitic) and autochthonous breccia formation, as well as shock effects. The hydrothermal regimes developed at Manicouagan are akin to systems proposed for Noachian (>3.5 Ga) Mars that involve alteration of impact melts via meteoritic and surface waters, with the generation of phyllosilicates, zeolites, hematite, sulfates and sulfides that can contribute to martian soil formation and sedimentation processes.

Spray, John G.; Thompson, Lucy M.; Biren, Marc B.; O'Connell-Cooper, Catherine



Structural bisphenol analogues differentially target steroidogenesis in murine MA-10 Leydig cells as well as the glucocorticoid receptor.  


Although much information on the endocrine activity of bisphenol A (BPA) is available, a proper human hazard assessment of analogues that are believed to have a less harmful toxicity profile is lacking. Here the possible effects of BPA, bisphenol F (BPF), bisphenol S (BPS), as well as the brominated structural analogue and widely used flame retardant tetrabromobisphenol A (TBBPA) on human glucocorticoid and androgen receptor (GR and AR) activation were assessed. BPA, BPF, and TBBPA showed clear GR and AR antagonism with IC50 values of 67?M, 60?M, and 22nM for GR, and 39?M, 20?M, and 982nM for AR, respectively, whereas BPS did not affect receptor activity. In addition, murine MA-10 Leydig cells exposed to the bisphenol analogues were assessed for changes in secreted steroid hormone levels. Testicular steroidogenesis was altered by all bisphenol analogues tested. TBBPA effects were more directed towards the male end products and induced testosterone synthesis, while BPF and BPS predominantly increased the levels of progestagens that are formed in the beginning of the steroidogenic pathway. The MA-10 Leydig cell assay shows added value over the widely used H295R steroidogenesis assay because of its fetal-like characteristics and specificity for the physiologically more relevant testicular ?4 steroidogenic pathway. Therefore, adding an in vitro assay covering fetal testicular steroidogenesis, such as the MA-10 cell line, to the panel of tests used to screen potential endocrine disruptors, is highly recommendable. PMID:25576683

Roelofs, Maarke J E; Berg, Martin van den; Bovee, Toine F H; Piersma, Aldert H; Duursen, Majorie B M van



Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues  

PubMed Central

2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, (±)-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of (±)-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of (±)-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT. PMID:24494745



Structure-activity relationships of dynorphin a analogues modified in the address sequence.  


The peptide [Pro3]Dyn A(1-11)-NH2 2 exhibits high affinity (K(i) = 2.4 nM) and over 2000-fold selectivity for the opioid receptor. Stepwise removal of the C-terminal residues from this ligand demonstrated that its positively charged Arg residues, particularly Arg6 and Arg7, were crucial for binding to the kappa receptor. Analogues shorter than seven amino acids lacked significant affinity for opioid receptors. Comparison with a series of truncated analogues of Dyn A showed that the relative losses in binding potency differed only slightly between the two series. The neutral residues Ile8 and Pro10 could be removed without significant loss in affinity for the kappa receptor. Their replacement, in the Pro3 analogue, with additional Arg residues led to analogues with improved kappa affinity (e.g., [Pro3,Arg8]Dyn A(1-11)-NH2 20: K(i)(kappa) = 0.44 nM). This type of modification did not compromise the high kappa selectivity of the Pro3 analogues. These findings support the view that a negatively charged domain in the putative second extracellular loop of the kappa receptor selectively recognizes residues 6-11 of dynorphin through electrostatic interactions. As with parent compound 2, analogue 20 and related compounds displayed kappa antagonist properties. PMID:12747782

Schlechtingen, Georg; DeHaven, Robert N; Daubert, Jeffrey D; Cassel, Joel A; Chung, Nga N; Schiller, Peter W; Taulane, Joseph P; Goodman, Murray



Biofunctional constituent isolated from Citrullus colocynthis fruits and structure-activity relationships of its analogues show acaricidal and insecticidal efficacy.  


The acaricidal and insecticidal potential of the active constituent isolated from Citrullus colocynthis fruits and its structurally related analogues was evaluated by performing leaf disk, contact toxicity, and fumigant toxicity bioassays against Tetranychus urticae, Sitophilus oryzae, and Sitophilus zeamais adults. The active constituent of C. colocynthis fruits was isolated by chromatographic techniques and was identified as 4-methylquinoline on the basis of spectroscopic analyses. To investigate the structure-activity relationships, 4-methylquinoline and its structural analogues were tested against mites and two insect pests. On the basis of the LC50 values, 7,8-benzoquinoline was the most effective against T. urticae. Quinoline, 8-hydroxyquinoline, 2-methylquinoline, 4-methylquinoline, 6-methylquinoline, 8-methylquinoline, and 7,8-benzoquinoline showed high insecticidal activities against S. oryzae and S. zeamais regardless of the application method. These results indicate that introduction of a functional group into the quinoline skeleton and changing the position of the group have an important influence on the acaricidal and insecticidal activities. Furthermore, 4-methylquinoline isolated from C. colocynthis fruits, along with its structural analogues, could be effective natural pesticides for managing spider mites and stored grain weevils. PMID:25110971

Jeon, Ju-Hyun; Lee, Hoi-Seon



DNA binding ellipticine analogues: synthesis, biological evaluation, and structure-activity relationships.  


In connection with our interest in the synthesis and study of the biological properties of ellipticine analogues as anticancer agents, some 7H-pyrido[2,3-c]carbazoles (7H-PyC) and their corresponding tetrahydro derivatives (7H-THPyC) were synthesized. A common multistep pathway characterized by conventional reactions involving carbazole Fischer and Conrad-Limpach quinoline syntheses yielded the tetracyclic compounds. With the aim to improve the cytotoxic activity of the new 7H-PyC derivatives, we provided them with one or two diethylaminoethyl side chains. The new THPyCs, PyCs, and smaller pyrroloquinoline (PQ) derivatives were tested for their in vitro cytotoxic properties against several human tumor cell lines. Most of the compounds tested showed considerable cytotoxic activity, particularly compound 24, which, with two basic alkylamino chains, has IC(50) values in the sub-micromolar range, about one order of magnitude lower than those of the reference compound, ellipticine. Chemosensitivity tests on cisplatin-, mitoxantrone-, and multidrug-resistant (MDR) phenotypes indicated that compound 24 shows no cross-resistance; this suggests that, besides not being a potential MDR substrate, it might act as a mixed inhibitor of topoisomerases I and II. Flow cytometric and caspase-3 activation analyses revealed that 24 induces a caspase-3-dependent apoptotic cell-death mechanism. Linear dichroism and unwinding experiments suggested that the most active compounds act as DNA intercalators. For compound 24, an inhibitory concentration-dependent effect on topoisomerases II and I was demonstrated. Herein we discuss interesting structure-activity relationships with respect to molecular size and planarity, as well as the substitution and position of one side chain on the PyC nucleus, in comparison with corresponding smaller PQs. PMID:19197924

Ferlin, Maria Grazia; Marzano, Christine; Gandin, Valentina; Dall'Acqua, Stefano; Dalla Via, Lisa



Extracellular cellobiose lipid from yeast and their analogues: structures and fungicidal activities.  


Basidiomycetous yeasts Cryptococcus humicola and Pseudozyma fusiformata secrete cellobiose lipids into the culture broth. In the case of Cr. humicola, 16-(tetra-O-acetyl-beta-cellobiosyloxy)-2-hydroxyhexadecanoic acid was defined as major product and 16-(tetra-O-acetyl-beta-cellobiosyloxy)-2,15-dihydrohexadecanoic acid was defined as minor product, while Ps. fusiformata secreted mainly 16-[6-O-acetyl-2'-O-(3-hydroxyhexanoyl)-beta-cellobiosyloxy)-2,15-dihydroxyhexadecanoic acid. These compounds exhibit similar fungicidal activities against different yeasts including pathogenic Cryptococcus and Candida species. The cells of Filobasidiella neoformans causing systemic cryptococcosis completely died after 30-min incubation with 0.02 mg mL(-1) of cellobiose lipids. The same effect on ascomycetous yeast, including pathogenic Candida species, is achieved at 0.1-0.3 mg mL(-1) of cellobiose lipids depending on the test culture used. Cellobiose lipid of Ps. fusiformata inhibits the growth of phytopathogenic fungi Sclerotinia sclerotiorum and Phomopsis helianthi more efficiently than cellobiose lipids from Cr. humicola. Fully O-deacylated analogue, namely 16-(beta-cellobiosyloxy)-2-hydroxyhexadecanoic acid, and totally synthetic compound, 16-(beta-cellobiosyloxy)-hexadecanoic acid, do not inhibit the growth of F. neoformans and Saccharomyces cerevisiae, while 16-(beta-cellobiosyloxy)-2,15-dihydroxyhexadecanoic acid inhibits the growth of both test cultures but at higher concentrations than cellobiose lipids of Cr. humicola and Ps. fusiformata. The amide of 16-(beta-cellobiosyloxy)-2,15-dihydroxyhexadecanoic acid possessed no fungicide activity. Thus, the structures of both the carbohydrate part and fatty acid aglycon moiety are important for the fungicidal activity of cellobiose lipids. PMID:19202311

Kulakovskaya, Tatyana; Shashkov, Alexander; Kulakovskaya, Ekaterina; Golubev, Wladyslav; Zinin, Alexander; Tsvetkov, Yury; Grachev, Alexey; Nifantiev, Nikolay



Synthesis, structure-activity analysis, and biological evaluation of sanguinamide B analogues.  


We report the first synthesis of sanguinamide B analogues. Substituting N-methylated (N-Me) amino acids, glycine (Gly), and L- or D-phenylalanine (Phe) into the backbone of sanguinamide B showed that only l- and d-Phe residues controlled the macrocycle conformation. The N-methylated and glycine analogues all had multiple conformations, whereas the L- and D-Phe derivatives only had a single conformation. Testing of all conformer analogues showed that inclusion of an L- or D-Phe was a superior design element than incorporating the N-Me moiety that is often utilized to control macrocyclic conformation. Finally, we show that there is an ideal Phe residue (in this case L-Phe) for generating compounds that have the greatest inhibitory effect on bacterial motility. Our data support the hypothesis that the macrocyclic conformation is dictated by the benzyl moiety requiring a "pseudoequatorial" position, and all other energy considerations are secondary. PMID:23050835

Wahyudi, Hendra; Tantisantisom, Worawan; Liu, Xuechao; Ramsey, Deborah M; Singh, Erinprit K; McAlpine, Shelli R



Synthesis, properties and structures of NbOF3 complexes and comparisons with NbOCl3 analogues.  


The first series of complexes of niobium(v) oxide trifluoride, [NbOF3(OPR3)2] (R = Me or Ph), [NbOF3(dppmO2)] (dppmO2 = Ph2P(O)CH2P(O)Ph2), [NbOF3(dmso)2], [NbOF3(tmeda)] (tmeda = Me2N(CH2)2NMe2) and [NbOF3(diimine)] (diimine = 2,2'-bipy, 1,10-phen) have been prepared, either by reaction of the corresponding complexes of NbF5 and hexamethyldisiloxane (HMDSO) in CH2Cl2-MeCN solution, or directly from NbF5, ligand and HMDSO. They were characterised by IR, (1)H, (31)P{(1)H} and (19)F{(1)H} NMR spectroscopy, and X-ray crystal structures are reported for [NbOF3(OPR3)2] (R = Me or Ph) and [NbOF3(dppmO2)]. Complexes of NbOCl3, [NbOCl3(OPPh3)2], [NbOCl3(dppmO2)], [NbOCl3(dppeO2)] (dppeO2 = Ph2P(O)(CH2)2P(O)Ph2), [NbOCl3(tmeda)] and [NbOCl3(diimine)] were made from NbCl5 and HMDSO in MeCN (which forms [NbOCl3(MeCN)2] in situ), followed by addition of the neutral ligand. Their properties are compared with the oxide fluoride analogues. X-ray structures are reported for [NbOCl3(dppmO2)], [NbOCl3(dppeO2)], [NbOCl3(tmeda)] and [NbOCl3(2,2'-bipy)]. The synthesis and spectroscopic characterisation of [MF5L] (M = Nb or Ta; L = OPR3, OAsPh3) and [MF4(diimine)2][MF6] are also described, and the key properties of the four series of complexes compared. PMID:24413623

Levason, William; Reid, Gillian; Trayer, Jonathan; Zhang, Wenjian



A Ground Penetrating Radar Lunar Analogue Field Campaign in the Haughton Impact Structure, Canada  

NASA Astrophysics Data System (ADS)

Ground-Penetrating Radar (GPR) has been widely cited as an important scientific instrument for future Moon and Mars surface exploration missions. In support of GPR technique testing for lunar subsurface exploration, a series of overlapping 3D GPR surveys were conducted over impact melt rocks in the 39 Ma, 23 km diameter Haughton impact structure, Devon Island, Nunavut, Canada. The target consisted of calcite-dominated clast-rich impact melt rock with permafrost at depths less than one metre. The target rocks were chosen as a physical analogue to lunar electrical conditions: the electrical permittivity and conductivity in ice produce a better match for lunar electrical conditions than liquid water bearing sites. Using commercially available equipment, 50, 100 and 200 MHz GPR surveys were conducted in a high-resolution grid 30m by 30m totalling nearly 14 km of GPR lines. Lines ran in both X and Y directions with the following line spacings: 50 cm for 50 MHz for a total of 122 lines; 50 cm with a subset at 25 cm at 100 MHz totalling 162 lines; and subsets of the grid were done at 25 and 10 cm line spacings at 200 MHz totalling 182 lines. CMP surveys at each frequency were performed to provide velocity information for the active and permafrost layers with results ranging from 0.068 to 0.088 m/ns. Physical samples were obtained to confirm the electrical properties of the survey site for use in comparative modelling. Initial data show some shallow dipping features which vanish at depths of approximately 7, 4 and 2.5 metres at 50, 100 and 200 MHz respectively. These data are compared to a 100 MHz transect of nearby non-brecciated dolomitic limestone which shares a weathering processes and is compositionally similar. In the non-brecciated materials, clear reflectors are visible beyond a depth of 8 metres at 100 MHz. Thus, preliminary results show higher effective attenuation in the breccia than can be explained by conductivity alone. This suggests that the brecciated and melted medium is increasing signal attenuation due to scattering processes. This additional attenuation has implications for the usefulness of GPR as an exploration method in lunar mediums, particularly in seeing through regolith and impact breccias. Additional modelling and field surveys at other terrestrial impact structures are planned to confirm these results.

Unrau, T.; Tiampo, K. F.; Pratt, R. G.; Osinski, G.



A structure-based 3D-QSAR study of anthrapyrazole analogues of the anticancer agents losoxantrone and piroxantrone.  


A series of 13 anthrapyrazole compounds that are analogues of piroxantrone and losoxantrone were synthesized, and their cell growth inhibitory effects, DNA binding, topoisomerase IIalpha mediated (EC cleavage of DNA, and inhibition of DNA topoisomerase IIalpha decatenation catalytic activities were determined. Cell growth inhibitory activity was well-correlated with DNA binding, suggesting that these compounds may act by targeting DNA. However, cell growth inhibition was not well-correlated with the inhibition of topoisomerase IIalpha catalytic activity, suggesting that these anthrapyrazoles did not act solely by inhibiting the catalytic activity of topoisomerase II. Most of the analogues were able to induce DNA cleavage, and thus, it was concluded that they acted, at least in part, as topoisomerase II poisons. Structure-based three-dimensional quantitative structure-activity analyses (3D-QSAR) were carried out on the aligned structures of the anthrapyrazoles docked into DNA using comparative molecular field analysis (CoMFA) and comparative molecular similarity index (CoMSIA) analyses in order to determine the structural features responsible for their activity. Both CoMFA and CoMSIA yielded statistically significant models upon partial least-squares analyses. The 3D-QSAR analyses showed that hydrogen-bond donor interactions and electrostatic interactions with the protonated amino side chains of the anthrapyrazoles led to high cell growth inhibitory activity. PMID:16859314

Liang, Hong; Wu, Xing; Guziec, Lynn J; Guziec, Frank S; Larson, Kimberly K; Lang, Jennifer; Yalowich, Jack C; Hasinoff, Brian B



Structural Analogues of Smoothened Intracellular Loops as Potent Inhibitors of Hedgehog Pathway and Cancer Cell Growth  

PubMed Central

Smoothened is a critical component of the Hedgehog pathway that is essential for stem cell renewal and is dysregulated in many cancer types. We have found synthetic analogues of the second and third intracellular loops of smoothened to be potent inhibitors of the Hedgehog pathway. Palmitoylated peptides as short as 10 residues inhibited melanoma cells growth with IC50 in the low nanomolar range. The compounds are promising drug candidates and convenient tools for solving mechanisms of Hedgehog signaling. PMID:17685505

Remsberg, Jarrett R.; Lou, Hong; Tarasov, Sergey G.; Dean, Michael; Tarasova, Nadya I.



Structure-activity relationship studies on cholecystokinin: Analogues with partial agonist activity  

SciTech Connect

In the present study, hepta- and octapeptide analogues of the C-terminal part of cholecystokinin, modified on the C-terminal phenylalanine residue, were synthesized. CCK analogues were prepared in which the peptide bond between aspartic acid and phenylalanine had or had not been modified and were lacking the C-terminal primary amide function. These CCK derivatives were able to cause full stimulation of amylase release from rat pancreatic acini but without a decrease in amylase release at supramaximal concentrations. There was a close relationship between the abilities of these derivatives to stimulate amylase release and their abilities to inhibit binding of {sup 125}I-BH-CCK-9 to CCK receptors on rat and guinea pig pancreatic acini. These CCK analogues were also able to recognize the guinea pig brain CCK receptors, some of them being particularly potent. The findings indicate that the aromatic ring of phenylalanine is important for the binding to brain and pancreatic CCK receptors, whereas the C-terminal primary amide function is not essential for the binding to pancreatic CCK receptors but is crucial for biological activity of rat pancreatic acini.

Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. (Centre de Pharmacologie-Endocrinologie, Montpellier (France))



Biosynthetic incorporation of tryptophan analogues into staphylococcal nuclease: effect of 5-hydroxytryptophan and 7-azatryptophan on structure and stability.  

PubMed Central

5-Hydroxytryptophan (5HW) and 7-azatryptophan (7AW) are analogue of tryptophan that potentially can be incorporated biosynthetically into proteins and used as spectroscopic probes for studying protein-DNA and protein-protein complexes. The utility of these probes will depend on the extent to which they can be incorporated and the demonstration that they cause minimal perturbation of a protein's structure and stability. To investigate these factors in a model protein, we have incorporated 5HW and 7AW biosynthetically into staphylococcal nuclease A, using a trp auxotroph Escherichia coli expression system containing the temperature-sensitive lambda cI repressor, Both tryptophan analogues are incorporated into the protein with good efficiency. From analysis of absorption spectra, we estimate approximately 95% incorporation of 5HW into position 140 of nuclease, and we estimate approximately 98% incorporation of 7AW, CD spectra of the nuclease variants are similar to that of the tryptophan-containing protein, indicating that the degree of secondary structure is not changed by the tryptophan analogues. Steady-state fluorescence data show emission maxima of 338 nm for 5HW-containing nuclease and 355 nm for 7AW-containing nuclease. Time-resolved fluorescence intensity and anisotropy measurements indicate that the incorporated 5HW residue, like tryptophan at position 140, has a dominant rotational correlation time that is approximately the value expected for global rotation of the protein. Guanidine-hydrochloride-induced unfolding studies show the unfolding transition to be two-state for 5HW-containing protein, with a free energy change for unfolding that is equal to that of the tryptophan-containing protein. In contrast, the guanidine-hydrochloride-induced unfolding of 7AW-containing nuclease appears to show a non-two-state transition, with the apparent stability of the protein being less than that of the tryptophan form. PMID:9070451

Wong, C. Y.; Eftink, M. R.



Structure-activity relationship of indomethacin analogues for MRP-1, COX-1 and COX-2 inhibition. identification of novel chemotherapeutic drug resistance modulators.  


We report the screening of analogues of indomethacin to investigate the structure-activity relationship (SAR) of indomethacin-mediated multidrug resistance associated protein-1 (MRP-1) inhibition. By examining the activities of compounds with minor variations of the parent structure, we were able to separate MRP-1, glutathione-S-transferase (GST), cyclooxygenase (COX)-1 and COX-2 inhibitory activities. Combination cytotoxicity assays were utilised to identify agents which possess synergistic potential in MRP-1-expressing cell lines. MRP-1 Inside Out Vesicles (IOVs) were utilised to demonstrate the ability of the indomethacin analogues to inhibit the pump directly. Most of the indomethacin analogues active as MRP-1 inhibitors were poor GST inhibitors when compared with the GST-inhibitory activity of indomethacin. Two of the MRP-1 inhibitory analogues were found to have no COX-1 inhibitory activity and low COX-2 inhibitory activity, suggesting potentially reduced clinical toxicity. One MRP-1 inhibitory indomethacin analogue was also found to have low COX-1 inhibitory activity, but significant COX-2 inhibitory activity, making this analogue again interesting in terms of low potential toxicity, but with the possibility of direct inhibitory effects on tumour growth. PMID:12142058

Touhey, S; O'Connor, R; Plunkett, S; Maguire, A; Clynes, M



Quantitative structure-activity analysis of acetylcholinesterase inhibition by oxono and thiono analogues of organophosphorus compounds. (Reannouncement with new availability information)  

SciTech Connect

A comparison of the bimolecular rate constants (ki) for inhibition of electric eel acetylcholinesterase (AChE) by the oxono (i.e., P=O) and thiono (i.e., P=S) analogues of parathion, methylparathion, leptophos, fonofos, sarin, and soman revealed that the oxono/thiono ratios of ki values varied from 14 for soman to 1240 for parathion. Analysis of the relative importance of the dissociation equilibrium constant and the phosphorylation rate constant in producing this variation in ki values indicated that the oxono analogues had phosphorylation rate constant values that varied in a narrow range from 8- to 14-fold greater than their thiono counterparts, while the oxono/thiono ratios for dissociation constants varied widely from 1 for soman to 82 for fonofos. The lower affinities of thiono analogues for AChE probably resulted from differences in the hydrophobic binding of oxono and thiono analogues to the active site of AChE, inasmuch as the hydrophobicities (i.e., octanol/water partition coefficients) of thiono organophosphorus compounds were much greater than the hydrophobicities of their oxono analogues. Quantitative structure-activity analysis indicated that the hydrophobic effects of oxono and thiono moieties correlated with log ki for AChE inhibition to a greater extent (r2 = 0.79) than their electronic effects (r2 equal to or less than 0.48). These observations suggest that the differences in hydrophobicity of oxono and thiono analogues of organophosphorus compounds may be as important as their electronic differences in determining their effectiveness as AChE inhibitors. Acetylcholinesterase, soman (GD), structure-activity analysis inhibition, oxono analogues, thiono analogues.

Maxwell, D.M.; Brecht, K.M.



Three-dimensional quantitative structure-activity relationship study on antioxidant capacity of curcumin analogues  

NASA Astrophysics Data System (ADS)

A comparative molecular similarity indices analysis (CoMSIA) was performed on a set of 27 curcumin-like diarylpentanoid analogues with the radical scavenging activities. A significant cross-validated correlation coefficient Q2 (0.784), SEP (0.042) for CoMSIA were obtained, indicating the statistical significance of the correlation. Further we adopt a rational approach toward the selection of substituents at various positions in our scaffold,and finally find the favored and disfavoured regions for the enhanced antioxidative activity. The results have been used as a guide to design compounds that, potentially, have better activity against oxidative damage.

Chen, Bohong; Zhu, Zhibo; Chen, Min; Dong, Wenqi; Li, Zhen



Use of a hydrolytic procedure and spectrometric methods in the structure elucidation of a thiocarbonyl analogue of sildenafil detected as an adulterant in an over-the-counter herbal aphrodisiac.  


A sildenafil-related compound was detected in an herbal dietary supplement marketed as an aphrodisiac. The compound was identified as an analogue of sildenafil in which the carbonyl group in the pyrimidine ring of sildenafil was substituted with a thiocarbonyl group, and the methyl group on the piperazine ring was substituted with a hydroxyethyl group. Based on this structure, the compound was named thiohydroxyhomosildenafil. The structure of the compound was established using HPLCIMS, UV spectrometry, electrospray ionization-MS/MS, NMR spectrometry, and a hydrolytic process. One key product of hydrolysis was 1-(2-hydroxyethyl)-piperazine; the identification of this product defined the amine portion of the compound. Another key product of hydrolysis was hydroxyhomosildenafil, generated by hydrolysis of the thiocarbonyl group to a carbonyl group (C = S --> C = O). Hydroxyhomosildenafil was detected as a minor component in the dietary supplement. PMID:19916370

Reepmeyer, John C; D'Avignon, D André



Structural and vibrational properties of tetraoxaporphyrin dication, the oxygen analogue of porphyrin, and of isoelectronic diprotonated porphyrin.  


Structural calculations by means of the density functional method have been performed on tetraoxaporphyrin dication and on isoelectronic diprotonated porphyrin as well as on the sulfur and carbon analogues of porphyrin. A detailed study of the stable conformations of these compounds is reported starting with the most symmetrical conformations and lowering the symmetry along the vibrational coordinates with imaginary frequency. The calculated geometries are related to experimental structures available from X-ray diffraction studies. The Raman spectra of tetraoxaporphyrin dication exciting with micro-Raman instrumentation at 785 nm and of diprotonated porphyrin in near-resonance conditions with the Soret band have been measured. The correlation between frequencies calculated with the DF/B3-LYP/cc-pVDZ procedure for porphyrin, diprotonated porphyrin, and tetraoxaporphyrin dication has allowed for making a vibrational assignment for the latter two systems in excellent agreement with experiment using a single frequency scale factor. PMID:16838910

Jelovica, Ivana; Moroni, Laura; Gellini, Cristina; Salvi, Pier Remigio; Orli?, Nada



Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms.  


Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ?26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance. PMID:23327489

Salas, Paloma F; Herrmann, Christoph; Cawthray, Jacqueline F; Nimphius, Corinna; Kenkel, Alexander; Chen, Jessie; de Kock, Carmen; Smith, Peter J; Patrick, Brian O; Adam, Michael J; Orvig, Chris



Characterizing, identifying and mapping structural domains at rifted continental margins: insights from the Bay of Biscay margins and its Pyrenean fossil analogue  

NASA Astrophysics Data System (ADS)

The occurrence of hyperextended domains at rifted continental margins consisting of extremely thinned crust and/or exhumed mantle has been increasingly recognized over the past decades, both at present-day rifted margins and in deformed remnants preserved in collisional orogens. At present, most studies aiming to characterize rifted continental margin structure and the extreme thinning of the continental crust and lithosphere are either focused offshore using geophysical methods, or onshore on fossil analogues relying on geological field observations. Marine and onland examples provide complementary datasets, but their different scale and resolution of observations prevent straightforward correlations to be done. In this contribution, we use the Bay of Biscay and Western Pyrenees to develop and apply a geological/geophysical approach to characterize and identify distinctive rifted margin domains both in offshore and onshore settings. The Bay of Biscay and Western Pyrenees represent a unique natural laboratory that offer the possibility to have access to seismically imaged, drilled and exposed parts of one and the same hyperextended rift system. Quantitative techniques (gravity inversion and flexural backstripping) are used on offshore examples (Western Approach margin and Parentis basin) to estimate accommodation space, crustal thickness and lithosphere thinning while seismic interpretations enable the recognition of extensional settings (low- and high-? settings). Field observations (Mauléon basin) and drill-hole data (Parentis basin) focused on key outcrops enables the description of the nature of sediment and basement rocks and of the structures forming fossil remnants of rifted margins. This qualitative and quantitative characterisation provides diagnostic elements to identify and map structural domains at magma-poor rifted margins and their fossil analogues. We name these 5 domains proximal, necking, hyperthinned, exhumed mantle and oceanic. This new geological/geophysical approach can be further used as an interface between onshore and offshore observations. Offshore seismic interpretations can take advantage of onshore observations on the nature of sediment, basement and of their interface. The large scale geometry and stratigraphic architecture imaged offshore can be used to restore onshore fossil remnants back into a rifted margin context. The application of this multidisciplinary approach to the Bay of Biscay margins and their onshore Pyrenean fossils remnants enables us to propose a new map of the different rift systems preserved at the transition between the European and Iberian plates. The approach underlying this mapping has general global application to unravelling the spatial and temporal complexity of rifted margin structural domains.

Tugend, Julie; Manatschal, Gianreto; Kusznir, Nick J.




EPA Science Inventory

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...


Key Derivation Algorithms for Monotone Access Structures in Large File Systems  

E-print Network

Key Derivation Algorithms for Monotone Access Structures in Large File Systems Mudhakar Srivatsa policies on the file system? The former problem is handled using a cryptographic file system, while management algorithms to support monotone access structures on large file systems. We use key derivation

Liu, Ling


Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2.  


Melatonin exerts its biological effects through at least two transmembrane G-protein-coupled receptors, MT1 and MT2, and a lower-affinity cytosolic binding site, designated MT3. MT3 has recently been identified as QR2 (quinone reductase 2) (EC which is of significance since it links the antioxidant effects of melatonin to a mechanism of action. Initially, QR2 was believed to function analogously to QR1 in protecting cells from highly reactive quinones. However, recent studies indicate that QR2 may actually transform certain quinone substrates into more highly reactive compounds capable of causing cellular damage. Therefore it is hypothesized that inhibition of QR2 in certain cases may lead to protection of cells against these highly reactive species. Since melatonin is known to inhibit QR2 activity, but its binding site and mode of inhibition are not known, we determined the mechanism of inhibition of QR2 by melatonin and a series of melatonin and 5-hydroxytryptamine (serotonin) analogues, and we determined the X-ray structures of melatonin and 2-iodomelatonin in complex with QR2 to between 1.5 and 1.8 A (1 A=0.1 nm) resolution. Finally, the thermodynamic binding constants for melatonin and 2-iodomelatonin were determined by ITC (isothermal titration calorimetry). The kinetic results indicate that melatonin is a competitive inhibitor against N-methyldihydronicotinamide (K(i)=7.2 microM) and uncompetitive against menadione (K(i)=92 microM), and the X-ray structures shows that melatonin binds in multiple orientations within the active sites of the QR2 dimer as opposed to an allosteric site. These results provide new insights into the binding mechanisms of melatonin and analogues to QR2. PMID:18254726

Calamini, Barbara; Santarsiero, Bernard D; Boutin, Jean A; Mesecar, Andrew D



Identification of enterodiol as a masker for caffeine bitterness by using a pharmacophore model based on structural analogues of homoeriodictyol.  


Starting from previous structure-activity relationship studies of taste modifiers based on homoeriodictyol, dihydrochalcones, deoxybenzoins, and trans-3-hydroxyflavones as obvious analogues were investigated for their masking effect against caffeine. The most active compounds of the newly investigated taste modifiers were phloretin, the related dihydrochalcones 3-methoxy-2',4,4'-trihydroxydihydrochalcone and 2',4-dihydroxy-3-methoxydihydrochalcone, and the deoxybenzoin 2-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)ethanone. Starting with the whole set of compounds showing activity >22%, a (Q)SAR pharmacophore model for maskers of caffeine bitterness was calculated to explain the structural requirements. After docking of the pharmacophore into a structural model of the broadly tuned bitter receptor hTAS2R10 and docking of enterolactone and enterodiol as only very weakly related structures, it was possible to predict qualitatively their modulating activity. Enterodiol (25 mg L(-1)) reduced the bitterness of the 500 mg L(-1) caffeine solution by about 30%, whereas enterolactone showed no masking but a slight bitter-enhancing effect. PMID:22670770

Ley, Jakob P; Dessoy, Marco; Paetz, Susanne; Blings, Maria; Hoffmann-Lücke, Petra; Reichelt, Katharina V; Krammer, Gerhard E; Pienkny, Silke; Brandt, Wolfgang; Wessjohann, Ludger



Molecular Structure of the Rat Vitamin D Receptor Ligand Binding Domain Complexed with 2-Carbon-Substituted Vitamin D3 Hormone Analogues and a  

E-print Network

Molecular Structure of the Rat Vitamin D Receptor Ligand Binding Domain Complexed with 2-Carbon-Substituted Vitamin D3 Hormone Analogues and a LXXLL-Containing Coactivator Peptide, Janeen L. Vanhooke,*,| Matthew M of the ligand binding domain (LBD) of the rat vitamin D receptor in ternary complexes with a synthetic LXXLL

Pike, J. Wesley



EPA Science Inventory

We have carried out an ab initio STO-5G computational analysis of the electrostatic potential of four structural analogues of the highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and four related aromatic systems: benzo[a]pyrene, benz[a]anthracene and two isomeric benzofla...


Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors  

PubMed Central

A series of novel bis-tetrahydropyran 1,4-triazole analogues based on the acetogenin framework display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness. A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure activity relationship studies. PMID:25145275

Florence, Gordon J.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Menzies, Stefanie K.; Morris, Joanne C.; Tulloch, Lindsay B.; Smith, Terry K.



Sphingolipid Analogues Inhibit Development of Malaria Parasites  

PubMed Central

Plasmodium-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species Plasmodium falciparum and Plasmodium knowlesi, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo. PMID:24900369



Design, conformational studies and analysis of structure-function relationships of PTH (1-11) analogues: the essential role of Val in position 2.  


The N-terminal 1-34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it elicits all the biological responses characteristic of the native intact PTH. Recent studies reported potent helical analogues of the PTH (1-11) with helicity-enhancing substitutions. This work describes the synthesis, biological activity, and conformational studies of analogues obtained from the most active non-natural PTH (1-11) peptide H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2; specifically, the replacement of Val in position 2 with D-Val, L-(?Me)-Val and N-isopropyl-Gly was studied. The synthesized analogues were characterized functionally by in-cell assays and their structures were determined by CD and NMR spectroscopy. To clarify the relationship between the structure and activity, the structural data were used to generate a pharmacophoric model, obtained overlapping all the analogues. This model underlines the fundamental functional role of the side chain of Val2 and, at the same time, reveals that the introduction of conformationally constrained C?-tetrasubstituted ?-amino acids in the peptides increases their helical content, but does not necessarily ensure significant biological activity. PMID:21918876

Caporale, A; Gesiot, L; Sturlese, M; Wittelsberger, A; Mammi, S; Peggion, E



Analysis of Wave Propagation in Stratified Structures Using Circuit Analogues, with Application to Electromagnetic Absorbers  

ERIC Educational Resources Information Center

This paper presents an overview of how circuit models can be used for analysing wave propagation in stratified structures. Relatively complex structures can be analysed using models which are accessible to undergraduate students. Homogeneous slabs are modelled as transmission lines, and thin sheets between the slabs are modelled as lumped…

Sjoberg, Daniel



Aspartame and Its Analogues  

NASA Astrophysics Data System (ADS)

The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.



Structural diversity of lamellar zeolite Nu-6(1)--postsynthesis of delaminated analogues.  


Nu-6(1) zeolite, the lamellar precursor of NSI topology, was firstly synthesized with 4'4-bipyridine as the structure-directing agent (SDA) and then subjected to HCl-EtOH treatment for the purpose of structural modification. Interlayer deconstruction and reconstruction took place alternately in this acid treatment. An intermediate named ECNU-4 was separated at the initial stage of this continuous treatment process, which exhibited a special X-ray diffraction pattern without obvious reflection peaks at low angles. The zeolitic structure in the intralayer sheets was supposed to be well preserved in ECNU-4, whereas the interlayer structure became extremely disordered. The ECNU-4 intermediate showed structural diversity. It was converted into the reconstructed and interlayer expanded zeolite IEZ-NSI without an external silicon source by prolonging the HCl-EtOH treatment to 24 h. Moreover, with a partially delaminated structure, ECNU-4 was easily interlayer swollen at room temperature with cetyltrimethyl ammonium bromide in the presence of tetrapropyl ammonium hydroxide. The swollen material was further sonicated to yield a more deeply delaminated zeolite, Del-Nu-6. ECNU-4 and Del-Nu-6 differed in delamination degree, structural disordering and textural properties, especially surface area. PMID:24658572

Xu, Hao; Jia, Lili; Wu, Haihong; Yang, Boting; Wu, Peng



Synthesis and structural characterization of tin analogues of N-heterocyclic carbenes.  


The synthesis and X-ray crystal structures of five N-heterocyclic stannylenes are reported. These compounds, containing a variety of backbones, were prepared by the salt metathesis of the appropriate dilithiated diamide with SnCl(2) and show a high degree of thermal stability compared to the corresponding species with unsaturated backbones. If bulky diisopropylphenyl groups are attached to the nitrogen centers then the structures are monomeric, but when the less bulky mesityl groups are employed the solid-state structure was shown to be dimeric. PMID:18989921

Mansell, Stephen M; Russell, Christopher A; Wass, Duncan F



Conformational features responsible for the binding of cyclic analogues of enkephalin to opioid receptors. II. Models of mu- and delta-receptor-bound structures for analogues containing Phe4.  


Models of mu- and delta-receptor-bound backbone conformations of enkephalin cyclic analogues containing Phe4 were determined by comparing geometrical similarity among the previously found low-energy backbone structures of [D-Cys2,Cys5]-enkephalinamide, [D-Cys2,D-Cys5]-enkephalinamide, [D-Pen2,L-Pen5]-enkephalin and [D-Pen2,D-Pen5]-enkephalin. The present mu-receptor-bound conformation resembles a beta-I bend in the peptide backbone centred on the Gly3-Phe4 region. Two slightly different models were found for the delta-receptor-bound conformation; both of them are more extended than the mu-receptor-bound conformation and include a gamma-turn (or a gamma-like turn) on the Gly3 residue. Energetically favourable rotamers of Tyr and Phe side chains were also determined for the mu- and delta-conformations. The present models of mu- and delta-conformations share geometrical similarity with the low-energy structures of Leu-enkephalin and the Tyr-D-Lys-Gly-Phe-analogue. PMID:2177733

Nikiforovich, G V; Golbraikh, A A; Shenderovich, M D; Balodis, J



Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors.  


Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis-tetrahydropyran 1,4-triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure-activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti-HAT agents. PMID:25145275

Florence, Gordon J; Fraser, Andrew L; Gould, Eoin R; King, Elizabeth F B; Menzies, Stefanie K; Morris, Joanne C; Tulloch, Lindsay B; Smith, Terry K



Sparsely substituted chlorins as core constructs in chlorophyll analogue chemistry. III. Spectral and structural properties  

PubMed Central

The availability of stable chlorins bearing few or no substituents has enabled a variety of fundamental studies. The studies described herein report absorption spectra of diverse chlorins, comparative NMR features of chlorins bearing 0–3 meso-aryl substituents, and X-ray structures of the fully unsubstituted chlorin and the oxochlorin. PMID:17479169

Taniguchi, Masahiko; Ptaszek, Marcin; McDowell, Brian E.; Boyle, Paul D.; Lindsey, Jonathan S.



Structure Activity Relationship and Mechanism of Action Studies of Manzamine Analogues for the Control of Neuroinflammation and Cerebral Infections  

PubMed Central

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinol isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g. Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3? (GSK-3?), which is a putative target of manzamines. Based on the results presented here it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases. PMID:20017491

Peng, Jiangnan; Kudrimoti, Sucheta; Prasanna, Sivaprakasam; Odde, Srinivas; Doerksen, Robert J.; Pennaka, Hari K; Choo, Yeun-Mun; Rao, Karumanchi V.; Tekwani, Babu L.; Madgula, Vamsi; Khan, Shabana I.; Wang, Bin; Mayer, Alejandro M. S.; Jacob, Melissa R.; Tu, Lan Chun; Gertsch, Jürg; Hamann, Mark T.



Structure-activity studies on the anti-proliferation activity of ajoene analogues in WHCO1 oesophageal cancer cells.  


The organosulfur compound ajoene derived from the rearrangement of allicin found in crushed garlic can inhibit the proliferation of tumour cells by inducing G(2)/M cell cycle arrest and apoptosis. We report on the application of a concise four-step synthesis (Hunter et al., 2008 [1]) that allows access to ajoene analogues with the end allyl groups substituted. A library of twelve such derivatives tested for their anti-proliferation activity against WHCO1 oesophageal cancer cells has identified a derivative containing p-methoxybenzyl (PMB)-substituted end groups that is twelve times more active than Z-ajoene, with an IC(50) of 2.1?M (Kaschula et al., 2011 [2]). Structure-activity studies involving modification of the sulfoxide and vinyl disulfide groups of this lead have revealed that the disulfide is the ajoene pharmacophore responsible for inhibiting WHCO1 cell growth, inducing G(2)/M cell cycle arrest and apoptosis by caspase-3 activation, and that the vinyl group serves to enhance the anti-proliferation activity a further eightfold. Reaction of the lead with cysteine in refluxing THF as a model reaction for ajoene's mechanism of action based on a thiol/disulfide exchange reveals that the allylic sulfur of the vinyl disulfide is the site of thiol attack in the exchange. PMID:22381354

Kaschula, Catherine H; Hunter, Roger; Stellenboom, Nashia; Caira, Mino R; Winks, Susan; Ogunleye, Thozama; Richards, Philip; Cotton, Jonathan; Zilbeyaz, Kani; Wang, Yabing; Siyo, Vuyolwethu; Ngarande, Ellen; Parker, M Iqbal



Structure-toxicity relationship study of para-halogenated styrene analogues in CYP2E1 transgenic cells.  


Styrene is one of the most important industrial intermediates consumed in the world and is mainly used as a monomer for reinforced plastics and rubber. Styrene has been found to be hepatotoxic and pneumotoxic in humans and experimental animals. The toxicity of styrene is suggested to be metabolism-dependent. Styrene-7,8-oxide has been considered as the major metabolite responsible for styrene-induced cytotoxicity. The objective of the study was to investigate the correlation between cytotoxicity of styrene and chemical and biochemical properties of the vinyl group of styrene by development of structure activity relationships (SAR). 4-Fluorostyrene, 4-chlorostyrene and 4-bromostyrene were selected for the SAR study. Cytotoxicity of styrene and the halogenated styrene derivatives with an order of 4-bromostyrene>4-chlorostyrene>4-fluorostyrene?styrene was observed in CYP2E1 transgenic cells. Similar orders in the efficiency of the metabolism of styrene and the halogenated styrene analogues to their oxides and in the electrophilicity of the corresponding oxides were observed. Additionally, the order of the potency of cellular glutathione depletion and the degree of protein adduction induced by styrene and the halogenated styrenes were consistent with that of their cytotoxicities. The wild-type cells were less susceptible to the toxicity of the corresponding model compounds than CYP2E1 cells. The present study provided insight into the roles of the biochemical and chemical properties of styrene in its cytotoxicity. PMID:22366341

Chung, Jou-Ku; Shen, Shuijie; Jiang, Zhiteng; Yuan, Wei; Zheng, Jiang



Structuring institutional analysis for urban ecosystems: A key to sustainable urban forest management  

E-print Network

fertilization of institutional analysis between rural SESs and urban ecosystems. Keywords Urban forestStructuring institutional analysis for urban ecosystems: A key to sustainable urban forest M. Vogt # Springer Science+Business Media New York 2013 Abstract A decline in urban forest structure

Evans, Tom


proteinsSTRUCTURE O FUNCTION O BIOINFORMATICS Dynamic property is a key determinant  

E-print Network

proteinsSTRUCTURE O FUNCTION O BIOINFORMATICS Dynamic property is a key determinant for protein­protein in the docking of cAMP-dependent protein kinase against its ligands.16 In recent protein­ protein interaction or protein­protein dock study,17 methods consider- ing the dynamic property of proteins structures were

Luhua, Lai


Translation of Structure-Activity Relationships from Cyclic Mixed Efficacy Opioid Peptides to Linear Analogues  

PubMed Central

Most opioid analgesics used in the treatment of pain are mu opioid receptor (MOR) agonists. While effective, there are significant drawbacks to opioid use, including the development of tolerance and dependence. However, the co-administration of a MOR agonist with a delta opioid receptor (DOR) antagonist slows the development of MOR-related side effects, while maintaining analgesia. We have previously reported a series of cyclic mixed efficacy MOR agonist/DOR antagonist ligands. Here we describe the transfer of key features from these cyclic analogs to linear sequences. Using the linear MOR/DOR agonist, Tyr-DThr-Gly-Phe-Leu-Ser-NH2 (DTLES), as a lead scaffold, we replaced Phe4 with bulkier and/or constrained aromatic residues shown to confer DOR antagonism in our cyclic ligands. These replacements failed to confer DOR antagonism in the DTLES analogs, presumably because the more flexible linear ligands can adopt binding poses that will fit in the narrow binding pocket of the active conformations of both MOR and DOR. Nonetheless, the pharmacological profile observed in this series, high affinity and efficacy for MOR and DOR with selectivity relative to KOR, has also been shown to reduce the development of unwanted side effects. We further modified our lead MOR/DOR agonist with a C-terminal glucoserine to improve bioavailability. The resulting ligand displayed high efficacy and potency at both MOR and DOR and no efficacy at KOR. PMID:24436042

Anand, Jessica P.; Porter-Barrus, Vanessa R.; Waldschmidt, Helen V.; Yeomans, Larisa; Pogozheva, Irina D.; Traynor, John R.



Crystal structure of Trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase complexed with an analogue of 1,3-bisphospho-d-glyceric acid.  


We report here the first crystal structure of a stable isosteric analogue of 1,3-bisphospho-d-glyceric acid (1,3-BPGA) bound to the catalytic domain of Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) in which the two phosphoryl moieties interact with Arg249. This complex possibly illustrates a step of the catalytic process by which Arg249 may induce compression of the product formed, allowing its expulsion from the active site. Structural modifications were introduced into this isosteric analogue and the respective inhibitory effects of the resulting diphosphorylated compounds on T. cruzi and Trypanosoma brucei gGAPDHs were investigated by enzymatic inhibition studies, fluorescence spectroscopy, site-directed mutagenesis, and molecular modelling. Despite the high homology between the two trypanomastid gGAPDHs (> 95%), we have identified specific interactions that could be used to design selective irreversible inhibitors against T. cruzi gGAPDH. PMID:14622286

Ladame, Sylvain; Castilho, Marcelo S; Silva, Carlos H T P; Denier, Colette; Hannaert, Véronique; Périé, Jacques; Oliva, Glaucius; Willson, Michèle



Synthesis and structure of dirhodium analogue of octaborane-12 and decaborane-14.  


We present the results of our investigation of a thermally driven cluster expansion of rhodaborane systems with BH(3)·THF. Four novel rhodaborane clusters, for example, nido-[(Cp*Rh)(2)B(6)H(10)], 1; nido-[(Cp*Rh)B(9)H(13)], 2; nido-[(Cp*Rh)(2)B(8)H(12)], 3; and nido-[(Cp*Rh)(3)B(8)H(9)(OH)(3)], 4 (Cp* = ?(5)-C(5)Me(5)), have been isolated from the thermolysis of [Cp*RhCl(2)](2) and borane reagents in modest yields. Rhodaborane 1 has a nido geometry and is isostructural with [B(8)H(12)]. The low temperature (11)B and (1)H NMR data demonstrate that compound 1 exists in two isomeric forms. The framework geometry of 2 and 3 is similar to that of [B(10)H(14)] with one BH group in 2 (3-position), and two BH groups in 3 (3, 4-positions) are replaced by an isolobal {Cp*Rh} fragment. The 11 vertex cluster 4 has a nido structure based on the 12 vertex icosahedron, having three rhodium and eight boron atoms. In addition, the reaction of rhodaborane 1 with [Fe(2)(CO)(9)] yielded a condensed cluster [(Cp*Rh)(2){Fe(CO)(3)}(2)B(6)H(10)], 5. The geometry of 5 consists of [Fe(2)B(2)] tetrahedron and an open structure of [(Cp*Rh)(2)B(6)], fused through two boron atoms. The accuracy of these results in each case is established experimentally by spectroscopic characterization in solution and structure determinations in the solid state. PMID:22998603

Roy, Dipak Kumar; Bose, Shubhankar Kumar; Anju, R S; Ramkumar, V; Ghosh, Sundargopal



Structural investigation of Np2Co17 and analogue compounds under pressure  

NASA Astrophysics Data System (ADS)

The structural behavior of Np2Co17 is investigated by means of high-pressure diamond-anvil compression measurements and is compared with that of the isostructural compounds Lu2Co17 and Lu2Ni17. The Th2Ni17-type hexagonal crystal structure is preserved with no measurable discontinuous volume collapses up to the highest achieved pressure, p=43 GPa. For Np2Co17, fits to the Birch-Murnaghan and Vinet equations of state give values of the isothermal bulk modulus and its pressure derivative of B0=286 GPa and B0'=3, revealing that this Np compound is a highly incompressible solid with stiffness comparable to that of superhard covalently bonded materials. For the Lu2T17 (T = Co, Ni) compounds, the measured bulk modulus changes from B0=137 GPa for T = Co to B0=257 GPa for T = Ni. The isothermal equation of state for the studied compounds are in excellent agreement with the results of ab initio fully relativistic, full-potential local spin-density functional calculations. Theoretical estimates of the bulk modulus are given also for Np2Ni17, for which B0 is predicted to assume values intermediate between those measured for Lu2Ni17 and Np2Co17.

Hen, A.; Heathman, S.; Eloirdi, R.; Griveau, J.-C.; Elgazzar, S.; Oppeneer, P. M.; Halevy, I.; Orion, I.; Caciuffo, R.



Use of synthetic analogues in confirmation of structure of the peptide antibiotics Maltacines  

NASA Astrophysics Data System (ADS)

Maltacines comprise a family of cyclic peptide lactone antibiotics produced by a strain of Bacillus subtilis. The previously proposed amino acid sequences of the linear ring-opened molecules show similarity to the lipopeptide antibiotic Fengycin IX that is also produced by a strain of B. subtilisE There were some discrepancies in the Maltacin data that could not be explained. To address this and gain more information into the structure of the linear ring-opened Maltacines, the two members D1c, E1b and Fengycin IX acid were synthesised and their MS2, MS3 and MS4 spectra compared. The similarity of the product ion spectra of Maltacin and Fengycin IX acid revealed that proline occupies an internal position in Maltacin. This finding led to revision of the interpretation of the amino acid sequences of the Maltacines. The proposed new structures of the Maltacines shows that the cyclic part of the molecules is the same as in Fengycin IX acid and Fengycin XII acid, but they have unique N-terminal sequences not found in Fengycins, and thus represent novel lipopeptide antibiotics.

Hagelin, Gunnar; Indrevoll, Bård; Hoeg-Jensen, Thomas



Structural studies of "aggregation-prone" peptide-analogues of teleostean egg chorion ZPB proteins.  


Egg envelopes of vertebrates are composed of a family of proteins called zona pellucida (ZP) proteins, which are distinguished by the presence of a common structural polymerizing motif, known as ZP domain. Teleostean fish chorion is a fibrous structure, consisting of protein members of the ZPB/ZP1 and the ZPC/ZP3 families, which are incorporated as tandemly repeating heterodimers inside chorion fibers. Computational analysis of multiple ZPB/ZP1 proteins from several teleostean species, reveals two potential "aggregation-prone" sequence segments, forming a specific polymerization interface (AG interface). These two peptides were synthesized and results are presented in this work from transmission electron microscopy, Congo red staining, X-ray fiber diffraction and ATR FT-IR, which clearly display the ability of these peptides to self-aggregate, forming amyloid-like fibrils. This, most probably implies that the AG interface of ZPB/ZP1 proteins plays an important role for the formation of the repeating ZPB-ZPC heterodimers, which constitute teleostean chorion fibrils. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 427-436, 2014. PMID:25229478

Louros, Nikolaos N; Petronikolou, Nektaria; Karamanos, Theodoros; Cordopatis, Paul; Iconomidou, Vassiliki A; Hamodrakas, Stavros J



2.0 Å X-ray structure of the ternary complex of 7,8-dihydro-6-hydroxymethylpterinpyrophosphokinase from Escherichia coli with ATP and a substrate analogue  

Microsoft Academic Search

The X-ray crystal structure of 7,8-dihydro-6-hydroxymethylpterinpyrophosphokinase (PPPK) in a ternary complex with ATP and a pterin analogue has been solved to 2.0 Å resolution, giving, for the first time, detailed information of the PPPK\\/ATP intermolecular interactions and the accompanying conformational change. The first 100 residues of the 158 residue peptide contain a ?????? motif present in several other proteins including

David K Stammers; Aniruddha Achari; Donald O’N Somers; Patrick K Bryant; Jane Rosemond; David L Scott; John N Champness



Syntheses and structural characterizations of inorganic ansa-metallocene analogues: ansa-ferratricarbadecaboranes.  


New linked cyclopentadienyl-tricarbadecaboranyl and bis-tricarbadecaboranyl dianions have been used to form the first examples of ansa-metallatricarbadecaboranyl complexes. The hybrid cyclopentadienyl-tricarbadecaboranyl dianion, Li2(+)[6-C5H4-(CH2)2-nido-5,6,9-C3B7H9](2-) (1), was produced by an initial carbon-insertion reaction of a nitrile-substituted cyclopentadiene with the arachno-4,6-C2B7H12(-) anion, followed by deprotonation to the dianion with LiH. The linked-cage bis-tricarbadecaboranyl dianion, Li2(+)[6,6'-(CH2)2-nido-(5,6,9-C3B7H9)2](2-) (2), was produced by a similar carbon-insertion route involving the reaction of two equivalents of arachno-4,6-C2B7H12(-) with succinonitrile. The reaction of 1 with an equivalent of FeCl2 produced the hybrid complex, ansa-(2-(CH2)2)-(1-?(5)-C5H4-closo-1,2,3,4-C3B7H9)Fe (3), with a crystallographic determination confirming the formation of a sandwich structure where the ring and cage are linked by the ansa -CH2CH2- group with attachment to the cage at the C2 carbon. The reaction of 2 with FeCl2 produced three isomeric ansa-(CH2)2-ferrabistricarbadecaboranyl sandwich complexes, ansa-(CH2)2-(closo-C3B7H9)2Fe (4, 5 and 6). Crystallographic determinations showed that in 4, the two tricarbadecaboranyl ligands are linked by the ansa-CH2CH2- group at the C2 and C2' cage carbons, whereas in 5 and 6 they are linked at their C2 and C4' carbons, with the structures of 5 and 6 differing in the relative positions of the C4' carbons in the two cages of each complex. The structural determinations also showed that, depending upon the linking position of the ansa-tether, constraints in cage-orientation, such as observed in 4, produce unfavorable intercage steric interactions. However, the cage fragments in these complexes can readily undergo a cage-carbon migration that moves one -carbon and its tether linkage to the more favorable 4-position. This isomerization reduces the cage steric interactions and produces configurations, such as those found for 5 and 6, where the iron cage bonding is enhanced as a result of the binding effect of the tether. PMID:23930745

Gleeson, Brendan; Carroll, Patrick J; Sneddon, Larry G



Activation of adenylate cyclase and inhibition of glucose transport in rat adipocytes by forskolin analogues: structural determinants for distinct sites of action.  


Forskolin and four analogues of forskolin, 7-beta-[gamma-(N'-methylpiperazino)-butyryloxy]-7-desacet ylforskolin, 7-desacetylforskolin, 7-tosyl-7-desacetylforskolin, and 1,9-dideoxyforskolin, were tested for their ability to activate adenylate cyclase, inhibit glucose transport, and inhibit cytochalasin B binding in rat adipocyte membranes. Forskolin was the most potent analogue in activating adenylate cyclase with an EC50 of 2 microM, whereas 7-beta-[gamma-(N'-methylpiperazino)butyryloxy]-7-desacety lforskolin and 7-desacetylforskolin were less potent, with EC50 values of 3 microM and 20 microM, respectively. The 7-tosyl-7-desacetylforskolin and 1,9-dideoxyforskolin did not stimulate adenylate cyclase even at the highest concentrations tested (100 microM). In contrast, forskolin and all of the analogues were able to fully inhibit glucose transport in adipocyte plasma membranes. The order of potency for the inhibition was forskolin greater than 7-beta-[gamma-(N'-methylpiperazino)butyryloxy]-7-desacety lforskolin greater than 7-desacetylforskolin greater than 7-tosyl-7-desacetylforskolin greater than 1,9-dideoxyforskolin, and the EC50 values were 0.24 microM, 1.8 microM, 7.1 microM, 8.8 microM, and 12.8 microM, respectively. Cytochalasin B binding to rat adipocyte membranes was inhibited by forskolin and the four analogues with the same order of potency as observed for the inhibition of glucose transport. Thus, the site of action of forskolin which is responsible for the inhibition of glucose transport and cytochasin B binding exhibits structural requirements for forskolin and its analogues that are different from those of the site responsible for the activation of adenylate cyclase. PMID:3357486

Joost, H G; Habberfield, A D; Simpson, I A; Laurenza, A; Seamon, K B



Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site  

PubMed Central

Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization. PMID:24489681

Kwon, Young Do; LaLonde, Judith M.; Yang, Yongping; Elban, Mark A.; Sugawara, Akihiro; Courter, Joel R.; Jones, David M.; Smith, Amos B.; Debnath, Asim K.; Kwong, Peter D.



Aromaticity in heterocyclic analogues of benzene: comprehensive analysis of structural aspects, electron delocalization and magnetic characteristics.  


The degree of aromaticity of six-membered monoheterocycles with IV-VI group heteroatoms (C(6)H(5)X, where X = SiH, GeH, N, P, As, O(+), S(+), Se(+)) was analyzed using the results of ab initio calculations at the MP2/cc-pvtz level. Values of common aromaticity indices including those based on electronic delocalization properties, structural-dynamic features and magnetic properties all indicate high aromaticity of all considered heterocycles. A decrease in aromaticity is observed with increasing atomic number of the heteroatom, except in the case of the pyrylium cation. However, not all types of indices or even different indices within the same type correlate well among each other. Ring currents have been obtained at the HF/cc-pvdz level using the ipsocentric formulation. Ring current maps indicate that in the case of cationic heterocycles the ring current persists in all molecules under consideration. The different conclusions reached depending on the type of index used are a manifestation of the fact that when not dealing with hydrocarbons, aromaticity is ill-defined. One should always express explicitly which property of the molecules is considered to establish a degree of "aromaticity". PMID:21725559

Omelchenko, Irina V; Shishkin, Oleg V; Gorb, Leonid; Leszczynski, Jerzy; Fias, Stijn; Bultinck, Patrick



Synthesis and molecular structure of a zinc complex of the vitamin K3 analogue phthiocol  

NASA Astrophysics Data System (ADS)

The complex [Zn(phthiocol)2(H2O)2]; 1, where phthiocol is 2-hydroxy-3-methyl-1,4-naphthoquinone, has been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-vis spectroscopy, thermogravimetric (TG) analysis, electrochemical and single crystal X-ray diffraction studies. The ?CO stretch shifts to lower frequencies upon complexation of phthiocol to Zn2+. 1H NMR spectra show an upfield shift of the benzenoid ring protons in 1. There is a bathochromic shift of the LMCT band in the UV-vis spectra of 1. Single crystal X-ray structure of 1 show distorted octahedral geometry around Zn2+. Two phthiocol ligands are in plane with the metal, while water molecules are trans to this plane. Coordination of deprotonated phthiocol ligands is 'trans, trans' to Zn2+. Intra as well as intermolecular interactions are observed in 1. Molecules of 1 show three dimensional network through CH⋯O and OH⋯O interactions. Additional anodic peaks are observed in cyclic voltammogram of phthiocol ligand due to oxidation of reduced species formed during reduction. One-electron reduction of 1 is shown to be reversible and DFT studies define this redox event as ligand-centered.

Kathawate, Laxmi; Sproules, Stephen; Pawar, Omkar; Markad, Ganesh; Haram, Santosh; Puranik, Vedavati; Salunke-Gawali, Sunita



The role of pre-existing tectonic structures and magma chamber shape on the geometry of resurgent blocks: Analogue models  

NASA Astrophysics Data System (ADS)

A set of analogue models has been carried out to understand the role of an asymmetric magma chamber on the resurgence-related deformation of a previously deformed crustal sector. The results are then compared with those of similar experiments, previously performed using a symmetric magma chamber. Two lines of experiments were performed to simulate resurgence in an area with a simple graben-like structure and resurgence in a caldera that collapsed within the previously generated graben-like structure. On the basis of commonly accepted scaling laws, we used dry-quartz sand to simulate the brittle behaviour of the crust and Newtonian silicone to simulate the ductile behaviour of the intruding magma. An asymmetric shape of the magma chamber was simulated by moulding the upper surface of the silicone. The resulting empty space was then filled with sand. The results of the asymmetric-resurgence experiments are similar to those obtained with symmetrically shaped silicone. In the sample with a simple graben-like structure, resurgence occurs through the formation of a discrete number of differentially displaced blocks. The most uplifted portion of the deformed depression floor is affected by newly formed, high-angle, inward-dipping reverse ring-faults. The least uplifted portion of the caldera is affected by normal faults with similar orientation, either newly formed or resulting from reactivation of the pre-existing graben faults. This asymmetric block resurgence is also observed in experiments performed with a previous caldera collapse. In this case, the caldera-collapse-related reverse ring-fault is completely erased along the shortened side, and enhances the effect of the extensional faults on the opposite side, so facilitating the intrusion of the silicone. The most uplifted sector, due to an asymmetrically shaped intrusion, is always in correspondence of the thickest overburden. These results suggest that the stress field induced by resurgence is likely dictated by the geometry of the intruding magma body, and the related deformation is partially controlled by pre-existing tectonic and/or volcano-tectonic structures.

Marotta, Enrica; de Vita, Sandro



Cation radii induced structural variation in fluorescent alkaline earth networks constructed from tautomers of a nucleobase analogue.  


Nucleobase tautomers and their metal complexes have attracted considerable attention due to their fascinating architectures along with wide applications. In this paper, 4,6-dihydroxypyrimidine (H(2)DHP), an analogue of uracil and thymine, was employed to react with the vital elements of alkaline earth metals in an aqueous solution and lead to the formation of four novel complexes, [Mg(HDHP)(2) (H(2)O)(4)] (1), [Ca(HDHP)(2)(H(2)O)(3)](n)·nH(2)O (2), [Sr(HDHP)(2)(H(2)O)(3)](n)·nH(2)O (3), and [Ba(HDHP)(2)(H(2)O)(2)](n)·nH(2)O (4), which have been characterized by elemental analysis, IR, TG, UV-Vis, PL, powder and single-crystal X-ray diffraction and progressively evolve from zero-dimensional (0D) mononuclear, one-dimensional (1D) zig-zag double chain, two-dimensional (2D) double layer, to a three-dimensional (3D) porous network along with the increase of cation radii. This tendency in dimensionality follows salient crystal engineering principles and can be explained by considering factors such as hard-soft acid-base principles and cation radii. The deprotonated H(2)DHP ligand exhibits four new coordination modes, namely, O-monodentate (complex 1), N,O-chelating (complexes 2 and 3), O,O-bridging (complexes 2 and 3), and ?(1)O:?(2)O-bridging mode (complex 4). Interestingly, the structural investigation indicates that the HDHP(-) monoanion shows three unusual types of tautomers, which are essential for the diagnosis of disease and investigation of medicine. Furthermore, the four complexes exhibit strong blue emission compared to free H(2)DHP ligand at room temperature and may be potential candidates for blue fluorescent biological materials used in organisms. PMID:22635055

Deng, Zhao-Peng; Kang, Wei; Zhu, Zhi-Biao; Huo, Li-Hua; Zhao, Hui; Gao, Shan



Structures of ceftazidime and its transition-state analogue in complex with AmpC beta-lactamase: Implications for resistance mutations and inhibitor design  

SciTech Connect

Third-generation cephalosporins are widely used {beta}-lactam antibiotics that resist hydrolysis by {beta}-lactamases. Recently, mutant {beta}-lactamases that rapidly inactivate these drugs have emerged. To investigate why third-generation cephalosporins are relatively stable to wild-type class C {beta}-lactamases and how mutant enzymes might overcome this, the structures of the class C {beta}-lactamase AmpC in complex with the third-generation cephalosporin ceftazidime and with a transition-state analogue of ceftazidime were determined by X-ray crystallography to 2.0 and 2.3 {angstrom} resolution, respectively. Comparison of the acyl-enzyme structures of ceftazidime and loracarbef, a {beta}-lactam substrate, reveals that the conformation of ceftazidime in the active site differs from that of substrates. Comparison of the structures of the acyl-enzyme intermediate and the transition-state analogue suggests that ceftazidime blocks formation of the tetrahedral transition state, explaining why it is an inhibitor of AmpC. Ceftazidime cannot adopt a conformation competent for catalysis due to steric clashes that would occur with conserved residues Val211 and Tyr221. The X-ray crystal structure of the mutant {beta}-lactamase GC1, which has improved activity against third-generation cephalosporins, suggests that a tandem tripeptide insertion in the {Omega} loop, which contains Val211, has caused a shift of this residue and also of Tyr221 that would allow ceftazidime and other third-generation cephalosporins to adopt a more catalytically competent conformation. These structural differences may explain the extended spectrum activity of GC1 against this class of cephalosporins. In addition, the complexed structure of the transition-state analogue inhibitor (K{sub i} 20 nM) with AmpC reveals potential opportunities for further inhibitor design.

Powers, R.A.; Caselli, E.; Focia, P.J.; Prati, F.; Shoichet, B.K.



Structural insights into the interactions of xpt riboswitch with novel guanine analogues: a molecular dynamics simulation study.  


Ligand recognition in purine riboswitches is a complex process requiring different levels of conformational changes. Recent efforts in the area of purine riboswitch research have focused on ligand analogue binding studies. In the case of the guanine xanthine phosphoribosyl transferase (xpt) riboswitch, synthetic analogues that resemble guanine have the potential to tightly bind and subsequently influence the genetic expression of xpt mRNA in prokaryotes. We have carried out 25 ns Molecular Dynamics (MD) simulation studies of the aptamer domain of the xpt G-riboswitch in four different states: guanine riboswitch in free form, riboswitch bound with its cognate ligand guanine, and with two guanine analogues SJ1 and SJ2. Our work reveals novel interactions of SJ1 and SJ2 ligands with the binding core residues of the riboswitch. The ligands proposed in this work bind to the riboswitch with greater overall stability and lower root mean square deviations and fluctuations compared to guanine ligand. Reporter gene assay data demonstrate that the ligand analogues, upon binding to the RNA, lower the genetic expression of the guanine riboswitch. Our work has important implications for future ligand design and binding studies in the exciting field of riboswitches. PMID:24404773

Jain, Swapan S; Sonavane, Uddhavesh B; Uppuladinne, Mallikarjunachari V N; McLaughlin, Emily C; Wang, Weiqing; Black, Sheneil; Joshi, Rajendra R



Pyrazolate-Bridging Dinucleating Ligands Containing Hydrogen-Bond Donors: Synthesis and Structure of Their Cobalt Analogues  

E-print Network

of Their Cobalt Analogues Paul J. Zinn, Douglas R. Powell, Victor W. Day, Michael P. Hendrich, Thomas N. Sorrell correspondence should be addressed. E-mail: (T.N.S.), (A.S.B.). University

Hendrich, Mike


Structural Integrity of the Greek Key Motif in ??-Crystallins Is Vital for Central Eye Lens Transparency  

PubMed Central

Background We highlight an unrecognized physiological role for the Greek key motif, an evolutionarily conserved super-secondary structural topology of the ??-crystallins. These proteins constitute the bulk of the human eye lens, packed at very high concentrations in a compact, globular, short-range order, generating transparency. Congenital cataract (affecting 400,000 newborns yearly worldwide), associated with 54 mutations in ??-crystallins, occurs in two major phenotypes nuclear cataract, which blocks the central visual axis, hampering the development of the growing eye and demanding earliest intervention, and the milder peripheral progressive cataract where surgery can wait. In order to understand this phenotypic dichotomy at the molecular level, we have studied the structural and aggregation features of representative mutations. Methods Wild type and several representative mutant proteins were cloned, expressed and purified and their secondary and tertiary structural details, as well as structural stability, were compared in solution, using spectroscopy. Their tendencies to aggregate in vitro and in cellulo were also compared. In addition, we analyzed their structural differences by molecular modeling in silico. Results Based on their properties, mutants are seen to fall into two classes. Mutants A36P, L45PL54P, R140X, and G165fs display lowered solubility and structural stability, expose several buried residues to the surface, aggregate in vitro and in cellulo, and disturb/distort the Greek key motif. And they are associated with nuclear cataract. In contrast, mutants P24T and R77S, associated with peripheral cataract, behave quite similar to the wild type molecule, and do not affect the Greek key topology. Conclusion When a mutation distorts even one of the four Greek key motifs, the protein readily self-aggregates and precipitates, consistent with the phenotype of nuclear cataract, while mutations not affecting the motif display ‘native state aggregation’, leading to peripheral cataract, thus offering a protein structural rationale for the cataract phenotypic dichotomy “distort motif, lose central vision”. PMID:23936409

Vendra, Venkata Pulla Rao; Agarwal, Garima; Chandani, Sushil; Talla, Venu; Srinivasan, Narayanaswamy; Balasubramanian, Dorairajan



Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase.  


Safinamide, (S)-N2-{4-[(3-fluorobenzyl)oxy]benzyl}alaninamide methanesulfonate, which is in phase III clinical trials as an anti-Parkinson drug, and a library of alkanamidic analogues were prepared through an expeditious solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) inhibitory activity and selectivity. (S)-3-Chlorobenzyloxyalaninamide (8) and (S)-3-chlorobenzyloxyserinamide (13) derivatives proved to be more potent MAO-B inhibitors than safinamide (IC50 = 33 and 43 nM, respectively, vs 98 nM) but with a lower MAO-B selectivity (SI = 3455 and 1967, respectively, vs 5918). The highest MAO-B inhibitory potency (IC50 = 17 nM) and a good selectivity (SI = 2941) were displayed by (R)-21, a tetrahydroisoquinoline analogue of safinamide. Structure-affinity relationships and docking simulations pointed out strong negative steric effects of alpha-aminoamide side chains and para substituents of the benzyloxy groups and favorable hydrophobic interactions of meta substituents. The significantly diverse MAO-B affinities of a number of R and S alpha-aminoamide enantiomers, including the two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymatic binding sites. PMID:17824599

Leonetti, Francesco; Capaldi, Carmelida; Pisani, Leonardo; Nicolotti, Orazio; Muncipinto, Giovanni; Stefanachi, Angela; Cellamare, Saverio; Caccia, Carla; Carotti, Angelo



OptZyme: Computational Enzyme Redesign Using Transition State Analogues  

PubMed Central

OptZyme is a new computational procedure for designing improved enzymatic activity (i.e., kcat or kcat/KM) with a novel substrate. The key concept is to use transition state analogue compounds, which are known for many reactions, as proxies for the typically unknown transition state structures. Mutations that minimize the interaction energy of the enzyme with its transition state analogue, rather than with its substrate, are identified that lower the transition state formation energy barrier. Using Escherichia coli ?-glucuronidase as a benchmark system, we confirm that KM correlates (R2?=?0.960) with the computed interaction energy between the enzyme and the para-nitrophenyl- ?, D-glucuronide substrate, kcat/KM correlates (R2?=?0.864) with the interaction energy of the transition state analogue, 1,5-glucarolactone, and kcat correlates (R2?=?0.854) with a weighted combination of interaction energies with the substrate and transition state analogue. OptZyme is subsequently used to identify mutants with improved KM, kcat, and kcat/KM for a new substrate, para-nitrophenyl- ?, D-galactoside. Differences between the three libraries reveal structural differences that underpin improving KM, kcat, or kcat/KM. Mutants predicted to enhance the activity for para-nitrophenyl- ?, D-galactoside directly or indirectly create hydrogen bonds with the altered sugar ring conformation or its substituents, namely H162S, L361G, W549R, and N550S. PMID:24116038

Grisewood, Matthew J.; Gifford, Nathanael P.; Pantazes, Robert J.; Li, Ye; Cirino, Patrick C.; Janik, Michael J.; Maranas, Costas D.



Structure of a proteolytically resistant analogue of (NLys)5SFTI-1 in complex with trypsin: evidence for the direct participation of the Ser214 carbonyl group in serine protease-mediated proteolysis.  


Peptide-peptoid hybrids are found to be potent inhibitors of serine proteases. These engineered peptidomimetics benefit from both types of units of the biopolymeric structure: the natural inhibitor part serves as a good binding template, while the P1-positioned peptoid component provides complete resistance towards proteolysis. In this report, the mechanism of proteolytic resistance of a P1 peptoid-containing analogue is postulated based on the crystal structure of the (NLys)(5)-modified sunflower trypsin inhibitor SFTI-1 in complex with bovine trypsin solved at 1.29?Å resolution. The structural differences between the (NLys)(5)SFTI-1-trypsin complex and the native SFTI-1-trypsin complex are surprisingly small and reveal the key role of the carbonyl group of the Ser214 residue of the enzyme, which is crucial for binding of the inhibitor and plays a crucial role in proteolysis mediated by serine proteases. The incorporated NLys5 peptoid residue prevents Ser214 from forming a hydrogen bond to the P1 residue, and in turn Gln192 does not form a hydrogen bond to the carbonyl group of the P2 residue. It also increases the distance between the Ser214 carbonyl group and the Ser195 residue, thus preventing proteolysis. The hybrid inhibitor structure reported here provides insight into protein-protein interaction, which can be efficiently and selectively probed with the use of peptoids incorporated within endogenous peptide ligands. PMID:24598736

Krzywda, Szymon; Jaskolski, Mariusz; Rolka, Krzysztof; Stawikowski, Maciej J



Rational design of antimicrobial C3a analogues with enhanced effects against Staphylococci using an integrated structure and function-based approach.  


The anaphylatoxin C3a and its inactivated derivative C3adesArg, generated during complement activation, exert direct antimicrobial effects, mediated via its C-terminal region [Nordahl et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 16879-16884]. During evolution, this region of C3a displays subtle changes in net charge, while preserving a moderate but variable amphipathicity [Pasupuleti et al. (2007) J. Biol. Chem. 282, 2520-2528]. In this study, we mimic these evolutionary changes, employing a design approach utilizing selected amino acid substitutions at strategic and structurally relevant positions in the original human C3a peptide CNYITELRRQHARASHLGLA, followed by structure-activity studies incorporating sequence-dependent QSAR models as tools for generation of C3a peptide variants with enhanced effects. While the native peptide and related amphipathic analogues of moderate positive net charge were active against the Gram-negative Escherichia coli, activity against the Gram-positive Staphylococcus aureus was primarily observed for peptides characterized by a combination of a relatively high net charge (+6-7) and a propensity to adopt an alpha-helical conformation with amphipathic character. Such increased helicity and charge also conferred activity against the fungus Candida albicans. A central histidine residue (H11), evolutionarily conserved among vertebrates, conferred high selectivity toward microbes, while substitutions with leucine rendered the peptides hemolytic. Selected C3a analogues retained their specificity against staphylococci in the presence of human plasma, while showing low cytotoxicity. The work illustrates structure-activity relationships underlying the function and specificity of antimicrobial C3a and related analogues and provides insights into the forces that drive evolution of antimicrobial peptides. PMID:18690701

Pasupuleti, Mukesh; Walse, Björn; Svensson, Bo; Malmsten, Martin; Schmidtchen, Artur



Structure–antifungal activity relationship of His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH 2 and analogues  

Microsoft Academic Search

The synthesis, in vitro evaluation and conformational study of His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 and analogues acting as antifungal agents are reported. Among them, His-Phe-Lys-Trp-Gly-Arg-Phe-Val-NH2 exhibited a moderate but significant antifungal activity against Cryptococcus neoformans, Candida albicans and Candida tropicalis. A theoretical study allows us to propose a biologically relevant conformation for these octapeptides acting as antifungal agents. In addition, these theoretical calculations allow

Marcelo F. Masman; Csaba Somlai; Francisco M. Garibotto; Ana M. Rodríguez; Agustina de la Iglesia; Susana A. Zacchino; Botond Penke; Ricardo D. Enriz



Preliminary results of a multi-scale structural analisys in an analogue carbonate reservoir (Hyblean Plateau, Sicily, Italy)  

NASA Astrophysics Data System (ADS)

With the aim of studying the multi-scale fault architecture and permeability in hydrocarbon-rich porous carbonate rocks, we are currently involved in a project focused on the structural analysis of fractured and faulted platform-to-ramp carbonates cropping out in the Hyblean Plateau (Sicily, Italy). The Hyblean Plateau is part of the Maghrebian foreland and forms the northern portion of the African plate. The plateau is a NE-oriented structural high crosscut by a large-scale N10°-20°E oriented strike-slip fault system, named Scicli-Ragusa, which was affected by right-lateral kinematics during the Upper Miocene-Lower Pliocene. Some authors documented a recent activity of the Scicli-Ragusa fault system, during the Quaternary, characterized by left-lateral kinematics. The portion of the Hyblean Plateau crosscut by this fault system represents an excellent example of an outcropping analogue of a fractured carbonate reservoir. By taking advantage of the several oil shows located along the Scicli-Ragusa fault system, we combine stratigraphic-structural analyses, both at outcrop and microscopic scales, to assess the structural control exerted by faults and fractures on hydrocarbon migration and storage. The field work focused on the geological mapping, at 1:10.000 scale, on detailed stratigraphic characterization of the outcropping layered carbonates (Ragusa Fm.) and on traditional faults and fractures analysis. Sample collection was also performed in order to conduct, in the laboratory, optical microscope and image analyses. The Oligo-Miocenic Ragusa Fm. is comprised of two main members: i) the lower Leonardo Member, which is characterised by well-cemented carbonate packstones intercalated with marl-rich levels; ii) the upper Irminio Member, characterised by an alternation of well-cemented and poorly-cemented grainstones/packstones. According to both orientations and kinematics, we grouped the fault segments of the Scicli-Ragusa fault system into three major sets: (i) NNE-striking faults with predominant right-lateral kinematics, (ii) ENE-striking faults with left-lateral kinematics, and (iii) NE-striking faults characterized by normal slip. Conversely, based on the fault attributes we subdivided the outcropping faults into four main categories: (i) Major faults, comprised of well-developed fault cores (made up of cataclastic rocks and main slip surfaces) flanked by thicker fault damage zones, which are up to 18 km-long and have throws in the order of 100's of meters. (ii) Medium faults containing thin and discontinuous fault cores of brecciated and cataclastic fault rocks and through-going slip surfaces encompassed within the fault damage zones, which are long up to several 100's of meters and have throws up to 10's of meters. (iii) Small faults made up of isolated and discontinuous fault cores of faults breccias and through-going slip surfaces, which are up to a few m-long and have throws in order of several 10's of cm and a few meters. (iv) Incipient faults consist, predominantly, of sheared pre-existing fractures confined within the individual carbonate beds; the maximum throw < 10 cm. The meso-structural analysis performed to define the background deformation allowed us to identify mainly three different typology of structures: i) joints, ii) stylolites, and iii) shear bands. On the basis of their abutting relationships first originated bed-parallel stylolites and then two coeval sets of bed perpendicular joints. Shear bands nucleated by shearing of previously formed bed-parallel and bed-perpendicular structures. Another important data came out from preliminary microscope analysis carried out within mines of tar rich carbonates. Here, shear bands within porous layers behaved as a seal for oil migration whereas joints, localized in well cemented layers, acted as conduct for hydrocarbons. Finally, as planned work, we are going to combine fault architecture data with petrophysical analyses conducted on samples belonging to different structural domains in order to define hydraulic behaviours of the studied faults.

Cilona, Antonino; Agosta, Fabrizio; Criscenti, Alessandro; Dipasquale, Mario; Giunta, Giuseppe; Napoli, Giuseppe; Occhipinti, Rosario; Renda, Pietro; Tondi, Emanuele



Key technological issues in LMFBR high-temperature structural design - the US perspective  

SciTech Connect

The purpose of this paper is: (1) to review the key technological issues in LMFBR high-temperature structural design, particularly as they relate to cost reduction; and (2) to provide an overview of activities sponsored by the US Department of Energy to resolve the issues and to establish stable, standardized, and defensible structural design methods and criteria. Specific areas of discussion include: weldments, structural validation tests, simplified design analysis procedures, design procedures for piping, validation of the methodology for notch-like geometries, improved life assessment procedures, thermal striping, extension of the methodology to new materials, and ASME high-temperature Code reform needs. The perceived problems and needs in each area are discussed, and the current status of related US activities is given.

Corum, J.M.



In vitro evaluation of 9-(2-phosphonylmethoxyethyl)adenine ester analogues, a series of anti-HBV structures with improved plasma stability and liver release.  


Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis and hepatocellular carcinoma, but few drugs are available for its treatment. Acyclic nucleoside phosphonates (ANPs) have remarkable antivirus activities but are not easily absorbed from the gastrointestinal tract and accumulate in the kidneys, resulting in nephrotoxicity. Therefore, there is a need to find effective liver site-specific prodrugs. The dipivaloyloxymethyl ester of 9-(2-phosphonylmethoxyethyl)adenine (PMEA)-adefovir dipivoxil (ADV)-is a first-line therapy drug for chronic hepatitis B with a low therapeutic index because of renal toxicity and low hepatic uptake. In this study, a series of PMEA derivatives were synthesized to enhance plasma stability and liver release. The metabolic stability of ADV (Chemical I) and its two analogues (Chemicals II and III) was evaluated in rat plasma and liver homogenate in vitro. An ion-pair reverse-phase HPLC-UV method and a hybrid ion trap and high-resolution time-of-flight mass spectrometry (LC-IT-TOF-MS) were used to evaluate the degradation rate of the analogues and to identify their intermediate metabolites, respectively. Chemicals I and II were hydrolyzed by cleavage of the C-O bond to give monoesters. Sufficient enzymatic activation in the liver homogenate through a relatively simple metabolic pathway, in addition to a favorable stability profile in rat plasma, made Chemical II an optimal candidate. Next, six analogues based on the structure of Chemical II were synthesized and evaluated in plasma and liver homogenate. Compared to Chemical II, these compounds generated less active PMEA levels in rat liver homogenate. Therefore, chemical modification of Chemical II may lead to new promising PMEA derivatives with enhanced plasma stability and liver activation. PMID:24338503

Liao, Sha; Fan, Shi-Yong; Liu, Qin; Li, Chang-Kun; Chen, Jia; Li, Jing-Lai; Zhang, Zhi-Wei; Zhang, Zhen-Qing; Zhong, Bo-Hua; Xie, Jian-Wei



Silicon analogues of the nonpeptidic GnRH antagonist AG-045572: syntheses, crystal structure analyses, and pharmacological characterization.  


AG-045572 (CMPD1, 1?a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1?b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1?a, 1?b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1?a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1?a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing. PMID:21953839

Barnes, Matthew J; Burschka, Christian; Büttner, Matthias W; Conroy, Richard; Daiss, Jürgen O; Gray, Ian C; Hendrick, Alan G; Tam, L H; Kuehn, Diana; Miller, David J; Mills, John S; Mitchell, Philip; Montana, John G; Muniandy, Parameswary A; Rapley, Helen; Showell, Graham A; Tebbe, David; Tacke, Reinhold; Warneck, Julie B H; Zhu, Bin



Synthesis and structure--activity relationships of substituted cinnamic acids and amide analogues: a new class of herbicides.  


In the present investigation, substituted cinnamic acids (3-hydroxy, 4-hydroxy, 2-nitro, 3-nitro, 4-nitro, 3-chloro, and 4-methoxy) and their amide analogues with four different types of substituted anilines have been synthesized. The synthesized compounds have been screened for their germination inhibition activity on radish (Raphanus sativus L. var. Japanese White) seeds at 50, 100, and 200 ppm concentrations, and the activity was compared with standard herbicide, metribuzin formulation (sencor). Significant activity was exhibited by all of the compounds. It was observed that with the increase in concentration of the test solution, the activity also increased. All of the compounds showed more than 70% inhibition at 100 ppm concentration except 4-hydroxy cinnamanilide. The compound, 2-chloro (4'-hydroxy) cinnamanilide was the best among the tested compounds, and it was found to be at par with the standard, metribuzin at all concentrations. Thus, it can be concluded that substituted cinnamic acids and their amide analogues may be developed as potential herbicides. PMID:19368353

Vishnoi, Shipra; Agrawal, Vikash; Kasana, Virendra K



One pot synthesis, structural and spectral analysis of some symmetrical curcumin analogues catalyzed by calcium oxide under microwave irradiation  

NASA Astrophysics Data System (ADS)

A series of sixteen number of curcumin analogues have been synthesized under microwave irradiation using calcium oxide as a catalyst. The synthesized compounds have been characterized using FT-IR, MS, elemental analysis, 1H and 13C NMR spectroscopic techniques. The UV-Vis absorption studies for these compounds have been studied in order to provide the electronic transitions taking place in the molecule. When compared to the curcumin ((1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one), the absorption maxima, ?max for all the synthesized curcumin analogues with a variety of substituents gets blue shifted i.e., hypsochromic shift was observed. This shift may be assigned to the change of dipole moment within the solvated molecule. Theoretical calculations regarding the optimization of the synthesized molecules, electronic properties like highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and mapped electron density surface diagrams were done. The geometrical energy, dipole moments and heat of formation values have also been calculated using the ArgusLab package by AM1 semi-empirical method.

Elavarasan, S.; Bhakiaraj, D.; Chellakili, B.; Elavarasan, T.; Gopalakrishnan, M.



New Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C8 Substitution in Structural Analogues of S-Adenosylmethionine†  

PubMed Central

S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C8-substituted adenine analogues bound in the active site. PMID:19209891



New structural insights into the apelin receptor: identification of key residues for apelin binding.  


Apelin is the endogenous ligand of the orphan 7-transmembrane domain GPCR APJ, now named the apelin receptor (ApelinR). Apelin plays a prominent role in body fluid and cardiovascular homeostasis. To better understand the structural organization of the ApelinR, we built 3 homology 3-dimensional (3D) models of the human ApelinR using the validated cholecystokinin receptor-1 3D model or the X-ray structures of the ?2-adrenergic and CXCR4 receptors as templates. Docking of the pyroglutamyl form of apelin 13 (pE13F) into these models revealed the conservation at the bottom of the binding site of a hydrophobic cavity in which the C-terminal Phe of pE13F was embedded. In contrast, at the top of the binding site, depending on the model, different interactions were visualized between acidic residues of the ApelinR and the basic residues of pE13F. Using site-directed mutagenesis, we showed that Asp 92, Glu 172, and Asp 282 of rat ApelinR are key residues in apelin binding by interacting with Lys 8, Arg 2, and Arg 4 of pE13F, respectively. These residues are only seen in the CXCR4-based ApelinR 3D model, further validating this model. These findings bring new insights into the structural organization of the ApelinR and the mode of apelin binding.-Gerbier, R., Leroux, V., Couvineau, P., Alvear-Perez, R., Maigret, B., Llorens-Cortes, C., Iturrioz, X. New structural insights into the apelin receptor: identification of key residues for apelin binding. PMID:25359495

Gerbier, Romain; Leroux, Vincent; Couvineau, Pierre; Alvear-Perez, Rodrigo; Maigret, Bernard; Llorens-Cortes, Catherine; Iturrioz, Xavier



The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis  

PubMed Central

Myelin oligodendrocyte glycoprotein (MOG) is a key CNS-specific autoantigen for primary demyelination in multiple sclerosis. Although the disease-inducing role of MOG has been established, its precise function in the CNS remains obscure. To gain new insights into the physiological and immunopathological role of MOG, we determined the 1.8-Å crystal structure of the MOG extracellular domain (MOGED). MOGED adopts a classical Ig (Ig variable domain) fold that was observed to form an antiparallel head-to-tail dimer. A dimeric form of native MOG was observed, and MOGED was also shown to dimerize in solution, consistent with the view of MOG acting as a homophilic adhesion receptor. The MOG35-55 peptide, a major encephalitogenic determinant recognized by both T cells and demyelinating autoantibodies, is partly occluded within the dimer interface. The structure of this key autoantigen suggests a relationship between the dimeric form of MOG within the myelin sheath and a breakdown of immunological tolerance to MOG that is observed in multiple sclerosis. PMID:12960396

Clements, Craig S.; Reid, Hugh H.; Beddoe, Travis; Tynan, Fleur E.; Perugini, Matthew A.; Johns, Terrance G.; Bernard, Claude C. A.; Rossjohn, Jamie



Comprehensive analysis of three-dimensional activity cliffs formed by kinase inhibitors with different binding modes and cliff mapping of structural analogues.  


Kinases are among the structurally most extensively characterized therapeutic targets. For many kinases, X-ray structures of inhibitor complexes are publicly available. We have identified all three-dimensional activity cliffs (3D-cliffs) formed by kinase inhibitors. More than 1300 X-ray structures of unique kinase-inhibitor complexes and associated activity data were analyzed. On the basis of binding mode comparison and 3D similarity calculations, 105 3D-cliffs were detected for type I, type II, or type III inhibitors of 13 different kinases. Many of these activity cliffs revealed clear interaction differences between highly and weakly potent inhibitors. More than 200 structural analogues of 3D-cliff compounds were identified whose structure-activity relationships (SARs) can be further explored in three dimensions on the basis of the corresponding 3D-cliffs. In addition to SAR exploration, 3D-cliffs provide useful interaction hypotheses for structure-based design. The kinase inhibitor and activity cliff information is made freely available as a part of our study. PMID:25054653

Furtmann, Norbert; Hu, Ye; Bajorath, Jürgen



Use of liquid chromatography-mass spectrometry and a chemical cleavage reaction for the structure elucidation of a new sildenafil analogue detected as an adulterant in an herbal dietary supplement.  


An herbal dietary supplement, marketed as a natural product for the enhancement of sexual function, was analyzed by HPLC with photodiode array and mass spectral detection and found to contain a compound related to the synthetic phosphodiesterase-5 (PDE-5) inhibitors. Based on UV spectra, mass spectra and direct infusion MS(n), the structure of the compound was tentatively identified as a sildenafil analogue in which the sulfonyl group had been replaced with an acetyl group. This new analogue is similar to acetildenafil, a previously reported sildenafil analogue, but differs in that it contains an N-methyl group where acetildenafil contains an N-ethyl group. The structure of the unknown was unequivocally established by chemical cleavage of the phenacylamine group of the molecule to generate N-methylpiperazine; other cleavage products matched those generated from acetildenafil. Since the new compound has one less CH(2) group than acetildenafil, it was named nor-acetildenafil. PMID:17532168

Reepmeyer, John C; Woodruff, Jeffrey T



Pseudocyanides of sanguinarine and chelerythrine and their series of structurally simple analogues as new anticancer lead compounds: Cytotoxic activity, structure-activity relationship and apoptosis induction.  


6-Cyano dihydrosanguinarine (CNS) and 6-cyano dihydrochelerythrine (CNC) are respectively artificial derivatives of sanguinarine and chelerythrine, two anticancer quaternary benzo[c]phenanthridine alkaloids (QBAs) while 1-cyano-2-aryl-1,2,3,4-tetrahydroisoquinolines (CATHIQs) are a class of structurally simple analogues of CNS or CNC. This study investigated the inhibition activity of CNS, CNC and CATHIQs on cancer cells, apoptosis induction as well as their preliminary SAR. The results showed that CNS and 18 out of CATHIQs showed IC50 values of 0.53 and 0.62-2.24?M against NB4 and 1.53 and 2.99-11.17?M against MKN-45 cells, respectively, superior to a standard anticancer drug cis-platinum with IC50 of 2.39 and 11.36?M. CNC showed a higher activity against NB4 cells (IC50=1.85?M) and a moderate activity against MKN-45 cells (IC50=12.72?M). Among all CATHIQs, 2 and 17 gave the highest activity against NB4 cells and MKN-45 cells (IC50=0.62 and 2.99?M), respectively. DAPI staining, AO/EB staining and ultrastructure analysis of cells demonstrated that CATHIQs were able to induce apoptosis of the cells in a concentration-dependent manner. SAR showed that substitution patterns on the N-aromatic ring significantly influenced the activity of CATHIQs. The general trend was that the introduction of electron-withdrawing substituents like halogen atom, nitro, trifluoromethyl led to a significant improvement of the activity, while the presence of electron-donating groups like methyl, methoxyl caused a reduction of the activity. In most cases, the 2' site was the most favorable substitution position for the improvement of the activity. Thus, the present results strongly suggested that QBA-type pseudocyanides may serve as potential alternatives of anticancer QBAs while CATHIQs should be a class of promising lead compounds for the development of new QBA-like-type anticancer drugs. CNS exhibited the highest cytotoxicities with IC50 values of 0.53?M on NB4 cells and 1.53?M on MKN-45 cells. PMID:25444843

Cao, Fang-Jun; Yang, Rui; Lv, Chao; Ma, Qun; Lei, Ming; Geng, Hui-Ling; Zhou, Le



1.45 A resolution crystal structure of recombinant PNP in complex with a pM multisubstrate analogue inhibitor bearing one feature of the postulated transition state  

SciTech Connect

Low molecular mass purine nucleoside phosphorylases (PNPs, E.C. are homotrimeric enzymes that are tightly inhibited by immucillins. Due to the positive charge on the ribose like part (iminoribitol moiety) and protonation of the N7 atom of the purine ring, immucillins are believed to act as transition state analogues. Over a wide range of concentrations, immucillins bind with strong negative cooperativity to PNPs, so that only every third binding site of the enzyme is occupied (third-of-the-sites binding). 9-(5',5'-difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) shares with immucillins the protonation of the N7, but not the positive charge on the ribose like part of the molecule. We have previously shown that DFPP-DG interacts with PNPs with subnanomolar inhibition constant. Here, we report additional biochemical experiments to demonstrate that the inhibitor can be bound with the same K{sub d} ({approx}190 pM) to all three substrate binding sites of the trimeric PNP, and a crystal structure of PNP in complex with DFPP-DG at 1.45 A resolution, the highest resolution published for PNPs so far. The crystals contain the full PNP homotrimer in the asymmetric unit. DFPP-DG molecules are bound in superimposable manner and with full occupancies to all three PNP subunits. Thus the postulated third-of-the-sites binding of immucillins should be rather attribute to the second feature of the transition state, ribooxocarbenium ion character of the ligand or to the coexistence of both features characteristic for the transition state. The DFPP-DG/PNP complex structure confirms the earlier observations, that the loop from Pro57 to Gly66 covering the phosphate-binding site cannot be stabilized by phosphonate analogues. The loop from Glu250 to Gln266 covering the base-binding site is organized by the interactions of Asn243 with the Hoogsteen edge of the purine base of analogues bearing one feature of the postulated transition state (protonated N7 position).

Chojnowski, Grzegorz [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland) [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland); International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland); Breer, Katarzyna; Narczyk, Marta; Wielgus-Kutrowska, Beata [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland)] [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland); Czapinska, Honorata [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland)] [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland); Hashimoto, Mariko; Hikishima, Sadao; Yokomatsu, Tsutomu [School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)] [School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan); Bochtler, Matthias [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland) [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland); Schools of Chemistry and Biosciences, Park Place, CF10 3AT Cardiff (United Kingdom); Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01309 Dresden (Germany); Girstun, Agnieszka; Staron, Krzysztof [Department of Molecular Biology, Institute of Biochemistry, University of Warsaw, Miecznikowa 1, 02-096 Warsaw (Poland)] [Department of Molecular Biology, Institute of Biochemistry, University of Warsaw, Miecznikowa 1, 02-096 Warsaw (Poland); Bzowska, Agnieszka, E-mail: [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland)] [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland)



Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles.  


In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels. PMID:24405213

St Jean, David J; Ashton, Kate S; Bartberger, Michael D; Chen, Jie; Chmait, Samer; Cupples, Rod; Galbreath, Elizabeth; Helmering, Joan; Hong, Fang-Tsao; Jordan, Steven R; Liu, Longbin; Kunz, Roxanne K; Michelsen, Klaus; Nishimura, Nobuko; Pennington, Lewis D; Poon, Steve F; Reid, Darren; Sivits, Glenn; Stec, Markian M; Tadesse, Seifu; Tamayo, Nuria; Van, Gwyneth; Yang, Kevin C; Zhang, Jiandong; Norman, Mark H; Fotsch, Christopher; Lloyd, David J; Hale, Clarence



Revealing the Mass Loss Structures of Four Key Massive Binaries Using Optical Spectropolarimetry  

NASA Astrophysics Data System (ADS)

The majority of massive stars are members of binary systems. However, in order to understand their evolutionary pathways, mass and angular momentum loss from these systems needs to be well characterized. Self-consistent explanations for their behavior across many wavelength regimes need to be valid in order to illuminate key evolutionary phases. I present the results of linear spectropolarimetric studies of three key binaries (? Lyrae, V356 Sgr, V444 Cyg, and WR 140) which reveal important geometric information about their circumstellar material. ? Lyrae exhibits a repeatable discrepancy between secondary eclipse in the total and polarized light curves that indicates an accretion hot spot has formed on the edge of the disk in the system. The existence of this hot spot and its relationship to bipolar outflows within the system is important in the understanding of mass transfer dynamics in Roche-lobe overflow binaries. Preliminary work on V356 Sgr suggests the system maybe surrounded by a common envelope. V444 Cyg shows evidence that its shock creates a cone with a large opening angle of missing material around the WN star. This suggests the effects of radiative inhibition or braking, can be significant contributors to the location and shape of the shock within colliding wind binaries. The intrinsic polarization component of WR 140 is likely due to the formation of dust within the system near periastron passages. Continued work on these and additional objects will provide new and important constraints on the mass loss structures within binary systems.

Lomax, Jamie R.



Natural analogues of nuclear waste glass corrosion.  

SciTech Connect

This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.



Key Plant Structural and Allocation Traits Depend on Relative Age in the Perennial Herb Pimpinella saxifraga  

PubMed Central

• Background and Aims Perennial plant formations always include a mixture of various-aged individuals of community-creating species, but the physiological and competitive potentials of plants of differing age and the importance on whole community functioning are still not entirely known. The current study tested the hypothesis that ontogenetically old plants have limited biomass investments in leaves and enhanced foliage support costs. • Methods Leaf structure, size and biomass allocation were studied in the perennial herb Pimpinella saxifraga during plant ontogeny from seedling to senile phases to determine age-dependent controls on key plant structural traits. The average duration of the full ontogenetic cycle is approx. 5–10 years in this species. Plants were sampled from shaded and open habitats. • Key Results Leaflet dry mass per unit area (MA) increased, and the fraction of plant biomass in leaflets (FL) decreased with increasing age, leading to a 5- to 11-fold decrease in leaf area ratio (LAR = FL/MA) between seedlings and senescent plants. In contrast, the fraction of below-ground biomass increased with increasing age. Leaflet size and number per leaf increased with increasing age. This was not associated with enhanced support cost in older plants as age-dependent changes in leaf shape and increased foliage packing along the rachis compensated for an overall increase in leaf size. Age-dependent trends were the same in habitats with various irradiance, but the LAR of plants of varying age was approx. 1·5-fold larger in the shade due to lower MA and larger FL. • Conclusions As plant light interception per unit total plant mass scales with LAR, these data demonstrate major age-dependent differences in plant light-harvesting efficiency that are further modified by site light availability. These ontogenetic changes reduce the differences among co-existing species in perennial communities, and therefore need consideration in our understanding of how herbaceous communities function. PMID:15965271




Utility of Remote Sensing, Robotic Precursor Data and a Focused Science Hypothesis for a Follow-On Human Exploration Lunar Analogue Mission at the Mistastin Lake (Kamestastin) Impact Structure  

NASA Astrophysics Data System (ADS)

Here we summarize how remote sensing, robotic precursor data and a focused science hypothesis augmented the results from a lunar analogue mission to the Mistastin impact structure in Labrador, Canada. Join me as we go on a magical tour of this crater.

Tornabene, L. L.; Osinski, G. R.; Mader, M. M.; Chanou, A.; Francis, R.; Joliff, B. L.; Marion, C.; McCullough, E.; Pickersgill, A.; Sapers, H.; Souders, K.; Sylvester, P.; Young, K.; Zanetti, M.; Krash Operations; Science Team



Glutamate provides a key structural contact between reticulon-4 (Nogo-66) and phosphocholine.  


Human reticulon 4 (RTN-4) has been identified as the neurite outgrowth inhibitor (Nogo). This protein contains a span of 66 amino acids (Nogo-66) flanked by two membrane helices at the C-terminus. We previously determined the NMR structure of Nogo-66 in a native-like environment and defined the regions of Nogo-66 expected to be membrane embedded. We hypothesize that aromatic groups and a negative charge hyperconserved among RTNs (Glu26) drive the remarkably strong association of Nogo-66 with a phosphocholine surface. Glu26 is an isolated charge with no counterion provided by nearby protein groups. We modeled the docking of dodecylphosphocholine (DPC) with Nogo-66 and found that a lipid choline group could form a stable salt bridge with Glu26 and serve as a membrane anchor point. To test the role of the Glu26 anion in binding choline, we mutated this residue to alanine and assessed the structural consequences, the association with lipid and the affinity for the Nogo receptor. In an aqueous environment, Nogo-66 Glu26Ala is more helical than WT and binds the Nogo receptor with higher affinity. Thus, we can conclude that in the absence of a neutralizing positive charge provided by lipid, the glutamate anion is destabilizing to the Nogo-66 fold. Although the Nogo-66 Glu26Ala free energy of transfer from water into lipid is similar to that of WT, NMR data reveal a dramatic loss of tertiary structure for the mutant in DPC micelles. These data show that Glu26 has a key role in defining the structure of Nogo-66 on a phosphocholine surface. This article is part of a special issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova. PMID:24863057

Alhoshani, Ali; Vithayathil, Rosemarie; Bandong, Jonathan; Chrunyk, Katherine M; Moreno, Gabriel O; Weiss, Gregory A; Cocco, Melanie J



Synthesis and Antibacterial Activities of Yanglingmycin Analogues.  


The synthesis of Yanglingmycin and its enantiomer, along with eighteen Yanglingmycin analogues is reported. The structures were confirmed mainly by analyses of NMR spectral data. Antibacterial activity assays showed that Yanglingmycin and some of its analogues exhibited significant antibacterial activities against two important agricultural pathogenic bacteria, Ralstonia solanacearum and Pseudomonas syringae pv. actinidiae, with MIC values ranging from 3.91 to 15.62 ?g/mL. The antibacterial activities exhibited by Yanglingmycin and its analogues are promising, suggesting potential in the development of compounds for novel bactericides. PMID:25355464

Li, Long-Bo; Dan, Wen-Jia; Tan, Fang-Fang; Cui, Li-Hui; Yuan, Zhi-Peng; Wu, Wen-Jun; Zhang, Ji-Wen



NMR structure determination of a synthetic analogue of bacillomycin Lc reveals the strategic role of L-Asn1 in the natural iturinic antibiotics  

NASA Astrophysics Data System (ADS)

Iturins are a group of antifungal produced by Bacillus subtilis. All are cyclic lipopeptides with seven ?-amino acids of configuration LDDLLDL and one ?-amino fatty acid. The bacillomycin L is a member of this family and its NMR structure was previously resolved using the sequence Asp-Tyr-Asn-Ser-Gln-Ser-Thr. In this work, we carefully examined the NMR spectra of this compound and detected an error in the sequence. In fact, Asp1 and Gln5 need to be changed into Asn1 and Glu5, which therefore makes it identical to bacillomycin Lc. As a consequence, it now appears that all iturinic peptides with antibiotic activity share the common ?-amino fatty acid 8- L-Asn1- D-Tyr2- D-Asn3 sequence. To better understand the conformational influence of the acidic residue L-Asp1, present, for example in the inactive iturin C, the NMR structure of the synthetic analogue SCP [cyclo ( L-Asp1- D-Tyr2- D-Asn3- L-Ser4- L-Gln5- D-Ser6- L-Thr7-?-Ala8)] was determined and compared with bacillomycin Lc recalculated with the corrected sequence. In both cases, the conformers obtained were separated into two families of similar energy which essentially differ in the number and type of turns. A detailed analysis of both cyclopeptide structures is presented here. In addition, CD and FTIR spectra were performed and confirmed the conformational differences observed by NMR between both cyclopeptides.

Volpon, Laurent; Tsan, Pascale; Majer, Zsuzsa; Vass, Elemer; Hollósi, Miklós; Noguéra, Valérie; Lancelin, Jean-Marc; Besson, Françoise



Ligand-dependent active-site closure revealed in the crystal structure of Mycobacterium tuberculosis MenB complexed with product analogues.  


1,4-Dihydroxy-2-naphthoyl coenzyme A (DHNA-CoA) synthase catalyzes an essential intramolecular Claisen condensation in menaquinone biosynthesis and is an important target for the development of new antibiotics. This enzyme in Mycobacterium tuberculosis is cofactor-free and is classified as a type II DHNA-CoA synthase, differing from type I enzymes, which rely on exogenous bicarbonate for catalysis. Its crystal structures in complex with product analogues have been determined at high resolution to reveal ligand-dependent structural changes, which include the ordering of a 27-residue active-site loop (amino acids 107-133) and the reorientation of the carboxy-terminal helix (amino acids 289-301) that forms part of the active site from the opposing subunit across the trimer-trimer interface. These structural changes result in closure of the active site to the bulk solution, which is likely to take place through an induced-fit mechanism, similar to that observed for type I DHNA-CoA synthases. These findings demonstrate that the ligand-dependent conformational changes are a conserved feature of all DHNA-CoA synthases, providing new insights into the catalytic mechanism of this essential tubercular enzyme. PMID:25372686

Song, Haigang; Sung, Hoi Pang; Tse, Yuk Sing; Jiang, Ming; Guo, Zhihong



Tropiporphyrins, cycloheptatrienyl analogues of the porphyrins: synthesis, spectroscopy, chemistry, and structural characterization of a silver(III) derivative.  


Tripyrranes were condensed with 1,3,5-cycloheptriene-1,6-dicarbaldehyde in TFA-CH(2)Cl(2) to give, following oxidation with 0.1% aqueous ferric chloride solutions, a series of tropiporphyrins 9. These cycloheptatrienyl analogues of the porphyrins show strong diatropic ring currents by proton NMR spectroscopy where the internal CH gives a resonance at -7.3 ppm, although the meso-protons are not shifted as far downfield as most aromatic porphyrinoid systems. These data indicate that the seven-membered ring distorts the porphyrinoid macrocycle and decreases the overall diatropicity in tropiporphyrins. Addition of trace amounts of TFA to solutions of 9 affords the corresponding aromatic monocations, and at higher acid concentrations a nonaromatic dication is generated. The dication has undergone C-protonation at one of the meso-bridges and has lost the plane of symmetry present in the parent system. This species shows significant downfield shifts to the cycloheptatrienyl protons, indicating that this unit has taken on tropylium character. Tropiporphyrin 9a underwent a Diels-Alder cycloaddition with dimethyl acetylenedicarboxylate in refluxing xylenes to give modest yields of the related adduct. The Diels-Alder adduct 17 showed an increased diatropic ring current where the internal proton shifted beyond -9 ppm, and this indicates that the [18]annulene substructure has flattened out compared to 9a. Diimide reduction of 9a afforded a dihydrotropiporphyrin that also showed a stronger ring current. Tropiporphyrins 9 were also shown to react with silver(I) acetate in the presence of DBU in refluxing pyridine to give the corresponding silver(III) organometallic derivatives. The meso-protons for these metal complexes give proton NMR chemical shift values similar to those for the parent tropiporphyrins, indicating that the macrocycle is still distorted, but the external olefinic protons are shifted downfield compared to 9. A diphenyl-substituted silver(III) derivative 18b was further characterized by X-ray crystallography. This shows that the cycloheptatriene unit takes on a highly twisted geometry that distorts the overall conformation of the porphyrinoid macrocycle. PMID:15527266

Bergman, Katrina M; Ferrence, Gregory M; Lash, Timothy D



Micro Electret Energy Harvesting Device with Analogue Impedance Conversion Circuit  

E-print Network

Micro Electret Energy Harvesting Device with Analogue Impedance Conversion Circuit Yuji Suzuki1 using a low-power-consumption impedance conversion circuit. Key words: Energy harvesting, Electret, CYTOP, Parylene spring, Impedance conversion 1. INTRODUCTION Energy harvesting from environmental

Kasagi, Nobuhide


Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design  

E-print Network

,§ My Le Shaw,| Sam S. Shin, Lisa N. Nguyen, Stephen Suresh,,# Frederick S. Buckner, Wesley C. Van, Biochemistry, Medicine, and Biological Structure, University of Washington, Seattle, Washington 98195, Biomolecular Structure Center and Howard Hughes Medical Institute, Seattle, Washington 98195, Department

Gelb, Michael


Structural Analysis of Peptide-Analogues of Human Zona Pellucida ZP1 Protein with Amyloidogenic Properties: Insights into Mammalian Zona Pellucida Formation  

PubMed Central

Zona pellucida (ZP) is an extracellular matrix surrounding and protecting mammalian and fish oocytes, which is responsible for sperm binding. Mammalian ZP consists of three to four glycoproteins, called ZP1, ZP2, ZP3, ZP4. These proteins polymerize into long interconnected filaments, through a common structural unit, known as the ZP domain, which consists of two domains, ZP-N and ZP-C. ZP is related in function to silkmoth chorion and in an evolutionary fashion to the teleostean fish chorion, also fibrous structures protecting the oocyte and embryo, that both have been proven to be functional amyloids. Two peptides were predicted as ‘aggregation-prone’ by our prediction tool, AMYLPRED, from the sequence of the human ZP1-N domain. Here, we present results from transmission electron microscopy, X-ray diffraction, Congo red staining and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR FT-IR), of two synthetic peptide-analogues of these predicted ‘aggregation-prone’ parts of the human ZP1-N domain, that we consider crucial for ZP protein polymerization, showing that they both self-assemble into amyloid-like fibrils. Based on our experimental data, we propose that human ZP (hZP) might be considered as a novel, putative, natural protective amyloid, in close analogy to silkmoth and teleostean fish chorions. Experiments are in progress to verify this proposal. We also attempt to provide insights into ZP formation, proposing a possible model for hZP1-N domain polymerization. PMID:24069181

Louros, Nikolaos N.; Iconomidou, Vassiliki A.; Giannelou, Polina; Hamodrakas, Stavros J.



Inhibition of Siderophore Biosynthesis in Mycobacterium tuberculosis with Nucleoside Bisubstrate Analogues: Structure–Activity Relationships of the Nucleobase Domain of 5?-O-[N-(Salicyl)sulfamoyl]adenosine  

PubMed Central

5?-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure–activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 µM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence. PMID:18690677

Neres, João; Labello, Nicholas P.; Somu, Ravindranadh V.; Boshoff, Helena I.; Wilson, Daniel J.; Vannada, Jagadeshwar; Chen, Liqiang; Barry, Clifton E.; Bennett, Eric M.; Aldrich, Courtney C.



Biological activity in Technosols as a key factor of their structure  

NASA Astrophysics Data System (ADS)

The studies of the dynamics of organic matters within soils, show that their structural stability depends on the biological activity bound to the degradation of organic products. We wondered what it was for Technosols there. We then tried to specify the contribution of this biological activity to the structure of three contrasted technosols : - Technosol 1: a material originated from a former steel industry containing steel and coke residues, which was deposited two years ago in lysimetric plots - Technosol 2: a constructed soil (30 months) resulting from the combination of paper-mill sludge, thermally treated soil material excavated from a former coking plant site, and green-waste compost - Technosol 3: 30 years old technosol developed on flotation ponds of a former steel mill with strong metallic pollution, on which grows a forest ecosystem If these 3 technosols presented initially a similar organic carbon content (around 70, the origin of organic matters was different A follow-up of the structural stability of these 3 systems, based on techniques of granulometric soil fractionation and morphological/analytical characterization at ultrastructural scale (TEM/EDX), was realized. Results showed the specific contribution of organic matters to the formation of stable organo-mineral associations, in particular those belonging to (0-50 ?m) fraction. They mainly involved organic matter from vegetal origin coming from the spontaneous colonization of these 3 sites, but also from microbial origin corresponding to rhizospheric bacteria producing exopolymers. Organic matters from the compost and cellulosic fibers from the paper-mill sludge also contributed to the formation of organo-mineral associations all the more that compost was also a source of microorganisms. Organic matters were also associated to pollutant metallic elements (Pb, Zn, Mn) initially brought by the materials, then highlighting their possible transfer and questioning about their (bio)availability. HAP also contributed to the aggregation of technogenic constituents in Technosol 1. The biological activity generated by the presence of exogenous organic matter is thus in short (0-2 years) and mean (30 years) terms, a key factor of the structuration and by there of the pedogenesis of Technosols.

Watteau, Françoise; Villemin, Geneviève; Bouchard, Adeline; Monserié, Marie-France; Séré, Geoffroy; Schwartz, Christophe; Morel, Jean-Louis



Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step  

PubMed Central

Summary Piperazirum, isolated from Arum palaestinum Boiss, was originally assigned as r-3,c-5-diisobutyl-c-6-isopropylpiperazin-2-one. The reported structure was synthesised diastereoselectively using a key nitro-Mannich reaction to set up the C5/C6 relative stereochemistry. The structure was unambiguously assigned by single crystal X-ray diffraction but the spectroscopic data did not match those reported for the natural product. The structure of the natural product must therefore be revised. PMID:24062836

Kalogirou, Andreas S; Porter, Michael J; Tizzard, Graham J



Structural changes accompanying GTP hydrolysis in microtubules: information from a slowly hydrolyzable analogue guanylyl-(alpha,beta)- methylene-diphosphonate  

PubMed Central

We have used cryoelectron microscopy to try to understand the structural basis for the role of GTP hydrolysis in destabilizing the microtubule lattice. We have measured a structural difference introduced into microtubules by replacing GTP with guanylyl- (alpha,beta)-methylene-diphosphonate (GMPCPP). In a stable GMPCPP microtubule lattice, the moire patterns change and the tubulin subunits increase in size by 1.5 A. This information provides a clue to the role of hydrolysis in inducing the structural change at the end of a microtubule during the transition from a growing to a shrinking phase. PMID:7822409



Blackbody Infrared Radiative Dissociation of Bradykinin and Its Analogues: Energetics, Dynamics, and Evidence for Salt-Bridge Structures in the Gas Phase  

PubMed Central

Blackbody infrared radiative dissociation (BIRD) spectra of singly and doubly protonated bradykinin and its analogues are measured in a Fourier-transform mass spectrometer. Rate constants for dissociation are measured as a function of temperature with reaction delays up to 600 s. From these data, Arrhenius activation parameters in the zero-pressure limit are obtained. The activation parameters and dissociation products for the singly protonated ions are highly sensitive to small changes in ion structure. The Arrhenius activation energy (Ea) and pre-exponential (or frequency factor, A) of the singly protonated ions investigated here range from 0.6 to 1.4 eV and 105 to 1012 s?1, respectively. For bradykinin and its analogues differing by modification of the residues between the two arginine groups on either end of the molecule, the singly and doubly protonated ions have average activation energies of 1.2 and 0.8 eV, respectively, and average A values of 108 and 1012 s?1, respectively, i.e., the presence of a second charge reduces the activation energy by 0.4 eV and decreases the A value by a factor of 104. This demonstrates that the presence of a second charge can dramatically influence the dissociation dynamics of these ions. The doubly protonated methyl ester of bradykinin has an Ea of 0.82 eV, comparable to the value of 0.84 eV for bradykinin itself. However, this value is 0.21 ± 0.08 eV greater than that of singly protonated methyl ester of bradykinin, indicating that the Coulomb repulsion is not the most significant factor in the activation energy of this ion. Both singly and doubly protonated Lys-bradykinin ions have higher activation energies than the corresponding bradykinin ions indicating that the addition of a basic residue stabilizes these ions with respect to dissociation. Methylation of the carboxylic acid group of the C-terminus reduces the Ea of bradykinin from 1.3 to 0.6 eV and the A factor from 1012 to 105 s?1. This modification also dramatically changes the dissociation products. Similar results are observed for [Ala6]-bradykinin and its methyl ester. These results, in combination with others presented here, provide experimental evidence that the most stable form of singly protonated bradykinin is a salt-bridge structure. PMID:16525512

Schnier, Paul D.; Price, William D.; Jockusch, Rebecca A.




EPA Science Inventory

Experimental and theoretical evidence pertaining to cytotoxic and genotoxic activity of paracetamol in biological systems was used to formulate a simple mechanistic hypothesis to explain the relative inhibition of replicative DNA synthesis by a series of 19 structurally similar p...


Phosphorus oxynitride PON, a silica analogue: structure and compression of the cristobalite-like phase; P? – T phase diagram  

Microsoft Academic Search

The structure of the cristobalite-like polymorph of phosphorus oxynitride PON has been refined using neutron powder diffraction\\u000a data. It is tetragonal, space group I&4macr;2d, Z=4. The four P–(O,N) distances are equal but the tetrahedron is compressed along c. In AX2 or ABX4 compounds, the tetragonal I&4macr;2d or I&4macr; structure is obtained when the average ratio of the cation to anion

J. M. Léger; J. Haines; C. Chateau; G. Bocquillon; M. W. Schmidt; S. Hull; F. Gorelli; A. Lesauze; R. Marchand



Nonstationary analogue black holes  

E-print Network

We study the existence of analogue nonstationary spherically symmetric black holes. The prime example is the acoustic model (cf. [V], [U]). We consider also a more general class of metrics that could be useful in other physical models of analogue black and white holes. We give examples of the appearance of black holes and of disappearance of white holes. We also discuss the relation between the apparent and the event horizons for the case of analogue black holes. In the end we study the inverse problem of determination of black or white holes by boundary measurements for the spherically symmetric nonstationary metrics.

Gregory Eskin



Detection of sildenafil analogues in herbal products for erectile dysfunction.  


Sildenafil, the active ingredient in Viagra (Pfizer), is a prescription medicine used for erectile dysfunction. Compounds with chemical structures similar to that of sildenafil were isolated and purified during the analysis of some herbal products marketed for treatment of erectile dysfunction. Structural elucidation using liquid chromatography-diode array detection, infrared spectroscopy, liquid chromatography-tandem mass spectrometry, and nuclear magnetic resonance spectroscopy confirmed that the compounds were homosildenafil, hydroxyhomosildenafil, and acetildenafil. The implications of adulteration by compounds structurally related to prescription drugs are discussed. Unlike established drugs, the efficacy and safety of such analogues are largely unknown. This poses a great challenge for safety and health administrators to detect these modified structures and to regulate them. Consumers who use such adulterated products are at risk of developing serious adverse reactions, potentially leading to death. Greater collaboration and exchange of information between various health authorities, health professionals, academics, researchers, and industry, as well as public education, are key steps in the efforts to stem the growing trend of adulteration of herbal products by analogues of prescription drugs. PMID:16982533

Oh, Sharon Sze-Yin; Zou, Peng; Low, Min-Yong; Koh, Hwee-Ling



Synthesis of isoxazolidine-containing uridine derivatives as caprazamycin analogues.  


Simplification of caprazamycins, which are promising antibacterial nucleoside natural products, was conducted by scaffold-hopping of the structurally complex diazepanone moiety to the isoxazolidine scaffold. The designed isoxazolidine-containing uridine derivatives were synthesized by an intramolecular 1,3-dipolar cycloaddition of alkenyl nitrone as a key step. The lactone-fused isoxazolidine intermediate was easily converted to the target compounds by sequential introduction of key substituents upon ring-opening the lactone moiety by nucleophilic substitution and electrophilic capping of the resulting primary alcohol. Several analogues exhibited good activity against H. influenzae ATCC 10211 (MIC 0.25-0.5 ?g mL(-1)) and moderate activity against vancomycin-resistant E. faecalis SR7914 (MIC 4-8 ?g mL(-1)). PMID:25428330

Yamaguchi, Mayumi; Matsuda, Akira; Ichikawa, Satoshi



Structured Codes Improve the Bennett-Brassard-84 Quantum Key Rate  

E-print Network

A central goal in information theory and cryptography is finding simple characterizations of optimal communication rates subject to various restrictions and security requirements. Ideally, the optimal key rate for a quantum key distribution (QKD) protocol would be given by {\\em single-letter formula} involving a simple optimization over a single use of an effective channel. We explore the possibility of such a formula for one of the simplest and most widely used QKD protocols--Bennett-Brassard-84 (BB84) with one way classical post-processing. We show that a conjectured single-letter key-rate formula is false, uncovering a deep ignorance about asymptotically good private codes and pointing towards unfortunate complications in the theory of QKD. These complications are not without benefit--with added complexity comes better key rates than previously thought possible. We improve the threshold for secure key generation from a bit error rate of 0.124 to 0.129.

Graeme Smith; Joseph M. Renes; John A. Smolin



The fluorite related modulated structures of the Gd2(Zr2-xCex)O7 solid solution: An analogue for Pu disposition  

NASA Astrophysics Data System (ADS)

We present an overview of the Gd2(Zr2-xCex)O7 phase diagram, of interest as a model system for ceramic disposition of Pu (with Ce as a Pu surrogate). The fluorite related structures of this solid solution were determined using a modulated structure approach, to identify the underlying cation and vacancy ordering mechanisms from analysis of key satellite reflections in selected zone axis electron diffraction patterns. This revealed the formation of four structure types: pyrochlore for x<0.25, defect fluorite for 0.5structure for x=1.00, and a C-type structure for x>1.50. X-ray absorption (XAS) and electron energy loss (EELS) spectra confirmed the presence of Ce4+ as the dominant species in compositions across this system, remaining analogous to Pu4+.

Reid, D. P.; Stennett, M. C.; Hyatt, N. C.



Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents  

Technology Transfer Automated Retrieval System (TEKTRAN)

Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...


Novel sorafenib-based structural analogues: in-vitro anticancer evaluation of t-MTUCB and t-AUCMB  

E-print Network

-MTUCB), that are structurally similar to sorafenib. These compounds show strong cytotoxic responses in various cancer cell lines & Wilkins. Anti-Cancer Drugs 2014, 25:433­446 Keywords: autophagy, hepatoma cells, kinase selectivity,d,f and Bruce D. Hammocka,c In the current work, we carried out a mechanistic study on the cytotoxicity of two

Hammock, Bruce D.


New Kagome metal Sc?Mn?Al?Si? and its gallium-doped analogues: synthesis, crystal structure, and physical properties.  


We report the synthesis, crystal structure, and basic properties of the new intermetallic compound Sc3Mn3Al7Si5. The structure of the compound was established by single-crystal X-ray diffraction, and it crystallizes with a hexagonal structure (Sc3Ni11Si4 type) with Mn atoms forming the Kagome nets. The dc magnetic susceptibility measurements reveal a Curie-Weiss moment of ~0.51 ?(B)/Mn; however, no magnetic order is found for temperatures as low as 1.8 K. Electrical resistivity and heat capacity measurements show that this compound is definitively metallic, with a relatively large specific heat Sommerfeld coefficient, indicating strong electronic correlations. Intriguingly, these features have revealed Sc3Mn3Al7Si5 as a possible quantum spin liquid. With chemical and lattice disorder introduced by doping, a spin liquid to spin glass transition is observed in the highest Ga-doped compounds. The roles of the geometrically frustrated structure and Mn-ligand hybridization in the magnetism of the title compounds are also discussed. PMID:25144523

He, Hua; Miiller, Wojciech; Aronson, Meigan C



Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues.  


Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines. Acute imipramine (IMI, 15 mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60 mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity). Only IMI, MB (15, 30, 60 mg/kg) and MG (7.5, 25, 40 mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15 mg/kg) increased noradrenergic behaviour in the FST, while MB (15 mg/kg) and MG (15 mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels. MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal. PMID:20699087

Harvey, Brian H; Duvenhage, Ingrid; Viljoen, Francois; Scheepers, Nellie; Malan, Sarel F; Wegener, Gregers; Brink, Christiaan B; Petzer, Jacobus P



The crystal structures at 80 K and IR spectra of the complex of 4-methylpyridine with pentachlorophenol and its deuterated analogue  

NASA Astrophysics Data System (ADS)

The crystal structures of the complex of 4-methylpyridine with pentachlorophenol (MP?PCP) and its deuterated analogue (MP?PCP- d) were determined at 80 K by X-ray diffraction. The MP?PCP complex crystallizes in the space group P 1¯ with a = 7.267(7), b = 8.966(9), c = 13.110(14) Å, ? = 99.70(8), ? = 118.16(9), ? = 103.38(8)° and Z = 2 and the MP?PCP- d complex in the monoclinic Cc space group with a = 3.826(2), b = 27.54(2), c = 13.209(12) Å, ? = 101.38(9)° and Z = 4. The O…H…N bridge bond distance of 2.515(4) Å is significantly shorter than that determined at room temperature (2.552(4) Å) and the O?D…N bond length of 2.628(6) Å is only slightly shorter than at room temperature (2.638(3) Å). The temperature dependence of the IR spectra confirms the symmetrization of the OHN hydrogen bond.

Malarski, Z.; Majerz, I.; Lis, T.



Evaluation of Cancer Preventive Activity and Structure-Activity Relationships of 3-Demethylubiquinone Q2, Isolated from the Ascidian Aplidium glabrum, and its Synthetic Analogues  

PubMed Central

Purpose 3-Demethylubiquinone Q2 (1) was isolated from the ascidian Aplidium glabrum. The cancer preventive properties and the structure-activity relationship for 3-demethylubiquinone Q2 (1) and 12 of its synthetic analogues (3–14) are reported. Methods Compounds 3–14, having one or several di- or triprenyl substitutions and quinone moieties with methoxyls in different positions, were synthesized. The cancer preventive properties of compounds 1 and 3–14 were tested in JB6 Cl41 mouse skin cells, using a variety of assessments, including the MTS assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance. Results All quinones tested were shown to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1 and NF-?B activity, and to inhibit p53 activity. The most promising effects were indicated for compounds containing two isoprene units in a side chain and a methoxyl group at the para-position to a polyprenyl substitution. Conclusions Quinones 1 and 3–14 demonstrated cancer preventive activity in JB6 Cl41 cells, which may be attributed to the induction of p53-independent apoptosis. These activities depended on the length of side chains and on the positions of the methoxyl groups in the quinone part of the molecule. PMID:16320003

Fedorov, Sergey N.; Radchenko, Oleg S.; Shubina, Larisa K.; Balaneva, Nadezhda N.; Bode, Ann M.; Stonik, Valentin A.; Dong, Zigang



Mutation of a conserved residue enhances the sensitivity of analogue-sensitised kinases to generate a novel approach to the study of mitosis in fission yeast.  


The chemical genetic strategy in which mutational enlargement of the ATP-binding site sensitises of a protein kinase to bulky ATP analogues has proved to be an elegant tool for the generation of conditional analogue-sensitive kinase alleles in a variety of model organisms. Here, we describe a novel substitution mutation in the kinase domain that can enhance the sensitivity of analogue-sensitive kinases. Substitution of a methionine residue to phenylalanine in the +2 position after HRDLKxxN motif of the subdomain VIb within the kinase domain markedly increased the sensitivities of the analogue-sensitive kinases to ATP analogues in three out of five S. pombe kinases (i.e. Plo1, Orb5 and Wee1) that harbor this conserved methionine residue. Kinome alignment established that a methionine residue is found at this site in 5-9% of kinases in key model organisms, suggesting that a broader application of this structural modification may enhance ATP analogue sensitivity of analogue-sensitive kinases in future studies. We also show that the enhanced sensitivity of the wee1.as8 allele in a cdc25.22 background can be exploited to generate highly synchronised mitotic and S phase progression at 36°C. Proof-of-principle experiments show how this novel synchronisation technique will prove of great use in the interrogation of the mitotic or S-phase functions through temperature sensitivity mutation of molecules of interest in fission yeast. PMID:23986474

Tay, Ye-Dee; Patel, Avinash; Kaemena, Daniel F; Hagan, Iain M



Synthesis and structure–activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors  

Microsoft Academic Search

A series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the aromatase inhibitor, letrozole 1. Compound 10a, bearing a 1,2,3-triazole, is also 10000-times more tightly binding than the corresponding analogue 25 bearing

Jérémie Doiron; Al Haliffa Soultan; Ryan Richard; Mamadou Mansour Touré; Nadia Picot; Rémi Richard; Miroslava ?uperlovi?-Culf; Gilles A. Robichaud; Mohamed Touaibia



A thiamin-bound, pre-decarboxylation reaction intermediate analogue in the pyruvate dehydrogenase E1 subunit induces large scale disorder-to-order transformations in the enzyme and reveals novel structural features in the covalently bound adduct.  


The crystal structure of the E1 component from the Escherichia coli pyruvate dehydrogenase multienzyme complex (PDHc) has been determined with phosphonolactylthiamin diphosphate (PLThDP) in its active site. PLThDP serves as a structural and electrostatic analogue of the natural intermediate alpha-lactylthiamin diphosphate (LThDP), in which the carboxylate from the natural substrate pyruvate is replaced by a phosphonate group. This represents the first example of an experimentally determined, three-dimensional structure of a thiamin diphosphate (ThDP)-dependent enzyme containing a covalently bound, pre-decarboxylation reaction intermediate analogue and should serve as a model for the corresponding intermediates in other ThDP-dependent decarboxylases. Regarding the PDHc-specific reaction, the presence of PLThDP induces large scale conformational changes in the enzyme. In conjunction with the E1-PLThDP and E1-ThDP structures, analysis of a H407A E1-PLThDP variant structure shows that an interaction between His-407 and PLThDP is essential for stabilization of two loop regions in the active site that are otherwise disordered in the absence of intermediate analogue. This ordering completes formation of the active site and creates a new ordered surface likely involved in interactions with the lipoyl domains of E2s within the PDHc complex. The tetrahedral intermediate analogue is tightly held in the active site through direct hydrogen bonds to residues His-407, Tyr-599, and His-640 and reveals a new, enzyme-induced, strain-related feature that appears to aid in the decarboxylation process. This feature is almost certainly present in all ThDP-dependent decarboxylases; thus its inclusion in our understanding of general thiamin catalysis is important. PMID:16531404

Arjunan, Palaniappa; Sax, Martin; Brunskill, Andrew; Chandrasekhar, Krishnamoorthy; Nemeria, Natalia; Zhang, Sheng; Jordan, Frank; Furey, William



An Attempt to Infer the Electrophysiological Functions of Some Intracellular Structures in Cardiac Cells by an Electronic Analogue  

PubMed Central

A circuit which simulates the electrical conduction characteristics of the neuron has been modified by the addition of a feedback loop to simulate the electrical properties of some of the “specialized” tissues of the mammalian heart. It is suggested that there is similar electrical feedback in the muscle cells which is responsible for their electrical properties, and possible relationships between the feedback and observed structures are discussed. PMID:5903154

Challice, C. E.; Clark, T. A.



Key words Science of information, spatio-temporal, semantic and structural information, Darwin channel, noisy constrained capacity.  

E-print Network

Key words ­ Science of information, spatio-temporal, semantic and structural information, Darwin argue that a new science of information is to rekindle for extraction, comprehension, and manipulation channel, noisy constrained capacity. Wojciech SZPANKOWSKI Department of Computer Science Purdue University

Szpankowski, Wojciech


1 Hippocampal structure and human cognition: Key role of 2 spatial processing and evidence supporting the efficiency  

E-print Network

U N C O R R E C T E D P R O O F 1 Hippocampal structure and human cognition: Key role of 2 spatial processing and evidence supporting the efficiency 3 hypothesis in females 4 RobertoQ1 Colom a,b, , Jason L, and processing speed. After permutation tests corrected for multiple com- 25parisons across vertices (pb.05

Wang, Yalin


1. Keyed Search Structures Lecture III Page 1 "Trees are the earth's endless effort to speak to the listening heaven."  

E-print Network

§1. Keyed Search Structures Lecture III Page 1 "Trees are the earth's endless effort to speak to the listening heaven." ­ Rabindranath Tagore, Fireflies, 1928 Lecture III BALANCED SEARCH TREES Anthropologists equivalent of `snow' is the tree word: (a, b)-tree, AVL tree, B-tree, binary search tree, BSP tree

Yap, Chee


A tandem regression-outlier analysis of a ligand cellular system for key structural modifications around ligand binding  

PubMed Central

Background A tandem technique of hard equipment is often used for the chemical analysis of a single cell to first isolate and then detect the wanted identities. The first part is the separation of wanted chemicals from the bulk of a cell; the second part is the actual detection of the important identities. To identify the key structural modifications around ligand binding, the present study aims to develop a counterpart of tandem technique for cheminformatics. A statistical regression and its outliers act as a computational technique for separation. Results A PPAR? (peroxisome proliferator-activated receptor gamma) agonist cellular system was subjected to such an investigation. Results show that this tandem regression-outlier analysis, or the prioritization of the context equations tagged with features of the outliers, is an effective regression technique of cheminformatics to detect key structural modifications, as well as their tendency of impact to ligand binding. Conclusions The key structural modifications around ligand binding are effectively extracted or characterized out of cellular reactions. This is because molecular binding is the paramount factor in such ligand cellular system and key structural modifications around ligand binding are expected to create outliers. Therefore, such outliers can be captured by this tandem regression-outlier analysis. PMID:23627990



Mobilizing Communities around HIV Prevention for Youth: How Three Coalitions Applied Key Strategies to Bring about Structural Changes  

ERIC Educational Resources Information Center

Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community…

Chutuape, Kate S.; Willard, Nancy; Sanchez, Kenia; Straub, Diane M.; Ochoa, Tara N.; Howell, Kourtney; Rivera, Carmen; Ramos, Ibrahim; Ellen, Jonathan M.



New bitter-masking compounds: hydroxylated benzoic acid amides of aromatic amines as structural analogues of homoeriodictyol.  


Starting from the known bitter-masking flavanones eriodictyol and homoeriodictyol from herba santa some structurally related hydroxybenzoic acid amides of benzylamines were synthesized and evaluated as masking agents toward bitterness of caffeine by sensory methods. The closest structural relatives of homoeriodictyol, the hydroxybenzoic acid vanillylamides 5-9, were the most active and were able to reduce the bitterness of a 500 mg L(-1) caffeine solution by about 30% at a concentration of 100 mg L(-1). 2,4-Dihydroxybenzoic acid vanillylamide 7 showed a clear dose-dependent activity as inhibitor of the bitter taste of caffein between 5 and 500 mg L(-1). Additionally, it was possible to reduce the bitterness of quinine and salicine but not of the bitter peptide N-l-leucyl-l-tryptophan. Combinations of homoeriodictyol and amide 7 showed no synergistic or antagonistic changes in activity. The results for model compound 7 suggested that the hitherto unknown masking mechanism is probably the same for flavanones and the new amides. In the future, the new amides may be alternatives for the expensive flavanones to create flavor solutions to mask bitterness of pharmaceuticals or foodstuffs. PMID:17061836

Ley, Jakob P; Blings, Maria; Paetz, Susanne; Krammer, Gerhard E; Bertram, Heinz-Jürgen



3D structure of a heparin mimetic analogue of a FGF-1 activator. A NMR and molecular modelling study.  


The motional behaviour of heparin oligosaccharides in solution is best described as a top rotor having two perpendicular rotation axes. This prevents an accurate extraction of interprotonic distances by NOESY/ROESY based methods. In this paper, we describe the solution structure of the hexasaccharide 1 calculated from high exactitude distance data obtained from off-resonance ROESY combined with a long MD simulation of 500 ns. In previous studies, we have found that two synthetic hexasaccharides having the sulphate groups directed towards one side of its central plane have an opposite biological activity, while 1 is unable to activate the FGF-1 signalling pathway, the other (2) is even more active than the regular region derived hexasaccharide (3) that mimics the natural active compound, heparin. From the structural analysis it was concluded that 1 has similar three-dimensional characteristics to 2 or 3 and therefore the differences in the activity should be due to the arrangement of the sulphate groups within the hexasaccharidic sequence. PMID:24178304

Muñoz-García, Juan C; Solera, Cristina; Carrero, Paula; de Paz, José L; Angulo, Jesús; Nieto, Pedro M



A Mission Control Architecture for robotic lunar sample return as field tested in an analogue deployment to the sudbury impact structure  

NASA Astrophysics Data System (ADS)

A Mission Control Architecture is presented for a Robotic Lunar Sample Return Mission which builds upon the experience of the landed missions of the NASA Mars Exploration Program. This architecture consists of four separate processes working in parallel at Mission Control and achieving buy-in for plans sequentially instead of simultaneously from all members of the team. These four processes were: science processing, science interpretation, planning and mission evaluation. science processing was responsible for creating products from data downlinked from the field and is organized by instrument. Science Interpretation was responsible for determining whether or not science goals are being met and what measurements need to be taken to satisfy these goals. The Planning process, responsible for scheduling and sequencing observations, and the Evaluation process that fostered inter-process communications, reporting and documentation assisted these processes. This organization is advantageous for its flexibility as shown by the ability of the structure to produce plans for the rover every two hours, for the rapidity with which Mission Control team members may be trained and for the relatively small size of each individual team. This architecture was tested in an analogue mission to the Sudbury impact structure from June 6-17, 2011. A rover was used which was capable of developing a network of locations that could be revisited using a teach and repeat method. This allowed the science team to process several different outcrops in parallel, downselecting at each stage to ensure that the samples selected for caching were the most representative of the site. Over the course of 10 days, 18 rock samples were collected from 5 different outcrops, 182 individual field activities - such as roving or acquiring an image mosaic or other data product - were completed within 43 command cycles, and the rover travelled over 2200 m. Data transfer from communications passes were filled to 74%. Sample triage was simulated to allow down-selection to 1 kg of material for return to Earth.

Moores, John E.; Francis, Raymond; Mader, Marianne; Osinski, G. R.; Barfoot, T.; Barry, N.; Basic, G.; Battler, M.; Beauchamp, M.; Blain, S.; Bondy, M.; Capitan, R.-D.; Chanou, A.; Clayton, J.; Cloutis, E.; Daly, M.; Dickinson, C.; Dong, H.; Flemming, R.; Furgale, P.; Gammel, J.; Gharfoor, N.; Hussein, M.; Grieve, R.; Henrys, H.; Jaziobedski, P.; Lambert, A.; Leung, K.; Marion, C.; McCullough, E.; McManus, C.; Neish, C. D.; Ng, H. K.; Ozaruk, A.; Pickersgill, A.; Preston, L. J.; Redman, D.; Sapers, H.; Shankar, B.; Singleton, A.; Souders, K.; Stenning, B.; Stooke, P.; Sylvester, P.; Tornabene, L.



Structural Analysis of Metabolites of Asiatic Acid and Its Analogue Madecassic Acid in Zebrafish Using LC/IT-MSn.  


Although zebrafish has become a significant animal model for drug discovery and screening, drug metabolism in zebrafish remains largely unknown. Asiatic acid (AA) and madecassic acid (MA), two natural pentacyclic triterpenoids mainly obtained from Centella asiatica (L.) Urban, have been found to possess many pharmacological effects. This study is to probe the metabolic capability of zebrafish via investigation of the drug metabolism of AA and MA in zebrafish, using a sensitive LC/IT-MSn method. In addition, the main fragmentation pathways of AA and MA were reported for the first time. Nineteen metabolites of AA and MA were firstly identified after zebrafish was exposed to the drug, which all were the phase I metabolites and mainly formed from hydroxylation, dehydrogenation, hydroxylation and dehydrogenation, dihydroxylation and dehydrogenation, and dehydroxylation reaction. The results indicated that zebrafish possessed strong metabolic capacity, and the metabolites of AA and MA were formed via similar metabolic pathways and well matched with the known metabolic rules in vivo and in vitro, which supports the widely use of this system in drug metabolism research. This investigation would also contribute to the novel information on the structural elucidation, in vivo metabolites and metabolic mechanism of pentacyclic triterpenoids. PMID:25685908

Xia, Binbin; Bai, Lu; Li, Xiaorong; Xiong, Jie; Xu, Pinxiang; Xue, Ming



Block of voltage-operated sodium channels by 2,6-dimethylphenol, a structural analogue of lidocaine's aromatic tail  

PubMed Central

The structural features that determine the state-dependent interaction of local anaesthetics with voltage-operated sodium channels are still a matter of debate. We have studied the blockade of sodium channels by 2,6-dimethylphenol, a phenol derivative which resembles the aromatic tail of lidocaine, etidocaine, and bupivacaine. The effects of 2,6-dimethylphenol were studied on heterologously (HEK 293) expressed rat neuronal (rat brain IIA) and human skeletal muscle (hSkM1) sodium channels using whole-cell voltage-clamp experiments. 2,6-Dimethylphenol was effective in blocking whole-cell sodium inward currents. Its potency was comparable to the potency of lidocaine previously obtained with similar protocols by others. The IC50 at ?70 mV holding potential was 150 and 187 ?M for the skeletal muscle and the neuronal isoform, respectively. In both isoforms, the blocking potency increased with the fraction of inactivated channels at depolarized holding potentials. However, the block achieved at ?70 mV with respect to ?150 mV holding potential was significantly higher only in the skeletal muscle isoform. The estimated dissociation constant Kd from the inactivated state was 25 ?M and 28 ?M in the skeletal muscle and the neuronal isoform, respectively. The kinetics of drug equilibration between resting and inactivated channel states were about 10 fold faster compared with lidocaine. Our results show that the blockade induced by 2,6-dimethylphenol retains voltage-dependency, a typical feature of lidocaine-like local anaesthetics. This is consistent with the hypothesis that the ‘aromatic tail' determines the state-dependent interaction of local anaesthetics with the sodium channel. PMID:12208786

Haeseler, Gertrud; Bufler, Johannes; Merken, Sarah; Dengler, Reinhard; Aronson, Jeffrey; Leuwer, Martin



Stabilization of the potent odorant 2-acetyl-1-pyrroline and structural analogues by complexation with zinc halides.  


2-Acetyl-1-pyrroline (2AP) and the structurally similar compounds 6-acetyl-2,3,4,5-tetrahydropyridine (ATHP, along with its tautomer 6-acetyl-1,2,3,4-tetrahydropyridine), 2-propionyl-1-pyrroline (2PP), and 2-acetyl-2-thiazoline (2A2T) are well-known potent odorants in various food products. However, due to the highly unstable nature of these compounds, especially 2AP and ATHP, they are scarcely used commercially in flavor formulations. A novel and attractive method for the stabilization of these potent odorants in dry powder form is presented. Coordination of 2AP, ATHP, 2PP, and 2A2T to zinc ions (ZnI2, ZnBr2, or ZnCl2) resulted in the formation in high yields of stable crystalline complexes, which upon hydration release the free odorant. Infrared spectroscopy was used to study the coordination complexes. 2AP contains donor atoms, which coordinate (with covalent character) through both the heterocyclic nitrogen and carbonyl oxygen atoms to the zinc ion. This is also the case for ATHP and 2PP, but not for 2A2T, because the sulfur group in 2A2T provides a third possible donor site. Stability studies showed that the 2AP-ZnI2 complex (with 14% loading) maintained >94% retention of 2AP after 3 months of storage at ambient temperature in a dry environment. Meanwhile, the ATHP-ZnI2 complex was similarly stable and retained 89% of the ATHP after 3 months of storage. This stabilization technology may enable the commercial use of this powerful aroma compound as a flavoring agent. PMID:25147956

Fang, Ming-Chih; Cadwallader, Keith R



Nitrogen Analogues of Thiele's Hydrocarbon.  


A series of bis[N,N-di-(4-methoxylphenyl)amino]arene dications 1(2+) -3(2+) have been synthesized and characterized. Their electronic structures were investigated by various experiments assisted by theoretical calculations. It was found that they are singlets in the ground state and that their diradical character is dependent on the bridging moiety. 3(2+) has a smaller singlet-triplet energy gap and its excited triplet state is thermally readily accessible. The work provides a nitrogen analogue of Thiele's hydrocarbon with considerable diradical character. PMID:25504531

Su, Yuanting; Wang, Xingyong; Li, Yuantao; Song, You; Sui, Yunxia; Wang, Xinping



A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells  

Microsoft Academic Search

SUMMARY The most highly conserved noncoding ele- ments (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding de- velopmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific

Bradley E. Bernstein; Tarjei S. Mikkelsen; Xiaohui Xie; Michael Kamal; Dana J. Huebert; James Cuff; Ben Fry; Alex Meissner; Marius Wernig; Kathrin Plath; Rudolf Jaenisch; Alexandre Wagschal; Robert Feil; Stuart L. Schreiber; Eric S. Lander



How does conformational flexibility influence key structural features involved in activation of anaplastic lymphoma kinase?  


Anaplastic Lymphoma Kinase (ALK) plays a major role in developing tumor processes and therefore has emerged as a validated therapeutic target. Applying atomistic molecular dynamics simulations on the wild type enzyme and the nine most frequently occurring and clinically important activation mutants we revealed important conformational effects on key interactions responsible for the activation of the enzyme. PMID:24675991

Karabencheva, Tatyana G; Lee, Christian C; Black, Gary W; Donev, Rossen; Christov, Christo Z



Preparation of glutamate analogues by enzymatic transamination.  


Aminotransferases are key enzymes of the metabolism of proteinogenic amino acids. These ubiquitous biocatalysts show high specific activities and relaxed substrate specificities making them valuable tools for the stereoselective synthesis of unnatural amino acids. We describe here the application of aspartate aminotransferase and branched chain aminotransferase from E. coli for the synthesis of various glutamate analogues, molecules of particular interest regarding the neuroactive properties of glutamic acid. PMID:21956556

Gefflaut, Thierry; Assaf, Zeinab; Sancelme, Martine



Assigning the protonation states of the key aspartates in ?-Secretase using QM/MM X-ray structure refinement  

PubMed Central

?-Secretase, a.k.a. ?-APP cleaving enzyme (BACE), is an aspartyl protease that has been implicated as a key target in the pathogenesis of Alzheimer’s disease (AD). The identification of the protonation states of the key aspartates in ?-secretase is of great interest both in understanding the reaction mechanism and in guiding the design of drugs against AD. However, the resolutions of currently available crystal structures for BACE are not sufficient to determine the hydrogen atom locations. We have assigned the protonation states of the key aspartates using a novel method, QM/MM X-ray refinement. In our approach, an energy function is introduced to the refinement where the atoms in the active site are modeled by quantum mechanics (QM) and the other atoms are represented by molecular mechanics (MM). The gradients derived from the QM/MM energy function are combined with those from the X-ray target to refine the crystal structure of a complex containing BACE and an inhibitor. A total number of 8 protonation configurations of the aspartyl dyad were considered and QM/MM X-ray refinements were performed for all of them. The relative stability of the refined structures was scored by constructing the thermodynamic cycle using the energetics calculated by fully quantum mechanical self-consistent reaction field (QM/SCRF) calculations. While all 8 refined structures fit the observed electron density about equally well, we find the mono-protonated configurations to be strongly favored energetically, especially the configuration with the inner oxygen of Asp32 protonated and the hydroxyl of the inhibitor pointing towards Asp228. It was also found that these results depend on the constraints imposed by the X-ray data. We suggest that one of the strengths of this approach is that the resulting structures are a consensus of theoretical and experimental data and remark on the significance of our results in structure based drug design and mechanistic studies. PMID:19079786

Yu, Ning; Hayik, Seth A.; Wang, Bing; Liao, Ning; Reynolds, Charles H.; Merz, Kenneth M.



New indolicidin analogues with potent antibacterial activity.  


Indolicidin is a 13-residue antimicrobial peptide amide, ILPWKWPWWPWRR-NH2, isolated from the cytoplasmic granules of bovine neutrophils. Indolicidin is active against a wide range of microorganisms and has also been shown to be haemolytic and cytotoxic towards erythrocytes and human T lymphocytes. The aim of the present paper is two-fold. First, we examine the importance of tryptophan in the antibacterial activity of indolicidin. We prepared five peptide analogues with the format ILPXKXPXXPXRR-NH2 in which Trp-residues 4,6,8,9,11 were replaced in all positions with X = a single non-natural building block; N-substituted glycine residue or nonproteinogenic amino acid. The analogues were tested for antibacterial activity against both Staphylococcus aureus American type culture collection (ATCC) 25923 and Escherichia coli ATCC 25922. We found that tryptophan is not essential in the antibacterial activity of indolicidin, and even more active analogues were obtained by replacing tryptophan with non-natural aromatic amino acids. Using this knowledge, we then investigated a new principle for improving the antibacterial activity of small peptides. Our approach involves changing the hydrophobicity of the peptide by modifying the N-terminus with a hydrophobic non-natural building block. We prepared 22 analogues of indolicidin and [Phe(4,6,8,9,11)] indolicidin, 11 of each, carrying a hydrophobic non-natural building block attached to the N-terminus. Several active antibacterial analogues were identified. Finally, the cytotoxicity of the analogues against sheep erythrocytes was assessed in a haemolytic activity assay. The results presented here suggest that modified analogues of antibacterial peptides, containing non-natural building blocks, are promising lead structures for developing future therapeutics. PMID:15485555

Ryge, T S; Doisy, X; Ifrah, D; Olsen, J E; Hansen, P R



Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues  

PubMed Central

Summary Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization. PMID:23946854

Li, Xu-Wen; Herrmann, Jennifer; Zang, Yi; Grellier, Philippe; Prado, Soizic



Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues.  


Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad-Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure-activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization. PMID:23946854

Li, Xu-Wen; Herrmann, Jennifer; Zang, Yi; Grellier, Philippe; Prado, Soizic; Müller, Rolf; Nay, Bastien



Photochemical synthesis of nucleoside analogues from cyclobutanones: bicyclic and isonucleosides.  


The preparation of two nucleoside analogues are reported. Both syntheses involve a key photochemical ring-expansion of cyclobutanones to an oxacarbene and its subsequent scavenging by 6-chloropurine. The synthesis of a bicyclic (locked) purine starts from a oxabicycloheptanone with a hydroxymethyl pendant. The preparation of an isonucleoside uses a cyclobutanone with an alpha-substituted 6-chloropurine. Irradiation of the latter produces an isonucleoside and acyclic nucleoside analogues. PMID:20657410

Jaffer, Mileina; Ebead, Abdelaziz; Lee-Ruff, Edward



Novel 3-substituted rimonabant analogues lack ?9-tetrahydrocannabinol-like abuse-related behavioural effects in mice  

PubMed Central

Background and Purpose Previous structure–activity relationship studies with analogues of the CB1 receptor antagonist rimonabant have demonstrated that a subset of these analogues with 3-substituent replacements of rimonabant's pyrazole core displayed cannabimimetic profiles seemingly independent of CB1 receptors. We sought to further evaluate these analogues in several behavioural models sensitive to detecting THC-like abuse liability. Experimental Approach Selected analogues were tested in a battery of tests in mice to replicate previous findings. Cross-generalization tests were conducted in mice trained to discriminate either THC or O-6629 from vehicle. Rimonabant and its analogues were also evaluated in substitution and challenge tests. Finally, development of cross-tolerance between THC and O-6211 in the mouse test battery was assessed. Key Results O-6629 and O-6658 produced dose-dependent acute cannabimimetic activity in mice, but neither substituted for nor antagonized THC's discriminative stimulus. Cross-substitution was observed with O-6658 in mice discriminating O-6629, whereas rimonabant neither substituted for nor attenuated the O-6629 discriminative stimulus. THC and morphine did not generate O-6629-like responding. Cross-tolerance did not develop in mice repeatedly treated with THC when tested with O-6211 in the mouse test battery. Conclusions and Implications While some overlap exists between the pharmacological profiles of THC and these 3-substituent rimonabant analogues, the effects are mediated by distinct neural targets. Notably, these analogues are unlikely to possess marijuana-like abuse liability in humans, but general abuse liability has not yet been determined. Efforts to determine the mechanism(s) of action of this seemingly unique class of compounds are underway. PMID:23297801

Walentiny, DM; Vann, RE; Mahadevan, A; Kottani, R; Gujjar, R; Wiley, JL



Impact melt-bearing breccias of the Mistastin Lake impact structure: A unique planetary analogue for ground-truthing proximal ejecta emplacement  

NASA Astrophysics Data System (ADS)

Impact craters are the dominant geological landform on rocky planetary surfaces; however, relationships between specific craters and their ejecta are typically poorly constrained. With limited planetary samples, scientists look to terrestrial craters as analogues. Impact ejecta is defined here as any target material, regardless of its physical state, that is transported beyond the rim of the transient cavity [1]. The original transient cavity reaches its maximum size during the excavation stage of crater formation, before rim collapse begins in the modification stage [2]. In complex craters, during the modification stage, rocks around the periphery of the bowl-shaped transient crater collapse downward and inward to form a series of terraces along the outer margin of the crater structure [3]. Proximal impact ejecta, can therefore be found on the terraces of the modified rim of a complex crater, interior to the final crater rim [1]. Although typically poorly preserved on Earth due to post-impact erosional processes, impact ejecta have been identified in the terraced rim region of the Mistastin Lake impact structure, located in northern Labrador, Canada (55°53'N; 63°18'W) [4]. The Mistastin Lake impact structure is an intermediate-size, complex crater (28 km apparent crater diameter) formed by a meteorite impact ~36 Ma in crystalline target rocks. The original crater has been differentially eroded; however, a terraced rim and distinct central uplift are still observed [5]. The inner portion of the structure is covered by the Mistastin Lake and the surrounding area is locally covered by soil/glacial deposits and vegetation. Locally, allochthonous impactites overlying fractured target rocks are exposed along the lakeshore and along banks of radially cutting streams. They define a consistent stratigraphy, including, from bottom to top: monomict, lithic breccias, allochthonous polymict lithic breccias, and allochthonous impact melt rocks. Mistastin impact breccias range in matrix content, melt-fragment concentration, and contact relationships with adjacent impactites. Initial findings suggest differing origins for impact melt-bearing breccias from a single impact event. Three examples are highlighted: 1) Impact melt-bearing breccias, on an inner terrace, formed in boundary zones where hot impact melt flowed over cooler, ballistically emplaced polymict impact breccias. 2) Locally, a dyke of impact melt-bearing breccia suggests that this unit originated as hot lithic flow that moved laterally along the ground and then intruded as a fracture fill into target rocks. 3) A m-scale lens of melt-bearing breccia within the middle of a thick, 80m impact melt rock unit situated on an inner terrace, suggests that this lens may have originated from the crater floor and been incorporated into the melt pond during emplacement (i.e. movement of the melt from the crater floor to terrace shelf). In summary, the Mistastin Lake impact structure displays a multiple layered ejecta sequence that is consistent with, and requires, a multi-stage ejecta emplacement model as proposed by [1]. References: [1] Osinski et al. (2011) EPSL (310:167-181. [2] Melosh (1989) Oxford Univ. 245 pp. [3] French B. M. (1998) LPI Contribution 954,120pp. [4] Mader et al. (2011) 42nd LPSC, No.1608. [5] Mader et al. (2013) 43rd LPSC, No. 2517.

Mader, M. M.; Osinski, G. R.



Structure-Activity Relationships for a Novel Series of Citalopram (1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile) Analogues at Monoamine Transporters  

PubMed Central

(±)-Citalopram (1, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile), and its eutomer, escitalopram (S(+)-1) are selective serotonin reuptake inhibitors (SSRIs) that are used clinically to treat anxiety and depression. To further explore structure-activity relationships at the serotonin transporter (SERT), a series of (±)-4- and 5-substituted citalopram analogues were designed, synthesized and evaluated for binding at the SERT, dopamine transporter (DAT) and norepinephrine transporter (NET) in native rodent tissue. Many of these analogues showed high SERT binding affinities (Ki = 1–40 nM) and selectivities over both NET and DAT. Selected enantiomeric pairs of analogues were synthesized and both retained enantioselectivity as with S- and R-1, wherein S > R at the SERT. In addition, the enantiomeric pairs of 1 and 5 were tested for binding at the homologous bacterial Leucine transporter (LeuT), wherein low affinities and the absence of enantioselectivity suggested distinctive binding sites for these compounds at SERT as compared to LeuT. These novel ligands will provide molecular tools to elucidate drug-protein interactions at the SERT and to relate those to behavioral actions, in vivo. PMID:20672825

Zhang, Peng; Cyriac, George; Kopajtic, Theresa; Zhao, Yongfang; Javitch, Jonathan A.; Katz, Jonathan L.; Newman, Amy Hauck



Crystal structure of LeuA from Mycobacterium tuberculosis, a key enzyme in leucine biosynthesis  

Microsoft Academic Search

The leucine biosynthetic pathway is essential for the growth of Mycobacterium tuberculosis and is a potential target for the design of new anti-tuberculosis drugs. The crystal structure of -isopropylmalate synthase, which catalyzes the first committed step in this pathway, has been determined by multiwavelength anomalous dispersion methods and refined at 2.0-Å resolution in complex with its substrate -ketoisovalerate. The structure

Nayden Koon; Christopher J. Squire; Edward N. Baker



Millennial Climatic Fluctuations Are Key to the Structure of Last Glacial Ecosystems  

PubMed Central

Whereas fossil evidence indicates extensive treeless vegetation and diverse grazing megafauna in Europe and northern Asia during the last glacial, experiments combining vegetation models and climate models have to-date simulated widespread persistence of trees. Resolving this conflict is key to understanding both last glacial ecosystems and extinction of most of the mega-herbivores. Using a dynamic vegetation model (DVM) we explored the implications of the differing climatic conditions generated by a general circulation model (GCM) in “normal” and “hosing” experiments. Whilst the former approximate interstadial conditions, the latter, designed to mimic Heinrich Events, approximate stadial conditions. The “hosing” experiments gave simulated European vegetation much closer in composition to that inferred from fossil evidence than did the “normal” experiments. Given the short duration of interstadials, and the rate at which forest cover expanded during the late-glacial and early Holocene, our results demonstrate the importance of millennial variability in determining the character of last glacial ecosystems. PMID:23613985

Huntley, Brian; Allen, Judy R. M.; Collingham, Yvonne C.; Hickler, Thomas; Lister, Adrian M.; Singarayer, Joy; Stuart, Anthony J.; Sykes, Martin T.; Valdes, Paul J.



Mycobacterium tuberculosis Glucosyl-3-Phosphoglycerate Synthase: Structure of a Key Enzyme in Methylglucose Lipopolysaccharide Biosynthesis  

PubMed Central

Tuberculosis constitutes today a serious threat to human health worldwide, aggravated by the increasing number of identified multi-resistant strains of Mycobacterium tuberculosis, its causative agent, as well as by the lack of development of novel mycobactericidal compounds for the last few decades. The increased resilience of this pathogen is due, to a great extent, to its complex, polysaccharide-rich, and unusually impermeable cell wall. The synthesis of this essential structure is still poorly understood despite the fact that enzymes involved in glycosidic bond synthesis represent more than 1% of all M. tuberculosis ORFs identified to date. One of them is GpgS, a retaining glycosyltransferase (GT) with low sequence homology to any other GTs of known structure, which has been identified in two species of mycobacteria and shown to be essential for the survival of M. tuberculosis. To further understand the biochemical properties of M. tuberculosis GpgS, we determined the three-dimensional structure of the apo enzyme, as well as of its ternary complex with UDP and 3-phosphoglycerate, by X-ray crystallography, to a resolution of 2.5 and 2.7 Å, respectively. GpgS, the first enzyme from the newly established GT-81 family to be structurally characterized, displays a dimeric architecture with an overall fold similar to that of other GT-A-type glycosyltransferases. These three-dimensional structures provide a molecular explanation for the enzyme's preference for UDP-containing donor substrates, as well as for its glucose versus mannose discrimination, and uncover the structural determinants for acceptor substrate selectivity. Glycosyltransferases constitute a growing family of enzymes for which structural and mechanistic data urges. The three-dimensional structures of M. tuberculosis GpgS now determined provide such data for a novel enzyme family, clearly establishing the molecular determinants for substrate recognition and catalysis, while providing an experimental scaffold for the structure-based rational design of specific inhibitors, which lay the foundation for the development of novel anti-tuberculosis therapies. PMID:19015727

Pereira, Pedro José Barbosa; Empadinhas, Nuno; Albuquerque, Luciana; Sá-Moura, Bebiana; da Costa, Milton S.; Macedo-Ribeiro, Sandra



Crystal structure of ATP sulfurylase from Saccharomyces cerevisiae, a key enzyme in sulfate activation  

PubMed Central

ATP sulfurylases (ATPSs) are ubiquitous enzymes that catalyse the primary step of intracellular sulfate activation: the reaction of inorganic sulfate with ATP to form adenosine-5?-phosphosulfate (APS) and pyrophosphate (PPi). With the crystal structure of ATPS from the yeast Saccharomyces cerevisiae, we have solved the first structure of a member of the ATP sulfurylase family. We have analysed the crystal structure of the native enzyme at 1.95 ? resolution using multiple isomorphous replacement (MIR) and, subsequently, the ternary enzyme product complex with APS and PPi bound to the active site. The enzyme consists of six identical subunits arranged in two stacked rings in a D3 symmetric assembly. Nucleotide binding causes significant conformational changes, which lead to a rigid body structural displacement of domains III and IV of the ATPS monomer. Despite having similar folds and active site design, examination of the active site of ATPS and comparison with known structures of related nucleotidylyl transferases reveal a novel ATP binding mode that is peculiar to ATP sulfuryl-ases. PMID:11157739

Ullrich, Tobias C.; Blaesse, Michael; Huber, Robert



Structural Insights into Maize Viviparous14, a Key Enzyme in the Biosynthesis of the Phytohormone Abscisic Acid[W  

PubMed Central

The key regulatory step in the biosynthesis of abscisic acid (ABA), a hormone central to the regulation of several important processes in plants, is the oxidative cleavage of the 11,12 double bond of a 9-cis-epoxycarotenoid. The enzyme viviparous14 (VP14) performs this cleavage in maize (Zea mays), making it a target for the rational design of novel chemical agents and genetic modifications that improve plant behavior through the modulation of ABA levels. The structure of VP14, determined to 3.2-Å resolution, provides both insight into the determinants of regio- and stereospecificity of this enzyme and suggests a possible mechanism for oxidative cleavage. Furthermore, mutagenesis of the distantly related CCD1 of maize shows how the VP14 structure represents a template for all plant carotenoid cleavage dioxygenases (CCDs). In addition, the structure suggests how VP14 associates with the membrane as a way of gaining access to its membrane soluble substrate. PMID:20884803

Messing, Simon A.J.; Gabelli, Sandra B.; Echeverria, Ignacia; Vogel, Jonathan T.; Guan, Jiahn Chou; Tan, Bao Cai; Klee, Harry J.; McCarty, Donald R.; Amzel, L. Mario



Structural Insights into Maize Viviparous14, a Key Enzyme in the Biosynthesis of the Phytohormone Abscisic Acid  

SciTech Connect

The key regulatory step in the biosynthesis of abscisic acid (ABA), a hormone central to the regulation of several important processes in plants, is the oxidative cleavage of the 11,12 double bond of a 9-cis-epoxycarotenoid. The enzyme viviparous14 (VP14) performs this cleavage in maize (Zea mays), making it a target for the rational design of novel chemical agents and genetic modifications that improve plant behavior through the modulation of ABA levels. The structure of VP14, determined to 3.2-{angstrom} resolution, provides both insight into the determinants of regio- and stereospecificity of this enzyme and suggests a possible mechanism for oxidative cleavage. Furthermore, mutagenesis of the distantly related CCD1 of maize shows how the VP14 structure represents a template for all plant carotenoid cleavage dioxygenases (CCDs). In addition, the structure suggests how VP14 associates with the membrane as a way of gaining access to its membrane soluble substrate.

Messing, Simon A.J.; Gabelli, Sandra B.; Echeverria, Ignacia; Vogel, Jonathan T.; Guan, Jiahn Chou; Tan, Bao Cai; Klee, Harry J.; McCarty, Donald R.; Amzel, L. Mario (JHU); (Florida)



Cell size as a key determinant of phytoplankton metabolism and community structure.  


Phytoplankton size structure controls the trophic organization of planktonic communities and their ability to export biogenic materials toward the ocean's interior. Our understanding of the mechanisms that drive the variability in phytoplankton size structure has been shaped by the assumption that the pace of metabolism decreases allometrically with increasing cell size. However, recent field and laboratory evidence indicates that biomass-specific production and growth rates are similar in both small and large cells but peak at intermediate cell sizes. The maximum nutrient uptake rate scales isometrically with cell volume and superisometrically with the minimum nutrient quota. The unimodal size scaling of phytoplankton growth arises from ataxonomic, size-dependent trade-off processes related to nutrient requirement, acquisition, and use. The superior ability of intermediate-size cells to exploit high nutrient concentrations explains their biomass dominance during blooms. Biogeographic patterns in phytoplankton size structure and growth rate are independent of temperature and driven mainly by changes in resource supply. PMID:25062405

Marañón, Emilio



Transverse analogue tomography in radiotherapy.  


This paper describes the design and development of a single unit to combine the advantages of precision high-energy simulation and X-ray body scanning. Good detail transverse-axial-tomograms are produced on the basis of analogue technology where the X-ray density values of the slice of the object are produced in analogue instead of digital form. In broad terms, the development of this unit now for the first time enables the radiotherapist (after localising the tumour site by conventional diagnostic X-ray screening on the simulator) to proceed immediately (without moving the patient) to transverse-axial-tomography, slicing the target volume to give three dimensional evidence of the spread and position of the growth relative to adjacent normal structures. This information is fed into a computer-controlled treatment-planning system quickly to facilitate the preparation of precise treatment presciriptions. The running costs and the staff needed to operate and maintain this dual-function machine do not appear greater than the normally accepted requirements for a conventional radiotherapy simulator. PMID:6769137

Crooks, S H; Hanna, F A



Comparing Religious Education in Canadian and Australian Catholic High Schools: Identifying Some Key Structural Issues  

ERIC Educational Resources Information Center

Religious education (RE) in Catholic high schools in Australia and Canada is compared by examining some of the underlying structural factors that shape the delivery of RE. It is argued that in Canadian Catholic schools RE is diminished by three factors that distinguish it from the Australian experience. These are: the level and history of…

Rymarz, Richard



In vivo effects of N\\/OFQ(1–13)NH 2 and its structural analogue [ORN 9 ]N\\/OFQ(1–13)NH 2 on carrageenan-induced inflammation: rat-paw oedema and antioxidant status  

Microsoft Academic Search

The effects of nociceptin(1–13)NH2 (N\\/OFQ(1–13)NH2) and its structural analogue [Orn9]N\\/OFQ(1–13)NH2 on acute carrageenan (CG)-induced peripheral inflammation and paw antioxidant status were studied. CG was injected intraplantarly\\u000a in the right hind paw of rats and the volume of the inflamed paw was measured each 30 min for a period of 4h. When administered\\u000a simultaneously with CG, N\\/OFQ(1–13)NH2 decreased the paw volume,

Rositsa Zamfirova; Elina Tzvetanova; Albena Alexandrova; Lubomir Petrov; Polina Mateeva; Almira Pavlova; Margarita Kirkova; Simeon Todorov



The HOBYS Key Program: When Herschel links high-mass star formation to cloud structure  

NASA Astrophysics Data System (ADS)

With its unprecedented spatial resolution and high sensitivity in the far-infrared to submillimetre regime, {Herschel} is revolutionizing our understanding of star formation. The HOBYS key program is an {Herschel} mapping survey dedicated to the formation of OB-type stars (Motte, Zavagno, Bontemps et al. 2010; see {}. HOBYS aims at 1) discovering and characterizing the progenitors of high-mass stars, 2) making the link between the latters and their filamentary background, and 3) assessing the importance of triggering. Among the HOBYS highlights is the discovery of ``mini-starburst ridges" defined as high-density dominating filaments supersonically contracting and efficiently forming clusters of high-mass stars. Their existence is predicted by dynamical models of cloud formation such as converging flows and is favoring a (high-mass) star formation scenario involving gas flows and global infall. The present star formation rate measured within these ridges is high enough for these 1-10 pc^2 regions to be considered as miniature and instantaneous models of extragalactic starbursts.

Motte, F.; Bontemps, S.; Hennemann, M.; Nguyen Luong, Q.; Schneider, N.; Didelon, P.; Zavagno, A.



Structure of the CRISPR Interference Complex CSM Reveals Key Similarities with Cascade  

PubMed Central

Summary The Clustered Regularly Interspaced Palindromic Repeats (CRISPR) system is an adaptive immune system in prokaryotes. Interference complexes encoded by CRISPR-associated (cas) genes utilize small RNAs for homology-directed detection and subsequent degradation of invading genetic elements, and they have been classified into three main types (I–III). Type III complexes share the Cas10 subunit but are subclassifed as type IIIA (CSM) and type IIIB (CMR), depending on their specificity for DNA or RNA targets, respectively. The role of CSM in limiting the spread of conjugative plasmids in Staphylococcus epidermidis was first described in 2008. Here, we report a detailed investigation of the composition and structure of the CSM complex from the archaeon Sulfolobus solfataricus, using a combination of electron microscopy, mass spectrometry, and deep sequencing. This reveals a three-dimensional model for the CSM complex that includes a helical component strikingly reminiscent of the backbone structure of the type I (Cascade) family. PMID:24119402

Rouillon, Christophe; Zhou, Min; Zhang, Jing; Politis, Argyris; Beilsten-Edmands, Victoria; Cannone, Giuseppe; Graham, Shirley; Robinson, Carol V.; Spagnolo, Laura; White, Malcolm F.



Key Performance Outcomes of Patient Safety Curricula: Root Cause Analysis, Failure Mode and Effects Analysis, and Structured Communications Skills  

PubMed Central

As colleges and schools of pharmacy develop core courses related to patient safety, course-level outcomes will need to include both knowledge and performance measures. Three key performance outcomes for patient safety coursework, measured at the course level, are the ability to perform root cause analyses and healthcare failure mode effects analyses, and the ability to generate effective safety communications using structured formats such as the Situation-Background-Assessment-Recommendation (SBAR) situational briefing model. Each of these skills is widely used in patient safety work and competence in their use is essential for a pharmacist's ability to contribute as a member of a patient safety team. PMID:22102754



Conformational aspects of antiviral activity of deoxyguanosine acyclic analogues.  

PubMed Central

Conformational possibilities of a series of deoxyguanosine analogues possessing or lacking antiviral activity were evaluated using methods of the molecular mechanics. Comparison of the spatial structures of acyclic analogues with one another and with the spatial structures of deoxyguanosine demonstrates restricted conformational mobility for compounds devoid of activity. The level of sterically allowed superposition of functional groups from the acyclic moieties of analogues and the corresponding atomic centres of deoxyribose could serve as a criterion of activity. The superposition could be performed in two different ways through either of the nonhydrogen substituents at the C1' atom in the five-membered ring. PMID:2798136

Golbraikh, A A; Betins, J; Balodis, J; Zhuk, R A; Nikiforovich, G V



The mechanism of retroviral integration through X-ray structures of its key intermediates  

PubMed Central

To establish successful infection, a retrovirus must insert a DNA replica of its genome into host cell chromosomal DNA1,2. This process is carried out by the intasome, a nucleoprotein complex comprised of a tetramer of integrase (IN) assembled on the viral DNA ends3,4. The intasome engages chromosomal DNA within a target capture complex to carry out strand transfer, irreversibly joining the viral and cellular DNA molecules. Although several intasome/transpososome structures from the DDE(D) recombinase superfamily were reported4-6, the mechanics of target DNA capture and strand transfer by these enzymes have not been established. Herein, we report crystal structures of the intasome from prototype foamy virus in complex with target DNA, elucidating the pre-integration target DNA capture and post-catalytic strand transfer intermediates of the retroviral integration process. The cleft between IN dimers within the intasome accommodates chromosomal DNA in a severely bent conformation, allowing widely spaced IN active sites to access the scissile phosphodiester bonds. Our results elucidate the structural basis for retroviral DNA integration and moreover provide a framework for the design of INs with altered target sequences. PMID:21068843

Maertens, Goedele N.; Hare, Stephen; Cherepanov, Peter



Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis.  


P2X receptors constitute a seven-member family (P2X1-7) of extracellular ATP-gated cation channels of widespread expression. Because P2X receptors have been implicated in neurological, inflammatory and cardiovascular diseases, they constitute promising drug targets. Since the first P2X cDNA sequences became available in 1994, numerous site-directed mutagenesis studies have been conducted to disclose key sites of P2X receptor function and oligomerization. The publication of the 3-A crystal structures of the zebrafish P2X4 (zfP2X4) receptor in the homotrimeric apo-closed and ATP-bound open states in 2009 and 2012, respectively, has ushered a new era by allowing for the interpretation of the wealth of molecular data in terms of specific three-dimensional models and by paving the way for designing more-decisive experiments. Thanks to these structures, the last five years have provided invaluable insight into our understanding of the structure and function of the P2X receptor class of ligandgated ion channels. In this review, we provide an overview of mutagenesis studies of the pre- and post-crystal structure eras that identified amino acid residues of key importance for ligand binding, channel gating, ion flow, formation of the pore and the channel gate, and desensitization. In addition, the sites that are involved in the trimerization of P2X receptors are reviewed based on mutagenesis studies and interface contacts that were predicted by the zfP2X4 crystal structures. PMID:25439586

Hausmann, Ralf; Kless, Achim; Schmalzing, Gunther



Keys for XML  

Microsoft Academic Search

We discuss the deflnition of keys for XML documents, paying particular attention to the concept of a relative key, which is commonly used in hierarchically structured documents and scientiflc databases.

Peter Buneman; Susan B. Davidson; Wenfei Fan; Carmem S. Hara; Wang-Chiew Tan



The current structure of key actors involved in research on land and soil degradation  

NASA Astrophysics Data System (ADS)

Land and soil conservation topics, the final mandate of the United Convention to Combat desertification in drylands, have been diagnosed as still suffering from a lack of guidance. On the contrary, climate change and biodiversity issues -the other two big subjects of the Rio Conventions- seem to progress and may benefit from the advice of international panels. Arguably the weakness of policy measures and hence the application of scientific knowledge by land users and stakeholders could be the expression of an inadequate research organization and a lack of ability to channel their findings. In order to better understand the size, breadth and depth of the scientific communities involved in providing advice to this convention and to other bodies, this study explores the corpus of international publications dealing with land and/or with soils. A database of several thousands records including a significant part of the literature published so far was performed using the Web of Science and other socio-economic databases such as FRANCIS and CAIRN. We extracted hidden information using bibliometric methods and data mining applied to these scientific publications to map the key actors (laboratories, teams, institutions) involved in research on land and on soils. Several filters were applied to the databases in combination with the word "desertification". The further use of Tetralogie software merges databases, analyses similarities and differences between keywords, disciplines, authors and regions and identifies obvious clusters. Assessing their commonalities and differences, the visualisation of links and gaps between scientists, organisations, policymakers and other stakeholders is possible. The interpretation of the 'clouds' of disciplines, keywords, and techniques will enhance the understanding of interconnections between them; ultimately this will allow diagnosing some of their strengths and weaknesses. This may help explain why land and soil degradation remains a serious global problem that lacks sufficient attention. We hope that this study will contribute to clarify the scientific landscape at stake to remediate possible weaknesses in the future.

Escadafal, Richard; Barbero, Celia; Exbrayat, Williams; Marques, Maria Jose; Ruiz, Manuel; El Haddadi, Anass; Akhtar-Schuster, Mariam



Identification of a novel vardenafil analogue in herbal product.  


A new herbal health product marketed for enhancing erectile function, namely Power58 Platinum, was purchased over-the-counter in Hong Kong. The product was tested for adulteration with sildenafil, tadalafil, and vardenafil as well as their structurally modified analogues. A new analogue of vardenafil, in which the N-ethylpiperazine ring and the sulphonyl group were removed from the vardenafil structure, was identified in the product. PMID:18248930

Lam, Ying-Hoo; Poon, Wing-Tat; Lai, Chi-Kong; Chan, Albert Yan-Wo; Mak, Tony Wing-Lai



Bithiopheneimide-dithienosilole/dithienogermole copolymers for efficient solar cells: information from structure-property-device performance correlations and comparison to thieno[3,4-c]pyrrole-4,6-dione analogues.  


Rational creation of polymeric semiconductors from novel building blocks is critical to polymer solar cell (PSC) development. We report a new series of bithiopheneimide-based donor-acceptor copolymers for bulk-heterojunction (BHJ) PSCs. The bithiopheneimide electron-deficiency compresses polymer bandgaps and lowers the HOMOs--essential to maximize power conversion efficiency (PCE). While the dithiophene bridge progression R(2)Si?R(2)Ge minimally impacts bandgaps, it substantially alters the HOMO energies. Furthermore, imide N-substituent variation has negligible impact on polymer opto-electrical properties, but greatly affects solubility and microstructure. Grazing incidence wide-angle X-ray scattering (GIWAXS) indicates that branched N-alkyl substituents increased polymer ?-? spacings vs linear N-alkyl substituents, and the dithienosilole-based PBTISi series exhibits more ordered packing than the dithienogermole-based PBTIGe analogues. Further insights into structure-property-device performance correlations are provided by a thieno[3,4-c]pyrrole-4,6-dione (TPD)-dithienosilole copolymer PTPDSi. DFT computation and optical spectroscopy show that the TPD-based polymers achieve greater subunit-subunit coplanarity via intramolecular (thienyl)S···O(carbonyl) interactions, and GIWAXS indicates that PBTISi-C8 has lower lamellar ordering, but closer ?-? spacing than does the TPD-based analogue. Inverted BHJ solar cells using bithiopheneimide-based polymer as donor and PC(71)BM as acceptor exhibit promising device performance with PCEs up to 6.41% and V(oc) > 0.80 V. In analogous cells, the TPD analogue exhibits 0.08 V higher V(oc) with an enhanced PCE of 6.83%, mainly attributable to the lower-lying HOMO induced by the higher imide group density. These results demonstrate the potential of BTI-based polymers for high-performance solar cells, and provide generalizable insights into structure-property relationships in TPD, BTI, and related polymer semiconductors. PMID:23030837

Guo, Xugang; Zhou, Nanjia; Lou, Sylvia J; Hennek, Jonathan W; Ponce Ortiz, Rocío; Butler, Melanie R; Boudreault, Pierre-Luc T; Strzalka, Joseph; Morin, Pierre-Olivier; Leclerc, Mario; López Navarrete, Juan T; Ratner, Mark A; Chen, Lin X; Chang, Robert P H; Facchetti, Antonio; Marks, Tobin J



Integrated Analysis of Residue Coevolution and Protein Structures Capture Key Protein Sectors in HIV-1 Proteins  

PubMed Central

HIV type 1 (HIV-1) is characterized by its rapid genetic evolution, leading to challenges in anti-HIV therapy. However, the sequence variations in HIV-1 proteins are not randomly distributed due to a combination of functional constraints and genetic drift. In this study, we examined patterns of sequence variability for evidence of linked sequence changes (termed as coevolution or covariation) in 15 HIV-1 proteins. It shows that the percentage of charged residues in the coevolving residues is significantly higher than that in all the HIV-1 proteins. Most of the coevolving residues are spatially proximal in the protein structures and tend to form relatively compact and independent units in the tertiary structures, termed as “protein sectors”. These protein sectors are closely associated with anti-HIV drug resistance, T cell epitopes, and antibody binding sites. Finally, we explored candidate peptide inhibitors based on the protein sectors. Our results can establish an association between the coevolving residues and molecular functions of HIV-1 proteins, and then provide us with valuable knowledge of pathology of HIV-1 and therapeutics development. PMID:25671429

Zhao, Yuqi; Wang, Yanjie; Gao, Yuedong; Li, Gonghua; Huang, Jingfei



Hantavirus Gn and Gc Envelope Glycoproteins: Key Structural Units for Virus Cell Entry and Virus Assembly  

PubMed Central

In recent years, ultrastructural studies of viral surface spikes from three different genera within the Bunyaviridae family have revealed a remarkable diversity in their spike organization. Despite this structural heterogeneity, in every case the spikes seem to be composed of heterodimers formed by Gn and Gc envelope glycoproteins. In this review, current knowledge of the Gn and Gc structures and their functions in virus cell entry and exit is summarized. During virus cell entry, the role of Gn and Gc in receptor binding has not yet been determined. Nevertheless, biochemical studies suggest that the subsequent virus-membrane fusion activity is accomplished by Gc. Further, a class II fusion protein conformation has been predicted for Gc of hantaviruses, and novel crystallographic data confirmed such a fold for the Rift Valley fever virus (RVFV) Gc protein. During virus cell exit, the assembly of different viral components seems to be established by interaction of Gn and Gc cytoplasmic tails (CT) with internal viral ribonucleocapsids. Moreover, recent findings show that hantavirus glycoproteins accomplish important roles during virus budding since they self-assemble into virus-like particles. Collectively, these novel insights provide essential information for gaining a more detailed understanding of Gn and Gc functions in the early and late steps of the hantavirus infection cycle. PMID:24755564

Cifuentes-Muñoz, Nicolás; Salazar-Quiroz, Natalia; Tischler, Nicole D.




PubMed Central

Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community coalitions located in Miami and Tampa, Florida, and San Juan, Puerto Rico engaged their respective communities in bringing about structural changes affecting policies, practices and programs related to HIV prevention for 12–24-year-olds. Outcomes of this work include increased access to HIV testing and counseling in the juvenile correctional system (Miami), increased monitoring of sexual abuse between young women and older men within public housing, and support services to deter age discordant relationships (Tampa) and increased access to community-based HIV testing (San Juan). PMID:20166784

Chutuape, Kate S.; Willard, Nancy; Sanchez, Kenia; Straub, Diane M.; Ochoa, Tara N.; Howell, Kourtney; Rivera, Carmen; Ramos, Ibrahim; Ellen, Jonathan M.



Thermophysical Fluid Dynamics: the Key to the Structures of Fluid Objects  

NASA Astrophysics Data System (ADS)

It has become customary to model the hydrodynamics of fluid planets like Jupiter and Saturn by spinning up general circulation models until they reach a statistical steady state. This approach is physically sound, based on the thermodynamic expectation that the system will eventually achieve a state of maximum entropy, but the models have not been specifically designed for this purpose. Over the course of long integrations, numerical artifacts can drive the system to a state that does not correspond to the physically realistic end state. A different formulation of the governing equations promises better results. The equations of motion are recast as scalar conservation laws in which the diabatic and irreversible terms (both entropy-changing) are clearly identified. The balance between these terms defines the steady state of the system analytically, without the need for any temporal integrations. The conservation of mass in this system is trivial. Conservation of angular momentum replaces the zonal momentum equation and determines the zonal wind from a balance between the tidal torque and frictional dissipation. The principle of wave-mean flow non-interaction is preserved. Bernoulli's Theorem replaces the energy equation. The potential temperature structure is determined by the balance between work done against friction and heat transfer by convection and radiation. An equation of state and the traditional momentum equations in the meridional plane are sufficient to complete the model. Based on the assumption that the final state vertical and meridional winds are small compared to the zonal wind (in any case they are impossible to predict ab initio as they are driven by wave flux convergences), these last equations determine the pressure and density (and hence gravity) fields of the basic state. The thermal wind relation (in its most general form with the axial derivative of the zonal wind balancing the baroclinicity) is preserved. The model is not hydrostatic (in the sense used in planetary modeling) and the zonal wind is not constant on cylinders. Rather, the zonal wind falls off more rapidly with depth --- at least as fast as r3. A similar reformulation of the equations of magnetohydrodynamics is possible. It is found that wave-mean flow non-interaction extends to Alfven waves. Bernoulli's Theorem is augmented by the Poynting Theorem. The components of the traditional dynamo equation can be written as conservation laws. Only a single element of the alpha tensor contributes to the generation of axisymmetric magnetic fields and the mean meridional circulation provides a significant feedback, quenching the omega effect and limiting the amplitudes of non-axisymmetric fields. Thus analytic models are available for all the state variables of Jupiter and Saturn. The unknown independent variables are terms in the equation of state, the eddy viscosity and heat transport coefficients, the magnetic resistivity, and the strength of the tidal torques (which are dependent on the vertical structure of the planet's troposphere). By making new measurements of the atmospheric structure and higher order gravitational moments of Jupiter, JUNO has the potential to constrain these unknowns and contribute greatly to our understanding of the interior of that planet.

Houben, H.



Structural and functional conservation of key domains in InsP[subscript 3] and ryanodine receptors  

SciTech Connect

Inositol-1,4,5-trisphosphate receptors (InsP{sub 3}Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca{sup 2+} channels. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP{sub 3}R gating is initiated by InsP{sub 3} binding to the InsP{sub 3}-binding core (IBC, residues 224-604 of InsP{sub 3}R1) and it requires the suppressor domain (SD, residues 1-223 of InsP{sub 3}R1). Here we present structures of the amino-terminal region (NT, residues 1-604) of rat InsP{sub 3}R1 with (3.6 {angstrom}) and without (3.0 {angstrom}) InsP{sub 3} bound. The arrangement of the three NT domains, SD, IBC-{beta} and IBC-{alpha}, identifies two discrete interfaces ({alpha} and {beta}) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP{sub 3}R and of the ABC domains docked into RyR are remarkably similar. The importance of the {alpha}-interface for activation of InsP{sub 3}R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations. Binding of InsP{sub 3} causes partial closure of the clam-like IBC, disrupting the {beta}-interface and pulling the SD towards the IBC. This reorients an exposed SD loop ('hotspot' (HS) loop) that is essential for InsP{sub 3}R activation. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP{sub 3}R, and an InsP{sub 3}R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP{sub 3} and blocked by ryanodine. Activation mechanisms are conserved between InsP{sub 3}R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-{beta} or B domain), to gate the pore.

Seo, Min-Duk; Velamakanni, Saroj; Ishiyama, Noboru; Stathopulos, Peter B.; Rossi, Ana M.; Khan, Samir A.; Dale, Philippa; Li, Congmin; Ames, James B.; Ikura, Mitsuhiko; Taylor, Colin W. (UCD); (Toronto); (Cambridge)



Structural heritage as a key factor controlling the South China Sea opening  

NASA Astrophysics Data System (ADS)

Since the Palaeozoic times, the South China Sea area has recorded multiple tectono-thermal events (Indosinian and Yenshanian orogeny) whose influence regarding the formation of the basin remains to be clarified. The aim of this work is to document the vertical movements associated with the extensional tectonic, and to address the issue of the role of the structural inheritance in the context of the opening of an oceanic basin. The work is based on a thermochronological multi-method approach, i.e., U/Pb on zircon and fission tracks on zircon (ZFT) and apatite (AFT). These thermochronological data were then combined with field observations, seismic lines and drill-holes data to perform a reconstruction of the pre-rifting stage of the South China Sea. Dating gives a Triassic to lower Cretaceous age for the emplacement of the Yenshanian granitic arc, which was quickly exhumed during the middle of the Cretaceous. Sample analyses from onland northern margin sediments indicate a range of burial temperatures from 120°C to 250°C. The cretaceous basins, filled with the erosional products of the Yanshanian granites, have been partly recycled within the tertiary basins. Thermochronometers from northern margin samples also attest for a middle-late Eocene cooling event below the 120°C isotherm. Thermochronological results from the Palawan Island, which consists of an inverted cretaceous basin, the Proto South China Sea (PSCS) whose crust has nowadays totally been subducted, show that the source of the sediments is the erosion of the Yanshanian magmatic arc. Finally, a middle-late Miocene cooling event recorded both by Apatite and Zircon attests of a major uplift stage that affected the whole Palawan and Borneo accretionary wedges. The interpretation of seismic and drill-hole data supports a new reconstruction of the SCS pre-rift setting that shows crustal necking zones filled with deep marine deposits, fault-bounded troughs showing thick pre-Tertiary syn-tectonic series and zones of thick crust covered by shallow marine sediments. We propose a step-by-step cartographic reconstruction of the SCS opening that emphasizes a partitioning process along major N-S strike-slip faults, probably corresponding to the on-land continuation of PSCS transform faults. The pre-rift architecture of the crust is characterised by fault-bounded depressions that had trapped Tertiary syn-rift sediments. These depressions delimit areas of thick crust often constituted by intruded Mesozoic granitic plutons on which SCS rifting faults tend to root. This work combining a thermochronological and a structural approach brings fundamental information regarding both the sources of the SCS syn-rift sediments and the pre-rift structures that control both the localisation of the deformation and the distribution of the syn-rift sediments.

Meresse, F.; Savva, D.; Wong, P.; Pubellier, M.; Chamot-Rooke, N.; Steuer, S.; Franke, D.; Sapin, F.; Auxietre, J.



On the mechanics of mother-of-pearl: A key feature in the material hierarchical structure  

NASA Astrophysics Data System (ADS)

Mother-of-pearl, also known as nacre, is the iridescent material which forms the inner layer of seashells from gastropods and bivalves. It is mostly made of microscopic ceramic tablets densely packed and bonded together by a thin layer of biopolymer. The hierarchical microstructure of this biological material is the result of millions of years of evolution, and it is so well organized that its strength and toughness are far superior to the ceramic it is made of. In this work the structure of nacre is described over several length scales. The tablets were found to have wavy surfaces, which were observed and quantified using various experimental techniques. Tensile and shear tests performed on small samples revealed that nacre can withstand relatively large inelastic strains and exhibits strain hardening. In this article we argue that the inelastic mechanism responsible for this behavior is sliding of the tablets on one another accompanied by transverse expansion in the direction perpendicular to the tablet planes. Three dimensional representative volume elements, based on the identified nacre microstructure and incorporating cohesive elements with a constitutive response consistent with the interface material and nanoscale features were numerically analyzed. The simulations revealed that even in the absence of nanoscale hardening mechanism at the interfaces, the microscale waviness of the tablets could generate strain hardening, thereby spreading the inelastic deformation and suppressing damage localization leading to material instability. The formation of large regions of inelastic deformations around cracks and defects in nacre are believed to be an important contribution to its toughness. In addition, it was shown that the tablet junctions (vertical junctions between tablets) strengthen the microstructure but do not contribute to the overall material hardening. Statistical variations within the microstructure were found to be beneficial to hardening and to the overall mechanical stability of nacre. These results provide new insights into the microstructural features that make nacre tough and damage tolerant. Based on these findings, some design guidelines for composites mimicking nacre are proposed.

Barthelat, F.; Tang, H.; Zavattieri, P. D.; Li, C.-M.; Espinosa, H. D.



Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: Preliminary structure-activity relationship and pharmacophore modeling  

PubMed Central

Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the ?7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisyntheti or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 ?M. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis. PMID:23769165

Eterovi?, Vesna A.; Valle-Rodriguez, Angelie Del; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A.; El Sayed, Khalid A.; Ferchmin, Pedro A.



Analogue-to-Digital and Digital-to-Analogue Conversion.  

ERIC Educational Resources Information Center

Discusses circuits for three-bit and four-bit analogue digital converters and digital analogue converters. These circuits feature slow operating speeds that enable the circuitry to be used to demonstrate the mode of operation using oscilloscopes and signal generators. (DDR)

Gregory, Martin



Use of lateral structures to monitor and evaluate degradation of key photovoltaic parameters in an organic bulk heterojunction material  

NASA Astrophysics Data System (ADS)

Charge transport and recombination mechanisms within organic bulk heterojunction (BHJ) systems have been studied using lateral devices to perform in situ potentiometry. We have developed a simplified measurement technique using two types of lateral structures to elicit key charge transport parameters and study the time and process dependence of the carrier mobilities and their ratio. Small geometry lateral devices are used to evaluate the mobility of the slower carrier within the P3HT:PCBM material system. Larger structures with 5 in situ voltage probes are used to construct a simple potential profile of the device channel and accurately determine the carrier mobility ratio. These two measurements enable the calculation of carrier densities and the recombination coefficient. We monitor the change in these parameters as the P3HT:PCBM film degrades in the presence of oxygen and also examine the effect of the solvent additive 1,8-diiodooctane on this degradation mechanism. By exposing ethanol vapor to the BHJ film, we induce traps in the material and monitor the shift in dominant nongeminate recombination mechanism to a more unimolecular type. We are also able to measure the resulting decrease in carrier mobilities due to the presence of dipole-induced traps. Lateral devices are useful material diagnostic structures for studying degradation in BHJ materials.

Danielson, Eric; Ooi, Zi-En; Dodabalapur, Ananth



Network structure and the role of key players in a translational cancer research network: a study protocol  

PubMed Central

Introduction Translational research networks are a deliberate strategy to bridge the gulf between biomedical research and clinical practice through interdisciplinary collaboration, supportive funding and infrastructure. The social network approach examines how the structure of the network and players who hold important positions within it constrain or enable function. This information can be used to guide network management and optimise its operations. The aim of this study was to describe the structure of a translational cancer research network (TCRN) in Australia over its first year, identify the key players within the network and explore these players' opportunities and constraints in maximising important network collaborations. Methods and analysis This study deploys a mixed-method longitudinal design using social network analysis augmented by interviews and review of TCRN documents. The study will use network documents and interviews with governing body members to explore the broader context into which the network is embedded as well as the perceptions and expectations of members. Of particular interest are the attitudes and perceptions of clinicians compared with those of researchers. A co-authorship network will be constructed of TCRN members using journal and citation databases to assess the success of past pre-network collaborations. Two whole network social network surveys will be administered 12?months apart and parameters such as density, clustering, centrality and betweenness centrality computed and compared using UCINET and Netdraw. Key players will be identified and interviewed to understand the specific activities, barriers and enablers they face in that role. Ethics and dissemination Ethics approvals were obtained from the University of New South Wales, South Eastern Sydney Northern Sector Local Health Network and Calvary Health Care Sydney. Results will be discussed with members of the TCRN, submitted to relevant journals and presented as oral presentations to clinicians, researchers and policymakers. PMID:22734122

Cunningham, Frances C; Braithwaite, Jeffrey



Inhibition of the bacterial enoyl reductase FabI by triclosan: a structure-reactivity analysis of FabI inhibition by triclosan analogues.  


To explore the molecular basis for the picomolar affinity of triclosan for FabI, the enoyl reductase enzyme from the type II fatty acid biosynthesis pathway in Escherichia coli, an SAR study has been conducted using a series of triclosan analogues. Triclosan (1) is a slow, tight-binding inhibitor of FabI, interacting specifically with the E.NAD(+) form of the enzyme with a K(1) value of 7 pM. In contrast, 2-phenoxyphenol (2) binds with equal affinity to the E.NAD(+) (K(1) = 0.5 microM) and E.NADH (K(2) = 0.4 microM) forms of the enzyme and lacks the slow-binding step observed for triclosan. Thus, removal of the three triclosan chlorine atoms reduces the affinity of the inhibitor for FabI by 70,000-fold and removes the preference for the E.NAD(+) FabI complex. 5-Chloro-2-phenoxyphenol (3) is a slow, tight-binding inhibitor of FabI and binds to the E.NAD(+) form of the enzyme (K(1) = 1.1 pM) 7-fold more tightly than triclosan. Thus, while the two ring B chlorine atoms are not required for FabI inhibition, replacement of the ring A chlorine increases binding affinity by 450,000-fold. Given this remarkable observation, the SAR study was extended to the 5-fluoro-2-phenoxyphenol (4) and 5-methyl-2-phenoxyphenol (5) analogues to further explore the role of the ring A substituent. While both 4 and 5 are slow, tight-binding inhibitors, they bind substantially less tightly to FabI than triclosan. Compound 4 binds to both E.NAD(+) and E.NADH forms of the enzyme with K(1) and K(2) values of 3.2 and 240 nM, respectively, whereas compound 5 binds exclusively to the E.NADH enzyme complex with a K(2) value of 7.2 nM. Thus, the ring A substituent is absolutely required for slow, tight-binding inhibition. In addition, pK(a) measurements coupled with simple electrostatic calculations suggest that the interaction of the ring A substituent with F203 is a major factor in governing the affinity of analogues 3-5 for the FabI complex containing the oxidized form of the cofactor. PMID:14736233

Sivaraman, Sharada; Sullivan, Todd J; Johnson, Francis; Novichenok, Polina; Cui, Guanglei; Simmerling, Carlos; Tonge, Peter J



Oxybenziporphyrins, oxypyriporphyrins, benzocarbaporphyrins, and their 23-oxa and 23-thia analogues: synthesis, spectroscopic characterization, metalation, and structural characterization of a palladium(II) organometallic derivative.  


A series of nine porphyrin analogues have been synthesized using the "3 + 1" variant on the MacDonald condensation. Tripyrrane-type systems with a centrally unsubstituted pyrrole, furan, or thiophene ring were prepared using conventional methods, and these were condensed with indene-1,3-dicarbaldehyde, 5-formylsalicylaldehyde, or 3-hydroxy-2,6-pyridinedicarbaldehyde in the presence of TFA to generate benzocarba-, oxybenzi-, and oxypyriporphyrins, respectively. The furan-containing analogues proved to be highly basic and could only be isolated as the corresponding hydrochloride salts. All nine analogue systems showed porphyrin-like UV-vis spectra with one or two Soret absorptions near 400 nm and a series of weaker bands at longer wavelengths. These systems also showed large diatropic ring currents by proton NMR spectroscopy that were comparable to true porphyrins. In the presence of trace amounts of TFA, benzocarbaporphyrin 12 formed a monocation, and in 50% TFA a C-protonated dication was generated. The 23-oxacarbaporphyrin 14 gave a monocation in chloroform, although the free base was generated in 5% Et(3)N-chloroform. In 50% TFA-CHCl(3), 14 afforded a mixture of mono- and diprotonated species. Thiacarbaporphyrin 15 also formed a monocation in the presence of TFA, but C-protonation was relatively disfavored for this system. Nonetheless, in the presence of TFA-d, 12, 14, and 15 all showed rapid exchange of the internal NH and CH protons. Carbaporphyrin 12 also showed slow exchange at the meso-positions, but this process was not observed for its heteroanalogues 14 and 15. Protonation studies were also conducted for oxybenziporphyrins and oxypyriporphyrins 16-21. Oxacarbaporphyrin 14 was shown to be a superior organometallic ligand and afforded good yields of the related nickel(II) and palladium(II) derivatives under mild conditions. A low yield of the platinum(II) complex could also be isolated. All three complexes retained their aromatic character, although the Pd(II) derivative appeared to possess a slightly larger diatropic ring current. The palladium(II) complex 27 was further characterized by X-ray crystallography. The macrocyclic core was shown to be highly planar where the dihedral angles of the component pyrrole, furan and indene rings relative to the mean [18]annulene plane were all

Liu, Dachun; Ferrence, Gregory M; Lash, Timothy D



Quantum analogues of Schubert varieties in the grassmannian.  

E-print Network

Quantum analogues of Schubert varieties in the grassmannian. T.H. Lenagan and L. Rigal Abstract We study quantum Schubert varieties from the point of view of regularity conditions. More precisely, we which of them are AS-Gorenstein. One key fact that enables us to prove these results is that quantum

Lenagan, Tom


Structure of the Trehalose-6-phosphate Phosphatase from Brugia malayi Reveals Key Design Principles for Anthelmintic Drugs  

PubMed Central

Parasitic nematodes are responsible for devastating illnesses that plague many of the world's poorest populations indigenous to the tropical areas of developing nations. Among these diseases is lymphatic filariasis, a major cause of permanent and long-term disability. Proteins essential to nematodes that do not have mammalian counterparts represent targets for therapeutic inhibitor discovery. One promising target is trehalose-6-phosphate phosphatase (T6PP) from Brugia malayi. In the model nematode Caenorhabditis elegans, T6PP is essential for survival due to the toxic effect(s) of the accumulation of trehalose 6-phosphate. T6PP has also been shown to be essential in Mycobacterium tuberculosis. We determined the X-ray crystal structure of T6PP from B. malayi. The protein structure revealed a stabilizing N-terminal MIT-like domain and a catalytic C-terminal C2B-type HAD phosphatase fold. Structure-guided mutagenesis, combined with kinetic analyses using a designed competitive inhibitor, trehalose 6-sulfate, identified five residues important for binding and catalysis. This structure-function analysis along with computational mapping provided the basis for the proposed model of the T6PP-trehalose 6-phosphate complex. The model indicates a substrate-binding mode wherein shape complementarity and van der Waals interactions drive recognition. The mode of binding is in sharp contrast to the homolog sucrose-6-phosphate phosphatase where extensive hydrogen-bond interactions are made to the substrate. Together these results suggest that high-affinity inhibitors will be bi-dentate, taking advantage of substrate-like binding to the phosphoryl-binding pocket while simultaneously utilizing non-native binding to the trehalose pocket. The conservation of the key residues that enforce the shape of the substrate pocket in T6PP enzymes suggest that development of broad-range anthelmintic and antibacterial therapeutics employing this platform may be possible. PMID:24992307

Farelli, Jeremiah D.; Galvin, Brendan D.; Li, Zhiru; Liu, Chunliang; Aono, Miyuki; Garland, Megan; Hallett, Olivia E.; Causey, Thomas B.; Ali-Reynolds, Alana; Saltzberg, Daniel J.; Carlow, Clotilde K. S.; Dunaway-Mariano, Debra; Allen, Karen N.



Synthesis and Biological Activity of Two C-7 Methyl Analogues of Vitamin D.  


Two novel vitamin D analogues of the hormone 1?,25-(OH)2D3 modified at C-7, namely, 7-methyl-1?,25-(OH)2D3 (12) and 7-methyl-1?,25-(OH)2-19-nor-D3 (26), were synthesized and biologically evaluated to gain further insights into the structure-function relationships of vitamin D. Key steps in the synthesis of 12 include the functionalization at C-7 by an efficient regioselective hydrostannylation of an allene precursor, and the construction of the triene framework by a palladium-catalyzed intramolecular cyclization-Suzuki-Miyaura coupling cascade. Since the calcitriol analogue 12 was prone to conversion into its previtamin D form by thermal equilibration, the corresponding 19-nor-compound 26 was also synthesized. The diene moiety of compound 26 was constructed by a modified Julia coupling. UV data as well as X-ray analysis indicate that introduction of the methyl group at C-7 results in a significant deviation from planarity of the 5,7-diene moiety. The new vitamin D analogues 12 and 26 retained good VDR binding ability. PMID:25396296

Sokolowska, Katarzyna; Carballa, Diego; Seoane, Samuel; Pérez-Fernández, Román; Mouriño, Antonio; Sicinski, Rafal R



Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency1  

PubMed Central

Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH2) displayed a 1,000-fold increase in both potency (IC50=62 nM) and binding affinity for C3b (KD=2.3 nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues. PMID:21067811

Qu, Hongchang; Magotti, Paola; Ricklin, Daniel; Wu, Emilia L.; Kourtzelis, Ioannis; Wu, You-Qiang; Kaznessis, Yiannis N.; Lambris, John D.



Polyamine analogues modulate gene expression by inhibiting Lysine-Specific Demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells  

PubMed Central

Aberrant epigenetic repression of gene expression has been implicated in most cancers, including breast cancer. The nuclear amine oxidase, lysine-specific demethylase 1 (LSD1) has the ability to broadly repress gene expression by removing the activating mono- and di-methylation marks at the lysine 4 residue of histone 3 (H3K4me1 & me2). Additionally, LSD1 is highly expressed in estrogen receptor ? negative (ER?) breast cancer cells. Since epigenetic marks are reversible, they make attractive therapeutic targets. Here we examine the effects of polyamine analogue inhibitors of LSD1 on gene expression, with the goal of targeting LSD1 as a therapeutic modality in the treatment of breast cancer. Exposure of the ER-negative human breast cancer cells, MDA-MB-231, to the LSD1 inhibitors, 2d or PG11144, significantly increases global H3K4me1 and H3K4me2, and alters gene expression. Array analysis indicated that 98 (75 up and 23 down) and 477 (237 up and 240 down) genes changed expression by at least 1.5-fold or greater after treatment with 2d and PG11144, respectively. The expression of twelve up-regulated genes by 2d and fourteen up-regulated genes by PG11144 was validated by quantitative RT-PCR. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated that up-regulated gene expression by polyamine analogues is associated with increase of the active histone marks H3K4me1, H3K4me2 and H3K9ac, and decrease of the repressive histone marks H3K9me2 and H3K27me3, in the promoter regions of the relevant target genes. These data indicate that the pharmacologic inhibition of LSD1 can effectively alter gene expression and that this therapeutic strategy has potential. PMID:21805138

Zhu, Qingsong; Huang, Yi; Marton, Laurence J.; Woster, Patrick M.; Davidson, Nancy E.; Casero, Robert A.



Formate--the analogue of azide: structural and magnetic properties of M(HCOO)2(4,4'-bpy).nH2O (M = Mn, Co, Ni; n = 0, 5).  


Reaction of transition metal formate M(HCOO)(2).2H2O (M = Mn, Co, Ni) with 4,4'-bpy (4,4-bipyridine) has led to four new compounds with the formula M(HCOO)2(4,4'-bpy).nH2O (M = Mn, Co (1.Mn, 2.Co), n = 0; M = Co, Ni (3.Co, 4.Ni), n = 5). Compounds 1.Mn and 2.Co are isomorphous and crystallized in the tetragonal crystal system with the chiral space group P4(1)2(1)2. They are of three-dimensional diamondoid structure connected by anti-anti formate with 4,4'-bpy in the cavities of the framework reinforcing the intermetallic connections; the diamond-like net was observed also in their azide analogue (Mn(N3)2(4,4'-bpy)). Compounds 3.Co and 4.Ni are isomorphous also but crystallized in the monoclinic crystal system with the space group Cc. Both structures are uninterpenetrated 3D "CdSO4" type with big channels, constructed by anti-anti formate and 4,4'-bpy. This type of net was not observed in their azide analogue. Residing in the channels, water molecules form a new type of 1D tape constructed by vertex-sharing cyclic pentamers. Magnetic measurements were performed on all of these four compounds. 1.Mn and 2.Co are weak ferromagnets with the critical temperature Tc = 5.3 and 7.4 K, respectively. 3.Co is an antiferromagnet with Neel temperature TN = 3.0 K, and 4.Ni is a weak ferromagnet below 20 K. Hysteresis loop can be observed for 2.Co and 4.Ni at 1.8 K. As an analogue of azide, formate can be used to construct molecular architectures, which structurally and magnetically have great similarities to and also differences from those of azide. This offers a promising method for the design of new molecular architectures with formate. PMID:15679387

Wang, Xin-Yi; Wei, Hai-Yan; Wang, Zhe-Ming; Chen, Zhi-Da; Gao, Song



A multiple sequence alignment algorithm for homologous proteins using secondary structure information and optionally keying alignments to functionally important sites.  


The programs described herein function as part of a suite of programs designed for pairwise alignment, multiple alignment, generation of randomized sequences, production of alignment scores and a sorting routine for analysis of the alignments produced. The sequence alignment programs penalize gaps (absences of residues) within regions of protein secondary structure and have the added option of 'fingerprinting' structurally or functionally important protein-residues. The multiple alignment program is based upon the sequence alignment method of Needleman and Wunsch and the multiple alignment extension of Barton and Sternberg. Our application includes the feature of optionally weighting active site, monomer--monomer, ligand contact or other important template residues to bias the alignment toward matching these residues. A sum-score for the alignments is introduced, which is independent of gap penalties. This score more adequately reflects the character of the alignments for a given scoring matrix than the gap-penalty-dependent total score described previously in the literature. In addition, individual amino acid similarity scores at each residue position in the alignments are printed with the alignment output to enable immediate quantitative assessment of homology at key sections of the aligned chains. PMID:2751764

Henneke, C M



Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling  

PubMed Central

TRIM (tripartite motif) proteins primarily function as ubiquitin E3 ligases that regulate the innate immune response to infection. TRIM25 [also known as Efp (oestrogen-responsive finger protein)] has been implicated in the regulation of oestrogen receptor ? signalling and in the regulation of innate immune signalling via RIG-I (retinoic acid-inducible gene-I). RIG-I senses cytosolic viral RNA and is subsequently ubiquitinated by TRIM25 at its N-terminal CARDs (caspase recruitment domains), leading to type I interferon production. The interaction with RIG-I is dependent on the TRIM25 B30.2 domain, a protein-interaction domain composed of the PRY and SPRY tandem sequence motifs. In the present study we describe the 1.8 Å crystal structure of the TRIM25 B30.2 domain, which exhibits a typical B30.2/SPRY domain fold comprising two N-terminal ?-helices, thirteen ?-strands arranged into two ?-sheets and loop regions of varying lengths. A comparison with other B30.2/SPRY structures and an analysis of the loop regions identified a putative binding pocket, which is likely to be involved in binding target proteins. This was supported by mutagenesis and functional analyses, which identified two key residues (Asp488 and Trp621) in the TRIM25 B30.2 domain as being critical for binding to the RIG-I CARDs. PMID:24015671

D'Cruz, Akshay A.; Kershaw, Nadia J.; Chiang, Jessica J.; Wang, May K.; Nicola, Nicos A.; Babon, Jeffrey J.; Gack, Michaela U.; Nicholson, Sandra E.



Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling.  


TRIM (tripartite motif) proteins primarily function as ubiquitin E3 ligases that regulate the innate immune response to infection. TRIM25 [also known as Efp (oestrogen-responsive finger protein)] has been implicated in the regulation of oestrogen receptor ? signalling and in the regulation of innate immune signalling via RIG-I (retinoic acid-inducible gene-I). RIG-I senses cytosolic viral RNA and is subsequently ubiquitinated by TRIM25 at its N-terminal CARDs (caspase recruitment domains), leading to type I interferon production. The interaction with RIG-I is dependent on the TRIM25 B30.2 domain, a protein-interaction domain composed of the PRY and SPRY tandem sequence motifs. In the present study we describe the 1.8 Å crystal structure of the TRIM25 B30.2 domain, which exhibits a typical B30.2/SPRY domain fold comprising two N-terminal ?-helices, thirteen ?-strands arranged into two ?-sheets and loop regions of varying lengths. A comparison with other B30.2/SPRY structures and an analysis of the loop regions identified a putative binding pocket, which is likely to be involved in binding target proteins. This was supported by mutagenesis and functional analyses, which identified two key residues (Asp(488) and Trp(621)) in the TRIM25 B30.2 domain as being critical for binding to the RIG-I CARDs. PMID:24015671

D'Cruz, Akshay A; Kershaw, Nadia J; Chiang, Jessica J; Wang, May K; Nicola, Nicos A; Babon, Jeffrey J; Gack, Michaela U; Nicholson, Sandra E



NASA/ESMD Analogue Mission Plans  

NASA Technical Reports Server (NTRS)

A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

Hoffman, Stephen J.



New materials for analogue experiments: Preliminary tests of magnetorheological fluids  

NASA Astrophysics Data System (ADS)

New materials and related apparatuses are welcome to advance analogue modelling techniques. In this contribution, we report on a first attempt to use magnetorheological (MR) fluids as analogue materials for simulating the mechanical behavior of mobile décollement layers that change their mechanical properties during deformation. For this purpose, a specific sandbox was designed to include the possibility of quickly applying and removing a magnetic field below a MR fluid layer, in order to induce an instantaneous change from a frictional to a viscous behavior in the basal décollement material. The simulation of gravitational gliding and sediment progradation above a basal mobile shale layer provided results that compare well with analogue models produced with other experimental techniques, and with natural structures like those developed in the Niger delta region. This pilot study thus encourages further research for optimizing the applicability of MR fluids to the analogue simulation of geological processes.

Cavozzi, C.; Storti, F.; Nestola, Y.; Salvi, F.; Davoli, G.



Divergent total synthesis of triptolide, triptonide, tripdiolide, 16-hydroxytriptolide, and their analogues.  


A divergent route was developed for the formal total synthesis of triptolide, triptonide, and tripdiolide, as well as a total synthesis of 16-hydroxytriptolide and their analogues in an enantioselective form. Common advanced intermediate 5 was concisely assembled by employing an indium(III)-catalyzed cationic polycyclization reaction and a palladium-catalyzed carbonylation-lactone formation reaction as key steps. This advanced intermediate was readily converted to the above natural products by using palladium-catalyzed cross-coupling or the Claisen rearrangement reaction as key steps. Additionally, preliminary structure-cytotoxic activity relationship studies of C13 suggested that it might be a new modification site that could still retain the cytotoxicity. PMID:25296383

Xu, Hongtao; Tang, Huanyu; Feng, Huijin; Li, Yuanchao



Inhibition of ATP Synthase by Chlorinated Adenosine Analogue  

PubMed Central

8-Chloroadenosine (8-Cl-Ado) is a ribonucleoside analogue that is currently in clinical trial for chronic lymphocytic leukemia. Based on the decline in cellular ATP pool following 8-Cl-Ado treatment, we hypothesized that 8-Cl-ADP and 8-Cl-ATP may interfere with ATP synthase, a key enzyme in ATP production. Mitochondrial ATP synthase is composed of two major parts; FO intermembrane base and F1 domain, containing ? and ? subunits. Crystal structures of both ? and ? subunits that bind to the substrate, ADP, are known in tight binding (?dp?dp) and loose binding (?tp?tp) states. Molecular docking demonstrated that 8-Cl-ADP/8-Cl-ATP occupied similar binding modes as ADP/ATP in the tight and loose binding sites of ATP synthase, respectively, suggesting that the chlorinated nucleotide metabolites may be functional substrates and inhibitors of the enzyme. The computational predictions were consistent with our whole cell biochemical results. Oligomycin, an established pharmacological inhibitor of ATP synthase, decreased both ATP and 8-Cl-ATP formation from exogenous substrates, however, did not affect pyrimidine nucleoside analogue triphosphate accumulation. Synthesis of ATP from ADP was inhibited in cells loaded with 8-Cl-ATP. These biochemical studies are in consent with the computational modeling; in the ?tp?tp state 8-Cl-ATP occupies similar binding as ANP, a non-hydrolyzable ATP mimic that is a known inhibitor. Similarly, in the substrate binding site (?dp?dp) 8-Cl-ATP occupies a similar position as ATP mimic ADP-BeF3 ?. Collectively, our current work suggests that 8-Cl-ADP may serve as a substrate and the 8-Cl-ATP may be an inhibitor of ATP synthase. PMID:19477165

Chen, Lisa S.; Nowak, Billie J.; Ayres, Mary L.; Krett, Nancy L.; Rosen, Steven T.; Zhang, Shuxing; Gandhi, Varsha



Structure of a Key Intermediate of the SMN Complex Reveals Gemin2’s Crucial Function in snRNP Assembly  

PubMed Central

Summary Assembly of heptameric Sm protein rings on snRNAs (Sm cores), essential for snRNP function, is mediated by the SMN complex. Specific Sm core assembly depends on Sm proteins and snRNA recognition by SMN/Gemin2- and Gemin5-containing subunits, respectively. The mechanism by which the Sm proteins are gathered and illicit Sm core assembly is prevented is unknown. Here, we describe the 2.5 Å crystal structure of Gemin2 bound to SmD1/D2/F/E/G pentamer and SMN’s Gemin2-binding domain, a key assembly intermediate. Remarkably, through its extended conformation, Gemin2 wraps around the crescent-shaped pentamer, interacting with all five Sm proteins and gripping its bottom- and top-sides and outer perimeter. It further reaches into its RNA-binding pocket, preventing it from binding RNA. Interestingly, SMN-Gemin2 interaction is abrogated by an SMA (spinal muscular atrophy)-causing mutation in an SMN helix that mediates Gemin2 binding. These findings provide mechanistic insights into SMN complex function, linking snRNP biogenesis and SMA pathogenesis. PMID:21816274

Zhang, Rundong; So, Byung Ran; Li, Pilong; Yong, Jeongsik; Glisovic, Tina; Wan, Lili; Dreyfuss, Gideon



Sensory-guided decomposition of red currant juice (Ribes rubrum) and structure determination of key astringent compounds.  


Sequential application of solvent extraction, gel permeation chromatography, and RP-HPLC in combination with taste dilution analyses, followed by LC-MS and 1D/2D NMR experiments, led to the discovery and structure determination of 25 key astringent compounds of red currant juice. Besides several flavonol glycosides, in particular, 3-carboxymethyl-indole-1-N-beta-D-glucopyranoside, 3-methylcarboxymethyl-indole-1-N-beta-D-glucopyranoside, and a family of previously not identified compounds, namely, 2-(4-hydroxybenzoyloxymethyl)-4-beta-D-glucopyranosyloxy-2(E)-butenenitrile, 2-(4-hydroxy-3-methoxybenzoyloxymethyl)-4-beta-D-glucopyranosyloxy-2(E)-butenenitrile, (E)-6-[3-hydroxy-4-(O-beta-D-glucopyranosyl)phenyl]-5-hexen-2-one named dehydrorubrumin, and (3E,5E)-6-[3-hydroxy-4-(O-beta-D-glucopyranosyl)phenyl]-3,5-hexadien-2-one named rubrumin, have been identified. Determination of the oral astringency thresholds by means of the half-tongue test revealed that the lowest thresholds of 0.3 and 1.0 nmol/L were found for the nitrogen-containing 3-carboxymethyl-indole-1-N-beta-D-glucopyranoside and 3-methylcarboxymethyl-indole-1-N-beta-D-glucopyranoside, which do not belong to the group of plant polyphenols. PMID:17261016

Schwarz, Bernd; Hofmann, Thomas



Synthesis of novel gamma-aminobutyric acid (GABA) uptake inhibitors. 5.(1) Preparation and structure-activity studies of tricyclic analogues of known GABA uptake inhibitors.  


On the basis of the SAR of a series of known gamma-aminobutyric acid (GABA) uptake inhibitors, including 4 (SKF 89976), new tricyclic analogues have been prepared. These novel compounds are derivatives of nipecotic acid, guvacine, and homo-beta-proline, substituted at the nitrogen of these amino acids by various lipophilic moieties such as (10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)alkoxyalkyl or (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)alkoxyalkyl. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound in this new series, and it was found that several of the novel compounds showed a high potency comparable with that of the reference compounds 4, 5 (tiagabine), and 6 (CI-966). Several of the novel compounds were also evaluated for their ability in vivo to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). One compound, (R)-1-(2-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid (23), was selected for further biological investigations and showed a protective index comparable to or slightly better than that of the recently launched anticonvulsant product 5 ((R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid). PMID:11405652

Andersen, K E; Sørensen, J L; Lau, J; Lundt, B F; Petersen, H; Huusfeldt, P O; Suzdak, P D; Swedberg, M D



Analogue to digital transformation  

NASA Astrophysics Data System (ADS)

ESDU 92044 examines the replacement of an analog controller element by an equivalent digital controller element while retaining for the new hybrid system performance characteristics that are acceptably similar to those of the original continuous system. The main features are described of a system containing both analog and digital elements within the same loop, and the analog-to-digital and digital-to-analog components that are then necessarily a part of the system. The frequency response characteristics of transformation are discussed, introducing the problem of aliasing whereby a digital output can be matched by continuous sine waves of different frequencies that are then indistinguishable to the digital sampler. The need to avoid aliasing is considered and the concept of a folding frequency introduced below which aliasing is impossible. Two transformation methods for designing digital filters equivalent to analog filters are discussed: the impulse invariance and bilinear transformations. They are compared by examining digital equivalents of such analogue filters as simple and compound first-order lag and lead filters, second-order lag filters and first-order notch filters. The methods are compared for two sampling rates using Bode plots illustrating the gain and phase variation with frequency. An example based on an electromechanical instrument servo illustrates the transformation of an analog lag-lead controller using the bilinear transformation.



Antimicrobial activity of resveratrol analogues.  


Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew). Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold). The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups) and antimicrobial activity. PMID:24918540

Chalal, Malik; Klinguer, Agnès; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle



Condensed matter analogues of cosmology  

NASA Astrophysics Data System (ADS)

It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the liveliest. A number of new experiments are reported here studying the dynamical evolution of domains and defects. Another phenomenon that played a key early role was the formation of vortices in the normal-to-superfluid transition in liquid helium-3. The complicated nature of the order parameter energy surface gives rise to a variety of intriguing effects. This too is still a vigorous field. Superconductivity is a special case because the symmetry that is broken is a gauge symmetry. This is also true in fundamental particle physics theories of relevance to cosmology, and for that reason experiments on superconductors are of particular interest to cosmologists. The situation in this case is more complicated because there are competing mechanisms of defect formation. Experiments in the field have not proved easy, either to perform or to interpret, but the papers in this collection show that good progress has been made of late. In recent years a new type of system has proved immensely fruitful, namely atomic Bose-Einstein or Fermi-gas condensates. Experiments on condensates with tunable parameters have in general provided broad support for the theory, and have also revealed a wide range of interesting and novel features, with intriguing possible analogues in cosmology (e.g. causal horizons and particle creation). The basic idea of the Kibble-Zurek mechanism has been shown to be relevant in this whole range of systems. But numerous complexities have also emerged, concerned for example with the role of inhomogeneity or the existence of composite defects. The field is still developing rapidly. Acknowledgments Finally, we would like to thank all the authors who have contributed to this issue, and the staff of Journal of Physics: Condensed Matter who have made it possible. Condensed matter analogues of cosmology contents Condensed matter analogues of cosmologyTom Kibble and Ajit Srivastava Symmetry breaking in nematic liquid crystals: analogy with cosmology and magnetismR Repnik, A Ranjkesh, V Simonka, M Ambrozic, Z Bradac and S Kralj Morphogenesis of defects and tactoids

Kibble, Tom; Srivastava, Ajit



Developing a framework to review near-miss maternal morbidity in India: a structured review and key stakeholder analysis.  


BackgroundIn India there is a thrust towards promoting institutional delivery, resulting in problems of overcrowding and compromise to quality of care. Review of near-miss obstetric events has been suggested to be useful to investigate health system functioning, complementing maternal death reviews. The aim of this project was to identify the key elements required for a near-miss review programme for India.MethodsA structured review was conducted to identify methods used in assessing near-miss cases. The findings of the structured review were used to develop a suggested framework for conducting near-miss reviews in India. A pool of experts in near-miss review methods in low and middle income countries (LMICs) was identified for vetting the framework developed. Opinions were sought about the feasibility of implementing near-miss reviews in India, the processes to be followed, factors that made implementation successful and the associated challenges. A draft of the framework was revised based on the experts¿ opinions.ResultsFive broad methods of near-miss case review/audit were identified: Facility-based near-miss case review, confidential enquiries, criterion-based clinical audit, structured case review (South African Model) and home-based interviews. The opinion of the 11 stakeholders highlighted that the methods that a facility adopts should depend on the type and number of cases the facility handles, availability and maintenance of a good documentation system, and local leadership and commitment of staff. A proposed framework for conducting near-miss reviews was developed that included a combination of criterion-based clinical audit and near-miss review methods.ConclusionThe approach allowed for development of a framework for researchers and planners seeking to improve quality of maternal care not only at the facility level but also beyond, encompassing community health workers and referral. Further work is needed to evaluate the implementation of this framework to determine its efficacy in improving the quality of care and hence maternal and perinatal morbidity and mortality. PMID:25391999

Bhattacharyya, Sanghita; Srivastava, Aradhana; Knight, Marian



Crystal structures and catalytic mechanism of the C-methyltransferase Coq5 provide insights into a key step of the yeast coenzyme Q synthesis pathway.  


Saccharomyces cerevisiae Coq5 is an S-adenosyl methionine (SAM)-dependent methyltransferase (SAM-MTase) that catalyzes the only C-methylation step in the coenzyme Q (CoQ) biosynthesis pathway, in which 2-methoxy-6-polyprenyl-1,4-benzoquinone (DDMQH2) is converted to 2-methoxy-5-methyl-6-polyprenyl-1,4-benzoquinone (DMQH2). Crystal structures of Coq5 were determined in the apo form (Coq5-apo) at 2.2?Å resolution and in the SAM-bound form (Coq5-SAM) at 2.4?Å resolution, representing the first pair of structures for the yeast CoQ biosynthetic enzymes. Coq5 displays a typical class I SAM-MTase structure with two minor variations beyond the core domain, both of which are considered to participate in dimerization and/or substrate recognition. Slight conformational changes at the active-site pocket were observed upon binding of SAM. Structure-based computational simulation using an analogue of DDMQH2 enabled us to identify the binding pocket and entrance tunnel of the substrate. Multiple-sequence alignment showed that the residues contributing to the dimeric interface and the SAM- and DDMQH2-binding sites are highly conserved in Coq5 and homologues from diverse species. A putative catalytic mechanism of Coq5 was proposed in which Arg201 acts as a general base to initiate catalysis with the help of a water molecule. PMID:25084328

Dai, Ya-Nan; Zhou, Kang; Cao, Dong-Dong; Jiang, Yong-Liang; Meng, Fei; Chi, Chang-Biao; Ren, Yan-Min; Chen, Yuxing; Zhou, Cong-Zhao



The 'Vertical Structure and Diabatic Processes of the Madden-Julian Oscillation' model evaluation project: Overview and key results (Invited)  

NASA Astrophysics Data System (ADS)

The Madden-Julian oscillation (MJO) is the dominant mode of tropical sub-seasonal (30-60 day) variability. By modulating regional monsoon circulation and precipitation, interacting with ENSO and influences modes of extra-tropical variability (e.g., the NAO), the MJO provides a key source of weekly and monthly predictability globally. Despite this, most weather and climate models exhibit large biases in their simulations of the MJO. We will introduce a model evaluation project, endorsed by YoTC and GASS, designed to identify and reduce sources of error in the models' MJO representations. A key advantage of this project over previous intercomparisons is that temperature, moisture and momentum tendencies have been requested from all sub-grid parameterization schemes. This allows detailed analysis of the links between biases in MJO activity and biases in the vertical profiles of diabatic heating, moistening and momentum. The project comprises three components: 20-year simulations, from which the overall level of MJO activity can be assessed; serial 2-day hindcasts of two strong events in winter 2009-2010, in which the behavior of model parameterizations can be evaluated close to the initial, observed state; and serial 20-day hindcasts of the same two MJO events, which bridge the gap between the other two components by permitting analysis of the degradation of the simulated MJO from the initial state towards the model's climatology. Analysis of the 20-year simulations suggests that many proposed process-oriented MJO metrics, such as the relationship between precipitation and the vertical structure of relative humidity, do not sufficiently distinguish between those models that simulate the MJO well and those that simulate it poorly. It is assumed that the processes described by these metrics are necessary, but not sufficient, for an adequate simulation of the MJO in GCMs. Analysis of the 2-day hindcasts demonstrates that models develop substantial biases in upper-level temperature and humidity, evaluated against YoTC analyses, within 48 hours. These biases stem from large differences in cloud cover above the freezing level in models, which lead to discrepancies in the magnitude and even sign of the radiative temperature increments; this points to errors in cloud-radiative interactions in these models. In the 20-day hindcasts, there is no relationship between a model's ability to predict the MJO and its vertical profile of diabatic heating; models with similar diabatic-heating profiles have very different levels of skill in these hindcasts. A more consistent association is found between MJO skill and diabatic-moistening profiles, with high-skill models showing a clear transition from shallow moistening in suppressed conditions to deep moistening during the active phase. We will present an overview of the evaluation project, its goals and objectives; highlight key results from each components of the project; and discuss the next steps for further analysis, including the dissemination of data to the wider community.

Klingaman, N. P.; Jiang, X.; Xavier, P.; Petch, J.; Waliser, D. E.; Woolnough, S.



The crystal structure of the ternary complex of phenylalanyl-tRNA synthetase with tRNAPhe and a phenylalanyl-adenylate analogue reveals a conformational switch of the CCA end.  


The crystal structure of the ternary complex of (alphabeta)(2) heterotetrameric phenylalanyl-tRNA synthetase (PheRS) from Thermus thermophilus with cognate tRNA(Phe) and a nonhydrolyzable phenylalanyl-adenylate analogue (PheOH-AMP) has been determined at 3.1 A resolution. It reveals conformational changes in tRNA(Phe) induced by the PheOH-AMP binding. The single-stranded 3' end exhibits a hairpin conformation in contrast to the partial unwinding observed previously in the binary PheRS.tRNA(Phe) complex. The CCA end orientation is stabilized by extensive base-specific interactions of A76 and C75 with the protein and by intra-RNA interactions of A73 with adjacent nucleotides. The 4-amino group of the "bulged out" C75 is trapped by two negatively charged residues of the beta subunit (Glubeta31 and Aspbeta33), highly conserved in eubacterial PheRSs. The position of the A76 base is stabilized by interactions with Hisalpha212 of motif 2 (universally conserved in PheRSs) and class II-invariant Argalpha321 of motif 3. Important conformational changes induced by the binding of tRNA(Phe) and PheOH-AMP are observed in the catalytic domain: the motif 2 loop and a "helical" loop (residues 139-152 of the alpha subunit) undergo coordinated displacement; Metalpha148 of the helical loop adopts a conformation preventing the 2'-OH group of A76 from approaching the alpha-carbonyl carbon of PheOH-AMP. The unfavorable position of the terminal ribose stems from the absence of the alpha-carbonyl oxygen in the analogue. Our data suggest that the idiosyncratic feature of PheRS, which aminoacylates the 2'-OH group of the terminal ribose, is dictated by the system-specific topology of the CCA end-binding site. PMID:16939209

Moor, Nina; Kotik-Kogan, Olga; Tworowski, Dmitry; Sukhanova, Maria; Safro, Mark



?–RgIA, a Novel Conotoxin that Blocks the ?9?10 nAChR: Structure and Identification of Key Receptor Binding Residues  

PubMed Central

?-Conotoxins are small disulfide-constrained peptides from cone snails which act as antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). The 13-residue peptide ?-RgIA is a member of the ?-4,3 family of ?-conotoxins and selectively blocks the ?9?10 nAChR subtype, in contrast to another well characterized member of this family, ?-ImI, which is a potent inhibitor of the ?7 and ?3?2 nAChR subtypes. In this study, we have altered side chains in both the 4-residue and 3-residue loops of ?-RgIA, and have modified its C-terminus. The effects of these changes on activity against ?9?10 and ?7 nAChRs were measured, the solution structures of ?-RgIA and its Y10W, D5E and P6V analogues were determined from NMR data, and resonance assignments made for ?-RgIA[R9A]. The structures for ?-RgIA and its three analogues were well-defined except at the chain termini. Comparison of these structures with reported structures of ?-ImI reveals a common two-loop backbone architecture within the ?-4,3 family, but with variations in side chain solvent accessibility and orientation. Asp5, Pro6 and Arg7 in loop 1 are critical for blockade of both the ?9?10 and ?7 subtypes. In loop 2, ?-RgIA[Y10W] had activity near that of wild-type ?-RgIA, with high potency for ?9?10 and low potency for ?7, and had a similar structure to wild-type. By contrast, Arg9, in loop 2, is critical for specific binding to the ?9?10 subtype, probably because it is larger and more solvent accessible than Ala9 in ?-ImI. Our findings contribute to a better understanding of the molecular basis for antagonism of the ?9?10 nAChR subtype, which is a target for the development of analgesics for treatment of chronic neuropathic pain. PMID:18295795

Ellison, Michael; Feng, Zhi-Ping; Park, Anthony J.; Zhang, Xuecheng; Olivera, Baldomero M.; McIntosh, J. Michael; Norton, Raymond S.



Influence of the Charge State on the Structures and Interactions of Vancomycin Antibiotics with Cell-Wall Analogue Peptides: Experimental and Theoretical Studies  

SciTech Connect

In this study we examined the effect of the charge state on the energetics and dynamics of dissociation of the non-covalent complex between the vancomycin and the cell wall peptide analogue N?,N?-diacetyl-L-Lys-D-Ala-D-Ala (V-Ac2KDADA). The binding energies between the vancomycin and the peptide were obtained from the RRKM modeling of the time- and energy resolved surface-induced dissociation (SID) experiments. Our results demonstrate that the stability of the complex toward fragmentation increases in the order: [V+Ac2KDADA+H]+2 < [V+Ac2KDADA+H]+ < [V+Ac2KDADA-H]-. Dissociation of the singly protonated and singly deprotonated complex is characterized by very large entropy effects indicating substantial increase in the conformational flexibility of the resulting products. The experimental threshold energies of 1.75 eV and 1.34 eV obtained for the [V+Ac2KDADA-H]- and [V+Ac2KDADA+H]+ , respectively, are in excellent agreement with the results of density functional theory (DFT) calculations. The increased stability of the deprotonated complex observed experimentally is attributed to the presence of three charged sites in the deprotonated complex as compared to only one charged site in the singly protonated complex. The low binding energy of 0.93 eV obtained for the doubly protonated complex suggests that this ion is destabilized by Coulomb repulsion between the singly protonated vancomycin and the singly protonated peptide comprising the complex.

Yang, Zhibo; Vorpagel, Erich R.; Laskin, Julia



Analogue spacetime based on 2-component Bose-Einstein condensates  

E-print Network

Analogue spacetimes are powerful models for probing the fundamental physical aspects of geometry - while one is most typically interested in ultimately reproducing the pseudo-Riemannian geometries of interest in general relativity and cosmology, analogue models can also provide useful physical probes of more general geometries such as pseudo-Finsler spacetimes. In this chapter we shall see how a 2-component Bose-Einstein condensate can be used to model a specific class of pseudo-Finsler geometries, and after suitable tuning of parameters, both bi-metric pseudo-Riemannian geometries and standard single metric pseudo-Riemannian geometries, while independently allowing the quasi-particle excitations to exhibit a "mass". Furthermore, when extrapolated to extremely high energy the quasi-particles eventually leave the phononic regime and begin to act like free bosons. Thus this analogue spacetime exhibits an analogue of the "Lorentz violation" that is now commonly believed to occur at or near the Planck scale defined by the interplay between quantum physics and gravitational physics. In the 2-component Bose-Einstein analogue spacetime we will show that the mass generating mechanism for the quasi-particles is related to the size of the Lorentz violations. This relates the "mass hierarchy" to the so-called "naturalness problem". In short the analogue spacetime based on 2-component Bose-Einstein condensates exhibits a very rich mathematical and physical structure that can be used to investigate many issues of interest to the high-energy physics, cosmology, and general relativity communities.

Silke Weinfurtner; Stefano Liberati; Matt Visser



On the robustness of entanglement in analogue gravity systems  

NASA Astrophysics Data System (ADS)

We investigate the possibility of generating quantum-correlated quasi-particles utilizing analogue gravity systems. The quantumness of these correlations is a key aspect of analogue gravity effects and their presence allows for a clear separation between classical and quantum analogue gravity effects. However, experiments in analogue systems, such as Bose-Einstein condensates (BECs) and shallow water waves, are always conducted at non-ideal conditions, in particular, one is dealing with dispersive media at non-zero temperatures. We analyse the influence of the initial temperature on the entanglement generation in analogue gravity phenomena. We lay out all the necessary steps to calculate the entanglement generated between quasi-particle modes and we analytically derive an upper bound on the maximal temperature at which given modes can still be entangled. We further investigate a mechanism to enhance the quantum correlations. As a particular example, we analyse the robustness of the entanglement creation against thermal noise in a sudden quench of an ideally homogeneous BEC, taking into account the super-sonic dispersion relations.

Bruschi, D. E.; Friis, N.; Fuentes, I.; Weinfurtner, S.



Phonon analogue of topological nodal semimetals  

E-print Network

Recently, Kane and Lubensky proposed a mapping between bosonic phonon problems on isostatic lattices to chiral fermion systems based on factorization of the dynamical matrix [Nat. Phys. 10, 39 (2014)]. The existence of topologically protected zero modes in such mechanical problems is related to their presence in the fermionic system and is dictated by a local index theorem. Here we adopt the proposed mapping to construct a two-dimensional mechanical analogue of a fermionic topological nodal semimetal that hosts a robust bulk node in its linearized phonon spectrum. Such topologically protected soft modes with tunable wavevector may be useful in designing mechanical structures with fault-tolerant properties.

Hoi Chun Po; Yasaman Bahri; Ashvin Vishwanath



Understanding complex structures in fold-and-thrust belts. Integration of geometric and growth strata analyses, paleomagnetism, AMS and analogue models in the Western termination of the Southern Pyrenees  

NASA Astrophysics Data System (ADS)

Classic 2D approaches have helped the understanding of the geometry and kinematics of fold-and-thrust belts belts (FAT belts) but are insufficient to unravel many natural cases. This is because deformation is 3D from the geometric point of view and, thus, cylindrical features may be considered as a simplification. On the other hand, deformation kinematics is usually complex, diachronic and poliphasic in real cases. Therefore, FAT belts have to be always considered in 4D. In this sense, the Southern Pyrenees is a perfect location to study the evolution of FAT belts because of the exceptional outcropping conditions of growth strata, the proven diachronic kinematics and the non-coaxial interference of deformation events. Within the vast catalogue of complex structures that includes superposed folding, conical and plunging folds, oblique thrust ramps, etc here, we have selected the westernmost termination of the South Pyrenean sole thrust to illustrate how the integration of geometric and kinematic analysis can help unraveling complex structures in FAT belts. The San Marzal pericline (4 km2 surface extension) is the lateral termination of the Sto. Domingo deca-kilometric fold. San Marzal looks like a large 70° plunging cylindrical structure. However the large magnitude (? 60-70°) of vertical axis rotations accommodated between its flanks cannot be explained without a conical geometry. In this work we will show how the structural analysis performed on this structure has disentangled its complex geometry. This analyses comprises several hundreds of bedding data, joints and veins and more than 150 standard paleomagnetic and AMS sites. Besides, we will show how the kinematic information derived from magnetostratigraphic sections (more than 8 km of sampled profiles) has helped to constraint the folding and rotation ages and velocities. Finally, all these complex geometric and kinematic features have inspired us to build an analogue model where we can explore the 3D distribution of strain ellipsoids.

Pueyo, Emilio L.; Sánchez, Elisa; Oliva-Urcia, Belén; José Ramón, Ma



Key Facts

Key Facts Scientists know that: I-131 breaks down rapidly in the atmosphere and environment Exposure was highest in the first few days after each nuclear test explosion Most exposure occurred through drinking fresh milk People received little exposure


The 2.5 Å crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition.  


The sirtuin SIRT1 is a NAD(+)-dependent histone deacetylase, a Sir2 family member, and one of seven human sirtuins. Sirtuins are conserved from archaea to mammals and regulate transcription, genome stability, longevity, and metabolism. SIRT1 regulates transcription via deacetylation of transcription factors such as PPAR?, NF?B, and the tumor suppressor protein p53. EX527 (27) is a nanomolar SIRT1 inhibitor and a micromolar SIRT2 inhibitor. To elucidate the mechanism of SIRT inhibition by 27, we determined the 2.5 Å crystal structure of the SIRT1 catalytic domain (residues 241-516) bound to NAD(+) and the 27 analogue compound 35. 35 binds deep in the catalytic cleft, displacing the NAD(+) nicotinamide and forcing the cofactor into an extended conformation. The extended NAD(+) conformation sterically prevents substrate binding. The SIRT1/NAD(+)/35 crystal structure defines a novel mechanism of histone deacetylase inhibition and provides a basis for understanding, and rationally improving, inhibition of this therapeutically important target by drug-like molecules. PMID:23311358

Zhao, Xun; Allison, Dagart; Condon, Bradley; Zhang, Feiyu; Gheyi, Tarun; Zhang, Aiping; Ashok, Sheela; Russell, Marijane; MacEwan, Iain; Qian, Yuewei; Jamison, James A; Luz, John Gately



Genuine modern analogues of Precambrian stromatolites from caldera lakes of Niuafo'ou Island, Tonga.  


Calcareous or dolomitic, often secondarily silicified, laminated microbial structures known as stromatolites are important keys to reconstruct the chemical and biotic evolution of the early ocean. Most authors assume that cyanobacteria-associated microbialitic structures described from Shark Bay, Western Australia, and Exuma Sound, Bahamas, represent modern marine analogues for Precambrian stromatolites. Although they resemble the Precambrian forms macroscopically, their microstructure and mineralogical composition differ from those characterizing their purported ancient counterparts. Most Precambrian stromatolites are composed of presumably in situ precipitated carbonates, while their assumed modern marine analogues are predominantly products of accretion of grains trapped and bound by microbial, predominantly cyanobacterial, benthic mats and biofilms and only occasionally by their physicochemical activity. It has therefore been suggested that the carbonate chemistry of early Precambrian seawater differed significantly from modern seawater, and that some present-day quasi-marine or non-marine environments supporting growth of calcareous microbialites reflect the hydrochemical conditions controlling the calcification potential of Precambrian microbes better than modern seawater. Here we report the discovery of a non-marine environment sustaining growth of calcareous cyanobacterial microbialites showing macroscopic and microscopic features resembling closely those described from many Precambrian stromatolites. PMID:16365738

Kazmierczak, Józef; Kempe, Stephan



The Algebra of a q-Analogue of Multiple Harmonic Series  

NASA Astrophysics Data System (ADS)

We introduce an algebra which describes the multiplication structure of a family of q-series containing a q-analogue of multiple zeta values. The double shuffle relations are formulated in our framework. They contain a q-analogue of Hoffman's identity for multiple zeta values. We also discuss the dimension of the space spanned by the linear relations realized in our algebra.

Takeyama, Yoshihiro



Florida Keys  

NASA Technical Reports Server (NTRS)

The Florida Keys are a chain of islands, islets and reefs extending from Virginia Key to the Dry Tortugas for about 309 kilometers (192 miles). The keys are chiefly limestone and coral formations. The larger islands of the group are Key West (with its airport), Key Largo, Sugarloaf Key, and Boca Chica Key. A causeway extends from the mainland to Key West.

This image was acquired on October 28, 2001, by the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) on NASA's Terra satellite. With its 14 spectral bands from the visible to the thermal infrared wavelength region, and its high spatial resolution of 15 to 90 meters (about 50 to 300 feet), ASTER images Earth to map and monitor the changing surface of our planet.

ASTER is one of five Earth-observing instruments launched December 18, 1999, on NASA's Terra satellite. The instrument was built by Japan's Ministry of Economy, Trade and Industry. A joint U.S./Japan science team is responsible for validation and calibration of the instrument and the data products.

The broad spectral coverage and high spectral resolution of ASTER will provide scientists in numerous disciplines with critical information for surface mapping, and monitoring of dynamic conditions and temporal change. Example applications are: monitoring glacial advances and retreats; monitoring potentially active volcanoes; identifying crop stress; determining cloud morphology and physical properties; wetlands evaluation; thermal pollution monitoring; coral reef degradation; surface temperature mapping of soils and geology; and measuring surface heat balance.

Dr. Anne Kahle at NASA's Jet Propulsion Laboratory, Pasadena, Calif., is the U.S. Science team leader; Bjorn Eng of JPL is the project manager. The Terra mission is part of NASA's Earth Science Enterprise, a long- term research effort to understand and protect our home planet. Through the study of Earth, NASA will help to provide sound science to policy and economic decision-makers so as to better life here, while developing the technologies needed to explore the universe and search for life beyond our home planet.

Size: 51.6 by 29.7 kilometers ( 32.0 by 18.4 miles) Location: 24.7 degrees North latitude, 81.5 degrees West longitude Orientation: North at top Image Data: ASTER bands 1, 2, and 3 Original Data Resolution: 15 meters (49.2 feet) Date Acquired: October 28, 2001



Metamorphic core complexes vs. synkinematic plutons in continental extension setting: insights from key structures (Shandong Province, eastern China)  

E-print Network

) the exhumation of the Late Jurassic-Early Cretaceous Linglong MCC below the SE-dipping Linglong detachment fault by partially-melted lower to middle crust upward into the Linglong MCC should be revised to Late Jurassic-Early Cretaceous period. Key-words: Mesozoic extension, eastern Asia, Metamorphic Core Complex, synkinematic pluton

Paris-Sud XI, Université de


Synthesis and structural, spectroscopic, and electrochemical characterization of benzo[c]quinolizinium and its 5-aza-, 6-aza, and 5,6-diaza analogues  

E-print Network

March 2011 a b s t r a c t Four heterocyclic salts 1aed were prepared by Ca2þ -assisted cyclization, such as arterial hypertension and asthma.5 It has also been used as a structural element of highly solvatochromic on the molecular and electronic properties of the cations. The preparation of cation 1a involves high temperature

Kaszynski, Piotr


Molecular modeling studies of atorvastatin analogues as HMGR inhibitors using 3D-QSAR, molecular docking and molecular dynamics simulations.  


3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) is generally regarded as targets for the treatment of hypercholesterolemia. HMGR inhibitors (more commonly known as statins) are discovered as plasma cholesterol lowering molecules. In this work, 120 atorvastatin analogues were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q(2)=0.558 and r(2)=0.977, and the best CoMSIA (comparative molecular similarity indices analysis) model has q(2)=0.582 and r(2)=0.919. Molecular docking and MD simulation explored the binding relationship of the ligand and the receptor protein. The calculation results indicated that the hydrophobic and electrostatic fields play key roles in QSAR model. After MD simulation, we found four vital residues (Lys735, Arg590, Asp690 and Asn686) and three hydrophobic regions in HMGR binding site. The calculation results show that atorvastatin analogues obtained by introduction of F atoms or gem-difluoro groups could obviously improve the inhibitory activity. The new HMGR inhibitor analogues design in this Letter had been submitted which is being currently synthesized by our laboratories. PMID:25022881

Wang, Zhi; Cheng, Liping; Kai, Zhenpeng; Wu, Fanhong; Liu, Zhuoyu; Cai, Minfeng



Transition state analogue L-leucinephosphonic acid bound to bovine lens leucine aminopeptidase: X-ray structure at 1.65 A resolution in a new crystal form.  


The three-dimensional structure of bovine lens leucine aminopeptidase (blLAP) complexed with L-Leucinephosphonic acid (LeuP) has been determined by molecular replacement using the structure of native blLAP as a starting model. Cocrystallization of the enzyme with the inhibitor yielded a new crystal form of space group P321 which has cell dimensions a = 130.4 A and c = 125.4 A. Refinement of the model against data from 7.0 to 1.65 A resolution resulted in a final structure with a crystallographic residual of 0.160 (R(free) = 0.191). The N-terminal amino group of LeuP is coordinated to Zn-489, one phosphoryl oxygen atom bridges both metal ions, and another phosphoryl oxygen atom is coordinated to Zn-488. The side chain of Arg-336 interacts with the inhibitor via three water molecules. LeuP resembles the presumed tetrahedral gem-diolate transition state after direct attack of a water or hydroxide ion nucleophile on the scissile peptide bond. On the basis of the LeuP binding mode and the previous structural and biochemical data, three plausible reaction pathways are evaluated. The two-metal ion mechanisms discussed herein share as common features a metal-bound hydroxide ion nucleophile and polarization of the carbonyl group by the zinc ions. Possible catalytic roles of Arg-336 and Lys-262 in the direct or indirect (through H2O) protonation of the leaving group, in the stabilization of a zinc-bound OH- nucleophile and in the stabilization of the negatively charged intermediate, are discussed. A site 3 metal ion approximately 12 A away from the active site 2 zinc ion probably serves a structural role. PMID:7619821

Sträter, N; Lipscomb, W N



Key Literature.  

ERIC Educational Resources Information Center

Provides an annotated bibliography of the literature considered by the contributing authors to this journal issue to be of key importance to the subjects covered in their articles. These subjects include: transfer, vocational education, remedial education, English as a second language (ESL), assessment, student services, faculty and professional…

New Directions for Community Colleges, 2002



Probing Human Red Cone Opsin Activity with Retinal Analogues?  

PubMed Central

Retinal analogues have been used to probe the chromophore binding pocket and function of the rod visual pigment, rhodopsin. Despite the high homology between rod and cone visual pigment proteins, conclusions drawn from rhodopsin studies should not necessarily be extrapolated to cone visual pigment proteins. In this study, the effects of full-length and truncated retinal analogues on the human red cone opsin’s ability to activate transducin, the G protein in visual transduction, were assessed. The result with beta-ionone (6) confirms that a covalent bond is not necessary to deactivate the red cone opsin. In addition, several small compounds were found able to deactivate this opsin. However, as the polyene chain is extended in a trans configuration beyond the 9-carbon position, the analogues became agonists up to all-trans-retinal (3). The 22-carbon analogue (2) appeared to be neither agonist nor inverse agonist. Although the all-trans-C17 (5) analogue was an agonist, the 9-cis-C17 (11) compound was an inverse agonist, a result that differs from that with rhodopsin. These results suggest that the red cone opsin has a more open structure in the chromophore binding region than rhodopsin and its activation or deactivation as a G-protein receptor may be less selective than rhodopsin. PMID:21314100

Kono, Masahiro; Crouch, Rosalie K.



Design of novel CSA analogues as potential safeners and fungicides.  


Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylbenzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA) as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably, two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further antifungal assay showed their excellent activity against Physollospora piricola. The structure-activity relationships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further molecular modification of new CSA analogues. PMID:25582601

Zheng, Yang; Liu, Bin; Gou, Zhaopin; Li, Yao; Zhang, Xiao; Wang, Yanqing; Yu, Shujing; Li, Yonghong; Sun, Dequn



Key distributionKey distribution Key distribution, symmetric encryption  

E-print Network

COMP 522 Key distributionKey distribution COMP 522 Key distribution, symmetric encryption From in a secure way and must keep the key secure" · Important issue: how to distribute secret keys? COMP 522 Key distribution, manual delivery For two parties A and B: · A key could be created by A and delivered physically

Fisher, Michael


Structure and magnetic properties of an unprecedented syn-anti ?-nitrito-1?O:2?O' bridged Mn(III)-salen complex and its isoelectronic and isostructural formate analogue.  


The preparation, crystal structures and magnetic properties of two new isoelectronic and isomorphous formate- and nitrite-bridged 1D chains of Mn(III)-salen complexes, [Mn(salen)(HCOO)](n) (1) and [Mn(salen)(NO(2))](n) (2), where salen is the dianion of N,N'-bis(salicylidene)-1,2-diaminoethane, are presented. The structures show that the salen ligand coordinates to the four equatorial sites of the metal ion and the formate or nitrite ions coordinate to the axial positions to bridge the Mn(III)-salen units through a syn-anti?-1?O:2?O' coordination mode. Such a bridging mode is unprecedented in Mn(III) for formate and in any transition metal ion for nitrite. Variable-temperature magnetic susceptibility measurements of complexes 1 and 2 indicate the presence of ferromagnetic exchange interactions with J values of 0.0607 cm(-1) (for 1) and 0.0883 cm(-1) (for 2). The ac measurements indicate negligible frequency dependence for 1 whereas compound 2 exhibits a decrease of ?(ac)' and a concomitant increase of ?(ac)'' on elevating frequency around 2 K. This finding is an indication of slow magnetization reversal characteristic of single-chain magnets or spin-glasses. The ?-nitrito-1?O:2?O' bridge seems to be a potentially superior magnetic coupler to the formate bridge for the construction of single-molecule/-chain magnets as its coupling constant is greater and the ?(ac)' and ?(ac)'' show frequency dependence. PMID:21344112

Kar, Paramita; Biswas, Rituparna; Drew, Michael G B; Ida, Yumi; Ishida, Takayuki; Ghosh, Ashutosh



Structural, electronic and charge transfer studies of dianthra[2,3-b:2?,3?-f]thieno[3,2-b]thiophene and its analogues: Quantum chemical investigations  

NASA Astrophysics Data System (ADS)

The ground state structures of dianthra[2,3-b:2',3'-f]thieno[3,2-b]thiophene, its derivatives and analogues have been optimized at B3LYP/6-31G** level of density functional theory. The computed geometrical parameters are in good agreement with the experimental data. The decrease in the bond length has been observed in the sequence, Ssbnd C > Bsbnd C > Osbnd C. The substitution of sbnd F and sbnd N has no effect to lengthen or shorten the nearest Csbnd C or central Csbnd C, Ssbnd C, Osbnd C, Bsbnd C bond lengths. The highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of all the molecules are spread over the whole pi-conjugated backbones with similar character. The HOMOs displays bonding character within each unit while the LUMOs exhibit the antibonding character. By substituting the boron (3), fluoro and nitrogen (4-6) make the LUMOs energy levels lower resulting higher electron mobility. The values of IPv/a and EAv/a increase from 1 to 6 except in 2 where EA decrease but the effect is not so significant. The high EAs of 3 and 6 revealed that these molecules would be more suitable for generating free electron. The positive correlation between EAv and the LUMO levels has been observed. The 3 and 6 would be better as n-type materials having EAs close to 3.0 eV. The electron reorganization energies for 1, 2, 4 and 5 are higher than hole reorganization energies while ?e are less than those of ?h for 3 and 6. In the last step, we have simulated and successfully regenerated the crystal structure of parent molecule by MM energy minimization approach.

Irfan, Ahmad; Al-Sehemi, Abdullah G.; Kalam, Abul



A fluoro analogue of the menadione derivative 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid is a suicide substrate of glutathione reductase. Crystal structure of the alkylated human enzyme.  


Glutathione reductase is an important housekeeping enzyme for redox homeostasis both in human cells and in the causative agent of tropical malaria, Plasmodium falciparum. Glutathione reductase inhibitors were shown to have anticancer and antimalarial activity per se and to contribute to the reversal of drug resistance. The development of menadione chemistry has led to the selection of 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid, called M(5), as a potent reversible and uncompetitive inhibitor of both human and P. falciparum glutathione reductases. Here we describe the synthesis and kinetic characterization of a fluoromethyl-M(5) analogue that acts as a mechanism-based inhibitor of both enzymes. In the course of enzymatic catalysis, the suicide substrate is activated by one- or two-electron reduction, and then a highly reactive quinone methide is generated upon elimination of the fluorine. Accordingly the human enzyme was found to be irreversibly inactivated with a k(inact) value of 0.4 +/- 0.2 min(-1). The crystal structure of the alkylated enzyme was solved at 1.7 A resolution. It showed the inhibitor to bind covalently to the active site Cys58 and to interact noncovalently with His467', Arg347, Arg37, and Tyr114. On the basis of the crystal structure of the inactivated human enzyme and stopped-flow kinetic studies with two- and four-electron-reduced forms of the unreacted P. falciparum enzyme, a mechanism is proposed which explains naphthoquinone reduction at the flavin of glutathione reductase. PMID:16910673

Bauer, Holger; Fritz-Wolf, Karin; Winzer, Andreas; Kühner, Sebastian; Little, Susan; Yardley, Vanessa; Vezin, Hervé; Palfey, Bruce; Schirmer, R Heiner; Davioud-Charvet, Elisabeth



Synthesis and evaluation of analogues of HYNIC as bifunctional chelators for technetium.  


6-Hydrazinonicotinic acid (HYNIC, 1) is a well-established bifunctional technetium-binding ligand often used to synthesise bioconjugates for radiolabelling with Tc-99m. It is capable of efficient capture of technetium at extremely low concentrations, but the structure of the labelled complexes is heterogeneous and incompletely understood. In particular, it is of interest to determine whether, at the no-carrier-added level, it acts in a chelating or non-chelating mode. Here we report two new isomers of HYNIC: 2-hydrazinonicotinic acid (2-HYNIC, 2), which (like 1) is capable of chelation through the mutually ortho hydrazine and pyridine nitrogens and 4-hydrazinonicotinic acid (4-HYNIC, 3), which is not (due to the para-relationship of the hydrazine and pyridine nitrogens). LC-MS shows that the coordination chemistry of 2 with technetium closely parallels that of conventional 1, and no advantages of one over the other in terms of potential labelling efficiency or isomerism were discernable. Both 1 and 2 formed complexes with the loss of 5 protons from the ligand set, whether the co-ligand was tricine or EDDA. Ligand 3, however, failed to complex technetium except at very high ligand concentration: the marked contrast with 1 and 2 suggests that chelation, rather than nonchelating coordination, is a key feature of technetium coordination by HYNIC. Two further new HYNIC analogues, 2-chloro-6-hydrazinonicotinic acid (2-chloro-HYNIC, 4a) and 2,6-dihydrazinonicotinic acid (diHYNIC, 5) were also synthesised. The coordination chemistry of 4a with technetium was broadly parallel to that of 1 and 2 although it was a less efficient chelator, while 5 also behaved as an efficient chelator of technetium, but its coordination chemistry remains poorly defined and requires further investigation before it can sensibly be adopted for (99m)Tc-labelling. The new analogues 4a and 5 present an opportunity to develop trifunctional HYNIC analogues for more complex bioconjugate synthesis. PMID:21350776

Meszaros, Levente K; Dose, Anica; Biagini, Stefano C G; Blower, Philip J



An evaluation of the structure-activity relationships of a series of analogues of mephenesin and strychnine on the response to pressure in mice.  

PubMed Central

1. A range of compounds structurally related to the centrally acting muscle relaxant mephenesin and to the chemical convulsant strychnine were synthesized and tested for their ability to alter the threshold pressures for the onset of high pressure convulsions in mice. 2. The ability of both groups of compounds to alter the threshold pressure for convulsions was found to be dependent on the nature of a simple molecular skeleton. Thus, compounds that possessed a negatively polarized group located both in the same plane as and some 4.5 A from an aromatic nucleus increased the thresholds whereas compounds with a positively polarized group at the same location reduced the thresholds. 3. These findings support the suggestion that pressure elicits convulsions via a selection action on a receptor protein complex rather than via some general perturbation of the lipid regions of cellular membranes. PMID:2743078

Bowser-Riley, F.; Daniels, S.; Hill, W. A.; Smith, E. B.



Kinetic, inhibition and structural studies on 3-oxoacyl-ACP reductase from Plasmodium falciparum, a key enzyme in fatty acid biosynthesis  

PubMed Central

Type II fatty acid biosynthesis represents an attractive target for the discovery of new antimalarial drugs. Previous studies have identified malarial ENR (enoyl acyl-carrier-protein reductase, or FabI) as the target for the antiseptic triclosan. In the present paper, we report the biochemical properties and 1.5 Å (1 Å=0.1 nm) crystal structure of OAR (3-oxoacyl acyl-carrier-protein reductase, or FabG), the second reductive step in fatty acid biosynthesis and its inhibition by hexachlorophene. Under optimal conditions of pH and ionic strength, Plasmodium falciparum OAR displays kinetic properties similar to those of OAR from bacteria or plants. Activity with NADH is <3% of that with NADPH. Fluorescence enhancement studies indicate that NADPH can bind to the free enzyme, consistent with kinetic and product inhibition studies suggesting a steady-state ordered mechanism. The crystal structure reveals a tetramer with a sulphate ion bound in the cofactor-binding site such that the side chains of the catalytic triad of serine, tyrosine and lysine are aligned in an active conformation, as previously observed in the Escherichia coli OAR–NADP+ complex. A cluster of positively charged residues is positioned at the entrance to the active site, consistent with the proposed recognition site for the physiological substrate (3-oxoacyl-acyl-carrier protein) in E. coli OAR. The antibacterial and anthelminthic agent hexachlorophene is a potent inhibitor of OAR (IC50 2.05 ?M) displaying non-linear competitive inhibition with respect to NADPH. Hexachlorophene (EC50 6.2 ?M) and analogues such as bithionol also have antimalarial activity in vitro, suggesting they might be useful leads for further development. PMID:16225460

Wickramasinghe, Sasala R.; Inglis, Kirstine A.; Urch, Jonathan E.; Müller, Sylke; van Aalten, Daan M. F.; Fairlamb, Alan H.



Trapping of a transcription complex using a new nucleotide analogue: AMP aluminium fluoride.  


Mechanochemical proteins rely on ATP hydrolysis to establish the different functional states required for their biological output. Studying the transient functional intermediate states these proteins adopt as they progress through the ATP hydrolysis cycle is key to understanding the molecular basis of their mechanism. Many of these intermediates have been successfully 'trapped' and functionally characterised using ATP analogues. Here, we present a new nucleotide analogue, AMP-AlF(x), which traps PspF, a bacterial enhancer binding protein, in a stable complex with the sigma(54)-RNA polymerase holoenzyme. The crystal structure of AMP-AlF(x)*PspF(1-275) provides new information on protein-nucleotide interactions and suggests that the beta and gamma phosphates are more important than the alpha phosphate in terms of sensing nucleotide bound states. In addition, functional data obtained with AMP-AlF(x) establish distinct roles for the conserved catalytic AAA(+) (ATPases associated with various cellular activities) residues, suggesting that AMP-AlF(x) is a powerful new tool to study AAA(+) protein family members and, more generally, Walker motif ATPases. PMID:18082766

Joly, Nicolas; Rappas, Mathieu; Buck, Martin; Zhang, Xiaodong



Synthesis, structure, magnetism, and spectroscopic properties of heterobinuclear copper(II)-zinc(II) complexes and their copper(II)-copper(II) analogues in asymmetric ligand environments.  


Heterobinuclear copper(II)-zinc(II) complexes and their homobinuclear dicopper(II) counterparts (1-4) of two asymmetric ligands (H2L1 and H2L2), based on 2-aminocyclopent-1-ene-1-dithiocarboxylate, are reported. The ligands are capable of providing both donor set and coordination number asymmetry in tandem. Metal centers in these complexes are connected by a micro-alkoxo and a bridging pyrazolate moiety, as confirmed by X-ray structure analyses of 1, 3, and 4. The Cu(1) site in the dicopper complex (1) is square planar and so are the copper sites in the Cu-Zn complexes 3 and 4. The pentacoordinated Zn sites in the latter complexes have distorted TBP geometry (tau = 0.74), while the corresponding Cu site in 1 has a highly distorted square pyramidal structure (tau = 0.54). The Cu...Zn separations in 3 and 4 are 3.3782 and 3.3403 angstroms, respectively, while the Cu...Cu distance in 1 is 3.3687 angstroms. The dicopper complexes are EPR silent at 77 K, in which the copper(II) centers are coupled by strong antiferromagnetic coupling (J = ca. -290 cm(-1)) as confirmed by variable-temperature (4-300 K) magnetic measurements. These compounds (1 and 2) undergo two one-electron reductions and a single step two-electron oxidation at ca. -0.26, -1.40, and 1.0 V vs Ag/AgCl reference, respectively, as indicated by cyclic and differential pulse voltammetry done at subambient temperatures. EPR spectra of 3 and 4 display axial anisotropy at 77 K with the gperpendicular region being split into multiple lines due to N-superhyperfine coupling (AN = 15.3 x 10(-4) cm(-1)). The observed trend in the spin-Hamiltonian parameters, gparallel > gperpendicular > 2.04 and |Aperpendicular| < |Aparallel| approximately (120-150) x 10(-4) cm(-1), indicates a d(x2-y2)-based ground state with tetragonal site symmetry for the Cu(II) center in these molecules. PMID:15360251

Ghosh, Dipesh; Kundu, Nabanita; Maity, Goutam; Choi, Ki-Young; Caneschi, Andrea; Endo, Akira; Chaudhury, Muktimoy



Secondary Structure of the rRNA ITS2 Region Reveals Key Evolutionary Patterns in Acroporid Corals  

Microsoft Academic Search

This study investigates the ribosomal RNA transcript secondary structure in corals as confirmed by compensatory base changes\\u000a in Isopora\\/Acropora species. These species are unique versus all other corals in the absence of a eukaryote-wide conserved structural component,\\u000a the helix III in internal transcriber spacer (ITS) 2, and their variability in the 5.8S-LSU helix basal to ITS2, a helix with\\u000a pairings

Annette W. Coleman; Madeleine J. H. van Oppen



Hexanuclear, heterometallic, Ni?Ln? complexes possessing O-capped homo- and heterometallic structural subunits: SMM behavior of the dysprosium analogue.  


The reaction of hetero donor chelating mannich base ligand 6,6'-{(2-(dimethylamino)ethylazanediyl)bis(methylene)}bis(2-methoxy-4-methylphenol) with Ni(ClO4)2·6H2O and lanthanide(III) salts [Dy(III) (1); Tb(III) (2); Gd (III) (3); Ho(III) (4); and Er(III) (5)] in the presence of triethylamine and pivalic acid afforded a series of heterometallic hexanuclear Ni(II)-Ln(III) coordination compounds, [Ni3Ln3(?3-O)(?3-OH)3(L)3(?-OOCCMe3)3]·(ClO4)·wCH3CN·xCH2Cl2·yCH3OH·zH2O [for 1, w = 8, x = 3, y = 0, z = 5.5; for 2, w = 0, x = 5, y = 0, z = 6.5; for 3, w = 15, x = 18, y = 3, z = 7.5; for 4, w = 15, x = 20, y = 6, z = 9.5; and for 5, w = 0, x = 3, y = 2, z = 3]. The molecular structure of these complexes reveals the presence of a monocationic hexanuclear derivative containing one perchlorate counteranion. The asymmetric unit of each of the hexanuclear derivatives comprises the dinuclear motif [NiLn(L)(?3-O)(?3-OH)(?-Piv)]. The cation contains three interlinked O-capped clusters: one Ln(III)3O and three Ni(II)Ln(III)2O. Each of the lanthanide centers is eight- coordinated (distorted trigonal-dodecahedron), while the nickel centers are hexacoordinate (distorted octahedral). The study of the magnetic properties of all compounds are reported and suggests single molecule magnet behavior for the Dy(III) derivative (1). PMID:25050753

Goura, Joydeb; Guillaume, Rogez; Rivière, Eric; Chandrasekhar, Vadapalli



Analogue models for FRW cosmologies  

E-print Network

It is by now well known that various condensed matter systems may be used to mimic many of the kinematic aspects of general relativity, and in particular of curved-spacetime quantum field theory. In this essay we will take a look at what would be needed to mimic a cosmological spacetime -- to be precise a spatially flat FRW cosmology -- in one of these analogue models. In order to do this one needs to build and control suitable time dependent systems. We discuss here two quite different ways to achieve this goal. One might rely on an explosion, physically mimicking the big bang by an outflow of whatever medium is being used to carry the excitations of the analogue model, but this idea appears to encounter dynamical problems in practice. More subtly, one can avoid the need for any actual physical motion (and avoid the dynamical problems) by instead adjusting the propagation speed of the excitations of the analogue model. We shall focus on this more promising route and discuss its practicality.

Carlos Barcelo; Stefano Liberati; Matt Visser



Substrate analogues for isoprenoid enzymes  

SciTech Connect

Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

Stremler, K.E.



Synthesis and anti-tumor activity of carbohydrate analogues of the tetrahydrofuran containing acetogenins  

PubMed Central

The tetrahydrofuran (THF) containing annonaceous acetogenins (AAs) are attractive candidates for drug development because of their potent cytotoxicity against a wide range of tumors and their relatively simple and robust structures. Replacement of the THF segment with a sugar residue may deliver analogues with improved tumor selectivity and pharmacokinetics and are therefore attractive for drug development. As a first test to the feasibility of such structures, a set of such monosaccharide analogues was synthesized and assayed against four human tumor cell lines, cervical (HeLa), breast (MDA-MB231), T-cell leukemia (Jurkat) and prostate (PC-3). Certain analogues showed low micromolar activity that was comparable to a structurally similar, naturally occurring mono-THF acetogenin. A preliminary examination of the structure-activity profile of these carbohydrate analogues suggests that they have a similar mechanism of action as their THF congeners. PMID:24045006

Bachan, Stewart; Tony, K. A.; Kawamura, Akira; Montenegro, Diego; Joshi, Anjali; Garg, Himanshu; Mootoo, David R.



Electromagnetic energy transport along arrays of closely spaced metal rods as an analogue to plasmonic devices  

E-print Network

Electromagnetic energy transport along arrays of closely spaced metal rods as an analogue of Applied Physics, California Institute of Technology, Pasadena, California 91125 Received 21 July 2000; accepted for publication 9 November 2000 The transport of electromagnetic energy along structures

Atwater, Harry


Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation.  


The secreted glycoprotein sclerostin has recently emerged as a key negative regulator of Wnt signaling in bone and has stimulated considerable interest as a potential target for therapeutics designed to treat conditions associated with low bone mass, such as osteoporosis. We have determined the structure of sclerostin, which resulted in the identification of a previously unknown binding site for heparin, suggestive of a functional role in localizing sclerostin to the surface of target cells. We have also mapped the interaction site for an antibody that blocks the inhibition of Wnt signaling by sclerostin. This shows minimal overlap with the heparin binding site and highlights a key role for this region of sclerostin in protein interactions associated with the inhibition of Wnt signaling. The conserved N- and C-terminal arms of sclerostin were found to be unstructured, highly flexible, and unaffected by heparin binding, which suggests a role in stabilizing interactions with target proteins. PMID:19208630

Veverka, Vaclav; Henry, Alistair J; Slocombe, Patrick M; Ventom, Andrew; Mulloy, Barbara; Muskett, Frederick W; Muzylak, Mariusz; Greenslade, Kevin; Moore, Adrian; Zhang, Li; Gong, Jianhua; Qian, Xueming; Paszty, Chris; Taylor, Richard J; Robinson, Martyn K; Carr, Mark D



Biological evaluation of a novel sorafenib analogue, t-CUPM.  


Sorafenib (Nexavar(®)) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib. PMID:25413440

Wecksler, Aaron T; Hwang, Sung Hee; Liu, Jun-Yan; Wettersten, Hiromi I; Morisseau, Christophe; Wu, Jian; Weiss, Robert H; Hammock, Bruce D



Liquid chromatography ion trap/time-of-flight mass spectrometric study on the fragmentation of an acetildenafil analogue.  


Liquid chromatography ion-trap time-of-flight mass spectrometry was employed to elucidate the fragmentation pathways of an analogue of acetildenafil. Based on the accurate masses of the parent ion, product ions and neutral losses of acetildenafil analogue, its fragmentation pathways were proposed. The information is useful for the on-line structural identification of unknown analogues of acetildenafil found as adulterants in herbal products. PMID:17881792

Zou, Peng; Oh, Sharon Sze-Yin; Kiang, Kin-Har; Low, Min-Yong; Koh, Hwee-Ling



The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor  

PubMed Central

In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as ‘designer drugs’ and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects. PMID:23527166

Roth, Bryan L.; Gibbons, Simon; Arunotayanun, Warunya; Huang, Xi-Ping; Setola, Vincent; Treble, Ric; Iversen, Les



Synthesis and evaluation of heterocyclic analogues of bromoxynil.  


One attractive strategy to discover more active and/or crop-selective herbicides is to make structural changes to currently registered compounds. This strategy is especially appealing for those compounds with limited herbicide resistance and whose chemistry is accompanied with transgenic tools to enable herbicide tolerance in crop plants. Bromoxynil is a photosystem II (PSII) inhibitor registered for control of broadleaf weeds in several agronomic and specialty crops. Recently at the University of Tennessee-Knoxville several analogues of bromoxynil were synthesized including a previously synthesized pyridine (2,6-dibromo-5-hydroxypyridine-2-carbonitrile sodium salt), a novel pyrimidine (4,6-dibromo-5-hydroxypyrimidine-2-carbonitrile sodium salt), and a novel pyridine N-oxide (2,6-dibromo-1-oxidopyridin-1-ium-4-carbonitrile). These new analogues of bromoxynil were also evaluated for their herbicidal activity on soybean (Glycine max), cotton (Gossypium hirsutum), redroot pigweed (Amaranthus retroflexus), velvetleaf (Abutilon theophrasti), large crabgrass (Digitaria sanguinalis), and pitted morningglory ( Ipomoea lacunose ) when applied at 0.28 kg ha(-1). A second study was conducted on a glyphosate-resistant weed (Amaranthus palmeri) with the compounds being applied at 0.56 kg ha(-1). Although all compounds were believed to inhibit PSII by binding in the quinone binding pocket of D1, the pyridine and pyridine-N-oxide analogues were clearly more potent than bromoxynil on Amaranthus retroflexus. However, application of the pyrimidine herbicide resulted in the least injury to all species tested. These variations in efficacy were investigated using molecular docking simulations, which indicate that the pyridine analogue may form a stronger hydrogen bond in the pocket of the D1 protein than the original bromoxynil. A pyridine analogue was able to control the glyphosate-resistant Amaranthus palmeri with >80% efficacy. The pyridine analogues of bromoxynil showed potential to have a different weed control spectrum compared to bromoxynil. A pyridine analogue of bromoxynil synthesized in this research controlled several weed species greater than bromoxynil itself, potentially due to enhanced binding within the PSII binding pocket. Future research should compare this analogue to bromoxynil using optimized formulations at higher application rates. PMID:24354444

Cutulle, Matthew A; Armel, Gregory R; Brosnan, James T; Best, Michael D; Kopsell, Dean A; Bruce, Barry D; Bostic, Heidi E; Layton, Donovan S



Antifreeze glycopeptide analogues: microwave-enhanced synthesis and functional studies.  


Antifreeze glycoproteins enable life at temperatures below the freezing point of physiological solutions. They usually consist of the repetitive tripeptide unit (-Ala-Ala-Thr-) with the disaccharide alpha-D-galactosyl-(1-3)-beta-N-acetyl-D-galactosamine attached to each hydroxyl group of threonine. Monoglycosylated analogues have been synthesized from the corresponding monoglycosylated threonine building block by microwave-assisted solid phase peptide synthesis. This method allows the preparation of analogues containing sequence variations which are not accessible by other synthetic methods. As antifreeze glycoproteins consist of numerous isoforms they are difficult to obtain in pure form from natural sources. The synthetic peptides have been structurally analyzed by CD and NMR spectroscopy in proton exchange experiments revealing a structure as flexible as reported for the native peptides. Microphysical recrystallization tests show an ice structuring influence and ice growth inhibition depending on the concentration, chain length and sequence of the peptides. PMID:19165574

Heggemann, Carolin; Budke, Carsten; Schomburg, Benjamin; Majer, Zsuzsa; Wissbrock, Marco; Koop, Thomas; Sewald, Norbert



Adenosine monophosphate-activated kinase and its key role in catabolism: structure, regulation, biological activity, and pharmacological activation.  


Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor, which once activated, plays a role in several processes within the cell to restore energy homeostasis. The protein enhances catabolic pathways, such as ?-oxidation and autophagy, to generate ATP, and inhibits anabolic processes that require energy, including fatty acid, cholesterol, and protein synthesis. Due to its key role in the regulation of critical cellular pathways, deregulation of AMPK is associated with the pathology of many diseases, including cancer, Wolff-Parkinson-White syndrome, neurodegenerative disorders, diabetes, and metabolic syndrome. In fact, AMPK is a target of some pharmacological agents implemented in the treatment of diabetes (metformin and thiazolidinediones) as well as other naturally derived products, such as berberine, which is used in traditional medicine. Due to its critical role in the cell and the pathology of several disorders, research into developing AMPK as a therapeutic target is becoming a burgeoning and exciting field of pharmacological research. A profound understanding of the regulation and activity of AMPK would enhance its development as a promising therapeutic target. PMID:25422142

Krishan, Sukriti; Richardson, Des R; Sahni, Sumit



Hippocampal structure and human cognition: key role of spatial processing and evidence supporting the efficiency hypothesis in females  

PubMed Central

Here we apply a method for automated segmentation of the hippocampus in 3D high-resolution structural brain MRI scans. One hundred and four healthy young adults completed twenty one tasks measuring abstract, verbal, and spatial intelligence, along with working memory, executive control, attention, and processing speed. After permutation tests corrected for multiple comparisons across vertices (p < .05) significant relationships were found for spatial intelligence, spatial working memory, and spatial executive control. Interactions with sex revealed significant relationships with the general factor of intelligence (g), along with abstract and spatial intelligence. These correlations were mainly positive for males but negative for females, which might support the efficiency hypothesis in women. Verbal intelligence, attention, and processing speed were not related to hippocampal structural differences.

Colom, Roberto; Stein, Jason L.; Rajagopalan, Priya; Martínez, Kenia; Hermel, David; Wang, Yalin; Álvarez-Linera, Juan; Burgaleta, Miguel; Quiroga, MªÁngeles; Shih, Pei Chun; Thompson, Paul M.



Key insights from structural studies of high-temperature superconductors : Is there a path to higher Tc?  

SciTech Connect

Structural studies have allowed the development of a model for the ''ideal'' high-temperature superconductor. For a given compound, the maximum T{sub c} is traditionally achieved by using a chemical variable to adjust the carrier concentration to the optimum value. When comparing different compounds at their optimum doping, the highest T{sub c} is observed for compounds with flat CuO{sub 2} planes. T{sub c} can also be enhanced if the charge reservoir region, or blocking layer, is metallic. In general, these three criteria cannot simultaneously be met by adjusting a single chemical/structural variable. Additionally, recent work on HgBa{sub 2}CuO{sub 4+x} and 123 compounds as a function of doping suggest that electronically-driven structural distortions may hinder attempts to produce higher T{sub c}'s by chemical substitutions. In spite of these challenges, the ideal high-T{sub c} compound has not yet been discovered and the search should continue.

Jorgensen, J. D.



Structure of the flavoprotein tryptophan 2-monooxygenase, a key enzyme in the formation of galls in plants.  


The flavoprotein tryptophan 2-monooxygenase catalyzes the oxidative decarboxylation of tryptophan to yield indole-3-acetamide. This is the initial step in the biosynthesis of the plant growth hormone indole-acetic acid by bacterial pathogens that cause crown gall and related diseases. The structure of the enzyme from Pseudomonas savastanoi has been determined by X-ray diffraction methods to a resolution of 1.95 Å. The overall structure of the protein shows that it has the same fold as members of the monoamine oxidase family of flavoproteins, with the greatest similarities to the l-amino acid oxidases. The location of bound indole-3-acetamide in the active site allows identification of residues responsible for substrate binding and specificity. Two residues in the enzyme are conserved in all members of the monoamine oxidase family, Lys365 and Trp466. The K365M mutation decreases the kcat and kcat/KTrp values by 60000- and 2 million-fold, respectively. The deuterium kinetic isotope effect increases to 3.2, consistent with carbon-hydrogen bond cleavage becoming rate-limiting in the mutant enzyme. The W466F mutation decreases the kcat value <2-fold and the kcat/KTrp value only 5-fold, while the W466M mutation results in an enzyme lacking flavin and detectable activity. This is consistent with a role for Trp466 in maintaining the structure of the flavin-binding site in the more conserved FAD domain. PMID:23521653

Gaweska, Helena M; Taylor, Alexander B; Hart, P John; Fitzpatrick, Paul F



The Structure of the Flavoprotein Tryptophan-2-Monooxygenase, a Key Enzyme in the Formation of Galls in Plants†  

PubMed Central

The flavoprotein tryptophan 2-monooxygenase catalyzes the oxidative decarboxylation of tryptophan to yield indole-3-acetamide. This is the initial step in the biosynthesis of the plant growth hormone indole-acetic-acid by bacterial pathogens that cause crown gall and related diseases. The structure of the enzyme from Pseudomonas savastanoi has been determined by X-ray diffraction methods to a resolution of 1.95 Å. The overall structure of the protein shows that it has the same fold as the monoamine oxidase family of flavoproteins, with the greatest similarities to the L-amino acid oxidases. The location of bound indole-3-acetamide in the active site enables identification of residues responsible for substrate binding and specificity. Two residues in the enzyme are conserved in all members of the monoamine oxidase family, Lys365 and Trp466. The K365M mutation decreases the kcat and kcat/KTrp values by 60,000 and 2 million-fold, respectively. The deuterium kinetic isotope effect increases to 3.2, consistent with carbon-hydrogen bond cleavage becoming rate-limiting in the mutant enzyme. The W466F mutation decreases the kcat value less than 2-fold and the kcat/KTrp value only 5-fold, while the W466M mutation results in enzyme lacking flavin and detectable activity. This is consistent with a role for Trp466 in maintaining the structure of the flavin binding site in the more conserved FAD domain. PMID:23521653

Gaweska, Helena M.; Taylor, Alexander B.; Hart, P. John; Fitzpatrick, Paul F.



Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogues  

PubMed Central

Background and purpose: Amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran, B2-O-CH2CH2-N-diethyl) is an effective class III antiarrhythmic drug demonstrating potentially life-threatening organ toxicity. The principal aim of the study was to find amiodarone analogues that retained human ether-a-go-go-related protein (hERG) channel inhibition but with reduced cytotoxicity. Experimental approach: We synthesized amiodarone analogues with or without a positively ionizable nitrogen in the phenolic side chain. The cytotoxic properties of the compounds were evaluated using HepG2 (a hepatocyte cell line) and A549 cells (a pneumocyte line). Interactions of all compounds with the hERG channel were measured using pharmacological and in silico methods. Key results: Compared with amiodarone, which displayed only a weak cytotoxicity, the mono- and bis-desethylated metabolites, the further degraded alcohol (B2-O-CH2-CH2-OH), the corresponding acid (B2-O-CH2-COOH) and, finally, the newly synthesized B2-O-CH2-CH2-N-pyrrolidine were equally or more toxic. Conversely, structural analogues such as the B2-O-CH2-CH2-N-diisopropyl and the B2-O-CH2-CH2-N-piperidine were significantly less toxic than amiodarone. Cytotoxicity was associated with a drop in the mitochondrial membrane potential, suggesting mitochondrial involvement. Pharmacological and in silico investigations concerning the interactions of these compounds with the hERG channel revealed that compounds carrying a basic nitrogen in the side chain display a much higher affinity than those lacking such a group. Specifically, B2-O-CH2-CH2-N-piperidine and B2-O-CH2-CH2-N-pyrrolidine revealed a higher affinity towards hERG channels than amiodarone. Conclusions and implications: Amiodarone analogues with better hERG channel inhibition and cytotoxicity profiles than the parent compound have been identified, demonstrating that cytotoxicity and hERG channel interaction are mechanistically distinct and separable properties of the compounds. PMID:18604229

Waldhauser, K M; Brecht, K; Hebeisen, S; Ha, H R; Konrad, D; Bur, D; Krähenbühl, S




EPA Science Inventory

Among the environmental chemicals believed to have the potential to disrupt the endocrine systems of animals including humans, the polychlorinated biphenyls are a chemical class of considerable concern. Possible mechanisms by which these chemicals may interfere with endocrine fun...


Rational Design of ?-Conotoxin Analogues Targeting ?7 Nicotinic Acetylcholine Receptors  

PubMed Central

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that belong to the superfamily of Cys loop receptors. Valuable insight into the orthosteric ligand binding to nAChRs in recent years has been obtained from the crystal structures of acetylcholine-binding proteins (AChBPs) that share significant sequence homology with the amino-terminal domains of the nAChRs. ?-Conotoxins, which are isolated from the venom of carnivorous marine snails, selectively inhibit the signaling of neuronal nAChR subtypes. Co-crystal structures of ?-conotoxins in complex with AChBP show that the side chain of a highly conserved proline residue in these toxins is oriented toward the hydrophobic binding pocket in the AChBP but does not have direct interactions with this pocket. In this study, we have designed and synthesized analogues of ?-conotoxins ImI and PnIA[A10L], by introducing a range of substituents on the Pro6 residue in these toxins to probe the importance of this residue for their binding to the nAChRs. Pharmacological characterization of the toxin analogues at the ?7 nAChR shows that although polar and charged groups on Pro6 result in analogues with significantly reduced antagonistic activities, analogues with aromatic and hydrophobic substituents in the Pro6 position exhibit moderate activity at the receptor. Interestingly, introduction of a 5-(R)-phenyl substituent at Pro6 in ?-conotoxin ImI gives rise to a conotoxin analogue with a significantly higher binding affinity and antagonistic activity at the ?7 nAChR than those exhibited by the native conotoxin. PMID:19131337

Armishaw, Christopher; Jensen, Anders A.; Balle, Thomas; Clark, Richard J.; Harpsøe, Kasper; Skonberg, Christian; Liljefors, Tommy; Strømgaard, Kristian



Design and synthesis of epicocconone analogues with improved fluorescence properties.  


Epicocconone is a natural latent fluorophore that is widely used in biotechnology because of its large Stokes shift and lack of fluorescence in its unconjugated state. However, the low photostability and quantum yields of epicocconone have limited its wider use, and in the absence of a total synthesis, this limitation has been a long-standing problem. Here we report a general strategy for the synthesis of epicocconone analogues that relies on a 2-iodoxybenzoic acid-mediated dearomatization and on the replacement of the triene tail of the natural product by an aromatic ring. This design element is general and the synthesis is straightforward, providing ready access to libraries of polyfunctional fluorophores with long Stokes shifts based on the epicocconone core. Our structural modifications resulted in analogues with increased photostability and quantum yields compared with the natural product. Staining proteomic gels with these new analogues showed significant lowering of the detection limit and a 30% increase in the number of low-abundance proteins detected. These epiccoconone analogues will substantially improve the discovery rate of biomarker needles in the proteomic haystack. PMID:25271695

Peixoto, Philippe A; Boulangé, Agathe; Ball, Malcolm; Naudin, Bertrand; Alle, Thibault; Cosette, Pascal; Karuso, Peter; Franck, Xavier



The Analogue-I and the Analogue-Me: The Avatars of the Self  

Microsoft Academic Search

The analogue-I and analogue-me refer to mental self-relevant images that take a first-person vs. third-person perspective, respectively. Mental self-analogues are essential for goal setting, planning, and rehearsal of behavioral strategies, but they often fuel emotional and interpersonal problems when people react to their analogue selves as if they were real. This article examines the beneficial and detrimental consequences of the

Mark R. Leary; Marie-Joelle Estrada; Ashley Batts Allen



A structurally dynamic N-terminal helix is a key functional determinant in staphylococcal complement inhibitor (SCIN) proteins.  


Complement is a network of interacting circulatory and cell surface proteins that recognizes, marks, and facilitates clearance of microbial invaders. To evade complement attack, the pathogenic organism Staphylococcus aureus expresses a number of secreted proteins that interfere with activation and regulation of the complement cascade. Staphylococcal complement inhibitors (SCINs) are one important class of these immunomodulators and consist of three active members (SCIN-A/-B/-C). SCINs inhibit a critical enzymatic complex, the alternative pathway C3 convertase, by targeting a functional "hot spot" on the central opsonin of complement, C3b. Although N-terminal truncation mutants of SCINs retain complement inhibitory properties, they are significantly weaker binders of C3b. To provide a structural basis for this observation, we undertook a series of crystallographic and NMR dynamics studies on full-length SCINs. This work reveals that N-terminal SCIN domains are characterized by a conformationally dynamic helical motif. C3b binding and functional experiments further demonstrate that this sequence-divergent N-terminal region of SCINs is both functionally important and context-dependent. Finally, surface plasmon resonance data provide evidence for the formation of inhibitor·enzyme·substrate complexes ((SCIN·C3bBb)·C3). Similar to the (SCIN·C3bBb)(2) pseudodimeric complexes, ((SCIN·C3bBb)·C3) interferes with the interaction of complement receptors and C3b. This activity provides an additional mechanism by which SCIN couples convertase inhibition to direct blocking of phagocytosis. Together, these data suggest that tethering multi-host protein complexes by small modular bacterial inhibitors may be a global strategy of immune evasion used by S. aureus. The work presented here provides detailed structure-activity relationships and improves our understanding of how S. aureus circumvents human innate immunity. PMID:23233676

Garcia, Brandon L; Summers, Brady J; Ramyar, Kasra X; Tzekou, Apostolia; Lin, Zhuoer; Ricklin, Daniel; Lambris, John D; Laity, John H; Geisbrecht, Brian V



The Valles natural analogue project  

SciTech Connect

The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

Stockman, H.; Krumhansl, J.; Ho, C. [Sandia National Labs., Albuquerque, NM (United States); McConnell, V. [Alaska Univ., Fairbanks, AK (United States). Geophysical Inst.



Synthetic analogues of chymostatin. Inhibition of chymotrypsin and Streptomyces griseus proteinase A.  

PubMed Central

A series of analogues of chymostatin, including Z-Arg-Leu-Phe-aldehyde (Z-Arg-Leu-Phe-H), have been synthesized. Analysis of the inhibitory potential of these analogues permits identification of residues and interactions that are important for inhibitory activity. Moreover, the structure-function relationship for Z-Arg-Leu-Phe-H and chymostatin inhibition of chymotrypsin and Streptomyces griseus proteinase A (SGPA) was probed further with the aid of molecular mechanics. This analysis identified interactions that provide an explanation for the enhanced activity of the natural product, chymostatin, over the synthetic analogues in the inhibition of chymotrypsin but not SGPA. PMID:1530579

Tomkinson, N P; Galpin, I J; Beynon, R J



Structural Characterization and Computer-aided Optimization of a Small Molecule Inhibitor of Arp2/3 Complex, a Key Regulator of the Actin Cytoskeleton  

PubMed Central

CK-666 (1) is a recently discovered small molecule inhibitor of the Arp2/3 complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and motility of cancer cells. While 1 is commercially available, the crystal structure of Arp2/3 (Actin-related protein 2/3) complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off target effects in vivo, complicating interpretation of its influence in cell biological studies and precluding its use in clinical applications. Here we report the crystal structure of 1 bound to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits to stabilize the inactive conformation of the complex. Based on the crystal structure, we used computational docking and free energy perturbation calculations of monosubstituted derivatives of 1 to guide optimization efforts. Biochemical assays of ten newly synthesized compounds led to the identification of compound 2, which exhibits a 3 fold increase in inhibitory activity in vitro. In addition, our computational analyses unveiled a surface groove at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization. PMID:22623398

Baggett, Andrew W.; Cournia, Zoe; Han, Min Suk; Patargias, George; Glass, Adam C.; Liu, Shih-Yuan; Nolen, Brad J.



Contact zones and hydrothermal systems as analogues to repository conditions  

SciTech Connect

Radioactive waste isolation efforts in the US are currently focused on examining basalt, tuff, salt, and crystalline rock as candidate rock types to encompass waste repositories. As analogues to near-field conditions, the distributions of radio- and trace-elements have been examined across contacts between these rocks and dikes and stocks that have intruded them. The intensive study of the Stripa quartz monzonite has also offered the opportunity to observe the distribution of uranium and its daughters in groundwater and its relationship to U associated with fracture-filling and alteration minerals. Investigations of intrusive contact zones to date have included (1) a tertiary stock into Precambrian gneiss, (2) a stock into ash flow tuff, (3) a rhyodacite dike into Columbia River basalt, and (4) a kimberlite dike into salt. With respect to temperature and pressure, these contact zones may be considered "worst-case scenario" analogues. Results indicate that there has been no appreciable migration of radioelements from the more radioactive intrusives into the less radioactive country rocks, either in response to the intrusions or in the fracture-controlled hydrological systems that developed following emplacement. In many cases, the radioelements are locked up in accessory minerals, suggesting that artificial analogues to these would make ideal waste forms. Emphasis should now shift to examination of active hydrothermal systems, studying the distribution of key elements in water, fractures, and alteration minerals under pressure and temperature conditions most similar to those expected in the near-field environment of a repository. 14 refs.

Wollenberg, H.A.; Flexser, S.



Astrobiology Field Research in Moon/Mars Analogue Environments: Preface  

NASA Technical Reports Server (NTRS)

Extreme environments on Earth often provide similar terrain conditions to landing/operation sites on Moon and Mars. Several field campaigns (EuroGeoMars2009 and DOMMEX/ILEWG EuroMoonMars from November 2009 to March 2010) were conducted at the Mars Desert Research Station (MDRS) in Utah. Some of the key astrobiology results are presented in this special issue on Astrobiology field research in Moon/Mars analogue environments relevant to investigate the link between geology, minerals, organics and biota. Preliminary results from a multidisciplinary field campaign at Rio Tinto in Spain are presented.

Foing, B. H.; Stoker, C.; Ehrenfreund, P.



Design, synthesis and biological evaluation of bridged epothilone D analogues  

PubMed Central

Six epothilone D analogues with a bridge between the C4-methyl and the C12-methyl carbons were prepared in an attempt to constrain epothilone D to its proposed tubulin-binding conformation. Ring-closing metathesis (RCM) was employed as the key step to build the C4-C26 bridge. In antiproliferative assays in the human ovarian cancer (A2780) and prostate cancer (PC3) cell lines, and also in tubulin assembly assay, all these compounds proved to be less active than epothilone D. PMID:19039362

Chen, Qiao-Hong; Ganesh, Thota; Brodie, Peggy; Slebodnick, Carla; Jiang, Yi; Banerjee, Abhijit; Bane, Susan; Snyder, James P.



Insulin analogues: fears, facts and fantasies  

Microsoft Academic Search

IGF-1 and insulin, acting through both IGF-1 and insulin receptors, have been studied widely to evaluate their oncogenic and teratogenic properties. These two properties need to be studied for each new insulin analogue, in addition to measurements of their metabolic and pharmacodynamic features. This editorial critiques a study in this issue of the journal of several insulin analogues in their

Renzo Cordera; Barbara Salani; Lucia Briatore



CO2 Capture with Enzyme Synthetic Analogue  

SciTech Connect

Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

Harry Cordatos



Antifouling Activity of Bromotyrosine-Derived Sponge Metabolites and Synthetic Analogues  

Microsoft Academic Search

Eighteen brominated sponge-derived metabolites and synthetic analogues were analyzed for antilarval settlement of Balanus improvisus. Only compounds exhibiting oxime substituents including bastadin-3 (4), ?4 (1), ?9 (2), and ?16 (3), hemibastadin-1 (6), aplysamine-2 (5), and psammaplin A (10) turned out to inhibit larval settling at 1 to 10 ?M. Analogues of hemibastadin-1 (6) were synthesized and tested for structure activity studies.

Sofia Ortlepp; Martin Sjögren; Mia Dahlström; Horst Weber; Rainer Ebel; RuAngelie Edrada; Carsten Thoms; Peter Schupp; Lars Bohlin; Peter Proksch



Volume 8 (2007), Issue 3, Article 65, 5 pp. ON INEQUALITIES FOR HYPERGEOMETRIC ANALOGUES OF THE  

E-print Network

OF THE ARITHMETIC-GEOMETRIC MEAN ROGER W. BARNARD AND KENDALL C. RICHARDS TEXAS TECH UNIVERSITY LUBBOCK, TEXAS 79409 present sharp inequalities relating hypergeometric analogues of the arithmetic-geometric mean discussed for the arithmetic-geometric mean established in [10]. Key words and phrases: Arithmetic-geometric mean

Barnard, Roger


Comparative transport efficiencies of urea analogues through urea transporter UT-B.  


Expression of urea transporter UT-B confers high urea permeability to mammalian erythrocytes. Erythrocyte membranes also permeate various urea analogues, suggesting common transport pathways for urea and structurally similar solutes. In this study, we examined UT-B-facilitated passage of urea analogues and other neutral small solutes by comparing transport properties of wildtype to UT-B-deficient mouse erythrocytes. Stopped-flow light-scattering measurements indicated high UT-B permeability to urea and chemical analogues formamide, acetamide, methylurea, methylformamide, ammonium carbamate, and acrylamide, each with P(s)>5.0 x 10(-6) cm/s at 10 degrees C. UT-B genetic knockout and phloretin treatment of wildtype erythrocytes similarly reduced urea analogue permeabilities. Strong temperature dependencies of formamide, acetamide, acrylamide and butyramide transport across UT-B-null membranes (E(a)>10 kcal/mol) suggested efficient diffusion of these amides across lipid bilayers. Urea analogues dimethylurea, acryalmide, methylurea, thiourea and methylformamide inhibited UT-B-mediated urea transport by >60% in the absence of transmembrane analogue gradients, supporting a pore-blocking mechanism of UT-B inhibition. Differential transport efficiencies of urea and its analogues through UT-B provide insight into chemical interactions between neutral solutes and the UT-B pore. PMID:17506977

Zhao, Dan; Sonawane, N D; Levin, Marc H; Yang, Baoxue



Identification of key structural elements for neuronal calcium sensor-1 function in the regulation of the temperature-dependency of locomotion in C. elegans  

PubMed Central

Background Intracellular Ca2+ regulates many aspects of neuronal function through Ca2+ binding to EF hand-containing Ca2+ sensors that in turn bind target proteins to regulate their function. Amongst the sensors are the neuronal calcium sensor (NCS) family of proteins that are involved in multiple neuronal signalling pathways. Each NCS protein has specific and overlapping targets and physiological functions and specificity is likely to be determined by structural features within the proteins. Common to the NCS proteins is the exposure of a hydrophobic groove, allowing target binding in the Ca2+-loaded form. Structural analysis of NCS protein complexes with target peptides has indicated common and distinct aspects of target protein interaction. Two key differences between NCS proteins are the size of the hydrophobic groove that is exposed for interaction and the role of their non-conserved C-terminal tails. Results We characterised the role of NCS-1 in a temperature-dependent locomotion assay in C. elegans and identified a distinct phenotype in the ncs-1 null in which the worms do not show reduced locomotion at actually elevated temperature. Using rescue of this phenotype we showed that NCS-1 functions in AIY neurons. Structure/function analysis introducing single or double mutations within the hydrophobic groove based on information from characterised target complexes established that both N- and C-terminal pockets of the groove are functionally important and that deletion of the C-terminal tail of NCS-1 did not impair its ability to rescue. Conclusions The current work has allowed physiological assessment of suggestions from structural studies on the key structural features that underlie the interaction of NCS-1 with its target proteins. The results are consistent with the notion that full length of the hydrophobic groove is required for the regulatory interactions underlying NCS-1 function whereas the C-terminal tail of NCS-1 is not essential. This has allowed discrimination between two potential modes of interaction of NCS-1 with its targets. PMID:23981466



Ungeremine and Its hemisynthesized analogues as bactericides against Flavobacterium columnare.  


The Gram-negative bacterium Flavobacterium columnare is the cause of columnaris disease, which can occur in channel catfish ( Ictalurus punctatus ). In a previous study, the betaine-type alkaloid ungeremine, 1, obtained from Pancratium maritimum L. was found to have strong antibacterial activity against F. columnare. In this study, analogues of 1 were evaluated using a rapid bioassay for activity against F. columnare to determine if the analogues might provide greater antibacterial activity and to determine structure-activity relationships of the test compounds. Several ungeremine analogues were prepared by hydrochlorination of the alkaloid and by selenium dioxide oxidation of both lycorine, 7, and pseudolycorine, 8, which yielded the isomer of ungeremine, 3, and zefbetaine, 4, respectively. The treatment of lycorine with phosphorus oxychloride allowed the synthesis of an anhydrolycorine lactam, 5, showing, with respect to 1, the deoxygenation and oxygenation of C-2 and C-7 of the C and B rings, respectively. The results of the structure-activity relationship studies showed that the aromatization of the C ring and the oxidation to an azomethine group of C-7 of the B ring are structural features important for antibacterial activity. In addition, the position of the oxygenation of the C ring as well as the presence of the 1,3-dioxole ring joined to the A ring of the pyrrolo[de]phenanthridine skeleton also plays a significant role in imparting antibacterial activity. On the basis of 24-h 50% inhibition concentration (IC(50)) results, ungeremine hydrochloride, 2, was similar in toxicity to 1, whereas 5 had the lowest activity. Analogue 2 is soluble in water, which may provide the benefit for use as an effective feed additive or therapeutant compared to ungeremine. PMID:23331165

Schrader, Kevin K; Avolio, Fabiana; Andolfi, Anna; Cimmino, Alessio; Evidente, Antonio



Analogue Transformations in Physics and their Application to Acoustics  

PubMed Central

Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an “analogue transformation acoustics” formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft. PMID:23774575

García-Meca, C.; Carloni, S.; Barceló, C.; Jannes, G.; Sánchez-Dehesa, J.; Martínez, A.



Synthesis and evaluation of electron-rich curcumin analogues  

PubMed Central

The natural product curcumin has long been recognized for its medicinal properties and is utilized for the treatment of many diseases. However, it remains unknown whether this activity is based on its presumably promiscuous scaffold, or if it results from the Michael acceptor properties of the ?,?-unsaturated 1,3-diketone moiety central to its structure. To probe this issue, electron-rich pyrazole and isoxazole analogues were prepared and evaluated against two breast cancer cell lines, which resulted in the identification of several compounds that exhibit low micromolar to mid nanomolar anti-proliferative activity. A conjugate addition study was also performed to compare the relative electrophilicity of the diketone, pyrazole and isoxazole analogues. PMID:19019687

Amolins, Michael W.; Peterson, Laura B.; Blagg, Brian S. J.



Somatostatin analogue treatment of neuroendocrine tumours.  

PubMed Central

The long-acting analogues of somatostatin have an established place in the medical treatment of patients with neuroendocrine tumours. They act through binding with specific, high-affinity membrane receptors. Somatostatin analogue therapy is an effective and safe treatment for most growth hormone and thyrothropin-secreting pituitary adenomas. The potential therapeutic consequences of the presence of somatostatin receptors on clinically 'nonfunctioning' pituitary tumours are still uncertain. Somatostatin analogues are not useful in the treatment of patients with prolactinomas, or adrenocorticotropin (ACTH)-secreting adenomas. However, the somatostatin analogue octreotide suppressed pathological ACTH release in some patients with Nelson's syndrome and ACTH and cortisol secretion in several patients with Cushing's syndrome caused by ectopic ACTH secretion. Somatostatin analogues are effective in the sympatomatic treatment of most (metastatic) pancreatic islet cell tumours and most (metastatic) carcinoids. In some of these patients, they also induce tumour stabilisation or reduction. In some patients with (metastatic) medullary thyroid carcinomas, continuous treatment with very high doses of octreotide can be of temporary relief. The clinical effectiveness of somatostatin analogues in patients with small cell lung cancer is currently under investigation. Long-term therapy with somatostatin analogues of catecholamine-secreting (malignant) paragangliomas and phaeochromocytomas has not shown clinical benefits. PMID:8935599

de Herder, W. W.; van der Lely, A. J.; Lamberts, S. W.



Synthesis and insecticidal activity of new deoxypodophyllotoxin-based phenazine analogues against Mythimna separata Walker.  


In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, a series of new deoxypodophyllotoxin-based phenazine analogues modified in their E-ring were prepared, and their structures were well characterized by ¹H NMR, HRMS, ESI-MS, IR, optical rotation, and mp. The absolute steric configuration of one key isomer was unambiguously confirmed by X-ray crystallography. Their insecticidal activity was examined against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at the concentration of 1 mg/mL. All derivatives showed delayed insecticidal activity. Especially compound 9i, containing p-methoxybenzoylamnio at the C-9' position of deoxypodophyllotoxin-based phenazine fragment, exhibited the most promising insecticidal activity with the final mortality rate of 72.4%. According to the symptoms of the tested M. separata, the derivatives likely displayed an antimolting hormone effect. In addition, preliminary structure-activity relationships were observed. These suggested that the proper length of the side chain of alkylacylamino might be important for their insecticidal activity, and introduction of the acylamino groups at the C-9' position of deoxypodophyllotoxin-based phenazine fragment usually afforded more potent compounds than those containing the same ones at the C-10' position. This will pave the way for further design, structural modification, and development of deoxypodophyllotoxin-based derivatives as insecticidal agents. PMID:23756712

Wang, Juanjuan; Zhi, Xiaoyan; Yu, Xiang; Xu, Hui



Plant volatile analogues strengthen attractiveness to insect.  


Green leaf bug Apolygus lucorum (Meyer-Dür) is one of the major pests in agriculture. Management of A. lucorum was largely achieved by using pesticides. However, the increasing population of A. lucorum since growing Bt cotton widely and the increased awareness of ecoenvironment and agricultural product safety makes their population-control very challenging. Therefore this study was conducted to explore a novel ecological approach, synthetic plant volatile analogues, to manage the pest. Here, plant volatile analogues were first designed and synthesized by combining the bioactive components of ?-ionone and benzaldehyde. The stabilities of ?-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than ?-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than ?-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

Sun, Yufeng; Yu, Hao; Zhou, Jing-Jiang; Pickett, John A; Wu, Kongming



Key-Insulated Public Key Cryptosystems  

Microsoft Academic Search

Cryptographic computations (decryption, signature generation, etc.) are often performed on a relatively insecure device (e.g., a mobile device or an Internet-connected host) which cannot be trusted to maintain secrecy of the pri- vate key. We propose and investigate the notion of key-insulated security whose goal is to minimize the damage caused by secret-key exposures. In our model, the secret key(s)

Yevgeniy Dodis; Jonathan Katz; Shouhuai Xu; Moti Yung



Phosphonomethyl analogues of phosphate ester glycolytic intermediates  

PubMed Central

Analogues of dihydroxyacetone phosphate and of 3-phosphoglycerate were made in which the phosphate group, –O–PO3H2, is replaced by the phosphonomethyl group, –CH2–PO3H2. The analogue of dihydroxyacetone phosphate is a substrate for aldolase and glycerol 1-phosphate dehydrogenase (Stribling, 1974), but not for triose phosphate isomerase. The analogue of 3-phosphoglycerate oxidizes NADH under the combined action of 3-phosphoglycerate kinase and glyceraldehyde 3-phosphate dehydrogenase if ATP is added. Thus four out of the five glycolytic enzymes tested handle the phosphonomethyl compounds like the natural phosphates. PMID:4377103

Dixon, Henry B. F.; Sparkes, Michael J.



Structural requirements for recognition of the HLA-Dw14 class II epitope: A key HLA determinant associated with rheumatoid arthritis  

SciTech Connect

Although HLA genes have been shown to be associated with certain diseases, the basis for this association is unknown. Recent studies, however, have documented patterns of nucleotide sequence variation among some HLA genes associated with a particular disease. For rheumatoid arthritis, HLA genes in most patients have a shared nucleotide sequence encoding a key structural element of an HLA class II polypeptide; this sequence element is critical for the interaction of the HLA molecule with antigenic peptides and with responding T cells, suggestive of a direct role for this sequence element in disease susceptibility. The authors describe the serological and cellular immunologic characteristics encoded by this rheumatoid arthritis-associated sequence element. Site-directed mutagenesis of the DRB1 gene was used to define amino acids critical for antibody and T-cell recognition of this structural element, focusing on residues that distinguish the rheumatoid arthritis-associated alleles Dw4 and Dw14 from a closely related allele, Dw10, not associated with disease. Both the gain and loss of rheumatoid arthritis-associated epitopes were highly dependent on three residues within a discrete domain of the HLA-DR molecule. Recognition was most strongly influenced by the following amino acids (in order): 70 > 71 > 67. Some alloreactive T-cell clones were also influenced by amino acid variation in portions of the DR molecule lying outside the shared sequence element.

Hiraiwa, Akikazu; Yamanaka, Katsuo; Kwok, W.W.; Nepom, G.T. (Virginia Mason Research Center, Seattle, WA (USA)); Mickelson, E.M.; Masewicz, S.; Hansen, J.A. (Fred Hutchinson Cancer Research Center, Seattle, WA (USA)); Radka, S.F. (Oncogen Corporation, Seattle, WA (USA))



Synthesis and evaluation of amide side-chain modified Agomelatine analogues as potential antidepressant-like agents.  


In this work, nineteen analogues of Agomelatine were readily synthesized through structural modification of the acetamide side-chain starting from the key common intermediate 2-(7-methoxynaphthalen-1-yl) ethanamine (3), which was prepared from commercially available compound 2-(7-methoxynaphthalen-1-yl) acetonitrile (2) in two steps. Corticosterone-induced PC12 pheochromocytoma cells phenotypic in vitro model was utilized to evaluate their potential antidepression activities. Imide compound 4a and acylamino carboxylic acid analogue 5b showed good protective effects on traumatic PC12 cells with protection rates of 34.2% and 23.2%, respectively. Further in vivo assessments in C57 mice FST (forced swim test) model demonstrated that compound 4a significantly reduced the immobility time of the tested subjects, indicating antidepressant-like activity. Preliminary toxicity assays conducted on human normal liver L02 cells and embryonic kidney 293 cells suggested a relatively low safety risk for compound 4a compared with the marketed drugs Agomelatine and Fluoxetine. The promising antidepressant-like efficacy of compound 4a, together with the relatively low toxicity to the normal tested cells and high liability of diffusion through the blood-brain barrier (BBB), presents us insights of exploration of me-better drug candidates of Agomelatine. PMID:24631187

Chang, Ying; Pi, Weiyi; Ang, Wei; Liu, Yuanyuan; Li, Chunlong; Zheng, Jiajia; Xiong, Li; Yang, Tao; Luo, Youfu



Space analogue studies in Antarctica  

NASA Astrophysics Data System (ADS)

Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mltogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

Lugg, D.; Shepanek, M.



Space analogue studies in Antarctica  

NASA Technical Reports Server (NTRS)

Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

Lugg, D.; Shepanek, M.



Metal oxide analogue of metal alloy catalysts  

NASA Astrophysics Data System (ADS)

Because of ion size, valence and oxide structure, hafnium and zirconium mixed oxide catalysts are ideal for study as a metal alloy analogue. Furthermore, hafnium oxide and zirconium oxide exhibit quite different selectivity for the conversion of 2-alcohols to alkene products. The alkene selectivity changed abruptly from that of pure HfO 2 to that of pure ZrO 2 at a composition with ca. 90 mol% Zr. Characterization of the catalysts by ESCA, Auger, and ISS spectroscopy show that the surface composition is very similar to the bulk composition and, thus, changes uniformly throughout the composition range rather than abruptly as does the alkene selectivity. Pure ZrO 2 impregnated with Hf to produce catalysts with the full range of Hf-Zr surface compositions showed a catalytic selectivity that paralleled the selectivity of the bulk composition catalysts. Zr or Th impregnated onto alumina serve as catalyst poisons; however, these two metals alter the selectivity in a quite different manner. The data indicate that the catalytic selectivity of these mixed oxide catalysts is determined by ligand, rather than bulk electronic, effects.

Davis, Burtron H.



Noble gas encapsulation: clathrate hydrates and their HF doped analogues.  


The significance of clathrate hydrates lies in their ability to encapsulate a vast range of inert gases. Although the natural abundance of a few noble gases (Kr and Xe) is poor their hydrates are generally abundant. It has already been reported that HF doping enhances the stability of hydrogen hydrates and methane hydrates, which prompted us to perform a model study on helium, neon and argon hydrates with their HF doped analogues. For this purpose 5(12), 5(12)6(8) and their HF doped analogues are taken as the model clathrate hydrates, which are among the building blocks of sI, sII and sH types of clathrate hydrate crystals. We use the dispersion corrected and gradient corrected hybrid density functional theory for the calculation of thermodynamic parameters as well as conceptual density functional theory based reactivity descriptors. The method of the ab initio molecular dynamics (AIMD) simulation is used through atom centered density matrix propagation (ADMP) techniques to envisage the structural behaviour of different noble gas hydrates on a 500 fs timescale. Electron density analysis is carried out to understand the nature of Ng-OH2, Ng-FH and Ng-Ng interactions. The current results noticeably demonstrate that the noble gas (He, Ne, and Ar) encapsulation ability of 5(12), 5(12)6(8) and their HF doped analogues is thermodynamically favourable. PMID:25047071

Mondal, Sukanta; Chattaraj, Pratim Kumar



Lobatamide C: total synthesis, stereochemical assignment, preparation of simplified analogues, and V-ATPase inhibition studies.  


The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues. A key fragment coupling employs base-mediated esterification of a beta-hydroxy acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C, stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity. PMID:12823009

Shen, Ruichao; Lin, Cheng Ting; Bowman, Emma Jean; Bowman, Barry J; Porco, John A



A photoactive isoprenoid diphosphate analogue containing a stable phosphonate linkage: synthesis and biochemical studies with prenyltransferases  

PubMed Central

A number of biochemical processes rely on isoprenoids, including the post-translational modification of signaling proteins and the biosynthesis of a wide array of compounds. Photoactivatable analogues have been developed to study isoprenoid utilizing enzymes such as the isoprenoid synthases and prenyltransferases. While these initial analogues proved to be excellent structural analogues with good cross linking capability, they lack the stability needed when the goals include isolation of cross-linked species, tryptic digestion, and subsequent peptide sequencing. Here, the synthesis of a benzophenone-based farnesyl diphosphate analogue containing a stable phosphonophosphate group is described. Inhibition kinetics, photolabeling experiments, as well as x-ray crystallographic analysis with a protein prenyltransferase are described, verifying this compound as a good isoprenoid mimetic. In addition, the utility of this new analogue was explored by using it to photoaffinity label crude protein extracts obtained from Hevea brasiliensis latex. Those experiments suggest that a small protein, Rubber Elongation Factor, interacts directly with farnesyl diphosphate during rubber biosynthesis. These results indicate that this benzophenone-based isoprenoid analogue will be useful for identifying enzymes that utilize farnesyl diphosphate as a substrate. PMID:17477573

DeGraw, Amanda J.; Zhao, Zongbao; Strickland, Corey L.; Taban, A. Huma; Hsieh, John; Michael, Jefferies; Xie, Wenshuang; Shintani, David; McMahan, Colleen; Cornish, Katrina; Distefano, Mark D.



Review of Current State of the Art and Key Design Issues With Potential Solutions for Liquid Hydrogen Cryogenic Storage Tank Structures for Aircraft Applications  

NASA Technical Reports Server (NTRS)

Due to its high specific energy content, liquid hydrogen (LH2) is emerging as an alternative fuel for future aircraft. As a result, there is a need for hydrogen tank storage systems, for these aircraft applications, that are expected to provide sufficient capacity for flight durations ranging from a few minutes to several days. It is understood that the development of a large, lightweight, reusable cryogenic liquid storage tank is crucial to meet the goals of and supply power to hydrogen-fueled aircraft, especially for long flight durations. This report provides an annotated review (including the results of an extensive literature review) of the current state of the art of cryogenic tank materials, structural designs, and insulation systems along with the identification of key challenges with the intent of developing a lightweight and long-term storage system for LH2. The broad classes of insulation systems reviewed include foams (including advanced aerogels) and multilayer insulation (MLI) systems with vacuum. The MLI systems show promise for long-term applications. Structural configurations evaluated include single- and double-wall constructions, including sandwich construction. Potential wall material candidates are monolithic metals as well as polymer matrix composites and discontinuously reinforced metal matrix composites. For short-duration flight applications, simple tank designs may suffice. Alternatively, for longer duration flight applications, a double-wall construction with a vacuum-based insulation system appears to be the most optimum design. The current trends in liner material development are reviewed in the case that a liner is required to minimize or eliminate the loss of hydrogen fuel through permeation.

Mital, Subodh K.; Gyekenyesi, John Z.; Arnold, Steven M.; Sullivan, Roy M.; Manderscheid, Jane M.; Murthy, Pappu L. N.



Chemical Synthesis and Molecular Recognition of Phosphatase-Resistant Analogues of Phosphatidylinositol-3-phosphate  

PubMed Central

The remodeling of phosphatidylinositol polyphosphates in cellular membranes by phosphatases and kinases orchestrates the signaling by these lipids in space and time. In order to provide chemical tools to study of the changes in cell physiology mediated by these lipids, three new metabolically-stabilized (ms) analogues of phosphatidylinositol-3-phosphate (PtdIns(3)P were synthesized. We describe herein the total asymmetric synthesis of 3-methylphosphonate, 3-monofluoromethylphosphonate and 3-phosphorothioate analogues of PtdIns(3)P. From differentially protected D-myo-inositol key intermediates, a versatile phosphoramidite reagent was employed in the synthesis of PtdIns(3)P analogues with diacylglyceryl moieties containing dioleoyl, dipalmitoyl and dibutyryl chains. In addition, we introduce a new phosphorlyation reagent, monofluoromethylphosphonyl chloride, which has general applications for the preparation of “pKa-matched” monofluorophosphonates. These ms-PtdIns(3)P analogues exhibited reduced binding activities with 15N-labelled FYVE and PX domains, as significant 1H and 15N chemical shift changes in the FYVE domain were induced by titrating ms-PtdIns(3)Ps into membrane-mimetic dodecylphosphocholine (DPC) micelles. In addition, the PtdIns(3)P analogues with dioleyl and dipalmitoyl chains were substrates for the 5-kinase enzyme PIKfyve; the corresponding phosphorylated ms-PI(3,5)P2 products were detected by radio-TLC analysis. PMID:16417379

Xu, Yong; Lee, Stephanie A.; Kutateladze, Tatiana G.; Sbrissa, Diego; Shisheva, Assia; Prestwich, Glenn D.



Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications.  


Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with ?,?-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design. PMID:25431858

Maderna, Andreas; Doroski, Matthew; Subramanyam, Chakrapani; Porte, Alexander; Leverett, Carolyn A; Vetelino, Beth C; Chen, Zecheng; Risley, Hud; Parris, Kevin; Pandit, Jayvardhan; Varghese, Alison H; Shanker, Suman; Song, Cynthia; Sukuru, Sai Chetan K; Farley, Kathleen A; Wagenaar, Melissa M; Shapiro, Michael J; Musto, Sylvia; Lam, My-Hanh; Loganzo, Frank; O'Donnell, Christopher J




ERIC Educational Resources Information Center

Provided is an overview of the analytical method known as structuralism. The first chapter discusses the three key components of the concept of a structure: the view of a system as a whole instead of so many parts; the study of the transformations in the system; and the fact that these transformations never lead beyond the system but always…

Piaget, Jean


Micelles of poly(ethylene oxide)-block-poly(N-alkyl stearate L-aspartamide): synthetic analogues of lipoproteins for drug delivery.  


Stearic acid esters of poly(ethylene oxide)-block-poly(hydroxyethyl L-aspartamide) and poly(ethylene oxide)-block-poly(hydroxyhexyl L-aspartamide) have been synthesized from poly(ethylene oxide)-block-poly(beta-benzyl L-aspartate) by polymer-analogous reactions and self-assembled into a micelle. Transmission electron microscopy and fluorescent probe studies reveal that the micelle mimics structural features of serum lipoproteins: it is nanoscopic, spherical, and has a supramolecular core-shell architecture, where the core is rich in fatty acid esters. As a result, the polymeric micelles effectively solubilize amphotericin B, a key drug for systemic mycoses. Serum lipoproteins solubilize many hydrophobic drugs as a biological transport system besides amphotericin B. A synthetic polymeric analogue may achieve the same aim, but with the ease of structural modification, safety, and stability. PMID:11033567

Lavasanifar, A; Samuel, J; Kwon, G S



Excited state properties of a short ?-electron conjugated peridinin analogue  

NASA Astrophysics Data System (ADS)

C29-peridinin is a synthetic analogue of the important, naturally-occurring carotenoid, peridinin, found in several marine algal species. C29-peridinin has five conjugated carbon-carbon double bonds compared to eight possessed by peridinin and also lacks the methyl group functionalities typically present along the polyene chain of carotenoids. These structural modifications lead to unique excited state properties and important insights regarding the factors controlling the photophysics of peridinin and other carbonyl-containing carotenoids, which are critical components of the light-harvesting systems of many photosynthetic organisms.

Magdaong, Nikki M.; Niedzwiedzki, Dariusz M.; Greco, Jordan A.; Liu, Hongbin; Yano, Koki; Kajikawa, Takayuki; Sakaguchi, Kazuhiko; Katsumura, Shigeo; Birge, Robert R.; Frank, Harry A.



Excited state properties of a short ?-electron conjugated peridinin analogue.  


C29-peridinin is a synthetic analogue of the important, naturally-occurring carotenoid, peridinin, found in several marine algal species. C29-peridinin has five conjugated carbon-carbon double bonds compared to eight possessed by peridinin and also lacks the methyl group functionalities typically present along the polyene chain of carotenoids. These structural modifications lead to unique excited state properties and important insights regarding the factors controlling the photophysics of peridinin and other carbonyl-containing carotenoids, which are critical components of the light-harvesting systems of many photosynthetic organisms. PMID:24678069

Magdaong, Nikki M; Niedzwiedzki, Dariusz M; Greco, Jordan A; Liu, Hongbin; Yano, Koki; Kajikawa, Takayuki; Sakaguchi, Kazuhiko; Katsumura, Shigeo; Birge, Robert R; Frank, Harry A



Synthesis, preliminary bioevaluation and computational analysis of caffeic acid analogues.  


A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO) generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for further structural optimization. Moreover, predication of the potential targets was also carried out by the PharmMapper server. These amide analogues represent a promising class of anti-inflammatory scaffold for further exploration and target identification. PMID:24857914

Liu, Zhiqian; Fu, Jianjun; Shan, Lei; Sun, Qingyan; Zhang, Weidong



Synthesis, Preliminary Bioevaluation and Computational Analysis of Caffeic Acid Analogues  

PubMed Central

A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO) generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for further structural optimization. Moreover, predication of the potential targets was also carried out by the PharmMapper server. These amide analogues represent a promising class of anti-inflammatory scaffold for further exploration and target identification. PMID:24857914

Liu, Zhiqian; Fu, Jianjun; Shan, Lei; Sun, Qingyan; Zhang, Weidong



Chalcogen-bonded complexes of some carbon dioxide analogues  

NASA Astrophysics Data System (ADS)

Ab initio calculations have been carried out on the sulphur-bonded van der Waals complexes formed between the carbon dioxide analogues carbonyl sulphide, carbon disulphide and thiocarbonyl selenide, and the common electron donors ammonia, water, phosphine and hydrogen sulphide. The structures of these twelve complexes are all similar, and involve an approximately linear XCS⋯Y fragment (X = O, S, Se; Y = N, O, P, S). These structures contrast with those of the oxygen-bound complexes of carbon dioxide, carbonyl sulphide and carbonyl selenide reported earlier which, with the exception of the hydrogen sulphide species, are characterized by four-membered rings with varying orientations involving the C, O, H and Y atoms. The molecular structures, interaction energies and vibrational spectra have been studied, and the variations in these properties have been correlated with the complex structures and with the molecular quadrupole moments of the acid monomers.

Ramasami, Ponnadurai; Ford, Thomas A.



Structure of Transmembrane Domain of Lysosome-associated Membrane Protein Type 2a (LAMP-2A) Reveals Key Features for Substrate Specificity in Chaperone-mediated Autophagy.  


Chaperone-mediated autophagy (CMA) is a highly regulated cellular process that mediates the degradation of a selective subset of cytosolic proteins in lysosomes. Increasing CMA activity is one way for a cell to respond to stress, and it leads to enhanced turnover of non-critical cytosolic proteins into sources of energy or clearance of unwanted or damaged proteins from the cytosol. The lysosome-associated membrane protein type 2a (LAMP-2A) together with a complex of chaperones and co-chaperones are key regulators of CMA. LAMP-2A is a transmembrane protein component for protein translocation to the lysosome. Here we present a study of the structure and dynamics of the transmembrane domain of human LAMP-2A in n-dodecylphosphocholine micelles by nuclear magnetic resonance (NMR). We showed that LAMP-2A exists as a homotrimer in which the membrane-spanning helices wrap around each other to form a parallel coiled coil conformation, whereas its cytosolic tail is flexible and exposed to the cytosol. This cytosolic tail of LAMP-2A interacts with chaperone Hsc70 and a CMA substrate RNase A with comparable affinity but not with Hsp40 and RNase S peptide. Because the substrates and the chaperone complex can bind at the same time, thus creating a bimodal interaction, we propose that substrate recognition by chaperones and targeting to the lysosomal membrane by LAMP-2A are coupled. This can increase substrate affinity and specificity as well as prevent substrate aggregation, assist in the unfolding of the substrate, and promote the formation of the higher order complex of LAMP-2A required for translocation. PMID:25342746

Rout, Ashok K; Strub, Marie-Paule; Piszczek, Grzegorz; Tjandra, Nico



Structural Basis for the Enzymatic Formation of the Key Strawberry Flavor Compound 4-Hydroxy-2,5-dimethyl-3(2H)-furanone  

PubMed Central

The last step in the biosynthetic route to the key strawberry flavor compound 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) is catalyzed by Fragaria x ananassa enone oxidoreductase (FaEO), earlier putatively assigned as quinone oxidoreductase (FaQR). The ripening-induced enzyme catalyzes the reduction of the exocyclic double bond of the highly reactive precursor 4-hydroxy-5-methyl-2-methylene-3(2H)-furanone (HMMF) in a NAD(P)H-dependent manner. To elucidate the molecular mechanism of this peculiar reaction, we determined the crystal structure of FaEO in six different states or complexes at resolutions of ?1.6 ?, including those with HDMF as well as three distinct substrate analogs. Our crystallographic analysis revealed a monomeric enzyme whose active site is largely determined by the bound NAD(P)H cofactor, which is embedded in a Rossmann-fold. Considering that the quasi-symmetric enolic reaction product HDMF is prone to extensive tautomerization, whereas its precursor HMMF is chemically labile in aqueous solution, we used the asymmetric and more stable surrogate product 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone (EHMF) and the corresponding substrate (2E)-ethylidene-4-hydroxy-5-methyl-3(2H)-furanone (EDHMF) to study their enzyme complexes as well. Together with deuterium-labeling experiments of EDHMF reduction by [4R-2H]NADH and chiral-phase analysis of the reaction product EHMF, our data show that the 4R-hydride of NAD(P)H is transferred to the unsaturated exocyclic C6 carbon of HMMF, resulting in a cyclic achiral enolate intermediate that subsequently becomes protonated, eventually leading to HDMF. Apart from elucidating this important reaction of the plant secondary metabolism our study provides a foundation for protein engineering of enone oxidoreductases and their application in biocatalytic processes. PMID:23589283

Schiefner, André; Sinz, Quirin; Neumaier, Irmgard; Schwab, Wilfried; Skerra, Arne



A positive Grassmannian analogue of the permutohedron  

E-print Network

The classical permutohedron Perm is the convex hull of the points (w(1),...,w(n)) in R^n where w ranges over all permutations in the symmetric group. This polytope has many beautiful properties -- for example it provides a way to visualize the weak Bruhat order: if we orient the permutohedron so that the longest permutation w_0 is at the "top" and the identity e is at the "bottom," then the one-skeleton of Perm is the Hasse diagram of the weak Bruhat order. Equivalently, the paths from e to w_0 along the edges of Perm are in bijection with the reduced decompositions of w_0. Moreover, the two-dimensional faces of the permutohedron correspond to braid and commuting moves, which by the Tits Lemma, connect any two reduced expressions of w_0. In this note we introduce some polytopes Br(k,n) (which we call bridge polytopes) which provide a positive Grassmannian analogue of the permutohedron. In this setting, BCFW bridge decompositions of reduced plabic graphs play the role of reduced decompositions. We define Br(k,n) and explain how paths along its edges encode BCFW bridge decompositions of the longest element pi(k,n) in the circular Bruhat order. We also show that two-dimensional faces of Br(k,n) correspond to certain local moves for plabic graphs, which by a result of Postnikov [Pos06], connect any two reduced plabic graphs associated to pi(k,n). All of these results can be generalized to the positive parts of Schubert cells. A useful tool in our proofs is the fact that our polytopes are isomorphic to certain Bruhat interval polytopes. Conversely, our results on bridge polytopes allow us to deduce some corollaries about the structure of Bruhat interval polytopes.

Lauren K. Williams



Quantitative comparisons of analogue models of brittle wedge dynamics  

NASA Astrophysics Data System (ADS)

Analogue model experiments are widely used to gain insights into the evolution of geological structures. In this study, we present a direct comparison of experimental results of 14 analogue modelling laboratories using prescribed set-ups. A quantitative analysis of the results will document the variability among models and will allow an appraisal of reproducibility and limits of interpretation. This has direct implications for comparisons between structures in analogue models and natural field examples. All laboratories used the same frictional analogue materials (quartz and corundum sand) and prescribed model-building techniques (sieving and levelling). Although each laboratory used its own experimental apparatus, the same type of self-adhesive foil was used to cover the base and all the walls of the experimental apparatus in order to guarantee identical boundary conditions (i.e. identical shear stresses at the base and walls). Three experimental set-ups using only brittle frictional materials were examined. In each of the three set-ups the model was shortened by a vertical wall, which moved with respect to the fixed base and the three remaining sidewalls. The minimum width of the model (dimension parallel to mobile wall) was also prescribed. In the first experimental set-up, a quartz sand wedge with a surface slope of ˜20° was pushed by a mobile wall. All models conformed to the critical taper theory, maintained a stable surface slope and did not show internal deformation. In the next two experimental set-ups, a horizontal sand pack consisting of alternating quartz sand and corundum sand layers was shortened from one side by the mobile wall. In one of the set-ups a thin rigid sheet covered part of the model base and was attached to the mobile wall (i.e. a basal velocity discontinuity distant from the mobile wall). In the other set-up a basal rigid sheet was absent and the basal velocity discontinuity was located at the mobile wall. In both types of experiments, models accommodated initial shortening by a forward- and a backward-verging thrust. Further shortening was taken up by in-sequence formation of forward-verging thrusts. In all experiments, boundary stresses created significant drag of structures along the sidewalls. We therefore compared the surface slope and the location, dip angle and spacing of thrusts in sections through the central part of the model. All models show very similar cross-sectional evolutions demonstrating reproducibility of first-order experimental observations. Nevertheless, there are significant along-strike variations of structures in map view highlighting the limits of interpretations of analogue model results. These variations may be related to the human factor, differences in model width and/or differences in laboratory temperature and especially humidity affecting the mechanical properties of the granular materials. GeoMod2008 Analogue Team: Susanne Buiter, Caroline Burberry, Jean-Paul Callot, Cristian Cavozzi, Mariano Cerca, Ernesto Cristallini, Alexander Cruden, Jian-Hong Chen, Leonardo Cruz, Jean-Marc Daniel, Victor H. Garcia, Caroline Gomes, Céline Grall, Cecilia Guzmán, Triyani Nur Hidayah, George Hilley, Chia-Yu Lu, Matthias Klinkmüller, Hemin Koyi, Jenny Macauley, Bertrand Maillot, Catherine Meriaux, Faramarz Nilfouroushan, Chang-Chih Pan, Daniel Pillot, Rodrigo Portillo, Matthias Rosenau, Wouter P. Schellart, Roy Schlische, Andy Take, Bruno Vendeville, Matteo Vettori, M. Vergnaud, Shih-Hsien Wang, Martha Withjack, Daniel Yagupsky, Yasuhiro Yamada

Schreurs, Guido



Theoretical study on absorption and emission spectra of pyrrolo-C analogues  

NASA Astrophysics Data System (ADS)

Fluorescent nucleoside analogues have attracted much attention in studying the structure and dynamics of nucleic acids in recent years. In the present work, we use theoretical calculations to investigate the structural and optical properties of Pyrrolo-C (PyC) and its analogues which are modified via the conjugation or fusion of different aromatic ring to the PyC core. We also consider the effects of aqueous solution and base pairing. The results show that the fluorescent pyrrolo-C analogues can pair with guanosine to form stable H-bonded WC base pairs. The calculated absorption peaks of modified deoxyribonucleosides agree well with the measured data. The absorption and emission maxima of the pyrrolo-C analogues are greatly red shifted compared with nature C. The solvent effects can induce wavelength blue shift and increase the oscillator strengths in both the absorption and emission spectra. With regard to the WC base pairs, the B3LYP functional reveals that the lowest energy transitions of modified GC base pairs are charge transfer excitation while the CAM-B3LYP functional predicts that all the lowest transitions are localised on the pyrrolo-C analogues. The M062X and CAM-B3LYP functionals show good agreement with respect to both the value of the lowest energy transitions as well as the oscillator strengths.

Liu, Hongxia; Liu, Jianhua; Yang, Yan; Li, Yan; Wang, Haijun



The Earliest Phases of Star Formation (EPoS): a Herschel key project. The thermal structure of low-mass molecular cloud cores  

NASA Astrophysics Data System (ADS)

Context. The temperature and density structure of molecular cloud cores are the most important physical quantities that determine the course of the protostellar collapse and the properties of the stars they form. Nevertheless, density profiles often rely either on the simplifying assumption of isothermality or on observationally poorly constrained model temperature profiles. The instruments of the Herschel satellite provide us for the first time with both the spectral coverage and the spatial resolution that is needed to directly measure the dust temperature structure of nearby molecular cloud cores. Aims: With the aim of better constraining the initial physical conditions in molecular cloud cores at the onset of protostellar collapse, in particular of measuring their temperature structure, we initiated the guaranteed time key project (GTKP) "The Earliest Phases of Star Formation" (EPoS) with the Herschel satellite. This paper gives an overview of the low-mass sources in the EPoS project, the Herschel and complementary ground-based observations, our analysis method, and the initial results of the survey. Methods: We study the thermal dust emission of 12 previously well-characterized, isolated, nearby globules using FIR and submm continuum maps at up to eight wavelengths between 100 ?m and 1.2 mm. Our sample contains both globules with starless cores and embedded protostars at different early evolutionary stages. The dust emission maps are used to extract spatially resolved SEDs, which are then fit independently with modified blackbody curves to obtain line-of-sight-averaged dust temperature and column density maps. Results: We find that the thermal structure of all globules (mean mass 7 M?) is dominated by external heating from the interstellar radiation field and moderate shielding by thin extended halos. All globules have warm outer envelopes (14-20 K) and colder dense interiors (8-12 K) with column densities of a few 1022 cm-2. The protostars embedded in some of the globules raise the local temperature of the dense cores only within radii out to about 5000 AU, but do not significantly affect the overall thermal balance of the globules. Five out of the six starless cores in the sample are gravitationally bound and approximately thermally stabilized. The starless core in CB 244 is found to be supercritical and is speculated to be on the verge of collapse. For the first time, we can now also include externally heated starless cores in the Lsmm/Lbol vs. Tbol diagram and find that Tbol < 25 K seems to be a robust criterion to distinguish starless from protostellar cores, including those that only have an embedded very low-luminosity object. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.Partially based on observations carried out with the IRAM 30 m Telescope, with the Atacama Pathfinder Experiment (APEX), and with the James Clerk Maxwell Telescope (JCMT). IRAM is supported by INSU/CNRS (France), MPG (Germany) and IGN (Spain). APEX is a collaboration between Max Planck Institut für Radioastronomie (MPIfR), Onsala Space Observatory (OSO), and the European Southern Observatory (ESO). The JCMT is operated by the Joint Astronomy Centre on behalf of the Particle Physics and Astronomy Research Council of the United Kingdom, the Netherlands Association for Scientific Research, and the National Research Council of Canada.Appendices A, B and C are available in electronic form at

Launhardt, R.; Stutz, A. M.; Schmiedeke, A.; Henning, Th.; Krause, O.; Balog, Z.; Beuther, H.; Birkmann, S.; Hennemann, M.; Kainulainen, J.; Khanzadyan, T.; Linz, H.; Lippok, N.; Nielbock, M.; Pitann, J.; Ragan, S.; Risacher, C.; Schmalzl, M.; Shirley, Y. L.; Stecklum, B.; Steinacker, J.; Tackenberg, J.



A boron-boron coupling reaction between two ethyl cation analogues.  


The design of larger architectures from smaller molecular building blocks by element-element coupling reactions is one of the key concerns of synthetic chemistry, so a number of strategies were developed for this bottom-up approach. A general scheme is the coupling of two elements with opposing polarity or that of two radicals. Here, we show that a B-B coupling reaction is possible between two boron analogues of the ethyl cation, resulting in the formation of an unprecedented dicationic tetraborane. The bonding properties in the rhomboid B? core of the product can be described as two B-B units connected by three-centre, two-electron bonds, sharing the short diagonal. Our discovery might lead the way to the long sought-after boron chain polymers with a structure similar to the silicon chains in ?-SiB?. Moreover, the reaction is a prime textbook example of the influence of multiple-centre bonding on reactivity. PMID:24256867

Litters, Sebastian; Kaifer, Elisabeth; Enders, Markus; Himmel, Hans-Jörg



A boron-boron coupling reaction between two ethyl cation analogues  

NASA Astrophysics Data System (ADS)

The design of larger architectures from smaller molecular building blocks by element-element coupling reactions is one of the key concerns of synthetic chemistry, so a number of strategies were developed for this bottom-up approach. A general scheme is the coupling of two elements with opposing polarity or that of two radicals. Here, we show that a B-B coupling reaction is possible between two boron analogues of the ethyl cation, resulting in the formation of an unprecedented dicationic tetraborane. The bonding properties in the rhomboid B4 core of the product can be described as two B-B units connected by three-centre, two-electron bonds, sharing the short diagonal. Our discovery might lead the way to the long sought-after boron chain polymers with a structure similar to the silicon chains in ?-SiB3. Moreover, the reaction is a prime textbook example of the influence of multiple-centre bonding on reactivity.

Litters, Sebastian; Kaifer, Elisabeth; Enders, Markus; Himmel, Hans-Jörg



Synthesis and Biological Evaluation of Analogues of AKT (Protein Kinase B) Inhibitor-IV  

PubMed Central

Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inhibitor-IV and 21 analogues using a novel six-step route based on ZrCl4-catalyzed cyclization of 1,2-arylenediamines with ?,?-unsaturated aldehydes. We examined effects on viability of HeLa carcinoma cells, viability of normal human cells (NHBE), replication of recombinant parainfluenza virus 5 (PIV5) in HeLa cells, and replication of the intracellular bacterium Mycobacterium fortuitum in HeLa cells. Replacement of the benzimidazole N-ethyl substitutent of AKT inhibitor-IV with N-hexyl and N-dodecyl groups enhanced antiviral activity and cytotoxicity against the cancer cell line, but these compounds showed substantially lower toxicity (from 6-fold to >20-fold) against NHBE cells, and no effect on M. fortuitum, suggesting inhibition of one or more host protein(s) required for proliferation of cancer cells and PIV5. The key structural elements identified here may facilitate identification of targets of this highly biologically active scaffold. PMID:21319800

Sun, Qi; Wu, Runzhi; Cai, Sutang; Lin, Yuan; Sellers, Llewlyn; Sakamoto, Kaori; He, Biao; Peterson, Blake R.



Directional flank spreading at Mount Cameroon volcano: Evidence from analogue modeling  

NASA Astrophysics Data System (ADS)

Cameroon is characterized by an elongated summit plateau, steep flanks, and topographic terraces around its base. Although some of these features can be accounted for by intrusion-induced deformation, we here focus on the contribution of edifice-scale gravitational spreading in the structure of Mount Cameroon. We review the existing geological and geophysical data and morphostructural features of Mount Cameroon and surrounding sedimentary basins. Volcanic ridge gravitational spreading is then simulated by scaled analogue models on which fault formation is recorded using digital image correlation. Three sets of models are presented (i) models recorded in cross section (Type I), (ii) models recorded from above with a uniform (Type IIa), and (iii) nonuniform ductile layer (Type IIb). Type I models illustrate the formation of faults accommodating summit subsidence and lower flank spreading. Type IIa models favor displacement perpendicular to the long axis, with formation of a summit graben and basal folds, but fail to reproduce the steep flanks. Type IIb models investigate the effect of spatial variations in sediment thickness and/or properties consistent with geological evidence. Directional spreading of the volcano's central part perpendicular to the long axis is accounted for by a sediment layer with restricted lateral extent and increasing thickness away from the volcano axis. The later model closely reproduces key features observed at Mount Cameroon: steep upper flanks are accounted for by enhanced lateral spreading of the lower flanks relative to the summit. The relevance of these findings for understanding flank instabilities at large oceanic volcanoes is finally highlighted.

Kervyn, M.; Wyk de Vries, B.; Walter, T. R.; Njome, M. S.; Suh, C. E.; Ernst, G. G. J.



Cooperative Binding of Cyclodextrin Dimers to Isoflavone Analogues Elucidated by Free Energy Calculations  

PubMed Central

Dimerization of cyclodextrin (CD) molecules is an elementary step in the construction of CD-based nanostructured materials. Cooperative binding of CD cavities to guest molecules facilitates the dimerization process and, consequently, the overall stability and assembly of CD nanostructures. In the present study, all three dimerization modes (head-to-head, head-to-tail, and tail-to-tail) of ?-CD molecules and their binding to three isoflavone drug analogues (puerarin, daidzin, and daidzein) were investigated in explicit water surrounding using molecular dynamics simulations. Total and individual contributions from the binding partners and solvent environment to the thermodynamics of these binding reactions are quantified in detail using free energy calculations. Cooperative drug binding to two CD cavities gives an enhanced binding strength for daidzin and daidzein, whereas for puerarin no obvious enhancement is observed. Head-to-head dimerization yields the most stable complexes for inclusion of the tested isoflavones (templates) and may be a promising building block for construction of template-stabilized CD nanostructures. Compared to the case of CD monomers, the desolvation of CD dimers and entropy changes upon complexation prove to be influential factors of cooperative binding. Our results shed light on key points of the design of CD-based supramolecular assemblies. We also show that structure-based calculation of binding thermodynamics can quantify stabilization caused by cooperative effects in building blocks of nanostructured materials. PMID:24719673



Seven-membered azabridged neonicotinoids: synthesis, crystal structure, insecticidal assay, and molecular docking studies.  


To study the influence of the ring sizes, 37 novel seven-membered azabridged neonicotinoid analogues were synthesized by reactions of nitromethylene analogues, succinaldehyde, and aniline hydrochlorides. Most of the title compounds presented higher insecticidal activities than that of imidacloprid (IMI), cycloxaprid (CYC), and eight-membered compounds against cowpea aphid (Aphis craccivora), armyworm (Pseudaletia separata Walker), and brown planthopper (Nilaparvata lugens), which indicated that introducing the structure of a seven-membered azabridge could significantly improve the insecticidal activities of neonicotinoid analogues. Docking study and binding mode analysis also revealed that introducing methyl group into position 2 of phenyl ring could increase the hydrophobic interactions with receptor, which implied that position 2 might be the key site to get high insecticidal compounds. PMID:25347284

Xu, Renbo; Luo, Ming; Xia, Rui; Meng, Xiaoqing; Xu, Xiaoyong; Xu, Zhiping; Cheng, Jiagao; Shao, Xusheng; Li, Houju; Li, Zhong



The Need for Analogue Missions in Scientific Human and Robotic Planetary Exploration  

NASA Technical Reports Server (NTRS)

With the increasing challenges of planetary missions, and especially with the prospect of human exploration of the moon and Mars, the need for earth-based mission simulations has never been greater. The current focus on science as a major driver for planetary exploration introduces new constraints in mission design, planning, operations, and technology development. Analogue missions can be designed to address critical new integration issues arising from the new science-driven exploration paradigm. This next step builds on existing field studies and technology development at analogue sites, providing engineering, programmatic, and scientific lessons-learned in relatively low-cost and low-risk environments. One of the most important outstanding questions in planetary exploration is how to optimize the human and robotic interaction to achieve maximum science return with minimum cost and risk. To answer this question, researchers are faced with the task of defining scientific return and devising ways of measuring the benefit of scientific planetary exploration to humanity. Earth-based and spacebased analogue missions are uniquely suited to answer this question. Moreover, they represent the only means for integrating science operations, mission operations, crew training, technology development, psychology and human factors, and all other mission elements prior to final mission design and launch. Eventually, success in future planetary exploration will depend on our ability to prepare adequately for missions, requiring improved quality and quantity of analogue activities. This effort demands more than simply developing new technologies needed for future missions and increasing our scientific understanding of our destinations. It requires a systematic approach to the identification and evaluation of the categories of analogue activities. This paper presents one possible approach to the classification and design of analogue missions based on their degree of fidelity in ten key areas. Various case studies are discussed to illustrate the approach.

Snook, K. J.; Mendell, W. W.



Blocking effects of promethazine, triprolidine and their analogues on the excitation caused by the peptide, achatin-I  

Microsoft Academic Search

An Achatina endogenous tetrapeptide, achatin-I (Gly-d-Phe-Ala-Asp), applied by brief pressure, produced an inward current (Iin) on an Achatina giant neurone type, PON (periodically oscillating neurone). Promethazine, triprolidine and their analogues tested, applied by perfusion, showed a tendency to inhibit the Iin, suggesting that the effective structures vary to a wide extent. With respect to promethazine and its analogues, the presence

Thucydides L. Salunga; Xiao Yan Han; Shu Min Wong; Hiroshi Takeuchi; Ken-ichi Matsunami; Christopher Upton; Amanda D. Mercer



Synthesis and evaluation of efavirenz (Sustiva) analogues as HIV-1 reverse transcriptase inhibitors: replacement of the cyclopropylacetylene side chain.  


Two series of efavirenz analogues have been developed: one in which the cyclopropane ring has been replaced by small heterocycles and another in which the entire acetylenic side chain has been replaced by alkyloxy groups. Several members of both series show equivalent potency to efavirenz against both wild-type virus and the key K103N mutant. PMID:11354371

Cocuzza, A J; Chidester, D R; Cordova, B C; Jeffrey, S; Parsons, R L; Bacheler, L T; Erickson-Viitanen, S; Trainor, G L; Ko, S S



S100A13-C2A binary complex structure-a key component in the acidic fibroblast growth factor for the non-classical pathway  

SciTech Connect

Fibroblast growth factors (FGFs) are key regulators of cell proliferation, differentiation, tumor-induced angiogenesis and migration. FGFs are essential for early embryonic development, organ formation and angiogenesis. They play important roles in tumor formation, inflammation, wound healing and restenosis. The biological effects of FGFs are mediated through the activation of the four transmembrane phosphotyrosine kinase receptors (FGFRs) in the presence of heparin sulfate proteoglycans (HSPGs) and therefore require the release of FGFs into the extracellular space. However, FGF-1 lacks the signal peptide required for the releasing of these proteins through the classical endoplasmic reticulum (ER)-Golgi secretary pathway. Maciag et al. demonstrated that FGF-1 is exported through a non-classical release pathway involving the formation of a specific multiprotein complex [M. Landriscina, R. Soldi, C. Bagala, I. Micucci, S. Bellum, F. Tarantini, I. Prudovsky, T. Maciag, S100A13 participates in the release of fibroblast growth factor 1 in response to heat shock in vitro, J. Biol. Chem. 276 (2001) 22544-22552; C.M. Carreira, T.M. LaVallee, F. Tarantini, A. Jackson, J.T. Lathrop, B. Hampton, W.H. Burgess, T. Maciag, S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro, J. Biol. Chem. 273 (1998) 22224-22231; T.M. LaValle, F. Tarantini, S. Gamble, C.M. Carreira, A. Jackson, T. Maciag, Synaptotagmin-1 is required for fibroblast growth factor-1 release, J. Biol. Chem. 273 (1998) 22217-22223; C. Bagala, V. Kolev, A. Mandinova, R. Soldi, C. Mouta, I. Graziani, I, Prudovsky, T. Maciag, The alternative translation of synaptotagmin 1 mediates the non-classical release of FGF1, Biochem. Biophys. Res. Commun. 310 (2003) 1041-1047]. The protein constituents of this complex include FGF-1, S100A13 (a Ca{sup 2+}-binding protein), and the p40 form of synaptotagmin 1 (Syt1). To understand the molecular events in the FGF-1 releasing pathway, we have studied the interactions of S100A13 with C2A by {sup 1}H-{sup 15}N HSQC titration and 3D-filtered NOESY experiments. We characterized the binary complex structure of S100A13-C2A by using a variety of multi-dimensional NMR experiments. This complex acts as a template for FGF-1 dimerization and multiprotein complex formation.

Mohan, Sepuru K.; Rani, Sandhya G.; Kumar, Sriramoju M. [Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Yu Chin [Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan (China)], E-mail:



Interaction of pentylsarin analogues with human acetylcholinesterase: a kinetic study.  


Previous kinetic studies investigating the interactions between human acetylcholinesterase (AChE), structurally different organophosphorus compounds (OP) and oximes did not reveal a conclusive structure-activity relationship of the different reactions. The only exception was for a homologous series of methylphosphonofluoridates bearing C1-C4 O-n- or O-i-alkyl residues. Hence, it was tempting to investigate the kinetic interactions between different pentylsarin analogues, human AChE and two oximes, obidoxime and HI 6, in order to increase the understanding of structure-activity relationship between highly toxic OP and human AChE. The rate constants for the inhibition of human erythrocyte AChE by four pentylsarin compounds (k(i)), for the spontaneous dealkylation (aging, k(a)) and reactivation (k(s)) of inhibited AChE as well as for the oxime-induced reactivation of inhibited AChE by obidoxime and HI 6 reflected by the dissociation constant (K(D)) and the reactivity constant (k(r)) were determined. All pentylsarin analogues had a high inhibitory potency towards AChE. Inhibited AChE was subject to spontaneous reactivation which outweighed aging substantially. Pentylsarin-inhibited AChE could be reactivated by oximes, HI 6 being more potent than obidoxime. The determination of inhibition, reactivation and aging kinetics of pentylsarin analogues with human AChE extends the database on interactions between AChE and methylphosphonofluoridate homologues with C1-C4 n- and i-alkyl residues demonstrating a structure-activity relationship depending on the chain length with certain differences regarding inhibition and post-inhibitory reactions. Unfortunately, no structure-activity relationship could be observed for the oxime-induced reactivation of inhibited AChE. In view of previous results with numerous structurally different organophosphates, organophosphonates and phosphoramidates it has to be concluded that up to now kinetic studies did not provide decisive information for the development of more effective oxime-based reactivators. PMID:19429253

Worek, F; Herkert, N M; Koller, M; Aurbek, N; Thiermann, H




E-print Network

envi- ronments. The concentration factor found in the known and describable food chain of the Salton in the simple linear food chain ex- isting in that isolated marine environment and that the cesium/potassium (CsUNSTRUCTURED MARINE FOOD WEBS AND "POLLUTANT ANALOGUES" JOHN D. ISAACS' ABSTRACT The several


Halogen bonded analogues of deep cavity cavitands.  


The first examples of halogen bonded analogues of deep cavity cavitands with guest binding properties, formed between N-alkyl ammonium resorcinarene halides as acceptors and bromotrichloromethane as the donor, are reported in the solid state and in solution. PMID:24407751

Beyeh, N Kodiah; Cetina, Mario; Rissanen, Kari



Natural analogues of nuclear waste glass corrosion  

Microsoft Academic Search

This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural

T. A. Jr. Abrajano; W. L. Ebert; J. S. Luo



Lunar Analogue Training at Meteor Crater, Arizona  

E-print Network

Lunar Analogue Training at Meteor Crater, Arizona & the San Francisco Volcanic Field, AZ April 28 Shaner Samuel Simmons Matt Weller Oliver White The left panel shows an aerial image of Meteor Crater, - 1 the most Meteor Crater-like of all lunar craters. #12;TABLE OF CONTENTS Reference

Rathbun, Julie A.


Analogue model for quantum gravity phenomenology  

E-print Network

So called "analogue models" use condensed matter systems (typically hydrodynamic) to set up an "effective metric" and to model curved-space quantum field theory in a physical system where all the microscopic degrees of freedom are well understood. Known analogue models typically lead to massless minimally coupled scalar fields. We present an extended "analogue space-time" programme by investigating a condensed-matter system - in and beyond the hydrodynamic limit - that is in principle capable of simulating the massive Klein-Gordon equation in curved spacetime. Since many elementary particles have mass, this is an essential step in building realistic analogue models, and an essential first step towards simulating quantum gravity phenomenology. Specifically, we consider the class of two-component BECs subject to laser-induced transitions between the components, and we show that this model is an example for Lorentz invariance violation due to ultraviolet physics. Furthermore our model suggests constraints on quantum gravity phenomenology in terms of the "naturalness problem" and "universality issue".

Silke Weinfurtner; Stefano Liberati; Matt Visser



CO2 Capture with Enzyme Synthetic Analogue  

SciTech Connect

Project overview provides background on carbonic anhydrase transport mechanism for CO2 in the human body and proposed approach for ARPA-E project to create a synthetic enzyme analogue and utilize it in a membrane for CO2 capture from flue gas.

Harry Cordatos



Analogues of stealth: Submarines and aircraft  

Microsoft Academic Search

Analogues of Stealth “ questions whether stealth technologies (measures designed to reduce the observable signature of a weapons platform) now being applied to aircraft will prove as successful as low?observable technologies and tactics employed by the submarine. To address that question, the article briefly explores the history of antisubmarine warfare, notes the failures of various technologies designed to counter the

Robert P. Haffa JR; James H. Patton JR



Analoguing Creativity & Culture: A Method for Metaphors.  

ERIC Educational Resources Information Center

Adding to the benefits of using metaphors as tools, "analoguing" (a method of analysis that focuses on metaphors for meanings in use and meanings of metaphors in use) helps avoid excessive categorization and separation by looking for unities and patterns in phenomena rather than for divisions. Six months of observation of patterns of sense-making…

Thompson, Timothy N.


Synthesis and biological activity of novel shikonin analogues.  


A series of shikonin analogues with side chain variants have been synthesized and evaluated for antitumor activity. These novel analogues show a broad spectrum of in vitro cytotoxicity against various cancer cell lines. Additionally, some analogues were also found to have the ability to decrease the expression level of HIF-1alpha in breast cancer cells MDA-MB-231 under hypoxia. The features of these analogues suggest their potential in cancer therapy. PMID:19111464

Wang, Wenjing; Dai, Mei; Zhu, Caihua; Zhang, Jiangang; Lin, Liping; Ding, Jian; Duan, Wenhu



Inhibition of topoisomerase II ? activity and induction of apoptosis in mammalian cells by semi-synthetic andrographolide analogues.  


Topoisomerase II ? enzyme plays a critical role in DNA replication process. It controls the topologic states of DNA during transcription and is essential for cell proliferation. Human DNA topoisomerase II ? (hTopo II ?) is a promising chemotherapeutic target for anticancer agents against a variety of cancer types. In the present study, andrographolide and its structurally modified analogues were investigated for their inhibitory activities on hTopo II ? enzyme. Five out of nine andrographolide analogues potently reduced hTopo II ? activity and inhibited cell proliferation in four mammalian cell lines (Hela, CHO, BCA-1 and HepG2 cells). IC50 values for cytotoxicity of analogues 3A.1, 3A.2, 3A.3, 1B and 2C were 4 to 7 ?M. Structure-activity relationship studies revealed that both core structure of andrographolide and silicon based molecule of functional group were important for the inhibition of hTopo II ? activity whereas position C-19 of analogues was required for anti-proliferation. In addition, the analogue 2C at 10 ?M concentration inhibited hTopo II ?, and induced apoptosis with nuclear fragmentation and formation of apoptotic bodies in HepG2 cells. The analogue 2C may, therefore, have a therapeutic potential as effective anticancer agent targeting the hTopo II ? functions. PMID:22899371

Nateewattana, Jintapat; Saeeng, Rungnapha; Kasemsook, Sakkasem; Suksen, Kanoknetr; Dutta, Suman; Jariyawat, Surawat; Chairoungdua, Arthit; Suksamrarn, Apichart; Piyachaturawat, Pawinee



Tetramic Acid Analogues Produced by Coculture of Saccharopolyspora erythraea with Fusarium pallidoroseum  

PubMed Central

Coculture of the fungus Fusarium pallidoroseum with the bacterium Saccharopolyspora erythraea was found to produce three new decalin-type tetramic acid analogues related to equisetin. The structures were determined by spectroscopic methods. The absolute configurations were established by circular dichroism spectroscopy and comparing the data with those of equisetin. PMID:24422636



Synthesis of the insecticide prothrin and its analogues from biomass-derived 5-(Chloromethyl) furfural  

Technology Transfer Automated Retrieval System (TEKTRAN)

Prothrin, a synthetic pyrethroid insecticide, was synthesized from the biomass-derived platform chemical 5 (chloromethyl)furfural in six steps and overall 65% yield. Two structural analogues of prothrin were also prepared following the same synthetic approach. Preliminary testing of these furan-base...


The antitumour effect of the somatostatin analogue TT232 depends on the treatment regimen  

Microsoft Academic Search

The somatostatin analogue TT-232, containing a five residue ring structure, has a strong antitumour activity both in vitro and in vivo. This peptide has no effect on growth hormone (GH) release, but exhibits a remarkable tyrosine kinase inhibitory effect and induced apoptosis. We studied the effect of TT-232 in different routes of administration and treatment schedules on various types of

Miguel Tejeda; Dezsõ Gaál; Orsolya Csuka; Axel Ullrich; Richárd Schwab; Ákos Pap; Anikó Horváth; György Kéri



Remarkable metal-complexed phosphorus analogues of the cyclopropenylcarbene-cyclobutadiene rearrangement.  


In situ-generated metal carbonyl-complexed cyclopropenylphosphinidenes undergo a sequence of structural changes leading to phosphorus analogues of Pettit's seminal (?(4)-cyclobutadiene)iron tricarbonyl complex via multiple valence isomers along the reaction pathway and the elimination of one molecule of carbon monoxide. PMID:21627326

Lyaskovskyy, Volodymyr; Elders, Niels; Ehlers, Andreas W; Lutz, Martin; Slootweg, J Chris; Lammertsma, Koop



Amyloid fibrillogenesis of silkmoth chorion protein peptide-analogues via a liquid-crystalline intermediate phase  

Microsoft Academic Search

Chorion, the major component of silkmoth eggshell, consists of the A and B classes of low-molecular weight structural proteins. Chorion protects the oocyte and the developing embryo from environmental hazards and this is due to the extraordinary physical and chemical properties of its constituent proteins. We have shown previously [FEBS Lett. 479 (2000) 141; 499 (2001) 268] that peptide-analogues of

S. J. Hamodrakas; A. Hoenger; V. A. Iconomidoua



Synthetic Analogues of Cysteinate-Ligated Non-Heme Iron and Non-Corrinoid Cobalt Enzymes  

E-print Network

Synthetic Analogues of Cysteinate-Ligated Non-Heme Iron and Non-Corrinoid Cobalt Enzymes Julie A June 24, 2003 Contents 1. Introduction to Non-Heme Iron Enzymes 825 2. Nitrile Hydratase (NHase) 826 2.1. Enzyme Function 826 2.2. Enzyme Active Site Structure 826 2.3. Spectroscopic Properties 827 2

Kovacs, Julie


Efficient synthesis of dichlorodenafil, an unapproved sildenafil analogue appearing in non-prescription supplements.  


We have developed an efficient synthesis of dichlorodenafil (4), an unapproved sildenafil analogue isolated from dietary supplements. Our sequence employs POCl(3)-mediated chlorination of readily available chloroacetyl compound 7 followed by selective hydrolysis of the chloro-heterocycle function. Our synthesis confirms the structure of the illegal additive, and will provide regulatory agencies with ready access to authentic standard samples of dichlorodenafil (4) to aid in their mission to protect the public from unapproved and potentially harmful erectile dysfunction (ED) drug analogues that are added to herbal and dietary supplements without providing users with appropriate toxicological or pharmacological information. PMID:23649199

Kim, Jong Yup; Hwang, In Gyun; Oh, Jae Ho; Kang, Il Hyun; Kwon, Sung Won; Kim, Deukjoon



Heteroatom Analogues of Hydrocodone: Synthesis and Biological Activity  

PubMed Central

Heteroatom analogues of hydrocodone, in which the N-methyl functionality was replaced with oxygen, sulfur, sulfoxide, and sulfone, were prepared by a short sequence from the ethylene glycol ketal of hydrocodone; a carbocyclic analogue of bisnorhydrocodone was also prepared. The compounds were tested for receptor binding and revealed moderate levels of activity for the sulfone analogue of hydrocodone. PMID:23397939

Giacometti, Robert D.; Duchek, Jan; Werner, Lukas; Husni, Afeef S.; McCurdy, Christopher R.; Cutler, Stephen J.; Cox, D. Phillip; Hudlicky, Tomas




E-print Network

A CMOS GENERAL-PURPOSE SAMPLED-DATA ANALOGUE MICROPROCESSOR Piotr Dudek and Peter J. Hicks functions as an analogue microprocessor (AµP). The AµP executes software programs, in a way akin to a digital microprocessor, while nevertheless operating on analogue sampled data values. This enables

Dudek, Piotr


Paper Synthesis, Cytotoxicity and Apoptosis Induction in Human Tumor Cells by Galaxamide and Its Analogues  

PubMed Central

Our previous study reported that galaxamide, which is a cyclo-pentapeptide containing five leucines that was extracted from Galaxaura filamentosa, displayed remarkable anticancer cytotoxicity. This novel cyclo-peptide provided a new skeleton for the structural modifications used in finding new drugs with better anticancer properties. In this study, five analogues were synthesized based on changing the number of d/l amino acids by adding a new amino acid, phenylalanine. Galaxamide and five of its analogues were evaluated through MTT assays to examine their cytotoxic activities. We found that modified analogue 5, which is referred to as A5, displayed broad spectrum cytotoxic activity toward every cell line tested; in addition, the IC50 of A5 was lower than that of galaxamide and the other analogues. Furthermore, we used flow cytometry and western blot assays to investigate whether galaxamide and A5 could induce cancer cell apoptosis. The flow cytometric studies showed that HepG2 cells treated with different concentrations of galaxamide or A5 over 72 h displayed significant and dose-dependent increases in the percentages of early-stage apoptotic cells. Western blotting revealed that both compounds induce caspase-dependent apoptosis in HepG2 cells through a mitochondria-mediated pathway. The results demonstrate that galaxamide and its analogues have potential applications as clinical anticancer drugs. PMID:25231922

Xiao, Xi; Liao, Xiaojian; Qiu, Shaoling; Liu, Zihao; Du, Bin; Xu, Shihai



Enzymatic tRNA acylation by acid and alpha-hydroxy acid analogues of amino acids.  


Incorporation of unnatural amino acids with unique chemical functionalities has proven to be a valuable tool for expansion of the functional repertoire and properties of proteins as well as for structure-function analysis. Incorporation of alpha-hydroxy acids (primary amino group is substituted with hydroxyl) leads to the synthesis of proteins with peptide bonds being substituted by ester bonds. Practical application of this modification is limited by the necessity to prepare corresponding acylated tRNA by chemical synthesis. We investigated the possibility of enzymatic incorporation of alpha-hydroxy acid and acid analogues (lacking amino group) of amino acids into tRNA using aminoacyl-tRNA synthetases (aaRSs). We studied direct acylation of tRNAs by alpha-hydroxy acid and acid analogues of amino acids and corresponding chemically synthesized analogues of aminoacyl-adenylates. Using adenylate analogues we were able to enzymatically acylate tRNA with amino acid analogues which were otherwise completely inactive in direct aminoacylation reaction, thus bypassing the natural mechanisms ensuring the selectivity of tRNA aminoacylation. Our results are the first demonstration that the use of synthetic aminoacyl-adenylates as substrates in tRNA aminoacylation reaction may provide a way for incorporation of unnatural amino acids into tRNA, and consequently into proteins. PMID:18067322

Owczarek, Alina; Safro, Mark; Wolfson, Alexey D



Synthesis and Biological Evaluation of Muraymycin Analogues Active against Anti-Drug-Resistant Bacteria  

PubMed Central

Muraymycin analogues with a lipophilic substituent were synthesized using an Ugi four-component assemblage. This approach provides ready access to a range of analogues simply by altering the aldehyde component. The impact of the lipophilic substituent on the antibacterial activity was very large, and analogues 7b?e and 8b?e exhibited good activity against a range of Gram-positive bacterial pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. This study also showed that the accessory urea-dipeptide motif contributes to MraY inhibitory and antibacterial activity. The knowledge obtained from our structure?activity relationship study of muraymycins provides further direction toward the design of potent MraY inhibitors. This study has set the stage for the generation of novel antibacterial “lead” compounds based on muraymycins. PMID:24900205



Thermodynamic epimeric equilibration and crystallisation-induced dynamic resolution of lobelanine, norlobelanine and related analogues.  


The step-economical synthesis of lobelanine involving a ring closing double aza-Michael (RCDAM) reaction is revisited and successfully extended to the synthesis of various configurationally more stable analogues. Owing to the presence of a configurationally labile ?-aminoketone subunit, lobelanine is prone to self-catalyze mutarotation in solution. Through the synthesis of original lobelanine analogues, we studied the influence of (i) the size of the central heterocycle, (ii) the bulkiness of the nitrogen protecting group, and (iii) the phenacyl arm substituent on the thermodynamic equilibrium and its displacement by crystallisation-induced dynamic resolution (CIDR). We demonstrated that fine structural tuning combined with optimized CIDR conditions favours the first efficient diastereoselective synthesis of lobelanine's analogues. PMID:25320963

Amara, Z; Bernadat, G; Venot, P-E; Retailleau, P; Troufflard, C; Drège, E; Le Bideau, F; Joseph, D



Exploiting Enzymatic Promiscuity to Engineer a Focused Library of Highly Selective Antifungal and Antiproliferative Aureothin Analogues  

PubMed Central

Aureothin is a shikimate-polyketide hybrid metabolite from Streptomyces thioluteus with a rare nitroaryl moiety, a chiral tetrahydrofuran ring and an O-methylated pyrone ring. The antimicrobial and antitumor activities of aureothin have caught our interest in modulating its structure as well as its bioactivity profile. In an integrated approach using mutasynthesis, biotransformation and combinatorial biosynthesis, a defined library of aureothin analogues was generated. The promiscuity of the polyketide synthase assembly line towards different starter units and the plasticity of the pyrone and tetrahydrofuran ring formation were exploited. A selection of fifteen new aureothin analogues with modifications at the aryl residue, the pyrone ring, and the oxygenated backbone was produced on a preparative scale and fully characterized. Remarkably, various new aureothin derivatives are less cytotoxic than aureothin but have improved antiproliferative activities. Furthermore, we found that the THF ring is crucial for the remarkably selective activity of aureothin analogues against certain pathogenic fungi. PMID:20662518

Werneburg, Martina; Busch, Benjamin; He, Jing; Richter, Martin E.A.; Xiang, Longkuan; Moore, Bradley S.; Roth, Martin; Dahse, Hans-Martin



Group key management  

SciTech Connect

This report describes an architecture and implementation for doing group key management over a data communications network. The architecture describes a protocol for establishing a shared encryption key among an authenticated and authorized collection of network entities. Group access requires one or more authorization certificates. The implementation includes a simple public key and certificate infrastructure. Multicast is used for some of the key management messages. An application programming interface multiplexes key management and user application messages. An implementation using the new IP security protocols is postulated. The architecture is compared with other group key management proposals, and the performance and the limitations of the implementation are described.

Dunigan, T.; Cao, C.



Modular Connector Keying Concept  

NASA Technical Reports Server (NTRS)

For panel-mount-type connectors, keying is usually "built-in" to the connector body, necessitating different part numbers for each key arrangement. This is costly for jobs that require small quantities. This invention was driven to provide a cost savings and to reduce documentation of individual parts. The keys are removable and configurable in up to 16 combinations. Since the key parts are separate from the connector body, a common design can be used for the plug, receptacle, and key parts. The keying can then be set at the next higher assembly.

Ishman, Scott; Dukes, Scott; Warnica, Gary; Conrad, Guy; Senigla, Steven



Natural analogue synthesis report, TDR-NBS-GS-000027 rev00 icn02  

SciTech Connect

The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the Yucca Mountain Site Description (CRWMS M&O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport, impact of radionuclide release on the biosphere, and potentially disruptive events. Results of these studies will be used to corroborate estimates of the magnitude and limitation of operative processes in order to build realism into conceptual and numerical process models used as a foundation for PA in the representative case of postclosure safety.

Simmons, A.; Nieder-Westermann, G.; Stuckless, J.; Dobson, P.; Unger, A.J.A.; Kwicklis, E.; Lichtner, P.; Carey, B.; Wolde, G.; Murrel,M.; Kneafsey, T.J.; Meijer, A.; Faybishenko, B.



Music summarization using key phrases  

Microsoft Academic Search

Systems to automatically provide a representative summary or `key phrase' of a piece of music are described. For a `rock' song with `verse' and `chorus' sections, we aim to return the chorus or in any case the most repeated and hence most memorable section. The techniques are less applicable to music with more complicated structure although possibly our general framework

Beth Logan; Stephen Chu



Aliphatic and heterocyclic analogues of arecaidine propargyl ester. Structure-activity relationships of mono- and bivalent ligands at muscarinic M1 (M4), M2 and M3 receptor subtypes.  


The pharmacological profiles of tertiary and quaternary monovalent (1b-6b) and bivalent ligands (7a-12b), closely related to arecaidine propargyl ester (CAS 35516-99-5, APE, 1a), were evaluated at muscarinic receptors in rat superior cervical ganglia (M1), rabbit was deferens (M1/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3). In the monovalent ligand series (1a-6b) APE (1a) displayed the highest potency at all three muscarinic receptors [M2 (-log EC50 = 8.12) > or = M3 (-log EC50 = 7.77) = M1/M4 (-log EC50/vas deferens = 7.72)], whereas in the bivalent ligand series (7a-12b) arecaidine 2-butyne-1,4-diyl bisester (bisABE, 7a) was the most potent agonist with functional selectivity for M1/M4 (-log EC50/vas deferens = 6.94) and M2 receptors (-log EC50 = 7.10) over M3 receptors (-log EC50 = 6.27). On ganglia bisABE elicited M2 receptor-mediated hyperpolarisations, which were followed by long-lasting pirenzepine-sensitive depolarisations. However, the potency at M1 receptors in ganglia of APE (-log EC50 = 6.96) and bisABE (-log EC50 = 5.69) was lower than that in rabbit vas deferens. All bivalent molecules exhibited decreased potencies when compared with their monovalent analogues. However, a change in potency profiles was often obtained. The quaternary isonicotinic acid 2-butyne-1,4-diyl bisester (10b) displayed some functional selectivity for M2 receptors (-log EC50 = 5.78) [6- to 9-fold over M1/M4 (-log EC50/vas deferens = 5.03) and M3 receptors (-log EC50 = 4.83)] without showing nicotinic effects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7779140

Moser, U; Gubitz, C; Galvan, M; Immel-Sehr, A; Lambrecht, G; Mutshcler, E



Anomeric selectivity and influenza A virus inhibition study on methoxylated analogues of Pentagalloylglucose.  


Anomeric selectivity in galloylation of d-glucose and d-mannose with carboxylic acid was explored under steglich conditions. Base catalyst 4-dimethylaminopyridine favored the formation of alpha-anomers, while adding an acid and carbodiimide favored the formation of beta-anomers. Steric hindrance between ?,?-unsaturated acid and C-2 OH stereochemistry (adjacent carbon to anomeric) influenced anomeric selectivity for both d-glucose and d-mannose. The influenza A virus inhibition activities of the synthesized compounds were evaluated in Madin-Darby canine kidney cell line using the cytopathic effect inhibition assay. All the synthetic methoxylated analogues showed more considerable activity against influenza A virus than their corresponding acids, which indicated the sugar core as key functionality for anti-viral activity. The activities of trimethoxy-cinnamic acid Pentagalloylglucose analogues, 3?, 3?, 4?, and 4? (IC50, 109.1?M, 134.4?M, 119.5?M, 111.1?M, respectively) were better than those of trimethoxy-benzoic acid Pentagalloylglucose analogues, 1-?? and 2?, 2? (IC50, 209.8?M, 132.9?M, 161.2?M, respectively), which suggested that the double bond in cinnamic acid Pentagalloylglucose analogues makes the major contribution for influenza A virus inhibitory activity. Notably, several anomeric mixtures showed better activities than pure alpha or beta anomer and were almost two times more effective than Ribavirin, a clinically used anti-viral drug. PMID:25498015

Qurat-Ul-Ain, Shaikh; Wang, Wei; Yang, Meiting; Du, Na; Wan, Shengbiao; Zhang, Lijuan; Jiang, Tao



Nanofluids Research: Key Issues  

PubMed Central

Nanofluids are a new class of fluids engineered by dispersing nanometer-size structures (particles, fibers, tubes, droplets) in base fluids. The very essence of nanofluids research and development is to enhance fluid macroscopic and megascale properties such as thermal conductivity through manipulating microscopic physics (structures, properties and activities). Therefore, the success of nanofluid technology depends very much on how well we can address issues like effective means of microscale manipulation, interplays among physics at different scales and optimization of microscale physics for the optimal megascale properties. In this work, we take heat-conduction nanofluids as examples to review methodologies available to effectively tackle these key but difficult problems and identify the future research needs as well. The reviewed techniques include nanofluids synthesis through liquid-phase chemical reactions in continuous-flow microfluidic microreactors, scaling-up by the volume averaging and constructal design with the constructal theory. The identified areas of future research contain microfluidic nanofluids, thermal waves and constructal nanofluids. PMID:20676214



S100A13-C2A binary complex structure—a key component in the acidic fibroblast growth factor for the non-classical pathway  

Microsoft Academic Search

Fibroblast growth factors (FGFs) are key regulators of cell proliferation, differentiation, tumor-induced angiogenesis and migration. FGFs are essential for early embryonic development, organ formation and angiogenesis. They play important roles in tumor formation, inflammation, wound healing and restenosis. The biological effects of FGFs are mediated through the activation of the four transmembrane phosphotyrosine kinase receptors (FGFRs) in the presence of

Sepuru K. Mohan; Sandhya G. Rani; Sriramoju M. Kumar; Chin Yu



Synthesis and biological evaluation of kendomycin and its analogues.  


Ansa compounds are gifts from microbes with intriguing molecular structures and highly potent bioactivities. One of the ansa compounds, kendomycin, has an oxa-metacyclophane skeleton with a quinone methide core and a fully substituted tetrahydropyran ring. Beyond a common synthetic strategy for construction of the ansa skeleton (i.e., elongation of an alkyl chain from an aromatic core followed by macrocyclization), we challenged a new method for construction of the ansa skeleton via simultaneous macrocyclization and benzannulation (using an intramolecular Dötz benzannulation). Understanding the reactivity of various Fischer-type ?-alkynyloxy chromium carbene complexes with kendomycin analogue syntheses led to achievement of the total synthesis of kendomycin. Investigations of structure-activity relationships revealed the need for an ansa skeleton for antimicrobial activity. Therefore, we envisage that this intramolecular Dötz benzannulation will enable divergent syntheses of ansa compounds which have important bioactive potential. PMID:25136928

Tanaka, Kyosuke; Matsuyama, Hiroshi; Watanabe, Masahito; Fujimori, Yukiko; Ishibashi, Kodai; Ozawa, Tomohiro; Sato, Tomoharu; Saikawa, Yoko; Nakata, Masaya



The Key to Security.  

ERIC Educational Resources Information Center

Provides tips on using low-tech, traditional key and lock systems for effectively securing university and college facilities. Discusses providing keys with utility patents as well as the need to design doors that offer greater deterrence to vandalism. (GR)

Kennedy, Mike



Public Key Cryptography.  

ERIC Educational Resources Information Center

Describes public key cryptography, also known as RSA, which is a system using two keys, one used to put a message into cipher and another used to decipher the message. Presents examples using small prime numbers. (MKR)

Tapson, Frank



Certificateless Public Key Cryptography  

Microsoft Academic Search

This paper introduces and makes concrete the concept of certiflcateless public key cryptography (CL-PKC), a model for the use of public key cryp- tography which avoids the inherent escrow of identity-based cryptography and yet which does not require certiflcates to guarantee the authenticity of public keys. The lack of certiflcates and the presence of an adversary who has access to

Sattam S. Al-riyami; Kenneth G. Paterson



Pharmacological actions of some cyclic analogues of choline.  

PubMed Central

Two cyclic choline analogues (3-hydroxy-N,N- dimethylpiperidinium and 2-hydroxymethyl-N,N- dimethylpiperidinium ) and two cyclic homocholine analogues (4-hydroxy-N,N- dimethylpiperidinium and 3-hydroxymethyl-N,N- dimethylpiperidinium ) have been studied with regard to their actions at the cholinergic synapse. All the analogues had some direct depolarizing activity on the frog rectus abdominis muscle but they were less potent in this respect than acetylcholine. Compared to physostigmine, the analogues were weak inhibitors of cholinesterase enzymes. All the analogues were found to have a presynaptic blocking action on the rat phrenic nerve-hemidiaphragm preparation, which was reversed by choline. In addition, they all inhibited the high affinity transport of choline into synaptosomes but only the cyclic choline analogues were found to be acetylated by soluble choline acetyltransferase in vitro. We conclude that the hydroxypiperidinium analogues caused the presynaptic block seen at the neuromuscular junction by inhibiting acetylcholine synthesis. PMID:6326923

Hemsworth, B. A.; Shreeve, S. M.; Veitch, G. B.



Why homogeneous boundary conditions lead to heterogeneous internal strain in analogue simple shear experiments - explained by numerical modeling  

NASA Astrophysics Data System (ADS)

Analogue modeling of geological structures, investigating for example the rotation and interaction of rigid or weak inclusions in a matrix, single layer folding, or fold interference patterns, commonly employs a linear simple shear or general shear rig. While the boundaries of such deformation rigs theoretically prescribe a homogeneous isochoric (plane strain) flow, the internal deformation pattern of the analogue material (paraffin wax or silicone putties) may strongly deviate from the intended homogeneous strain conditions. For example, in simple shear experiments (x-y-coordinate system, simple shear in x-direction) the following observations can be made: (1) Close to model boundaries initially parallel to the y-direction of the apparatus a prominent deflection of passive marker lines develops during the experiment, indicating a strong perturbation strain. (2) The central part of the model rotates with the opposite sense of rotation compared to the imposed vorticity, documented by the imposed marker grid. We employ two-dimensional numerical finite element models to investigate the observed deviation from a homogeneous simple shear flow field in simple shear rig experiments. A Newtonian rheology is used to represent the analogue material. We tested different boundary conditions that do not represent perfect simple shear boundary conditions, but could possibly be present in analogue experiments. The numerical results show that neither traction-free slip nor free surface boundary conditions at the four walls, nor any combination of these boundary conditions produces the deformation pattern observed in analogue experiments. Therefore, we conclude that the imposed boundary conditions at the walls of the analogue rigs are not the reason for the observed heterogeneous strain field. In analogue experiments, the analogue material commonly lies on top of a weak viscous material (e.g. vaseline) or is sandwiched between two layers of such a material. These layers are also deformed during an experiment and represent boundary conditions in the third dimension (i.e the z-direction). In the two-dimensional numerical simulation, this viscous shear boundary condition is represented by a velocity-dependent traction force that acts on the analogue material. The numerical simple shear experiments including this traction force precisely reproduce the heterogeneous strain observed in analogue experiments. Therefore, we conclude that boundary effects in the third dimension of simple shear rigs (i.e. weak viscous layers) are the primary reason for the observed heterogeneous strain field. As the viscous stresses arising from deforming the weak boundary layers are velocity dependent, the deviation from a homogeneous strain pattern in the analogue material depends on the applied shear strain rate. We thus recommend to run analogue models in shear boxes at preferably low strain rates.

Exner, Ulrike; Frehner, Marcel; Mancktelow, Neil S.; Grujic, Djordje



Analogue models of and for gravity  

E-print Network

Condensed matter systems, such as acoustics in flowing fluids, light in moving dielectrics, or quasiparticles in a moving superfluid, can be used to mimic aspects of general relativity. More precisely these systems (and others) provide experimentally accessible models of curved-space quantum field theory. As such they mimic kinematic aspects of general relativity, though typically they do not mimic the *dynamics*. Although these analogue models are thereby limited in their ability to duplicate all the effects of Einstein gravity they nevertheless are extremely important -- they provide black hole analogues (some of which have already been seen experimentally) and lead to tests of basic principles of curved-space quantum field theory. Currently these tests are s