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Causal structure of analogue spacetimes  

NASA Astrophysics Data System (ADS)

The so-called 'analogue models of general relativity' provide a number of specific physical systems, well outside the traditional realm of general relativity, that nevertheless are well-described by the differential geometry of curved spacetime. Specifically, the propagation of perturbations in these condensed matter systems is described by 'effective metrics' that carry with them notions of 'causal structure' as determined by an exchange of quasi-particles. These quasi-particle-induced causal structures serve as specific examples of what can be done in the presence of a Lorentzian metric without having recourse to the Einstein equations of general relativity. (After all, the underlying analogue model is governed by its own specific physics, not necessarily by the Einstein equations.) In this paper we take a careful look at what can be said about the causal structure of analogue spacetimes, focusing on those containing quasi-particle horizons, both with a view to seeing what is different from standard general relativity, and what the similarities might be. For definiteness, and because the physics is particularly simple to understand, we will phrase much of the discussion in terms of acoustic disturbances in moving fluids, where the underlying physics is ordinary fluid mechanics, governed by the equations of traditional hydrodynamics, and the relevant quasi-particles are the phonons. It must however be emphasized that this choice of example is only for the sake of pedagogical simplicity and that our considerations apply generically to wide classes of analogue spacetimes.

Barceló, Carlos; Liberati, Stefano; Sonego, Sebastiano; Visser, Matt



Evaluation of Chlorofusin, its Seven Chromophore Diastereomers, and Key Analogues  

PubMed Central

Chlorofusin, its seven chromophore diastereomers, and key analogues were comparatively examined for inhibition of MDM2–p53 binding revealing that the chromophore, but not simple replacements, contributes significantly to the natural products properties, and that this contribution is independent of its relative and absolute stereochemistry. PMID:20161293

Clark, Ryan C.; Lee, Sang Yeul; Hwang, Inkyu; Searcey, Mark; Boger, Dale L.



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.



Antimicrobial Activities of Jadomycin B and Structurally Related Analogues  

Microsoft Academic Search

Natural products are leads for new antibiotics as a result of their structural complexity and diversity. We have isolated a series of structurally related polyketide-derived natural products from Streptomyces venezuelae ISP5230. The most active of these jadomycin analogues showed good activity against a variety of staphylococci, including methicillin-resistant Staphylococcus aureus. Natural products, or natural-product derivatives, comprise the majority of clinically

David L. Jakeman; Srinivasulu Bandi; Cathy L. Graham; Taryn R. Reid; Jason R. Wentzell; Susan E. Douglas



Synthesis studies of structural analogues of tagetitoxin: 4-O- acetyl-3-amino-1,6-anhydro-3-deoxy- d-gulose 2-phosphate  

Microsoft Academic Search

Synthetic approaches to structural analogues of tagetitoxin (1) are described. The successful route to analogue 3 (X?O) has, as a key step, protection of the cis-vicinal amino alcohol moiety of compound 7 as an N-benzylated cyclic carbamate (9). X-Ray crystallographic analyses of the hydrochloride of compound 7 and of the hydroxyacid 56 are reported.

Barry R. Dent; Richard H. Furneaux; Graeme J. Gainsford; Gregory P. Lynch



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



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.



Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action.  


Thyroid hormones are essential for the development and differentiation of all cells of the human body. They regulate protein, fat, and carbohydrate metabolism. In this Account, we discuss the synthesis, structure, and mechanism of action of thyroid hormones and their analogues. The prohormone thyroxine (T4) is synthesized on thyroglobulin by thyroid peroxidase (TPO), a heme enzyme that uses iodide and hydrogen peroxide to perform iodination and phenolic coupling reactions. The monodeiodination of T4 to 3,3',5-triiodothyronine (T3) by selenium-containing deiodinases (ID-1, ID-2) is a key step in the activation of thyroid hormones. The type 3 deiodinase (ID-3) catalyzes the deactivation of thyroid hormone in a process that removes iodine selectively from the tyrosyl ring of T4 to produce 3,3',5'-triiodothyronine (rT3). Several physiological and pathological stimuli influence thyroid hormone synthesis. The overproduction of thyroid hormones leads to hyperthyroidism, which is treated by antithyroid drugs that either inhibit the thyroid hormone biosynthesis and/or decrease the conversion of T4 to T3. Antithyroid drugs are thiourea-based compounds, which include propylthiouracil (PTU), methimazole (MMI), and carbimazole (CBZ). The thyroid gland actively concentrates these heterocyclic compounds against a concentration gradient. Recently, the selenium analogues of PTU, MMI, and CBZ attracted significant attention because the selenium moiety in these compounds has a higher nucleophilicity than that of the sulfur moiety. Researchers have developed new methods for the synthesis of the selenium compounds. Several experimental and theoretical investigations revealed that the selone (C?Se) in the selenium analogues is more polarized than the thione (C?S) in the sulfur compounds, and the selones exist predominantly in their zwitterionic forms. Although the thionamide-based antithyroid drugs have been used for almost 70 years, the mechanism of their action is not completely understood. Most investigations have revealed that MMI and PTU irreversibly inhibit TPO. PTU, MTU, and their selenium analogues also inhibit ID-1, most likely by reacting with the selenenyl iodide intermediate. The good ID-1 inhibitory activity of PTU and its analogues can be ascribed to the presence of the -N(H)-C(?O)- functionality that can form hydrogen bonds with nearby amino acid residues in the selenenyl sulfide state. In addition to the TPO and ID-1 inhibition, the selenium analogues are very good antioxidants. In the presence of cellular reducing agents such as GSH, these compounds catalytically reduce hydrogen peroxide. They can also efficiently scavenge peroxynitrite, a potent biological oxidant and nitrating agent. PMID:23883148

Manna, Debasish; Roy, Gouriprasanna; Mugesh, Govindasamy



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.



Relationship between structure and histamine releasing action of polymyxin B and its analogues  

Microsoft Academic Search

The relationship between the structures of polymyxins and their histamine releasing action on rat mast cells was studied. Analogues of polymyxin B (PB) had different hydrophobic properties, positive charge and peptide chains (deca-, nona- and heptapeptides). The biologic activities of cyclic and decyclic heptapeptides (analogues of PB), and polymyxin M and its decyclic form were investigated. Removal of some amino

V. G. Voitenko; D. I. Bayramashvili; A. I. Zebrev; A. A. Zinchenko



Structure determination of new analogues of vardenafil and sildenafil in dietary supplements  

Microsoft Academic Search

New analogues of vardenafil and sildenafil illegally added to dietary supplements were detected by high-performance liquid chromatography (HPLC) analysis with a photodiode array detector (PDA). These compounds were isolated and their structures elucidated by mass spectrometry (MS), infrared (IR) spectroscopy, one- and two-dimensional nuclear magnetic resonance (NMR). One of the new analogues given the trivial name pseudovardenafil (compound 1) was

H. J. Park; H. K. Jeong; M. I. Chang; M. H. Im; J. Y. Jeong; D. M. Choi; M. K. Hong; J. Youm; S. B. Han; D. J. Kim; J. H. Park; S. W. Kwon



Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model.  


Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y'=3,5-(CF(3))(2), which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships. PMID:19932968

Patel, Sarjubhai A; Rajale, Trideep; O'Brien, Erin; Burkhart, David J; Nelson, Jared K; Twamley, Brendan; Blumenfeld, Alex; Szabon-Watola, Monika I; Gerdes, John M; Bridges, Richard J; Natale, Nicholas R



Structure and UV absorption of QCCs: Carbonaceous dust analogues  

Microsoft Academic Search

“Quenched Carbonaceous Composites (QCCs)” are carbonaceous interstellar dust analogues synthesized in the laboratory from a hydrocarbon plasma. We produced new types of carbonaceous condensates from the ejecta of plasma with mixtures of methane and hydrogen as source gases. We find that QCC with an absorbance peak at 220 nm is composed of onion-like spherules, and QCCs with an absorbance peak

S. Wada; C. Kaito; S. Kimura; A. T. Tokunaga



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



Structure and UV absorption of QCCs: carbonaceous dust analogues.  


"Quenched Carbonaceous Composites (QCCs)" are carbonaceous interstellar dust analogues synthesized in the laboratory from a hydrocarbon plasma. We produced new types of carbonaceous condensates from the ejecta of plasma with mixtures of methane and hydrogen as source gases. We find that QCC with an absorbance peak at 220 nm is composed of onion-like spherules, and QCCs with an absorbance peak at 230-240 nm are composed of polyhedral particles. The onion-like QCC contains aromatic hydrogen bonds, and it shows the 3.3 and 11.4 micrometers absorption bands. The QCC with an absorbance peak at 230-240 nm is composed of ribbons with bent graphitic layers. This suggests that the carrier of the interstellar 220 nm extinction band might also be an emitter of the interstellar diffuse emission bands. PMID:11543341

Wada, S; Kaito, C; Kimura, S; Tokunaga, A T



Structure and UV Absorption of QCCs: Carbonaceous Dust Analogues  

NASA Astrophysics Data System (ADS)

``Quenched Carbonaceous Composites (QCCs)'' are carbonaceous interstellar dust analogues synthesized in the laboratory from a hydrocarbon plasma. We produced new types of carbonaceous condensates from the ejecta of plasma with mixtures of methane and hydrogen as source gases. We find that QCC with an absorbance peak at 220 nm is composed of onion-like spherules, and QCCs with an absorbance peak at 230-240 nm are composed of polyhedral particles. The onion-like QCC contains aromatic hydrogen bonds, and it shows the 3.3 and 11.4 ?m absorption bands. The QCC with an absorbance peak at 230-240 nm is composed of ribbons with bent graphitic layers. This suggests that the carrier of the interstellar 220 nm extinction band might also be an emitter of the interstellar diffuse emission bands

Wada, S.; Kaito, C.; Kimura, S.; Tokunaga, A. T.



Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors.  


A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 ?M). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism. PMID:24730984

Deberardinis, Albert M; Madden, Daniel J; Banerjee, Upasana; Sail, Vibhavari; Raccuia, Daniel S; De Carlo, Daniel; Lemieux, Steven M; Meares, Adam; Hadden, M Kyle



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



4,4,9,9-Tetraphenyl pyrroloindolizine: a structural analogue of calix[2]pyrrole.  


Synthesis, spectral and structural characterization of a pyrroloindolizine derivative having structural similarity with calix[2]pyrrole is described. Here, two pyrrole rings are connected with two meso-carbon atoms having an N,?-linkage and an ?,?-linkage to afford the smallest analogue in the calixpyrrole family. Detailed NMR spectroscopic studies along with single crystal X-ray analysis confirm the assigned structure of the molecule. PMID:22466398

Sreedevi, K C Gowri; Thomas, Ajesh P; Ramakrishnan, S; Salini, P S; Holaday, M G Derry; Reddy, M L P; Srinivasan, A



Triptycene-derived homooxacalixarene analogues: synthesis, structures, and complexation with fullerenes C60 and C70.  


A series of triptycene-derived homooxacalixarene analogues were conveniently synthesized by a one-pot approach starting from 2,7-dihydroxytriptycene and 1,3-bisbromomethylbenzene derivatives under mild reaction conditions. Similarly, two pairs of "basket-like" triptycene-derived homooxacalixarene analogues were also designed and synthesized. Structures of these macrocyclic molecules in both solution and solid state were studied by NMR experiments and X-ray crystallography. Because of the rigid triptycene units, the homooxacalixarene analogues showed large cavities and fixed conformations even up to 380 K. It was also found that these novel macrocycles could be served as efficient host molecules for complexation with fullerenes C(60) and C(70). PMID:23270492

Xie, Tao; Hu, Shu-Zhen; Chen, Chuan-Feng



Synthesis of lipid A and its analogues for investigation of the structural basis for their bioactivity.  


As a step to elucidate the structural requirements for the endotoxic and antagonistic activity of lipid A derivatives, we have focused, in the present study, on the effects of the acyl moieties and acidic groups at the 1- and 4'- positions. We synthesized a new analogue corresponding to Rubrivivax gelatinosus lipid A, which has a characteristic symmetrical distribution of acyl groups on the two glucosamine residues with shorter acyl groups (decanoyl groups [C(10)] and lauryl groups [C(12)]) than Escherichia coli lipid A. Carboxymethyl analogues in which one of the phosphates was replaced with a carboxymethyl group were also synthesized with different distribution of acyl groups. Biological tests revealed that the distribution of acyl groups strongly affected the bioactivity. The synthetic Ru. gelatinosus type lipid A showed potent antagonistic activity against LPS, whereas its 1-O-carboxymethyl analogue showed weak endotoxic activity. These results demonstrated that when the lipid A has shorter (C(10), C(12)) hexa-acyl groups, the bioactivity of lipid A is easily affected with small structural difference, such as the difference of acidic group or the distribution of acyl groups, and the bioactivity changes from endotoxic to agonistic or vice versa at this structural boundary for the bioactivity. We also designed, based on molecular mechanics calculations, and synthesized lipid A analogues possessing acidic amino acid residues in place of the non-reducing end phosphorylated glucosamine. Definite switching of the endotoxic or antagonistic activity was also observed depending on the difference of the acidic groups (phosphoric acid or carboxylic acid) in the lipid A analogues. PMID:16303089

Fujimoto, Yukari; Adachi, Yo; Akamatsu, Masao; Fukase, Yoshiyuki; Kataoka, Mikayo; Suda, Yasuo; Fukase, Koichi; Kusumoto, Shoichi



Adaptive Hierarchical Key Structure Generation for Key Management in Wireless Sensor Networks using A  

Microsoft Academic Search

Wireless Sensor networks have a wide spectrum of civil and military applications that call for secure communication such as the terrorist tracking, target surveillance in hostile environments. For the secure communication in these application areas, we propose a method for generating a hierarchical key structure for the efficient group key management. In this paper, we apply A* algorithm in generating

Jin Myoung Kim; Tae Ho Cho



Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure–activity relationship  

Microsoft Academic Search

Resveratrol (trans-3,4?,5-trihydroxystilbene), a naturally occurring hydroxystilbene, is considered an essential antioxidative constituent of red wine possessing chemopreventive properties. However, resveratrol and even more its metabolite piceatannol were reported to have also cytostatic activities. In order to find out whether this is related to antioxidative properties of those compounds, we synthesized five other polyhydroxylated resveratrol analogues and studied structure–activity relationships between

Marek Murias; Walter Jäger; Norbert Handler; Thomas Erker; Zsuzsanna Horvath; Thomas Szekeres; Hans Nohl; Lars Gille



Structure-activity relationship of cinnamic acylsulfonamide analogues on the human EP3 prostanoid receptor.  


Potent and selective antagonists of the human EP3 receptor have been identified. The structure-activity relationship of the chemical series was conducted and we found several analogues displaying sub-nanomolar K(i) values at the EP3 receptor and micromolar activities at the EP1, EP2 and EP4 receptors. The effect of added human serum albumin (HSA) on the binding affinity at the EP3 receptor was also investigated. PMID:11504634

Juteau, H; Gareau, Y; Labelle, M; Sturino, C F; Sawyer, N; Tremblay, N; Lamontagne, S; Carrière, M C; Denis, D; Metters, K M



Solution structures of purine base analogues 6-chloroguanine, 8-azaguanine and allopurinol.  


Analogues of purine bases are highly relevant in the biological context and have been implicated as drug molecules for therapy against a number of diseases. Additionally, these molecules have been implicated to have a role in the prebiotic RNA world. However, experimental data on the structures of these molecules in aqueous solution is lacking. In this work, we report the ultraviolet resonance Raman spectra of 6-chloroguanine, 8-azaguanine and allopurinol, obtained with 260?nm excitation. The reported spectra have been assigned to normal modes computed from density functional theory (B3LYP/6-31G (d,p)) calculations. This work has been useful in identifying the solution-state structures of these molecules at neutral pH. We find that the guanine analogues 6-chloroguanine and 8-azaguanine exist as keto-N9H and keto-N7H tautomers in solution, respectively. On the other hand, the hypoxanthine analogue allopurinol exists as a mixture of keto-N9H and keto-N8H tautomers in solution. We predict that this work would be particularly useful in future vibrational studies where these molecules are present in complexes with their target proteins. PMID:23384120

Gogia, Spriha; Puranik, Mrinalini



Structural and biochemical studies of actin in complex with synthetic macrolide tail analogues.  


The actin filament-binding and filament-severing activities of the aplyronine, kabiramide, and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogues of aplyronine?C (SF-01 and GC-04) are shown to bind to G-actin with dissociation constants of (285±33) and (132±13)?nM, respectively. The crystal structures of actin complexes with GC-04, SF-01, and kabiramide?C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region to the SD1/SD3 cleft on the upper protomer, which displaces loop-D from the lower protomer on the same half-filament. With previous studies showing that the GC-04 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F-actin would make them more effective at severing filaments compared with plasma gelsolin. Structure-based analyses are used to suggest more reactive or targetable forms of GC-04 and SF-01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in children with cystic fibrosis. PMID:25047814

Pereira, Jose H; Petchprayoon, Chutima; Hoepker, Alexander C; Moriarty, Nigel W; Fink, Sarah J; Cecere, Giuseppe; Paterson, Ian; Adams, Paul D; Marriott, Gerard



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.


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.



Weed Identification: Using Plant Structures as a Key (Spanish)  

E-print Network

Weed identification is necessary to the success of any weed control program. Frequently, simple plant keys or "picture book identification guides are used to identify weeds. This handbook, which identifies and labels plant structures, is intended...

Baumann, Paul A.



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[triple bond, length as m-dash]N-Ni group) with active Mn(2+/3+) (Fe-C[triple bond, length as m-dash]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



Structure of human aspartyl aminopeptidase complexed with substrate analogue: insight into catalytic mechanism, substrate specificity and M18 peptidase family  

PubMed Central

Backround Aspartyl aminopeptidase (DNPEP), with specificity towards an acidic amino acid at the N-terminus, is the only mammalian member among the poorly understood M18 peptidases. DNPEP has implicated roles in protein and peptide metabolism, as well as the renin-angiotensin system in blood pressure regulation. Despite previous enzyme and substrate characterization, structural details of DNPEP regarding ligand recognition and catalytic mechanism remain to be delineated. Results The crystal structure of human DNPEP complexed with zinc and a substrate analogue aspartate-?-hydroxamate reveals a dodecameric machinery built by domain-swapped dimers, in agreement with electron microscopy data. A structural comparison with bacterial homologues identifies unifying catalytic features among the poorly understood M18 enzymes. The bound ligands in the active site also reveal the coordination mode of the binuclear zinc centre and a substrate specificity pocket for acidic amino acids. Conclusions The DNPEP structure provides a molecular framework to understand its catalysis that is mediated by active site loop swapping, a mechanism likely adopted in other M18 and M42 metallopeptidases that form dodecameric complexes as a self-compartmentalization strategy. Small differences in the substrate binding pocket such as shape and positive charges, the latter conferred by a basic lysine residue, further provide the key to distinguishing substrate preference. Together, the structural knowledge will aid in the development of enzyme-/family-specific aminopeptidase inhibitors. PMID:22720794



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



Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues.  


The tetrasaccharide heparan sulfate (HS) mimetic PG545, a clinical anti-cancer candidate, is an inhibitor of the HS-degrading enzyme heparanase. The kinetics of heparanase inhibition by PG545 and three structural analogues were investigated to understand their modes of inhibition. The cholestanol aglycon of PG545 significantly increased affinity for heparanase and also modified the inhibition mode. For the tetrasaccharides, competitive inhibition was modified to parabolic competition by the addition of the cholestanol aglycon. For the trisaccharides, partial competitive inhibition was modified to parabolic competition. A schematic model to explain these findings is presented. PMID:24251094

Hammond, Edward; Handley, Paul; Dredge, Keith; Bytheway, Ian



Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues?  

PubMed Central

The tetrasaccharide heparan sulfate (HS) mimetic PG545, a clinical anti-cancer candidate, is an inhibitor of the HS-degrading enzyme heparanase. The kinetics of heparanase inhibition by PG545 and three structural analogues were investigated to understand their modes of inhibition. The cholestanol aglycon of PG545 significantly increased affinity for heparanase and also modified the inhibition mode. For the tetrasaccharides, competitive inhibition was modified to parabolic competition by the addition of the cholestanol aglycon. For the trisaccharides, partial competitive inhibition was modified to parabolic competition. A schematic model to explain these findings is presented. PMID:24251094

Hammond, Edward; Handley, Paul; Dredge, Keith; Bytheway, Ian



Design, synthesis, crystal structures, and insecticidal activities of eight-membered azabridge neonicotinoid analogues.  


Three series of novel azabridge neonicotinoid analogues were designed and synthesized, which were constructed by starting material A, glutaraldehyde, and primary amine hydrochlorides (aliphatic amines, phenylhydrazines, and anilines). Most of the eight-membered azabridge compounds presented higher insecticidal activities than oxabridged compound B against cowpea aphid (Aphis craccivora) and brown planthopper (Nilaparvata lugens). Compared with imidacloprid, some azabridged compounds exhibited excellent insecticidal activity against brown planthopper. The crystal structures and bioassay indicated that changing bridge atoms from O to N could lead to entirely different conformations, which might be the important influential factor of the bioactivities. PMID:24364696

Xu, Renbo; Xia, Rui; Luo, Ming; Xu, Xiaoyong; Cheng, Jiagao; Shao, Xusheng; Li, Zhong



Naphthalene, Phenanthrene, and Pyrene as DNA Base Analogues: Synthesis, Structure, and Fluorescence in DNA  

PubMed Central

We describe the synthesis, structures, and DNA incorporation of deoxyribonucleosides carrying polycyclic aromatic hydrocarbons as the DNA “base” analogue. The new polycyclic compounds are 1-naphthyl, 2-naphthyl, 9-phenanthrenyl, and 1-pyrenyl deoxynucleosides. The compounds are synthesized using a recently developed C-glycosidic bond formation method involving organocadmium derivatives of the aromatic compounds coupling with a 1?-chlorodeoxyribose precursor. The principal products of this coupling are the ?-anomers of the deoxyribosides. An efficient method has also been developed for epimerization of the ?-anomers to ?-anomers by acid-catalyzed equilibration; this isomerization is successfully carried out on the four polycyclic nucleosides as well as two substituted phenyl nucleosides. The geometry of the anomeric substitution is derived from 1H NOE experiments and is also correlated with a single-crystal X-ray structure of one ?-isomer. Three of the polycyclic C-nucleoside derivatives are incorporated into DNA oligonucleotides via their phosphoramidite derivatives; the pyrenyl and phenanthrenyl derivatives are shown to be fluorescent in a DNA sequence. The results (1) broaden the scope of our C-glycoside coupling reaction, (2) demonstrate that (using a new acid-catalyzed epimerization) both ?- and ?-anomers are easily synthesized, and (3) constitute a new class of deoxynucleoside derivatives. Such nucleoside analogues may be useful as biophysical probes for the study of noncovalent interactions such as aromatic ?-stacking in DNA. In addition, the fluorescence of the phenanthrene and pyrene nucleosides may make them especially useful as structural probes. PMID:20865136

Ren, Rex X.-F.; Chaudhuri, Narayan C.; Paris, Pamela L.; Rumney, Squire; Kool, Eric T.



Charge Isomers of Myelin Basic Protein: Structure and Interactions with Membranes, Nucleotide Analogues, and Calmodulin  

PubMed Central

As an essential structural protein required for tight compaction of the central nervous system myelin sheath, myelin basic protein (MBP) is one of the candidate autoantigens of the human inflammatory demyelinating disease multiple sclerosis, which is characterized by the active degradation of the myelin sheath. In this work, recombinant murine analogues of the natural C1 and C8 charge components (rmC1 and rmC8), two isoforms of the classic 18.5-kDa MBP, were used as model proteins to get insights into the structure and function of the charge isomers. Various biochemical and biophysical methods such as size exclusion chromatography, calorimetry, surface plasmon resonance, small angle X-ray and neutron scattering, Raman and fluorescence spectroscopy, and conventional as well as synchrotron radiation circular dichroism were used to investigate differences between these two isoforms, both from the structural point of view, and regarding interactions with ligands, including calmodulin (CaM), various detergents, nucleotide analogues, and lipids. Overall, our results provide further proof that rmC8 is deficient both in structure and especially in function, when compared to rmC1. While the CaM binding properties of the two forms are very similar, their interactions with membrane mimics are different. CaM can be used to remove MBP from immobilized lipid monolayers made of synthetic lipids - a phenomenon, which may be of relevance for MBP function and its regulation. Furthermore, using fluorescently labelled nucleotides, we observed binding of ATP and GTP, but not AMP, by MBP; the binding of nucleoside triphosphates was inhibited by the presence of CaM. Together, our results provide important further data on the interactions between MBP and its ligands, and on the differences in the structure and function between MBP charge isomers. PMID:21647440

Wang, Chaozhan; Neugebauer, Ute; Burck, Jochen; Myllykoski, Matti; Baumgartel, Peter; Popp, Jurgen; Kursula, Petri



Total Synthesis and Evaluation of Cytostatin, its C10–C11 Diastereomers, and Additional Key Analogues: Impact on PP2A Inhibition  

PubMed Central

The total synthesis of cytostatin, an antitumor agent belonging to the fostriecin family of natural products is described in full detail. The convergent approach relied on a key epoxide opening reaction to join the two stereotriad units and a single-step late stage, stereoselective installation of the sensitive (Z,Z,E)-triene through a ?-chelation controlled nucleophilic addition. The synthetic route provided rapid access to the C4–C6 stereoisomers of the cytostatin lactone, which were prepared and used to define the C4–C6 relative stereochemistry of the natural product. In addition to the natural product, each of the C10–C11 diastereomers of cytostatin was divergently prepared (11 steps from key convergence step) by this route and used to unequivocally confirm the relative and absolute stereochemistry of cytostatin. Each of the cytostatin diastereomers exhibited a reduced activity towards inhibition of PP2A (>100-fold), demonstrating the importance of the presence and stereochemistry of the C10-methyl and C11-hydroxy groups for potent PP2A inhibition. Extensions of the studies provided dephosphocytostatin (40), sulfocytostatin (67, a key analogue related to the natural product sultriecin), 11-deshydroxycytostatin (78), and 72 lacking the entire C12–C18 (Z,Z,E)-triene segment and were used to define the magnitude of the C9-phosphate (>4000-fold), C11-alcohol (250-fold), and triene (220-fold) contribution to PP2A inhibition. A model of cytostatin bound to the active site of PP2A is presented, compared to that of fostriecin which is also presented in detail for the first time, and used to provide insights into the role of the key substituents. Notably, the ?,?-unsaturated lactone of cytostatin, like that of fostriecin, is projected to serve as a key electrophile providing a covalent adduct with Cys269 unique to PP2A contributing to its potency (?200-fold for fostriecin) and accounting for its selectivity. PMID:17177422

Lawhorn, Brian G.; Boga, Sobhana B.; Wolkenberg, Scott E.; Colby, David A.; Gauss, Carla-Maria; Swingle, Mark R.; Amable, Lauren; Honkanen, Richard E.; Boger, Dale L.



Synthesis of structurally diverse benzosuberene analogues and their biological evaluation as anti-cancer agents.  


Diversely functionalized, fused aryl-alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure-activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton's reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0 ?M) and strongly cytotoxic against selected human cancer cell lines (for example, GI50=5.47 nM against NCI-H460 cells with fluoro-benzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18 (referred to as KGP265, compound 44) and a water-soluble serinamide salt (compound 48) of KGP156 were also synthesized and evaluated in this study. PMID:24183586

Tanpure, Rajendra P; George, Clinton S; Strecker, Tracy E; Devkota, Laxman; Tidmore, Justin K; Lin, Chen-Ming; Herdman, Christine A; Macdonough, Matthew T; Sriram, Madhavi; Chaplin, David J; Trawick, Mary Lynn; Pinney, Kevin G



Band gap and chemically ordered domain structure of a graphene analogue BCN  

NASA Astrophysics Data System (ADS)

Chemically synthesized few layer graphene analogues of B xC yN z are characterized by aberration corrected transmission electron microscopy and high resolution electron energy loss spectroscopy (HREELS) to determine the local phase, electronic structure and band gap. HREELS band gap studies of a B xC yN z composition reveal absorption edges at 2.08, 3.43 and 6.01 eV, indicating that the B xC yN z structure may consist of domains of different compositions. The K-absorption edge energy position of the individual elements in B xC yN z is determined and compared with h-BN and graphite. An understanding of these experimental findings is developed with complementary first-principles based calculations of the various ordered configurations of B xC yN z.

Venu, K.; Kanuri, S.; Raidongia, K.; Hembram, K. P. S. S.; Waghmare, U. V.; Datta, R.



Structure-activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis.  


Novel methods for treatment of African trypanosomiasis, caused by infection with Trypanosoma brucei are needed. Cordycepin (3'-deoxyadenosine, 1a) is a powerful trypanocidal compound in vitro but is ineffective in vivo because of rapid metabolic degradation by adenosine deaminase (ADA). We elucidated the structural moieties of cordycepin required for trypanocidal activity and designed analogues that retained trypanotoxicity while gaining resistance to ADA-mediated metabolism. 2-Fluorocordycepin (2-fluoro-3'-deoxyadenosine, 1b) was identified as a selective, potent, and ADA-resistant trypanocidal compound that cured T. brucei infection in mice. Compound 1b is transported through the high affinity TbAT1/P2 adenosine transporter and is a substrate of T. b. brucei adenosine kinase. 1b has good preclinical properties suitable for an oral drug, albeit a relatively short plasma half-life. We present a rapid and efficient synthesis of 2-halogenated cordycepins, also useful synthons for the development of additional novel C2-substituted 3'-deoxyadenosine analogues to be evaluated in development of experimental therapeutics. PMID:24283924

Vodnala, Suman K; Lundbäck, Thomas; Yeheskieli, Esther; Sjöberg, Birger; Gustavsson, Anna-Lena; Svensson, Richard; Olivera, Gabriela C; Eze, Anthonius A; de Koning, Harry P; Hammarström, Lars G J; Rottenberg, Martin E



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.



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

SciTech Connect

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 {pi}-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the {pi}-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 H{sub 2}O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.

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



Structure-activity relationships of milrinone analogues determined in vitro in a rabbit heart membrane Ca(2+)-ATPase model.  


The cardiac activity of a series of analogues of the positive inotropic bipyridines amrinone (5-amino-[3,4'-bipyridin]-6(1H)-one) and milrinone (2-methyl-5-cyano-[3,4'-bipyridin]-6(1H)-one) was evaluated in vitro in a rabbit myocardial membrane Mg(2+)-dependent, Ca(2+)-stimulable adenosine triphosphatase (Ca(2+)-ATPase) model and structure-activity relationships were compared for nine closely related derivatives. In the present studies, a 5-bromo analogue of milrinone stimulated myocardial membrane Ca(2+)-ATPase significantly (10(-7) M; P < 0.001 vs control, with 67% of the activity of milrinone), whereas a 2'-methyl-2H-milrinone derivative was inactive. Although amrinone was inactive in this assay, its 2-methyl analogue was stimulatory. However, analogues lacking a 2-substituent (with or without a 5-cyano group) or with the 3-N position blocked by a methyl group did not stimulate myocardial membrane Ca(2+)-ATPase activity. Structural data for these bipyridines show that those with either a 2- or 2'-methyl substituent have a twist conformation, whereas those without are nearly planar. Activity data reveal that those bipyridines with a nonplanar conformation are more active in the Ca(2+)-ATPase assay. Further study of milrinone analogues with a 2'-methyl substituent shows that even though the effect on the twist angle is equivalent to that of 2-methyl substitution, these analogues are less potent. Data for this series reveal that the prerequisites for Ca(2+)-ATPase stimulation include not only a 2-methyl to maintain a twist conformation but also a free 3-N position and a 5-substituent. This model for optimal activity in the myocardial membrane Ca(2+)-ATPase system differs from those proposed for phosphodiesterase enzyme receptor recognition only in the requirement for a nonplanar molecule. We have previously shown that milrinone, but not amrinone, shares structural homology with thyroxine and was able to stimulate myocardial membrane Ca(2+)-ATPase activity in a manner similar to the thyroid hormone. Additionally, milrinone, but not amrinone, was an effective competitor for thyroxine binding to the serum transport protein transthyretin. Analysis of the milrinone-transthyretin crystal complex confirms the structural homology between milrinone and thyroid hormone which is not shared by amrinone. Modeling studies of the binding interactions of milrinone analogues indicate that the 2-desmethylmilrinone analogue, the most inhibitory analogue, lacks the hydrophobic contacts present in milrinone in its transthyretin-bound complex.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7783130

Cody, V; Wojtczak, A; Davis, F B; Davis, P J; Blas, S D



Extrapolating surface structures to depth in transpressional systems: the role of rheology and convergence angle deduced from analogue experiments  

NASA Astrophysics Data System (ADS)

The internal structure of major strike-slip faults is still poorly understood, particularly how the deep structure could be inferred from its surface expression (Molnar and Dayem, 2011 and references therein). Previous analogue experiments suggest that the convergence angle is the most influential factor (Leever et al., 2011). Further analogue modeling may allow a better understanding how to extrapolate surface structures to the subsurface geometry of strike-slip faults. Various scenarios of analogue experiments were designed to represent strike-slip faults in nature from different geological settings. As such key parameters, which are investigated in this study include: (a) the angle of convergence, (b) the thickness of brittle layer, (c) the influence of a rheological weak layer within the crust, and (d) influence of a thick and rheologically weak layer at the base of the crust. The latter aimed to simulate the effect of a hot metamorphic core complex or an alignment of uprising plutons bordered by a transtensional/transpressional strike-slip fault. The experiments are aimed to explain first order structures along major transcurrent strike-slip faults such as the Altyn, Kunlun, San Andrea and Greendale (Darfield earthquake 2010) faults. The preliminary results show that convergence angle significantly influences the overall geometry of the transpressive system with greater convergence angles resulting in wider fault zones and higher elevation. Different positions, densities and viscosities of weak rheological layers have not only different surface expressions but also affect the fault geometry in the subsurface. For instance, rheological weak material in the bottom layer results in stretching when experiment reaches a certain displacement and a buildup of a less segmented, wide positive flower structure. At the surface, a wide fault valley in the middle of the fault zone is the reflection of stretching along the velocity discontinuity at depth. In models with a thin and rheologically weaker layer in the middle of the brittle layer, deformation is distributed over more faults and the geometry of the fault zone below and above the weak zone shows significant differences, suggesting that the correlation of structures across a weak layer has to be supported by geophysical data, which help constraining the geometry of the deep part. This latter experiment has significantly similar phenomena in reality, such as few pressure ridges along Altyn fault. The experimental results underline the need to understand the role of the convergence angle and the influence of rheology on fault evolution, in order to connect between surface deformation and subsurface geometry. References Leever, K. A., Gabrielsen, R. H., Sokoutis, D., Willingshofer, E., 2011. The effect of convergence angle on the kinematic evolution of strain partitioning in transpressional brittle wedges: Insight from analog modeling and high-resolution digital image analysis. Tectonics, 30(2), TC2013. Molnar, P., Dayem, K.E., 2010. Major intracontinental strike-slip faults and contrasts in lithospheric strength. Geosphere, 6, 444-467.

Hsieh, Shang Yu; Neubauer, Franz; Cloetingh, Sierd; Willingshofer, Ernst; Sokoutis, Dimitrios



Structure-based optimization of Cephalothin-analogue boronic acids as ?-lactamase inhibitors  

PubMed Central

Boronic acids have proved to be promising selective inhibitors of ?-lactamases, acting as transition state analogues. Starting from a previously described nanomolar inhibitor of AmpC ?-lactamase, three new inhibitors were designed to gain interactions with highly conserved residues, such as Asn343, and to bind more tightly to the enzyme. Among these, one was obtained by stereoselective synthesis and succeeded in placing its anionic group into the carboxylate binding site of the enzyme, as revealed by X-ray crystallography of the complex inhibitor/AmpC. Nevertheless, it failed at improving affinity, when compared to the lead from which it was derived. The origins of this structural and energetic discrepancy are discussed. PMID:17997318

Morandi, Stefania; Morandi, Federica; Caselli, Emilia; Shoichet, Brian K.; Prati, Fabio



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



Synthesis of a nitrogen analogue of sphingomyelin as a sphingomyelinase inhibitor.  


[structure: see text] Sphingomyelin nitrogen analogue 1 was designed and synthesized as a sphingomyelinase inhibitor. The synthesis was established by continuous Hofmann rearrangement and Crutius rearrangement as key steps in constructing the 3-hydroxy-1,2-diamine structure in the backbone of 1. This analogue showed moderate inhibitory activity toward SMase isolated from B. cereus. PMID:12889878

Hakogi, Toshikazu; Taichi, Misako; Katsumura, Shigeo



Synthesis and structure-activity relationship studies of N-terminal analogues of the antimicrobial peptide tridecaptin A(1).  


Chemical synthesis was used to increase the potency of the antimicrobial lipopeptide tridecaptin A1. Lipid tail modification proved to be an ideal platform for synthesizing structurally simpler analogues that are not readily accessible by isolation. The stereochemical elements of the tridecaptin A1 lipid tail are not essential for antimicrobial activity and could be replaced with hydrophobic aliphatic or aromatic groups. Some simpler analogues displayed potent antimicrobial activity against Gram-negative bacteria, including Campylobacter jejuni, Escherichia coli O157:H7, and multidrug resistant Klebsiella pneumoniae. PMID:24479847

Cochrane, Stephen A; Lohans, Christopher T; Brandelli, Jeremy R; Mulvey, George; Armstrong, Glen D; Vederas, John C



Novel lopinavir analogues incorporating heterocyclic replacements of six-member cyclic urea--synthesis and structure-activity relationships.  


The HIV protease inhibitor ABT-378 (lopinavir) has a six-member cyclic urea in the P-2 position. A series of analogues in which the six-member cyclic urea is replaced by various heterocycles was synthesized and the structure-activity relationships explored. PMID:15109669

Sham, Hing L; Betebenner, David A; Rosenbrook, William; Herrin, Thomas; Saldivar, Ayda; Vasavanonda, Sudthida; Plattner, Jacob J; Norbeck, Daniel W



Novel lopinavir analogues incorporating non-Aromatic P-1 side chains--synthesis and structure--activity relationships.  


The HIV protease inhibitor Lopinavir has a pseudosymmetric core unit incorporating benzyl groups at both P-1, P-1' positions. A series of analogues incorporating non-aromatic side chains at the P-1 position were synthesized and the structure-activity relationships explored. PMID:12372511

Sham, Hing L; Zhao, Chen; Li, Leping; Betebenner, David A; Saldivar, Ayda; Vasavanonda, Sudthida; Kempf, Dale J; Plattner, Jacob J; Norbeck, Daniel W



Elucidation of the structure of constrained bicyclopeptides in solution by two-dimensional cross-relaxation spectroscopy: amatoxin analogues.  


The evaluation of peptide structures in solution is made feasible by the combined use of two-dimensional NMR in the laboratory (NOESY) and rotating frames (ROESY), and by the use of molecular dynamics calculations. The present paper describes how both the NMR method and molecular dynamics calculations were applied to very rigid synthetic bicycle peptides that are analogues of natural amatoxins. The NMR theory, which allows the estimate of interatomic distances between interacting nuclei, is briefly discussed. The experimental data were compared with those of known solid-state structures. Three amatoxin analogues have been examined. Of these, one is biologically active (S-deoxo gamma[R] OH-Ile3-amaninamide) and its structure in the solid state has recently been worked out. The second and third analogues (S-dexo-Ile3-Ala5-amaninamide and S-deoxo-D-Ile3-amaninamide, respectively) are inactive and their solid-state structures are unknown. The data presented confirm the authors previous hypothesis that lack of biological activity of S-deoxo-Ile3-Ala5-amaninamide is due to the masking of the tryptophan ring by the methyl group of L-Ala and not to massive conformational changes of the analogue. PMID:9225241

Isernia, C; Falcigno, L; Macura, S; Paolillo, L; Pastore, A L; Zanotti, G



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

Microsoft Academic Search

A number of benzoic acid analogues showed antifungal activity against strains of Aspergillus flavus, Aspergillus fumigatus and Aspergillus terreus, causative agents of human aspergillosis, in in vitro bioassays. Structure–activity analysis revealed that antifungal activities of benzoic and gallic acids were increased by addition of a methyl, methoxyl or chloro group at position 4 of the aromatic ring, or by esterification

Jong H. Kim; Bruce C. Campbell; Noreen Mahoney; Kathleen L. Chan; Russell J. Molyneux; Arunmozhi Balajee



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



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



Generation of anti-trypanosomal agents through concise synthesis and structural diversification of sesquiterpene analogues.  


To access high-quality small-molecule libraries to screen lead candidates for neglected diseases exemplified by human African trypanosomiasis, we sought to develop a synthetic process that would produce collections of cyclic scaffolds relevant to an assortment of natural products exhibiting desirable biological activities. By extracting the common structural features among several sesquiterpenes, including artemisinin, anthecularin, and transtaganolides, we designed six types of scaffolds with systematic structural variations consisting of three types of stereochemical relationships on the sp(3) ring-junctions and two distinct arrays of tricyclic frameworks. A modular and stereodivergent assembly of dienynes exploiting a versatile manifold produced a series of cyclization precursors. Divergent cyclizations of the dienynes employing tandem ring-closing metathesis reactions overrode variant reactivities of the cyclization precursors, leading to the six canonical sets of the tricyclic scaffolds incorporating a diene group. Screenings of trypanosomal activities of the canonical sets, as well as regio- and stereoisomers of the tricyclic dienes, allowed generation of several anti-trypanosomal agents defining the three-dimensional shape of the pharmacophore. The candidate tricyclic dienes were selected by primary screenings and further subjected to installation of a peroxide bridge, which generated artemisinin analogues that exhibited potent in vitro anti-trypanosomal activities comparable or even superior to those of artemisinin and the approved drugs, suramin and eflornithine. PMID:21413715

Oguri, Hiroki; Hiruma, Takahisa; Yamagishi, Yutaka; Oikawa, Hideaki; Ishiyama, Aki; Otoguro, Kazuhiko; Yamada, Haruki; ?mura, Satoshi



Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I. Exploration of alternative benzyl and privileged structure moieties  

PubMed Central

This Letter describes the first account of the synthesis and SAR, developed through an iterative analogue library approach, of analogues of the highly selective M1 allosteric agonist TBPB. With slight structural changes, mAChR selectivity was maintained, but the degree of partial M1 agonism varied considerably. PMID:18805692

Bridges, Thomas M.; Brady, Ashley E.; Kennedy, J. Phillip; Daniels, R. Nathan; Miller, Nicole R.; Kim, Kwango; Breininger, Micah L.; Gentry, Patrick R.; Brogan, John T.; Jones, Carrie K.; Conn, P. Jeffrey



Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor  

PubMed Central

The nociceptin/orphanin FQ (NOP) receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q2 of 0.501, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity. PMID:22272114

Bao, Pingping; Zhang, Xiaole; Ren, Hong; Li, Yan; Mu, Zulin; Zhang, Shuwei; Li, Guohui; Yang, Ling



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.


Antioxidant capacity of curcumin-directed analogues: Structure–activity relationship and influence of microenvironment  

Microsoft Academic Search

Curcumin is the active ingredient of turmeric powder with a variety of biological activities including antioxidative activity. In order to find more active antioxidants with curcumin as the lead compound we synthesised a series of enone analogues of curcumin. The present work studied and compared the capacity of curcumin-directed analogues to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and protect human red blood cells

Ya-Jing Shang; Xiao-Ling Jin; Xian-Ling Shang; Jiang-Jiang Tang; Guo-Yun Liu; Fang Dai; Yi-Ping Qian; Gui-Juan Fan; Qiang Liu; Bo Zhou



Structure-activity relationships of analogues of thapsigargin modified at O-11 and O-12.  


A number of analogues of thapsigargin have been synthesized by alkylating or acylating O-11 and O-12 in the lactol obtained by reducing thapsigargicin. Introduction of alpha-disposed substituents decreased the Ca(2+)-ATPase inhibitory potency of the analogue, whereas the enzyme was more tolerant toward beta-disposed substituents, indicating that the alpha-face of the lactone ring is in close contact with the binding site when the inhibitor is bound to the enzyme. PMID:7830270

Nielsen, S F; Thastrup, O; Pedersen, R; Olsen, C E; Christensen, S B



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



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.



Synthesis, structure, and glutathione peroxidase-like activity of amino acid containing ebselen analogues and diaryl diselenides.  


The synthesis of some ebselen analogues and diaryl diselenides, which have amino acid functions as an intramolecularly coordinating group (Se···O) has been achieved by the DCC coupling procedure. The reaction of 2,2'-diselanediylbis(5-tert-butylisophthalic acid) or the activated ester tetrakis(2,5-dioxopyrrolidin-1-yl) 2,2'-diselanediylbis(5-tert-butylisophthalate) with different C-protected amino acids (Gly, L-Phe, L-Ala, and L-Trp) afforded the corresponding ebselen analogues. The used precursor diselenides have been found to undergo facile intramolecular cyclization during the amide bond formation reaction. In contrast, the DCC coupling of 2,2'-diselanediyldibenzoic acid with C-protected amino acids (Gly, L/D-Ala and L-Phe) affords the corresponding amide derivatives and not the ebselen analogues. Some of the representative compounds have been structurally characterized by single-crystal X-ray crystallography. The glutathione peroxidase (GPx)-like activities of the ebselen analogues and the diaryl diselenides have been evaluated by using the coupled reductase assay method. Intramolecularly stabilized ebselen analogues show slightly higher maximal velocity (V(max)) than ebselen. However, they do not show any GPx-like activity at low GSH concentrations at which ebselen and related diselenides are active. This could be attributed to the peroxide-mediated intramolecular cyclization of the corresponding selenenyl sulfide and diaryl diselenide intermediates generated during the catalytic cycle. Interestingly, the diaryl diselenides with alanine (L,L or D,D) amide moieties showed excellent catalytic efficiency (k(cat)/K(M)) with low K(M) values in comparison to the other compounds. PMID:21956838

Selvakumar, Karuthapandi; Shah, Poonam; Singh, Harkesh B; Butcher, Ray J



Comparative Structure-Activity Relationships of Benztropine Analogues at the Dopamine Transporter and Histamine H1 Receptors  

PubMed Central

Benztropine (BZT) and its analogues inhibit dopamine uptake and bind with moderate to high affinity to the dopamine transporter (DAT). However, many of these compounds, in contrast to other monoamine uptake inhibitors, lack cocaine-like behavioral effects and fail to potentiate the effects of cocaine. The BZT analogues also exhibit varied binding affinities for muscarinic M1 and histamine H1 receptors. In this study a comparative analysis was conducted of pharmacophoric features with respect to the activities of BZT analogues at the DAT and at the histamine H1 receptor. The BZT analogues showed a wide range of histamine H1 receptor (Ki =16-37600 nM) and DAT (Ki=8.5-6370 nM) binding affinities. A stereoselective histamine H1-antagonist pharmacophore, using a five-point superimposition of classical antagonists on the template, cyproheptadine, was developed. A series of superimpositions and comparisons were performed with various analogues of BZT. In general, smaller substituents were well tolerated on the aromatic rings of the diphenyl methoxy group for both the DAT and H1 receptor, however for the H1 receptor, substitution at only one of the aromatic rings was preferred. The substituents at the 2- and N-positions of the tropane ring were preferred for DAT however these groups seem to overlap receptor essential regions in the histamine H1 receptor. Molecular models at the DAT and the histamine H1 receptor provide further insight into the structural requirements for binding affinity and selectivity that can be implemented in future drug design. PMID:16460947

Kulkarni, Santosh S.; Kopajtic, Theresa A.; Katz, Jonathan L.; Newman, Amy Hauck



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

E-print Network

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde- 3-phosphate, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various

Gelb, Michael


Synthesis, crystal structure and anti-inflammatory properties of curcumin analogues.  


Curcuminoids have been reported to possess multifunctional bioactivities, especially the ability to inhibit proinflammatory induction. Since it has been suggested that the seven-carbon beta-diketone linker in curcumin is responsible for its instability, nine mono-carbonyl five-carbon linker containing analogues were designed and synthesized. Their bioactivity against lipopolysaccharide-induced TNF-alpha amd IL-6 secretion was evaluated by using mouse J774.1 macrophages. The results showed that the 3'-methoxyl plays an important role in bioactivity and cyclohexanone containing analogues exhibited stronger inflammatory inhibition than acetone and cyclopentanone analogues. Subsequently the most active analogue 3c was determined using single-crystal X-ray diffraction. X-ray analysis and comparison with curcumin reveals that the presence of cyclohexanone in 3c, which remotely resembles the 6-membered ring in the enol tautomer in curcumin, may play an important role in the bioactivity. It is suggested that five-carbon linker analogues containing a cyclohexane ring which are synthetically assessable may be pharmacologically important. PMID:18336957

Liang, Guang; Yang, Shulin; Zhou, Huiping; Shao, Lili; Huang, Kexin; Xiao, Jian; Huang, Zhifeng; Li, Xiaokun



Structure-based design of an indolicidin peptide analogue with increased protease stability.  


Indolicidin is an antimicrobial cationic peptide with broad-spectrum activity isolated from bovine neutrophils. An indolicidin analogue CP-11, ILKKWPWWPWRRK-NH(2), with improved activity against Gram-negative bacteria had increased positive charge and amphipathicity while maintaining the short length of the parent molecule. The structure of CP-11 in the presence of dodecylphosphocholine (DPC) micelles was determined using nuclear magnetic resonance spectroscopy. CP-11 was found to be an amphipathic molecule with a U-shaped backbone bringing the N- and C-termini in close proximity. On the basis of this close proximity, a cyclic disulfide-bonded peptide cycloCP-11, ICLKKWPWWPWRRCK-NH(2), was designed to stabilize the lipid-bound structure and to increase protease resistance. The three-dimensional structure of cycloCP-11 was determined under the same conditions as for the linear peptide and was found to be similar to CP-11. Both CP-11 and cycloCP-11 associated with phospholipid membranes in a similar manner as indicated by circular dichroism and fluorescence spectra. The minimal inhibitory concentrations of CP-11 and cycloCP-11 for a range of bacteria differed by no more than 2-fold, and they were nonhemolytic at concentrations up to 256 microg/mL. Cyclization was found to greatly increase protease stability. The half-life of cycloCP-11 in the presence of trypsin was increased by 4.5-fold from 4 to 18 min. More importantly, the antibacterial activity of cycloCP-11, but not that of CP-11, in the presence of trypsin was completely retained up to 90 min since the major degradation product was equally active. A structural comparison of CP-11 and cycloCP-11 revealed that the higher trypsin resistance of cycloCP-11 may be due to the more compact packing of lysine and tryptophan side chains. These findings suggest that cyclization may serve as an important strategy in the rational design of antimicrobial peptides. PMID:14640680

Rozek, Annett; Powers, Jon-Paul S; Friedrich, Carol L; Hancock, Robert E W



Assessment of aquatic experimental versus predicted and extrapolated chronic toxicity data of four structural analogues.  


The present study was developed to assess the chronic toxicity predictions and extrapolations for a set of chlorinated anilines (aniline (AN), 4-chloroaniline (CA), 3,5-dichloroaniline (DCA) and 2,3,4-trichloroaniline (TCA)). Daphnia magna 21 d chronic experimental data was compared to the chronic toxicity predictions made by the US EPA ECOSAR QSAR tools and to acute-to-chronic extrapolations. Additionally, Species Sensitivity Distributions (SSDs) were constructed to assess the chronic toxicity variability among different species and to investigate the acute versus chronic toxicity in a multi-species context. Since chlorinated anilines are structural analogues with a designated polar narcotic mode of action, similar toxicity responses were assumed. However, rather large interchemical and interspecies differences in toxicity were observed. Compared to the other three test compounds, TCA exposure had a significantly larger impact on growth and reproduction of D. magna. Furthermore, this study illustrated that QSARs or a fixed ACR are not able to account for these interchemical and interspecies differences. Consequently, ECOSAR was found to be inadequate to predict the chronic toxicity of the anilines and the use of a fixed ACR (of 10) led to under of certain species. The experimental ACRs determined in D. magna were substantially different among the four aromatic amines (ACR of 32 for AN, 16.9 for CA, 5.7 for DCA and 60.8 for TCA). Furthermore, the SSDs illustrated that Danio rerio was rather insensitive to AN in comparison to another fish species, Phimphales promelas. It was therefore suggested that available toxicity data should be used in an integrative multi-species way, rather than using individual-based toxicity extrapolations. In this way, a relevant overview of the differences in species sensitivity is given, which in turn can serve as the basis for acute to chronic extrapolations. PMID:21944038

Dom, Nathalie; Knapen, Dries; Blust, Ronny



Information Theoretic Secret Key Generation: Structured Codes and Tree Packing  

ERIC Educational Resources Information Center

This dissertation deals with a multiterminal source model for secret key generation by multiple network terminals with prior and privileged access to a set of correlated signals complemented by public discussion among themselves. Emphasis is placed on a characterization of secret key capacity, i.e., the largest rate of an achievable secret key,…

Nitinawarat, Sirin



Structure-activity relationship of S-trityl-L-cysteine analogues as inhibitors of the human mitotic kinesin Eg5.  


The human kinesin Eg5 is a potential drug target for cancer chemotherapy. Eg5 specific inhibitors cause cells to block in mitosis with a characteristic monoastral spindle phenotype. Prolonged metaphase block eventually leads to apoptotic cell death. S-trityl-L-cysteine (STLC) is a tight-binding inhibitor of Eg5 that prevents mitotic progression. It has proven antitumor activity as shown in the NCI 60 tumor cell line screen. It is of considerable interest to define the minimum chemical structure that is essential for Eg5 inhibition and to develop more potent STLC analogues. An initial structure-activity relationship study on a series of STLC analogues reveals the minimal skeleton necessary for Eg5 inhibition as well as indications of how to obtain more potent analogues. The most effective compounds investigated with substitutions at the para-position of one phenyl ring have an estimated K i (app) of 100 nM in vitro and induce mitotic arrest with an EC 50 of 200 nM. PMID:18266314

Debonis, Salvatore; Skoufias, Dimitrios A; Indorato, Rose-Laure; Liger, François; Marquet, Bernard; Laggner, Christian; Joseph, Benoît; Kozielski, Frank



Fragmentation of Golgi membranes by norrisolide and designed analogues  

E-print Network

of norrisolide analogues in which the chemical functionalities present in the parent structure were altered of membranes that play a key role in the final structural modifications of proteins, their sorting network (TGN).4 Transport vesicles originating at the rough endoplasmic reticulum (ER) bring newly synthe

Theodorakis, Emmanuel


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.



Clarifying the structure of granadaene: total synthesis of related analogue [2]-granadaene and confirmation of its absolute stereochemistry.  


Streptococcus agalactiae is an important agent in the infection of neonates in the first world. One of the most extended methods for its identification is based on the detection of a characteristic red pigment in the patient samples, named [12]-granadaene (1). In this article, we present a modular and flexible approach to simple analogues of this ornithine rhamno-polyene 1 and the elucidation of the most important features of its structure: the absolute configuration at C-27, the stereochemistry of the anomeric center and the link of the amino acid ornithine to the rest of the structure. PMID:23043725

Paradas, Miguel; Jurado, Rocío; Haidour, Ali; Rodríguez Granger, Javier; Sampedro Martínez, Antonio; de la Rosa Fraile, Manuel; Robles, Rafael; Justicia, José; Cuerva, Juan M



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


A number of benzoic acid analogues showed antifungal activity against strains of Aspergillus flavus, Aspergillus fumigatus and Aspergillus terreus, causative agents of human aspergillosis, in in vitro bioassays. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased by addition of a methyl, methoxyl or chloro group at position 4 of the aromatic ring, or by esterification of the carboxylic acid with an alkyl group, respectively. Thymol, a natural phenolic compound, was a potent chemosensitizing agent when co-applied with the antifungal azole drugs fluconazole and ketoconazole. The thymol-azole drug combination demonstrated complete inhibition of fungal growth at dosages far lower than the drugs alone. Co-application of thymol with amphotericin B had an additive effect on all strains of aspergilli tested with the exception of two of three strains of A. terreus, where there was an antagonistic effect. Use of two mitogen-activated protein kinase (MAPK) mutants of A. fumigatus, sakA? and mpkC?, having gene deletions in the oxidative stress response pathway, indicated antifungal and/or chemosensitization activity of the benzo analogues was by disruption of the oxidative stress response system. Results showed that both these genes play overlapping roles in the MAPK system in this fungus. The potential of safe, natural compounds or analogues to serve as chemosensitizing agents to enhance efficacy of commercial antifungal agents is discussed. PMID:20943191

Kim, Jong H; Campbell, Bruce C; Mahoney, Noreen; Chan, Kathleen L; Molyneux, Russell J; Balajee, Arunmozhi



Analogue Gravity  

E-print Network

Analogue gravity is a research programme which investigates analogues of general relativistic gravitational fields within other physical systems, typically but not exclusively condensed matter systems, with the aim of gaining new insights into their corresponding problems. Analogue models of (and for) gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing) and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity).

Carlos Barcelo; Stefano Liberati; Matt Visser



New route to unsymmetrical phthalocyanine analogues by the use of structurally distorted subphthalocyanines  

SciTech Connect

In addition to traditional uses as dyes and in photocopying devices, phthalocyanines (Pcs) are now rapidly growing in importance in many fields such as chemical sensors, electrochromism, batteries, photodynamic cancer therapy, molecular metals, photochemical hole burning, and liquid crystals. In this communication, the authors present a completely new method for the preparation of monosubstituted type unsymmetrical Pcs and Pc analogues, which utilizes the so-called subphthalocyanines (SubPcs).

Kobayashi, Nagao; Kondo, Ryoko; Nakajima, Shinichiro; Osa, Tetsuo (Tohoku Univ., Sendai (Japan))



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))



Stabilization of microtubules by inorganic phosphate and its structural analogues, the fluoride complexes of aluminum and beryllium  

SciTech Connect

In order to elucidate how the elementary reactions of GTP cleavage and subsequent inorganic phosphate (P/sub i/) release, which accompany microtubule assembly, regulate microtubule dynamics, the effect of P/sub i/ and of its structural analogues AlF/sub 4//sup -/ and BeF/sub 3//sup -/ on the stability of GDP-microtubules has been investigated. Inorganic phosphate binds to microtubules with a low affinity (K/sub D/ = 25 mM) and slows down the rate of GDP-subunit dissociation by about 2 orders of magnitude. AlF/sub 4//sup -/ and BeF/sub 3//sup -/ exhibit phosphate-like effects with 1000-fold higher affinity. Evidence has been obtained for direct binding of BeF/sub 3//sup -/ to microtubules with a stoichiometry of 1 mol of BeF/sub 3//sup -/ per mole of GDP-subunit and an equilibrium dissociation constant of 12-15 AlF/sub 4//sup -/ and P/sub i/ compete for this site. Phosphate analogues abolish oscillatory polymerization kinetics and slow down microtubule turnover at steady state. In view of these results, the authors propose that P/sub i/ and its structural analogues bind to the site of the ..gamma..-phosphate of GTP in the E site and reconstitute a GDP-P/sub i/-microtubule, from which tubulin subunits dissociate very slowly. They therefore understand that, following GTP cleavage on microtubules, P/sub i/ release in the medium is accompanied by a structural change resulting in a large destabilization of the polymer. A cap of slowly dissociating GDP-P/sub i/-subunits prevents depolymerization of the microtubule GDP-core at steady state. The similarity with the actin system is studied.

Carlier, M.F.; Didry, D.; Melki, R.; Chabre, M.; Pantaloni, D.



A comparison of the antiatherogenic effects of probucol and of a structural analogue of probucol in low density lipoprotein receptor-deficient rabbits.  

PubMed Central

The efficacies of probucol and a close structural analogue as antioxidants in the prevention of atherogenesis in LDL receptor-deficient rabbits were compared. The antioxidant potency of the analogue in vitro was equal to that of probucol. Its biological availability was much greater: almost comparable concentrations in total plasma were achieved by feeding 1% probucol (wt/wt) and 0.05% analogue (wt/wt). Total plasma concentrations were comparable, but the concentration of probucol within the LDL fraction was about twice that of the analogue. Probucol slowed lesion progression by almost 50%, confirming earlier reports; the analogue, however, showed no detectable inhibitory effect on atherogenesis. Resistance of LDL to oxidation was measured at the end of the study by incubating it with Cu2+ and measuring the rate of diene conjugation. Probucol prolonged diene conjugation lag time from the control value of 130 min to values > 1,000 min. The analogue approximately tripled the lag time (mean, 410 min) and yet failed to slow the atherogenic process. The results suggest that LDL resistance to oxidation must reach some threshold level before there is significant protection against atherogenesis. However, probucol has additional biological effects, possibly not shared by the analogue, that could contribute to its antiatherogenic potential. Images PMID:8040279

Fruebis, J; Steinberg, D; Dresel, H A; Carew, T E



Discovery of Schaeffer's acid analogues as lead structures of mycobacterium tuberculosis type?II dehydroquinase using a rational drug design approach.  


Rational ligand design: Schaeffer's acid analogues were identified as novel inhibitors of M.?tuberculosis type II dehydroquinase, a key enzyme of the shikimate pathway. Their likely binding mode was predicted using a combination of ensemble docking and flexible active site residues. Potentially, this scaffold could provide a good starting point for the design of antitubercular agents. PMID:23169689

Schmidt, Marco F; Korb, Oliver; Howard, Nigel I; Dias, Marcio V B; Blundell, Tom L; Abell, Chris



Divalent and oxabridged neonicotinoids constructed by dialdehydes and nitromethylene analogues of imidacloprid: design, synthesis, crystal structure, and insecticidal activities.  


A series of divalent and oxabridged neonicotinoids were synthesized by reactions of nitromethylene analogues of imidacloprid and dialdehydes, and their structures were confirmed by (1)H NMR, (13)C NMR, high-resolution mass spectroscopy, and X-ray diffraction analysis. The bioassays indicated that some of them were endowed with excellent insecticidal activities against cowpea aphid ( Aphis craccivora ), armyworm ( Pseudaletia separata Walker), and brown planthopper ( Nilaparvata lugens ). Divalent neonicotinoid 6 and oxabridged 8a had higher activities than imidacloprid against cowpea aphids and armyworm; furthermore, the activity of 8a was 40.4-fold higher than that of imidacloprid against imidacloprid-resistant brown planthopper. PMID:20000569

Shao, Xusheng; Fu, Hua; Xu, Xiaoyong; Xu, Xinglei; Liu, Zewen; Li, Zhong; Qian, Xuhong



Comparison of the Structural Stability and Dynamic Properties of Recombinant Anthrax Protective Antigen and its 2-Fluorohistidine Labeled Analogue  

PubMed Central

Protective antigen (PA) is the primary protein antigenic component of both the currently used anthrax vaccine and related recombinant vaccines under development. An analogue of recombinant PA (2-FHis rPA) has been recently shown to block the key steps of pore formation in the process of inducing cytotoxicity in cells, and thus can potentially be used as an antitoxin or a vaccine. This rPA analogue was produced by fermentation to incorporate the unnatural amino acid 2-fluorohistidine (2-FHis). In this study, the effects of 2-FHis labeling on rPA antigen’s conformational stability and dynamic properties were investigated by various biophysical techniques. Temperature/pH stability profiles of rPA and 2-FHis rPA were analyzed by the empirical phase diagram (EPD) approach, and physical stability differences between them were identified. Results showed that rPA and 2-FHis rPA had similar stability at pH 7–8. With decreasing solution pH, however, 2-FHis rPA was found to be more stable. Dynamic sensitive measurements of the two proteins at pH 5 found that 2-FHis rPA was more dynamic and/or differentially hydrated under acidic pH conditions. The biophysical characterization and stability data provide information useful for the potential development of 2-FHis rPA as a more stable rPA vaccine candidate. PMID:22911632

Hu, Lei; Joshi, Sangeeta B.; Andra, Kiran K.; Thakkar, Santosh V.; Volkin, David B.; Bann, James G.; Middaugh, C. Russell



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.



Evidence for Phenylalanine Zipper-Mediated Dimerization in the X-Ray Crystal Structure of a Magainin 2 Analogue  

PubMed Central

High-resolution structure elucidation has been challenging for the large group of host-defense peptides that form helices on or within membranes but do not manifest a strong folding propensity in aqueous solution. Here we report the crystal structure of an analogue of the widely-studied host-defense peptide magainin 2. Ala8,13,18-magainin 2 is a designed variant that displays enhanced antibacterial activity relative to the natural peptide. The crystal structure of Ala8,13,18-magainin 2, obtained for the racemic form, features a dimerization mode that has previously been proposed to play a role in the antibacterial activity of magainin 2 and related peptides. PMID:24102563

Kreitler, Dale F.; Weisblum, Bernard; Forest, Katrina T.; Gellman, Samuel H.



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.



Effects of structural analogues of nociceptin(1-13)NH? on brain antioxidant status in kainic acid-treated rats.  


The in vivo effects of nociceptin (N/OFQ(1-13)NH(2) ) and its structural analogues ([Dab(9) ]N/OFQ(1-13)NH(2) , [Dap(9) ]N/OFQ(1-13)NH(2) and [Cav(9) ]N/OFQ(1-13)NH(2) ) on the levels of lipid peroxidation and cell antioxidants (enzyme and non-enzyme) in brain of control and kainic acid (KA)-treated rats were studied. In control animals, [Dab(9) ]N/OFQ(1-13)NH(2) and [Dap(9) ]N/OFQ(1-13)NH(2) , unlike N/OFQ(1-13)NH(2) and [Cav(9) ]N/OFQ(1-13)NH(2) , slightly increased the brain lipid peroxidation; the rest of the parameters were unchanged by all neuropeptides tested. KA (0.25?µg in 0.5?µl, i.c.v) increased the lipid peroxidation (4 and 24?h after KA-injection) and decreased the glutathione level (1?h after KA-administration). One hour after KA-administration, the neuropeptides (2?µg in 0.5?µl, injected 30?min before KA) showed the following effects: a slight decrease in the KA-induced lipid peroxidation by all nociceptin analogues and an enhancement of the KA-decreased GSH level, but by [Cav(9) ]N/OFQ(1-13)NH(2) only. The brain antioxidant enzyme activities were unchanged in all used experimental groups. In addition, the nociceptin analogues, especially [Can(9) ]N/OFQ(1-13)NH(2) , showed a good antioxidant capacity in chemical systems, generating reactive oxygen species. In conclusion, the substitution of lysin (Lys) in N/OFQ(1-13)NH(2) molecule with other amino acids might contribute to changes in its antioxidant properties. Copyright © 2011 John Wiley & Sons, Ltd. PMID:21287579

Tzvetanova, Elina; Nenkova, Galina; Georgieva, Almira; Alexandrova, Albena; Girchev, Radoslav; Kirkova, Margarita



Binding of bilirubin and its structural analogues to hepatic microsomal bilirubin UDP glucuronyltransferase  

SciTech Connect

Hepatic glucuronidation of the asymmetrical natural bilirubin molecule results in formation of two different positional isomers, bilirubin C-8 monoglucuronide and bilirubin C-12 monoglucuronide. In view of the existence of multiple isoforms of UDPglucuronyltransferase, which is the microsomal enzyme system responsible for bilirubin esterification, the authors performed kinetic analysis of microsomal glucuronidation of bilirubin and a number of its structural congeners to determine whether synthesis of the two monoglucuronide isomers involved two distinct substrate-binding sites or reflected two different modes of binding to a single catalytic site. Both isomers were found in all tested species (man, rat, guinea pig, sheep), but there were marked species differences in the C-8/C-12 ratio of monoglucuronide found in bile or formed by liver microsomes. Correspondence between in vivo and in vitro results for such regioselectivity of glucuronidation was excellent in each species. On the basis of these results of kinetic analysis of bilirubin esterification at variable pigment substrate concentrations and inhibition studies with alternative substrates, the authors postulate that both natural monoglucuronide isomers are synthesized at a single binding site. Possible mechanisms responsible for the markedly regioselective esterification of bilirubin by rat and sheep liver were investigated by study of glucuronidation of selected structural analgoues of the pigment. Collectively, their findings suggest that the molecular from(s) of bilirubin able to engage in catalytically effective binding to UDPglucuronyltransferase does (do) not correspond with intramolecularly hydrogen-bonded conformers and that the nature of the ..beta..-substituents of the outer pyrromethenone rings is a key determinant of glucuronidation rate.

Vanstapel, F.; Blanckaert, N.



Halogenated ?,?-methylene- and ethylidene-dGTP-DNA ternary complexes with DNA polymerase ?: structural evidence for stereospecific binding of the fluoromethylene analogues  

PubMed Central

?,?-Fluoromethylene analogues of nucleotides are considered to be useful mimics of the natural substrates, but direct structural evidence defining their active site interactions has not been available, including the influence of the new chiral center introduced at the CHF carbon, as in ?,?-fluoromethylene-dGTP, which forms a active site complex with DNA polymerase ?, a repair enzyme that plays an important role in base excision repair (BER) and oncogenesis. We report X-ray crystallographic results for a series of ?,?-CXY dGTP analogues, where X,Y = H, F, Cl, Br, and/or CH3. For all three monofluorinated analogues examined (CHF, 3/4; CCH3F, 13/14; CClF 15/16), a single CXF-diastereomer (3, 13, 15) is observed in the active site complex, with the CXF fluorine atom at a ~3 Å (bonding) distance to a guanidinium N of Arg183. In contrast, for the CHCl, CHBr and CHCH3 analogues, both diasteromers (6/7, 8/9, 10/11) populate the dGTP site in the enzyme complex about equally. The structures of the bound dichloro (5) and dimethyl (12) analogue complexes indicate little to no steric effect on the placement of the bound nucleotide backbone. The results suggest that introduction of a single fluorine atom at the ?,?-bridging carbon atom of these dNTP analogues enables a new, stereospecific interaction within the pre-organized active site complex that is unique to fluorine. The results also provide the first diverse structural dataset permitting an assessment of how closely this class of dNTP analogues mimics the conformation of the parent nucleotide within the active site complex. PMID:20465217

Batra, Vinod K.; Pedersen, Lars C.; Beard, William A.; Wilson, Samuel H.; Kashemirov, Boris A.; Upton, Thomas G.; Goodman, Myron F.; McKenna, Charles E.



Salmonella enterica MTAN at 1.36 ? resolution. Structure-based design of new transition state analogues  

PubMed Central

SUMMARY Accumulation of 5?-methylthioadenosine (MTA) and S-adenosylhomocysteine (SAH) in bacteria disrupts the S-adenosylmethionine pool to alter biological methylations, synthesis of polyamines and production of quorum sensing molecules. Bacterial metabolism of MTA and SAH depends on MTA/SAH nucleosidase (MTAN), an enzyme not present in humans, and a target for quorum sensing since MTAN activity is essential for synthesis of autoinducer-2 molecules. Crystals of Salmonella enterica MTAN with product and transition state analogues of MTA and SAH explain the pM binding affinity and reveal ‘water-wire’ channel for the catalytic nucleophile. The crystal structure shows an extension of the binding pocket filled with polyethylene glycol. We exploited that discovery by the design and synthesis of new modifications of the currently existing transition state analogues to fill this site. This site was previously unknown in MTANs and reveals powerful inhibitors with solvent access. Novel inhibitors with dissociation constants of 5 to 15 pM are characterized. PMID:23685211

Haapalainen, Antti M.; Thomas, Keisha; Tyler, Peter C.; Evans, Gary B.; Almo, Steven C.; Schramm, Vern L.



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.



The shell model approach: Key to hadron structure  

SciTech Connect

A shell model approach leads to a simple constituent quark model for hadron structure in which mesons and baryons consist only of constituent quarks. Hadron masses are the sums of the constituent quark effective masses and a hyperfine interaction inversely proportional to the product of these same masses. Hadron masses and magnetic moments are related by the assumption that the same effective mass parameter appears in the additive mass term, the hyperfine interaction, and the quark magnetic moment, both in mesons and baryons. The analysis pinpoints the physical assumptions needed for each relation and gives two new mass relations. Application to weak decays and recent polarized EMC data confirms conclusions previously obtained that the current quark contribution to the spin structure of the proton vanishes, but without need for the questionable assumption of SU(3) symmetry relating hyperon decays and proton structure. SU(3) symmetry breaking is clarified. 24 refs.

Lipkin, H.J. (Weizmann Inst. of Science, Rehovoth (Israel). Dept. of Nuclear Physics)




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...


Structural visualization of key steps in human transcription initiation  

PubMed Central

Eukaryotic transcription initiation requires the assembly of general transcription factors into a pre-initiation complex that ensures the accurate loading of RNA polymerase II at the transcription start site. The molecular mechanism and function of this assembly have remained elusive due to lack of structural information. We have used an in vitro reconstituted system to study the stepwise assembly of human TBP, TFIIA, TFIIB, Pol II, TFIIF, TFIIE, and TFIIH onto promoter DNA using cryo-electron microscopy. Our structural analyses provide pseudo-atomic models at various stages of transcription initiation that illuminate critical molecular interactions, including how TFIIF engages Pol II and promoter DNA to stabilize both the closed PIC and the open-promoter complex and regulate start site selection. Comparison of open versus closed pre-initiation complexes, combined with the localization of the TFIIH helicases XPD and XPB, supports a DNA translocation model of XPB and explains its essential role in promoter opening. PMID:23446344

He, Yuan; Fang, Jie; Taatjes, Dylan J.; Nogales, Eva



Structural analyses of covalent enzyme-substrate analogue complexes reveal strengths and limitations of de novo enzyme design  

PubMed Central

We report the cocrystal structures of a computationally designed and experimentally optimized retro-aldol enzyme with covalently bound substrate analogs. The structure with covalently bound substrate analog is similar but not identical to the design model, with an RMSD over the active site residues and equivalent substrate atoms of 1.4Å. As in the design model, the binding pocket orients the substrate through hydrophobic interactions with the naphthyl moiety such that the oxygen atoms analogous to the carbinolamine and ?-hydroxyl oxygens are positioned near a network of bound waters. However, there are differences between the design model and the structure: the orientation of the naphthyl group and the conformation of the catalytic lysine are slightly different; the bound water network appears to be more extensive; and the bound substrate analog exhibits more conformational heterogeneity than in typical native enzyme-inhibitor complexes. Alanine scanning of the active site residues shows that both the catalytic lysine and the residues around the binding pocket for the substrate naphthyl group make critical contributions to catalysis. Mutating the set of water-coordinating residues also significantly reduces catalytic activity. The crystal structure of the enzyme with a smaller substrate analogue that lacks the naphthyl rings shows the catalytic lysine to be more flexible than in the naphthyl substrate complex; increased preorganization of the active site would likely improve catalysis. The covalently bound complex structures and mutagenesis data highlight strengths and weaknesses of the de novo enzyme design strategy. PMID:22075445

Wang, Ling; Althoff, Eric A.; Bolduc, Jill; Jiang, Lin; Moody, James; Lassila, Jonathan K.; Giger, Lars; Hilvert, Donald; Stoddard, Barry; Baker, David



Unexpected N-glycosidation reaction of glycals with 1-amino-anthracene: structure revision and application to the synthesis of new analogues of marmycin A.  


An unexpected N-glycosidation reaction of anthracen-1-amine with glycals was identified, and its use in the synthesis of C1' N-linked analogues of natural product marmycin A was explored. The structures of all these products were determined by 1D and 2D NMR, CD spectra, and X-ray crystal analysis. These products were then subjected to Friedel-Crafts acylation, Dess-Martin oxidation and nucleophilic addition leading to novel natural product analogues bearing a quaternary carbon center. PMID:23328958

Zhang, Xuefeng; Jiang, Xiaolong; Ding, Chunyong; Yao, Qizheng; Zhang, Ao



Synthesis and in vitro anti-leukemic activity of structural analogues of JS-K, an anti-cancer lead compound  

Microsoft Academic Search

Structural analogues of JS-K, an anti-cancer lead compound, were prepared and their in vitro anti-leukemic activity was determined. The rate of nitric oxide release from the corresponding diazeniumdiolate anions did not appear to affect the anti-leukemic activity of the prodrug forms. Two compounds with potent inhibitory activity and a potentially favorable toxicological profile were identified.

Harinath Chakrapani; Michael M. Goodblatt; Vidya Udupi; Swati Malaviya; Paul J. Shami; Larry K. Keefer; Joseph E. Saavedra



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...


Structure-activity relationships for the inhibition of lipid peroxidation and the scavenging of free radicals by synthetic symmetrical curcumin analogues.  


A number of ring substituted analogues of curcumin were synthesized. Their antioxidant properties were studied using three models, inhibition of lipid peroxidation, scavenging of 1,1'-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethyl-benzthiazoline-6-sulphonate radical (ABTS+.). In all the models, the phenolic analogues were more active than the non-phenolic analogues, some of which were inactive. The highest antioxidant activity was obtained when the phenolic group was sterically hindered by the introduction of two methyl groups at the ortho position. This and several other compounds were more active than the standard antioxidants alpha-tocopherol and trolox. This study has demonstrated that the phenolic group is important for the antioxidant activity of curcumin and that the structural features that enhance the antioxidant properties of phenols are optimized in curcumin to a significant extent. PMID:11045893

Venkatesan, P; Rao, M N



Structure-activity relationship of biaryl acylsulfonamide analogues on the human EP(3) prostanoid receptor.  


Potent and selective ligands for the human EP3 prostanoid receptor are described. Biaryl compounds bearing a tethered ortho substituted acidic moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinity of key compounds on all eight human prostanoid receptors is reported. PMID:12182865

Gallant, M; Carrière, M C; Chateauneuf, A; Denis, D; Gareau, Y; Godbout, C; Greig, G; Juteau, H; Lachance, N; Lacombe, P; Lamontagne, S; Metters, K M; Rochette, C; Ruel, R; Slipetz, D; Sawyer, N; Tremblay, N; Labelle, M



Bisphenol A and Its Analogues Activate Human Pregnane X Receptor  

PubMed Central

Background: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA and its analogues are present in environmental and human samples. Many endocrine-disrupting chemicals, including BPA, have been shown to activate the pregnane X receptor (PXR), a nuclear receptor that functions as a master regulator of xenobiotic metabolism. However, the detailed mechanism by which these chemicals activate PXR remains unknown. Objective: We investigated the mechanism by which BPA interacts with and activates PXR and examined selected BPA analogues to determine whether they bind to and activate PXR. Methods: Cell-based reporter assays, in silico ligand–PXR docking studies, and site-directed mutagenesis were combined to study the interaction between BPA and PXR. We also investigated the influence of BPA and its analogues on the regulation of PXR target genes in human LS180 cells. Results: We found that BPA and several of its analogues are potent agonists for human PXR (hPXR) but do not affect mouse PXR activity. We identified key residues within hPXR’s ligand-binding pocket that constitute points of interaction with BPA. We also deduced the structural requirements of BPA analogues that activate hPXR. BPA and its analogues can also induce PXR target gene expression in human LS180 cells. Conclusions: The present study advances our understanding of the mechanism by which BPA interacts with and activates human PXR. Activation of PXR by BPA may explain some of the adverse effects of BPA in humans. PMID:22214767

Sui, Yipeng; Ai, Ni; Park, Se-Hyung; Rios-Pilier, Jennifer; Perkins, Jordan T.; Welsh, William J.



Designing prostacyclin analogues.  


A series of prostacyclin analogues were synthesized and investigated for influence on blood pressure in rats, in vivo inhibition of platelet aggregation in rats, and in vitro inhibition of platelet aggregation in human platelet-rich plasma. The common feature of the analogues described is a replacement of C1-C4 of prostacyclin by a carboxyphenylene residue. The following structure-activity relationships were obtained. Only the meta-carboxyphenylene derivatives yield substantial prostacyclin activity. The 2,3,4-trinor-1,5-inter-m-phenylene prostacyclin analogues in contrast to the natural prototype are reasonably stable against hydrolysis of the enolether bond. The corresponding 2,3,4-trinor-1,5-inter-m-phenylene analogues of carbaprostacyclin have a somewhat lower specific activity but are superior in stability at acid pH values. With regard to the stereoisomerism at the delta 5 double bond, the Z-isomers of the oxa-cyclic prostacyclin series and the E-isomers of the carba-cyclic prostacyclin series are substantially more active than their counterparts. As with natural prostacyclin, the OH group at C15 has to be present in S-configuration. The "wrong" isomers do not inhibit prostacyclin-dependent effects. Resistance against 15-hydroxyprostaglandin dehydrogenase is achieved by substitutions at or near C15. Optimum specific activity combined with resistance against all known prostaglandin-activating enzymes is observed in prostacyclin and carbaprostacyclin analogues, in which the terminal n-pentyl residue is replaced by cyclohexyl. Duration of action, i.e. lowering of blood pressure in anaesthesized rats and inhibition of platelet aggregation in anaesthesized rats, was investigated with selected analogues in order to check the consequences of chemical and metabolic stabilization.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6315026

Flohé, L; Böhlke, H; Frankus, E; Kim, S M; Lintz, W; Loschen, G; Michel, G; Müller, B; Schneider, J; Seipp, U



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.



Structure of the p300 histone acetyltransferase bound to acetyl-coenzyme A and its analogues.  


The p300 and CBP transcriptional coactivator paralogs (p300/CBP) regulate a variety of different cellular pathways, in part, by acetylating histones and more than 70 non-histone protein substrates. Mutation, chromosomal translocation, or other aberrant activities of p300/CBP are linked to many different diseases, including cancer. Because of its pleiotropic biological roles and connection to disease, it is important to understand the mechanism of acetyl transfer by p300/CBP, in part so that inhibitors can be more rationally developed. Toward this goal, a structure of p300 bound to a Lys-CoA bisubstrate HAT inhibitor has been previously elucidated, and the enzyme's catalytic mechanism has been investigated. Nonetheless, many questions underlying p300/CBP structure and mechanism remain. Here, we report a structural characterization of different reaction states in the p300 activity cycle. We present the structures of p300 in complex with an acetyl-CoA substrate, a CoA product, and an acetonyl-CoA inhibitor. A comparison of these structures with the previously reported p300/Lys-CoA complex demonstrates that the conformation of the enzyme active site depends on the interaction of the enzyme with the cofactor, and is not apparently influenced by protein substrate lysine binding. The p300/CoA crystals also contain two poly(ethylene glycol) moieties bound proximal to the cofactor binding site, implicating the path of protein substrate association. The structure of the p300/acetonyl-CoA complex explains the inhibitory and tight binding properties of the acetonyl-CoA toward p300. Together, these studies provide new insights into the molecular basis of acetylation by p300 and have implications for the rational development of new small molecule p300 inhibitors. PMID:24819397

Maksimoska, Jasna; Segura-Peña, Dario; Cole, Philip A; Marmorstein, Ronen



Crystal structure of hillebrandite: A natural analogue of calcium silicate hydrate (CSH) phases in Portland cement  

Microsoft Academic Search

The crystal structure of hillebrandite, Ca2Si03(OH)2, was solved and refined in space group Cmc21, a = 3.6389, b = 16.311, c = 11.829 A, to R = 0.041 using single-crystal X-ray data. The structure consists of a three-dimensional network of Ca-O polyhedra that accommodates wollastonite-type Si-O tetrahedral chains. Each of the wollastonite-type chains is an average of two symmetrically equivalent



Ab Initio Quantum Mechanical Study of the Structures and Energies for the Pseudorotation of 5-Dehydroxy Analogues of 2-Deoxyribose  

E-print Network

-(1-pyrollyl)tetrahydrofuran and 4-hydroxy-5-methyl-2-(1-pyrollyl)- tetrahydrofuran, close analogues of 2-4 In the case of tetrahydrofuran (THF) and the more complex 2-deoxyribose and ribose sugars, there are barriers

Goddard III, William A.


Interactions of taurine and structurally related analogues with the GABAergic system and taurine binding sites of rabbit brain  

PubMed Central

The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. Washed synaptic membranes (SM) from whole rabbit brain were able to bind [3H]muscimol. Saturation experiments of the binding of [3H]GABA to GABAB receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [3H]taurine in a saturable manner (Kd=249.0±6.3 nM and Bmax=3.4±1.0 pmol mg?1 prot). Among the 19 structural analogues of taurine, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (±)cis-2-aminocyclohexane sulfonic acids (CAHS) displaced [3H]taurine binding (Ki=0.13, 0.13, 13.5 and 4.0 ?M, respectively). These analogues did not interact with GABAA and GABAB receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity. 3-Aminopropanesulfonic acid (OMO), ?-alanine, pyridine-3-sulfonic acid, N,N,N-trimethyltaurine (TMT), 2-(guanidino)ethanesulfonic acid (GES), ethanolamine-O-sulphate, N,N-dimethyltaurine (DMT), taurine and (±)piperidine-3-sulfonic acid (PSA) inhibited [3H]muscimol binding to GABAA receptors with different affinities (Ki=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 ?M, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [3H]GABA to GABAB receptors with Ki's in the ?M range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC50=3.72 ?M) and PSA GABA transaminase activity (IC50=103.0 ?M). In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents. PMID:12684273

Frosini, Maria; Sesti, Casilde; Dragoni, Stefania; Valoti, Massimo; Palmi, Mitri; Dixon, Henry B F; Machetti, Fabrizio; Sgaragli, Giampietro



Semicarbazide-sensitive amine oxidase (SSAO) of the rat aorta. Interactions with some naturally occurring amines and their structural analogues.  


The influence of a number of naturally occurring amines and their structural analogues has been examined on the metabolism of radiolabelled benzylamine (BZ) by the membrane bound semicarbazide-sensitive amine oxidase (SSAO) of the rat aorta. Only primary monoamines were effective in reducing the deamination of BZ. In the phenylethylamine series, addition of hydroxyl groups to the benzene ring decreased their potency as inhibitors while addition of a hydroxyl group at the beta position increased the inhibitory potency. Stereoselectivity of action was shown with octopamine, the L-isomer being the more active form. Kinetic analysis of these interactions showed predominantly competitive inhibition and kynuramine had the lowest Ki of 5.4 microM. The aliphatic monoamines, isoamylamine and isobutylamine both competed with BZ. 5-Hydroxytryptamine (5-HT) was the only amine that inhibited non-competitively. Direct evidence for metabolism by SSAO of some of the competing amines such as isoamylamine, phenylethylamine, tyramine and tryptamine was obtained by fluorimetric or radiochemical assays. The inhibitors clorgyline and (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroallylamine (MDL 72145) were used to characterise the amine oxidase activity responsible for the deamination. Octopamine and phenylethanolamine (PeOH) were not SSAO substrates and inhibited BZ metabolism in the fluorimetric assay. It is possible that the activity of SSAO is controlled by octopamine released from sympathetic nerve endings or 5-HT released from platelets. PMID:2719723

Elliott, J; Callingham, B A; Sharman, D F



Stringent structural requirements for anti-Ras activity of S-prenyl analogues  

Microsoft Academic Search

The carboxy terminal S-farnesylcysteine of Ras oncoproteins is required for their membrane anchorage and transforming activities. We showed previously that S-farnesylthiosalicylic acid (FTS) affects the membrane anchorage of activated H-Ras in EJ cells and inhibits their growth. We report here on structural elements in S-prenyl derivatives that specifically inhibit the growth of EJ cells, but not of untransformed Rat-1 cells.

Ziporet Aharonson; Mali Gana-Weisz; Tal Varsano; Roni Haklai; Daniele Marciano; Yoel Kloog



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



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



Inhibition and Structure of Trichomonas vaginalis Purine Nucleoside Phosphorylase with Picomolar Transition State Analogues  

SciTech Connect

Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition stte mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a K{sub m}/K{sub d} ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a K{sub m}/K{sub d} ratio of 203,300. The tight binding of DADMe-ImmA supports a late S{sub N}1 transition state. Despite their tight binding to TvPNP, ImmA and DADMe-ImmA are weak inhibitors of human and P. falciparum PNPs. The crystal structures of the TvPNP-ImmA{center_dot}PO{sub 4} and TvPNP{center_dot}DADMe-ImmA{center_dot}PO{sub 4} ternary complexes differ from previous structures with substrate anologues. The tight binding with DADMe-ImmA is in part due to a 2.7 {angstrom} ionic interaction between a PO{sub 4} oxygen and the N1 cation of the hydroxypyrrolidine and is weaker in the TvPNP{center_dot}ImmA{center_dot}PO{sub 4} structure at 3.5 {angstrom}. However, the TvPNP{center_dot}ImmA{center_dot}PO{sub 4} structure includes hydrogen bonds between the 2'-hydroxyl and the protein that are not present in TvPNP{center_dot}DADMe-ImmA{center_dot}PO{sub 4}. These structures explain why DADMe-ImmA binds tighter than ImmA. Immucillin-H is a 12 nM inhibitor of TvPNP but a 56 pM inhibitor of human PNP. And this difference is explained by isotope-edited difference infrared spectroscopy with [6-{sup 18}O]ImmH to establish that O6 is the keto tautomer in TvPNP{center_dot}ImmH{center_dot}PO{sub 4}, causing an unfavorable leaving-group interaction.

Rinaldo-Matthis,A.; Wing, C.; Ghanem, M.; Deng, H.; Wu, P.; Gupta, A.; Tyler, P.; Evans, G.; Furneaux, R.; et al.



Synthesis, Nitric Oxide Release, and Anti-Leukemic Activity of Glutathione-Activated Nitric Oxide Prodrugs: Structural Analogues of PABA/NO, an Anti-Cancer Lead Compound  

PubMed Central

Diazeniumdiolate anions and their prodrug forms are reliable sources of nitric oxide (NO) that have generated interest as promising therapeutic agents. A number of structural analogues of O2-(2,4-dinitro-5-(4-(N-methylamino)benzoyloxy)phenyl) 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), an anti-cancer lead compound that is designed to release NO upon activation by glutathione, were prepared. The nitric oxide release patterns of these O2-(2,4-dinitrophenyl) diazeniumdiolates in the presence of glutathione were tested and it was found that in the absence of competing pathways, these compounds release nearly quantitative amounts of NO. The ability of PABA/NO and its structural analogues to inhibit human leukemia cell proliferation was determined and it was found that compounds releasing elevated amounts of NO displayed superior cytotoxic effects. PMID:18060792

Chakrapani, Harinath; Wilde, Thomas C.; Citro, Michael L.; Goodblatt, Michael M.; Keefer, Larry K.; Saavedra, Joseph E.



Crystal Structures of HIV-1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design  

PubMed Central

X-ray crystal structures at 2.9 Å resolution are reported for complexes of catechol diethers 1 and 2 with HIV-1 reverse transcriptase. The results help elucidate the structural origins of the extreme antiviral activity of the compounds. The possibility of halogen bonding between the inhibitors and Pro95 is addressed. Structural analysis reveals key interactions with conserved residues P95 and W229 of importance for design of inhibitors with high potency and favorable resistance profiles. PMID:23163887

Frey, Kathleen M.; Bollini, Mariela; Mislak, Andrea C.; Cisneros, Jose A.; Gallardo-Macias, Ricardo; Jorgensen, William L.; Anderson, Karen S.



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.



Oxinobactin and sulfoxinobactin, abiotic siderophore analogues to enterobactin involving 8-hydroxyquinoline subunits: thermodynamic and structural studies.  


The synthesis of two new iron chelators built on the tris-l-serine trilactone scaffold of enterobactin and bearing a 8-hydroxyquinoline (oxinobactin) or 8-hydroxyquinoline-5-sulfonate (sulfoxinobactin) unit has been described. The X-ray structure of the ferric oxinobactin has been determined, exhibiting a slightly distorted octahedral environment for Fe(III) and a ? configuration. The Fe(III) chelating properties have been examined by potentiometric and spectrophotometric titrations in methanol-water 80/20% w/w solvent for oxinobactin and in water for sulfoxinobactin. They reveal the extraordinarily complexing ability (pFe(III) values) of oxinobactin over the p[H] range 2-9, the pFe value at p[H] 7.4 being 32.8. This was supported by spectrophotometric competition showing that oxinobactin removes Fe(III) from ferric enterobactin at p[H] 7.4. In contrast, the Fe(III) affinity of sulfoxinobactin was largely lower as compared to oxinobactin but similar to that of the ligand O-TRENSOX having a TREN backbone. These results are discussed in relation to the predisposition by the trilactone scaffold of the chelating units. Some comparisons are also made with other quinoline-based ligands and hydroxypyridinonate ligand (hopobactin). PMID:23134487

du Moulinet d'Hardemare, Amaury; Gellon, Gisèle; Philouze, Christian; Serratrice, Guy



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



Highly potent HIV inhibition: engineering a key anti-HIV structure from PSC-RANTES into MIP-1 beta/CCL4.  


The HIV coreceptor CCR5 is a validated target for both the prevention and therapy of HIV infection. PSC-RANTES, an N-terminally modified analogue of one of the natural chemokine ligands of CCR5 (RANTES/CCL5), is a potent inhibitor of HIV entry into target cells. Here, we set out to engineer the anti-HIV activity of PSC-RANTES into another natural CCR5 ligand (MIP-1beta/CCL4), by grafting into it the key N-terminal pharmacophore region from PSC-RANTES. We were able to identify MIP-1beta/CCL4 analogues that retain the receptor binding profile of MIP-1beta/CCL4, but acquire the very high anti-HIV potency and characteristic inhibitory mechanism of PSC-RANTES. Unexpectedly, we discovered that in addition to N-terminal structures from PSC-RANTES, the side chain of Lys33 is also necessary for full anti-HIV potency. PMID:18178567

Gaertner, Hubert; Lebeau, Olivier; Borlat, Irène; Cerini, Fabrice; Dufour, Brigitte; Kuenzi, Gabriel; Melotti, Astrid; Fish, Richard J; Offord, Robin; Springael, Jean-Yves; Parmentier, Marc; Hartley, Oliver



Synthesis, antioxidant capacity, and structure-activity relationships of tri-O-methylnorbergenin analogues on tyrosinase inhibition.  


A series of tri-O-methylnorbergenin analogues 1-9 were synthesized and their antioxidant activities and inhibitory effects on tyrosinase were evaluated. Among tested analogues, compound 4 bearing cathechol moiety exhibited greater antioxidant activity and excellent inhibition on tyrosinase with IC50 value of 9.1 ?M, comparable to that of corresponding positive controls. The inhibition mechanism analysis of compound 4 demonstrated that it was a mixed-type inhibitor on tyrosinase. These results suggest that these compounds may serve as a useful clue for further designing and development of novel potential tyrosinase inhibitors. PMID:24268551

Kashima, Yusei; Miyazawa, Mitsuo



New potent biphalin analogues containing p -fluoro- l -phenylalanine at the 4,4? positions and non-hydrazine linkers  

Microsoft Academic Search

We report the synthesis and the biological evaluation of two new analogues of the potent dimeric opioid peptide biphalin.\\u000a The performed modification is based on the replacement of two key structural elements of the native biphalin, namely: the\\u000a hydrazine bridge which joins the two palindromic moieties and the phenylalanine residues at the 4,4? positions of the backbone.\\u000a The new analogues

Adriano MollicaFrancesco; Francesco Pinnen; Federica Feliciani; Azzurra Stefanucci; Gino Lucente; Peg Davis; Frank Porreca; Shou-Wu Ma; Josephine Lai; Victor J. Hruby



Structural Analysis of the Key Intermediate Formed during Transcription through a Nucleosome  

PubMed Central

Transcription through chromatin by different RNA polymerases produces different biological outcomes and is accompanied by either nucleosome survival at the original location (Pol II-type mechanism) or backward nucleosome translocation along DNA (Pol III-type mechanism). It has been proposed that differences in the structure of the key intermediates formed during transcription dictate the fate of the nucleosomes. To evaluate this possibility, structure of the key intermediate formed during transcription by Pol III-type mechanism was studied by DNase I footprinting and molecular modeling. The Pol III-type mechanism is characterized by less efficient formation of the key intermediate required for nucleosome survival (Ø-loop, Pol II-type mechanism), most likely due to steric interference between the RNA polymerase and DNA in the Ø-loop. The data suggest that the lower efficiency of Ø-loop formation induces formation of a lower nucleosomal barrier and nucleosome translocation during transcription by Pol III-type mechanism.

Chang, H.-W.; Shaytan, A. K.; Hsieh, F.-K.; Kulaeva, O. I.; Kirpichnikov, M. P.; Studitsky, V. M.



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.



Predicting Enzyme Functional Surfaces and Locating Key Residues Automatically from Structures  

E-print Network

and residue occurrence in active sites, we develop a method to identify functionally important surfaces on protein structures and to locate key residues. We discuss application of our methods to amylase.C.) numbers. However, in many cases there is no information about where the active site is located

Dai, Yang


Keying Results on the CELT-Structure Test to U.S. Grade Level Instructional Materials  

ERIC Educational Resources Information Center

It would be beneficial for ESL instructors to know the U.S. grade equivalent English ability of their students for placement purposes, especially if their instructional materials are keyed for U.S. classrooms. For this purpose, the Stanford Intermediate Level I Reading Comprehension Test was compared with the CELT-Structure Test. (Author/RM)

Moran, Ross T.



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



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



Raman spectroscopic characterisations and analytical discrimination between caffeine and demethylated analogues of pharmaceutical relevance  

NASA Astrophysics Data System (ADS)

The FT Raman spectrum of caffeine was analysed along with that of its demethylated analogues, theobromine and theophylline. The similar but not identical structures of these three compounds allowed a more detailed assignment of the Raman bands. Noticeable differences in the Raman spectra of these compounds were apparent and key marker bands have been identified for the spectroscopic identification of these three compounds.

Edwards, H. G. M.; Munshi, T.; Anstis, M.



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



Structural and functional properties of heparin analogues obtained by chemical sulphation of Escherichia coli K5 capsular polysaccharide.  

PubMed Central

Capsular polysaccharide from Escherichia coli K5, with the basic structure (GlcA beta 1-4GlcNAc alpha 1-4)n, was chemically modified through N-deacetylation, N-sulphation and O-sulphation [Casu, Grazioli, Razi, Guerrini, Naggi, Torri, Oreste, Tursi, Zoppetti and Lindahl (1994) Carbohydr. Res. 263, 271-284]. Depending on the reaction conditions, the products showed different proportions of components with high affinity for antithrombin (AT). A high-affinity subfraction, M(r) approx. 36,000, was shown by near-UV CD, UV-absorption difference spectroscopy and fluorescence to cause conformational changes in the AT molecule very similar to those induced by high-affinity heparin. Fluorescence titrations demonstrated about two AT-binding sites per polysaccharide chain, each with a Kd of approx. 200 nM. The anti-(Factor Xa) activity was 170 units/mg, similar to that of the IIId international heparin standard and markedly higher than activities of previously described heparin analogues. Another preparation, M(r) approx. 13,000, of higher overall O-sulphate content, exhibited a single binding site per chain, with Kd approx. 1 microM, and an anti-(Factor Xa) activity of 70 units/mg. Compositional analysis of polysaccharide fractions revealed a correlation between the contents of -GlcA-GlcNSO3(3,6-di-OSO3)- disaccharide units and affinity for AT; the 3-O-sulphated GlcN unit has previously been identified as a marker component of the AT-binding pentasaccharide sequence in heparin. The abundance of the implicated disaccharide unit approximately equalled that of AT-binding sites in the 36,000-M(r) polysaccharide fraction, and approached one per high-affinity oligosaccharide (predominantly 10-12 monosaccharide units) isolated after partial depolymerization of AT-binding polysaccharide. These findings suggest that the modified bacterial polysaccharide interacts with AT and promotes its anticoagulant action in a manner similar to that of heparin. PMID:7626010

Razi, N; Feyzi, E; Bjork, I; Naggi, A; Casu, B; Lindahl, U



Elwood Murray's Interdisciplinary Analogue Laboratory.  

ERIC Educational Resources Information Center

Describes Elwood Murray's Interdisciplinary Analogue Laboratory which was designed to identify analogous structures occurring in different fields of education. These basic structures could then serve as foundations of an integrated curriculum where students would be encouraged to view their subjects of study relationally. (JMF)

Brownell, Judith



Interaction of delta sleep-inducing peptide and its analogues with cellular membranes: A structure-function analysis  

Microsoft Academic Search

The possibility of a correlation between the membrane properties of the delta sleep-inducing peptide (DSIP) and its analogues\\u000a and their biological activity in vivo was examined by a comparative study of the membrane effects of these peptides. The peptides\\u000a exhibiting biological activity in vivo were shown to cause a statistically reliable disordering of lipids in thrombocyte plasma\\u000a membranes similar to

I. I. Mikhaleva; G. T. Rikhireva; I. A. Prudchenko; I. N. Golubev



Key factors for successful generation of protein-fragment structures requirement on protein, crystals, and technology.  


In the past two decades, fragment-based approaches have evolved as a predominant strategy in lead discovery. The availability of structural information on the interaction geometries of binding fragments is key to successful structure-guided fragment-to-lead evolution. In this chapter, we illustrate methodological advances for protein-fragment crystal structure generation in order to offer general lessons on the importance of fragment properties and the most appropriate crystallographic setup to evaluate them. We analyze elaborate protocols, methods, and clues applied to challenging complex formation projects. The results should assist medicinal chemists to select the most promising targets and strategies for fragment-based crystallography as well as provide a tutorial to structural biologists who attempt to determine protein-fragment structures. PMID:21371587

Böttcher, Jark; Jestel, Anja; Kiefersauer, Reiner; Krapp, Stephan; Nagel, Susanna; Steinbacher, Stefan; Steuber, Holger



Sequence Specific Molecular Recognition and Binding by a GC Recognizing Hoechst 33258 Analogue to the Decadeoxyribonucleotide d-[CATGGCCATG]2: Structural and Dynamic Aspects Deduced from High Field H-NMR Studies  

Microsoft Academic Search

The non-exchangeable and imino proton NMR resonances have been assigned of the 1:1 complex of an analogue 2 of Hoechst 33258 1 bound to the decadeoxyribonuycleotide d- [CATGGCCATG]2 by a combination of NOE difference, COSY and NOESYPH techniques. In contrast to Hoechst 33258 which recognizes 5?-AATT sequences exclusively, analogue 2 possesses structural features designed to permit the recognition of GC

Surat Kumar; Bathini Yadagiri; Jurg Zimmermann; Richard T. Pon; J. William Lown



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.



Lactam-stabilized helical analogues of the analgesic ?-conotoxin KIIIA  

PubMed Central

?-Conotoxin KIIIA (?-KIIIA) blocks mammalian voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. Previous structure-activity studies of ?-KIIIA identified a helical pharmacophore for VGSC blockade. This suggested a route for designing truncated analogues of ?-KIIIA by incorporating the key residues into an ?-helical scaffold. As (i, i+4) lactam bridges constitute a proven approach for stabilizing ?-helices, we designed and synthesized six truncated analogues of ?-KIIIA containing single lactam bridges at various locations. The helicity of these lactam analogues was analysed by NMR spectroscopy, and their activities were tested against mammalian VGSC subtypes NaV1.1 through 1.7. Two of the analogues, Ac-cyclo9/13[Asp9,Lys13]KIIIA7–14 and Ac-cyclo9/13[Lys9,Asp13]KIIIA7–14, displayed µM activity against VGSC subtypes NaV1.2 and NaV1.6; importantly, the subtype selectivity profile for these peptides matched that of ?-KIIIA. Our study highlights structure-activity relationships within these helical mimetics and provides a basis for the design of additional truncated peptides as potential analgesics. PMID:21962108

Khoo, Keith K.; Wilson, Michael J.; Smith, Brian J.; Zhang, Min-Min; Gulyas, Joszef; Yoshikami, Doju; Rivier, Jean E.; Bulaj, Grzegorz; Norton, Raymond S.



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



The crystal structure of an isopenicillin N synthase complex with an ethereal substrate analogue reveals water in the oxygen binding site.  


Isopenicillin N synthase (IPNS) is a non-heme iron oxidase central to the biosynthesis of ?-lactam antibiotics. IPNS converts the tripeptide ?-(L-?-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N while reducing molecular oxygen to water. The substrate analogue ?-(L-?-aminoadipoyl)-L-cysteinyl-O-methyl-D-threonine (ACmT) is not turned over by IPNS. Epimeric ?-(L-?-aminoadipoyl)-L-cysteinyl-O-methyl-D-allo-threonine (ACmaT) is converted to a bioactive penam product. ACmT and ACmaT differ from each other only in the stereochemistry at the ?-carbon atom of their third residue. These substrates both contain a methyl ether in place of the isopropyl group of ACV. We report an X-ray crystal structure for the anaerobic IPNS:Fe(II):ACmT complex. This structure reveals an additional water molecule bound to the active site metal, held by hydrogen-bonding to the ether oxygen atom of the substrate analogue. PMID:23860486

Clifton, Ian J; Ge, Wei; Adlington, Robert M; Baldwin, Jack E; Rutledge, Peter J



Asymmetric total synthesis of (+)- and ent-(-)-yatakemycin and duocarmycin SA: evaluation of yatakemycin key partial structures and its unnatural enantiomer.  


Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five-base-pair AT sequence, e.g., 5'-AAAAA), efficiency, relative rate, and reversibility of ent-(-)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nature of the DNA reaction, and comparisons of the cytotoxic activity of the natural product (L1210, IC50 = 5 pM) with those of its unnatural enantiomer (IC50 = 5 pM) and a series of key partial structures including those that probe the role of the C-terminus thiomethyl ester. The only distinguishing features between the enantiomers is that ent-(-)-yatakemycin alkylates DNA at a slower rate (krel = 0.13) and is reversible, whereas (+)-yatakemycin is not. Nonetheless, even ent-(-)-yatakemycin alkylates DNA at a faster rate and with a greater thermodynamic stability than (+)-duocarmycin SA, illustrating the unique characteristics of such "sandwiched" agents. PMID:17147378

Tichenor, Mark S; Trzupek, John D; Kastrinsky, David B; Shiga, Futoshi; Hwang, Inkyu; Boger, Dale L



Key issues in evaluating performance of different electrochemical corrosion protection systems on reinforced concrete structures  

SciTech Connect

Different types of electrochemical corrosion protection systems such as cathodic protection (CP), corrosion inhibitors (CI), and electrochemical chloride extraction (ECE), are currently available for prolonging the service life of reinforced concrete structures. All these protection systems have been utilized on numerous structures in many parts of the world. The present paper focuses on the above methods of corrosion protection with emphasis on the basic principles of application, test methods and criteria to evaluate their performance. Well-established test techniques that are used to evaluate the corrosion condition of reinforced concrete structures can be utilized to assess the performance of these protection techniques. However, some of the test techniques have shortcomings that can lead to erroneous conclusions. Key issues in properly using some of these test techniques and interpreting the data are discussed.

Jackson, D.R. [Federal Highway Administration, Washington, DC (United States). Office of Technology Applications; Islam, M. [CONCORR, Inc., Ashburn, VA (United States)



Simultaneous evaluation of multiple key material properties of complex stratified structures with large spatial extent  

NASA Astrophysics Data System (ADS)

Measured complex reflection coefficient of a spatially-extended stratified composite structure, using an open-ended waveguide, can be effectively used to extract key material and geometrical characteristics of any given layer. This is accomplished using a combination of an electromagnetic model and corresponding measurement data. Previously, it was shown that one parameter can be extracted if all others are known. However, practically it is desirable to extract as many pieces of information as possible. To this end the model must be "inverted". However, there is no closed-form solution for the inverse problem, given the mathematical complexity of the forward model. Consequently, we introduce a forward-iterative optimization method to simultaneously extract several pieces of information about the structure. This method defines key unknowns and uses an analytical approach to estimate the reflection coefficient by minimizing a cost-function using conjugate gradient descent (CGD) as optimizer. This paper presents this method along with an experimental result. Information such as thickness and dielectric properties of a layer in a stratified structure is shown to be extracted concurrently.

Fallahpour, M.; Kajbaf, H.; Ghasr, M. T.; Case, J. T.; Zoughi, R.



B38: an all-boron fullerene analogue  

NASA Astrophysics Data System (ADS)

Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue.Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr01846j

Lv, Jian; Wang, Yanchao; Zhu, Li; Ma, Yanming



Synthesis and structure of an open-cage thiafullerene C69S: reactivity differences of an open-cage C70 tetraketone relative to its C60 analogue.  


An open-cage C70 fullerene with a 13-membered ring-opening and a bis(hemiacetal) moiety was synthesized by the reaction of the corresponding open-cage C70 diketone with nucleophilic oxidizing agents. The size of the cage opening could be expanded by a subsequent dehydration reaction. Reaction of the thus obtained open-cage C70 tetraketone with elemental sulfur in the presence of tetrakis(dimethylamino)ethylene resulted in the formation of the first example of an open-cage C69S thiafullerene with a 12-membered ring-opening. The formation of this sulfur-containing heterofullerene reflects a significantly different chemical reactivity for the open-cage C70 tetraketone relative to its C60 analogue. The structures of all novel compounds were unambiguously determined by single crystal X-ray diffraction analyses, in addition to which the electrochemical properties of the thiafullerene C69S were examined and compared with those of the corresponding C70 analogue. PMID:24884230

Zhang, Rui; Futagoishi, Tsukasa; Murata, Michihisa; Wakamiya, Atsushi; Murata, Yasujiro



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



Polyamine analogues: potent inducers of nucleosomal array oligomerization and inhibitors of yeast cell growth  

PubMed Central

Polyamines are naturally occurring intracellular polycations that are essential for viability and growth of eukaryotes. Dysregulation of polyamine metabolism is a hallmark of cancer and the carcinogenic process, and consequently development of polyamine analogues has emerged as a viable strategy for therapeutic intervention. Previously, we showed that the naturally occurring polyamines spermidine and spermine were quite effective at inducing the oligomerization of nucleosomal arrays in vitro, suggesting that polyamines may play a key role in regulating higher order chromatin structures in vivo. Here, we analyse the ability of a number of synthetic polyamine analogues to potentiate formation of higher order chromatin structures in vitro. We find that a class of long-chain polyamines called oligoamines are potent inducers of nucleosomal array oligomerization in vitro and that these same polyamine analogues rapidly block yeast cell growth. PMID:17428198

Carruthers, Lenny M.; Marton, Laurence J.; Peterson, Craig L.



Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure-activity relationships for amylin receptor agonism.  


Pramlintide (Symlin®), a synthetic analogue of the naturally occurring pancreatic hormone amylin, is currently used with insulin in adjunctive therapy for type 1 and type 2 diabetes mellitus. Herein we report a systematic study into the effect that N-glycosylation of pramlintide has on activation of amylin receptors. A highly efficient convergent synthetic route, involving a combination of solid phase peptide synthesis and enzymatic glycosylation, delivered a library of N-glycosylated variants of pramlintide bearing either GlcNAc, the core N-glycan pentasaccharide [Man3(GlcNAc)2] or a complex biantennary glycan [(NeuAcGalGlcNAcMan)2Man(GlcNAc)2] at each of its six asparagine residues. The majority of glycosylated versions of pramlintide were potent receptor agonists, suggesting that N-glycosylation may be used as a tool to optimise the pharmacokinetic properties of pramlintide and so deliver improved therapeutic agents for the treatment of diabetes and obesity. PMID:25030939

Kowalczyk, Renata; Brimble, Margaret A; Tomabechi, Yusuke; Fairbanks, Antony J; Fletcher, Madeleine; Hay, Debbie L



Synthesis and Evaluation of ?-Thymidine Analogues as Novel Antimalarials  

PubMed Central

Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-?-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5?-urea-?- and ?-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme–inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5?-urea-?-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC50 = 28 nM; CC50 = 29 ?M). PMID:23240776



Synthesis and evaluation of ?-thymidine analogues as novel antimalarials.  


Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-?-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-?- and ?-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-?-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 ?M). PMID:23240776

Cui, Huaqing; Carrero-Lérida, Juana; Silva, Ana P G; Whittingham, Jean L; Brannigan, James A; Ruiz-Pérez, Luis M; Read, Kevin D; Wilson, Keith S; González-Pacanowska, Dolores; Gilbert, Ian H



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



Synthesis and biological evaluation of nucleoside analogues than contain silatrane on the basis of the structure of acyclovir (ACV) as novel inhibitors of hepatitis B virus (HBV).  


Hepatitis B virus (HBV) infection causes major public health problems worldwide. Acyclovir (ACV) is mainly used to inhibit herpes simplex virus (HSV) rather than HBV. In this study, we used the combination principle to design and synthesize nucleoside analogues that contain silatrane on the basis of the structure of ACV. We found that the compounds were effective inhibitors of HBV, both in vitro and in vivo. All of the compounds showed suppressive activity on the expression of HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) in the HepG2.2.15 cell line with low cytotoxicity. One of compounds was studied in HBV transgenic mice model, and the test results showed its ability to reduce the levels of HBsAg, HBeAg and HBV DNA by ELASE and qPCR. Furthermore, significant improvement of T lymphocyte was observed after treatment, as evaluated by flow cytometry (FCM). PMID:23369536

Han, Anyue; Li, Lingna; Qing, Kuiyou; Qi, Xiaolu; Hou, Leping; Luo, Xintong; Shi, Shaohua; Ye, Faqing



A key factor to the spin parameter of uniformly rotating compact stars: crust structure  

E-print Network

We study the key factor to determine the dimensionless spin parameter $j\\equiv cJ/(GM^2)$ of different kinds of uniformly rotating compact stars, including the traditional neutron stars, hyperonic neutron stars, and hybrid stars, and check the reliability of the results on various types of equations of state of dense matter. The equations of state from the relativistic mean field theory and the MIT bag model are adopted to simulate compact stars. Numerical calculations of rigidly rotating neutron stars are performed using the RNS code in the framework of general relativity by solving the Einstein equations for stationary axis-symmetric spacetime. The crust structure of compact stars is found to be a key factor to determine the maximum value of the spin parameter $j_{\\rm max}$. For the stars with inclusion of the crust, $j_{\\rm max}\\sim 0.7$ is sustained for various kinds of compact stars with $M>0.5 M_{\\odot}$, and is found to be insensitive to the mass of star and selected equations of state. For the traditi...

Qi, B; Sun, B Y; Wang, S Y; Gao, J H



Key structures of bacterial peptidoglycan and lipopolysaccharide triggering the innate immune system of higher animals: Chemical synthesis and functional studies  

PubMed Central

Chemistry-based investigation is reviewed which led to identification of the active entities responsible for the immunostimulating potencies of peptidoglycan and lipopolysaccharide. Though these glycoconjugates which ubiquitously occur in wide range of bacteria as the essential components of their cell envelopes have long been known to enhance the immunological responses of higher animals, neither the precise chemical structures required nor the mechanism of their action remained to be elucidated until early 1970s. Chemical synthesis of partial structures of peptidoglycan proved N-acetylmuramyl-L-alanyl-D-isoglutamine to be the minimum structure responsible for the activity and led to later identification of its receptor protein Nod2 present in animal cells. Another active partial structure of peptidoglycan, ?-D-glutamyl-meso-diaminopimelic acid, and its receptor Nod1 were also identified as well. With regard to lipopolysaccharide, its glycolipid part named lipid A was purified and the structure studied. Chemically synthesized lipid A according to the newly elucidated structure exhibited full activity described for lipopolysaccharide known as endotoxin. Synthetic homogeneous lipid A and its structural analogues and labeled derivatives enabled precise studies of their interaction with receptor proteins and the mechanism of their action. Chemical synthesis of homogeneous partial structures of peptidoglycan and lipopolysaccharide gave unequivocal evidences for the concept that definite small molecular parts of these complex macromolecular bacterial glycoconjugates are specifically recognized by their respective receptors and trigger our defense system now widely recognized as innate immunity. PMID:20431259

Kusumoto, Shoichi; Fukase, Koichi; Shiba, Tetsuo



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



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 factors limiting carbon nanotube yarn strength: exploring processing-structure-property relationships.  


Studies of carbon nanotube (CNT) based composites have been unable to translate the extraordinary load-bearing capabilities of individual CNTs to macroscale composites such as yarns. A key challenge lies in the lack of understanding of how properties of filaments and interfaces across yarn hierarchical levels govern the properties of macroscale yarns. To provide insight required to enable the development of superior CNT yarns, we investigate the fabrication-structure-mechanical property relationships among CNT yarns prepared by different techniques and employ a Monte Carlo based model to predict upper bounds on their mechanical properties. We study the correlations between different levels of alignment and porosity and yarn strengths up to 2.4 GPa. The uniqueness of this experimentally informed modeling approach is the model's ability to predict when filament rupture or interface sliding dominates yarn failure based on constituent mechanical properties and structural organization observed experimentally. By capturing this transition and predicting the yarn strengths that could be obtained under ideal fabrication conditions, the model provides critical insights to guide future efforts to improve the mechanical performance of CNT yarn systems. This multifaceted study provides a new perspective on CNT yarn design that can serve as a foundation for the development of future composites that effectively exploit the superior mechanical performance of CNTs. PMID:25353651

Beese, Allison M; Wei, Xiaoding; Sarkar, Sourangsu; Ramachandramoorthy, Rajaprakash; Roenbeck, Michael R; Moravsky, Alexander; Ford, Matthew; Yavari, Fazel; Keane, Denis T; Loutfy, Raouf O; Nguyen, SonBinh T; Espinosa, Horacio D



B38: an all-boron fullerene analogue.  


Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (?2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue. PMID:24993287

Lv, Jian; Wang, Yanchao; Zhu, Li; Ma, Yanming



The atomic structure of pentameric lumazine synthase from Saccharomyces cerevisiae at 1.85 A resolution reveals the binding mode of a phosphonate intermediate analogue.  


Lumazine synthase of Saccharomyces cerevisiae is a homopentamer with a molecular weight of 90 kDa. Crystals of the recombinant enzyme with a size of up to 1.6 mm were obtained. The space group is P4(1)2(1)2 with lattice dimensions 82.9 A x 82.9 A x 300.2 A. X-ray diffraction data collected under cryogenic conditions were complete to 1.85 A resolution. The structure of the enzyme in complex with the intermediate analogue, 5-(6-D-ribitylamino-2,4-dihydroxypyrimidine-5-yl)-1-pentyl-p hosphonic acid was solved via molecular replacement using the structure of the Bacillus subtilis enzyme as search model and was refined to a final R-factor of 19.8% (Rfree: 22.5%). The conformation of the active site ligand of the enzyme mimicks that of the Schiff base intermediate of the enzyme-catalyzed reaction. The data enable the reconstruction of the reactant topology during the early steps of the catalytic reaction. Structural determinants, which are likely to be responsible for the inability of the S. cerevisiae enzyme to form icosahedral capsids, will be discussed. PMID:10860731

Meining, W; Mörtl, S; Fischer, M; Cushman, M; Bacher, A; Ladenstein, R



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



Cel48A from Thermobifida fusca: structure and site directed mutagenesis of key residues.  


Lignocellulosic biomass is a potential source of sustainable transportation fuels, but efficient enzymatic saccharification of cellulose is a key challenge in its utilization. Cellulases from the glycoside hydrolase (GH) family 48 constitute an important component of bacterial biomass degrading systems and structures of three enzymes from this family have been previously published. We report a new crystal structure of TfCel48A, a reducing end directed exocellulase from Thermobifida fusca, which shows that this enzyme shares important structural features with the other members of the GH48 family. The active site tunnel entrance of the known GH48 exocellulases is enriched in aromatic residues, which are known to interact well with anhydroglucose units of cellulose. We carried out site-directed mutagenesis studies of these aromatic residues (Y97, F195, Y213, and W313) along with two non-aromatic residues (N212 and S311) also located around the tunnel entrance and a W315 residue inside the active site tunnel. Only the aromatic residues located around the tunnel entrance appear to be important for the ability of TfCel48A to access individual cellulose chains on bacterial cellulose (BC), a crystalline substrate. Both Trp residues were found to be important for the processivity of TfCel48A on BC and phosphoric acid swollen cellulose (PASC), but only W313 appears to play a role in the ability of the enzyme to access individual cellulose chains in BC. When acting on BC, reduced processivity was found to correlate with reduced enzyme activity. The reverse, however, is true when PASC is the substrate. Presumably, higher density of available cellulose chain ends and the amorphous nature of PASC explain the increased initial activity of mutants with lower processivity. PMID:24264519

Kostylev, Maxim; Alahuhta, Markus; Chen, Mo; Brunecky, Roman; Himmel, Michael E; Lunin, Vladimir V; Brady, John; Wilson, David B



Survey of Analogue Spacetimes  

NASA Astrophysics Data System (ADS)

Analogue spacetimes (and more boldly, analogue models both of and for gravity), have attracted significant and increasing attention over the last decade and a half. Perhaps the most straightforward physical example, which serves as a template for most of the others, is Bill Unruh's model for a dumb hole,(mute black hole, acoustic black hole), wherein sound is dragged along by a moving fluid—and can even be trapped behind an acoustic horizon. This and related analogue models for curved spacetimes are useful in many ways: analogue spacetimes provide general relativists with extremely concrete physical models to help focus their thinking, and conversely the techniques of curved spacetime can sometimes help improve our understanding of condensed matter and/or optical systems by providing an unexpected and countervailing viewpoint. In this chapter, I shall provide a few simple examples of analogue spacetimes as general background for the rest of the contributions.

Visser, Matt


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



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, Joao; 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.



Effects of Vegetation Structure and Elevation on Lower Keys Marsh Rabbit Density  

E-print Network

The Lower Keys marsh rabbit (Sylvilagus palustris hefneri, LKMR), 1 of 3 subspecies of Sylvilagus palustris, is endemic to the Lower Florida Keys. The LKMR is listed as an endangered species due to predation by feral and free roaming domestic cats...

Dedrickson, Angela



Direct exfoliation of carbon allotropes with structural analogues of self-assembled nanostructures and their photovoltaic applications.  


Aromatic amphiphiles were self-assembled into 2-D nanosheets and 1-D nanofibers by systematically varying the volume fraction of the hydrophilic coils, which enabled the direct exfoliation of carbon allotropes with high quality and quantity. A 2-D nanosheet structure was introduced as the hole transporting layer for improving the performance of organic photovoltaic devices. PMID:25325079

Lee, Woochul; Lee, Dong-Woo; Lee, Myongsoo; Hong, Jong-In



A model of antimycin A binding based on structure-activity studies of synthetic antimycin A analogues  

Microsoft Academic Search

The structural factors of antimycin A molecule required for inhibitory action were studied using newly synthesized antimycin A derivatives with bovine heart submitochondrial particles, in order to probe the interaction between antimycin A and its binding site. In particular, we focused upon the roles of the amide bond bridge, which connects the salicylic acid and dilactone ring moieties, and the

Hideto Miyoshi; Nobuya Tokutake; Yasuhiro Imaeda; Toshio Akagi; Hajime Iwamura



Chemical Synthesis, Crystal Structure and Enzymatic Evaluation of a Dinucleotide Spore Photoproduct Analogue Containing a Formacetal Linker  

PubMed Central

Spore photoproduct (SP) is the exclusive DNA photodamage product found in bacterial endospores. Its photoformation and repair by a metal-loenzyme spore photoproduct lyase (SPL) composes the unique SP biochemistry. Despite the fact that the SP was discovered almost 50 years ago, its crystal structure is still unknown and the lack of structural information greatly hinders the study of SP biochemistry. Employing a formacetal linker and organic synthesis, we successfully prepared a dinucleotide SP isostere 5R-CH2SP, which contains a neutral CH2 moiety between the two thymine residues instead of a phosphate. The neutral linker dramatically facilitates the crystallization process, allowing us to obtain the crystal structure for this intriguing thymine dimer half a century after its discovery. Further ROESY spectroscopic, DFT computational, and enzymatic studies of this 5R-CH2SP compound prove that it possesses similar properties with the 5R-SP species, suggesting that the revealed structure truly reflects that of SP generated in Nature. PMID:21780208

Lin, Gengjie; Chen, Chun-Hsing; Pink, Maren; Pu, Jingzhi; Li, Lei



Muscarinic agonists with antipsychotic-like activity: structure-activity relationships of 1,2,5-thiadiazole analogues with functional dopamine antagonist activity.  


Muscarinic agonists were tested in two models indicative of clinical antipsychotic activity: conditioned avoidance responding (CAR) in rats and inhibition of apomorphine-induced climbing in mice. The standard muscarinic agonists oxotremorine and pilocarpine were both active in these tests but showed little separation between efficacy and cholinergic side effects. Structure-activity relationships of the alkylthio-1,2,5-thiadiazole azacyclic type muscarinic partial agonists are shown, revealing the exo-6-(3-propyl/butylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane analogues (4a,b and 9a, b) to be the most potent antipsychotic agents with large separation between efficacy and cholinergic side effects. The lack of enantiomeric selectivity suggests the pharmacophoric elements are in the mirror plane of the compounds. A model explaining the potency differences of closely related compounds is offered. The data suggest that muscarinic agonists act as functional dopamine antagonists and that they could become a novel treatment of psychotic patients. PMID:9784113

Sauerberg, P; Jeppesen, L; Olesen, P H; Rasmussen, T; Swedberg, M D; Sheardown, M J; Fink-Jensen, A; Thomsen, C; Thøgersen, H; Rimvall, K; Ward, J S; Calligaro, D O; DeLapp, N W; Bymaster, F P; Shannon, H E



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



Crystal structure of activated tobacco rubisco complexed with the reaction-intermediate analogue 2-carboxy-arabinitol 1,5-bisphosphate.  

PubMed Central

The crystal structure of activated tobacco rubisco, complexed with the reaction-intermediate analogue 2-carboxy-arabinitol 1,5-bisphosphate (CABP) has been determined by molecular replacement, using the structure of activated spinach rubisco (Knight, S., Andersson, I., & Brändén, C.-I., 1990, J. Mol. Biol. 215, 113-160) as a model. The R-factor after refinement is 21.0% for 57,855 reflections between 9.0 and 2.7 A resolution. The local fourfold axis of the rubisco hexadecamer coincides with a crystallographic twofold axis. The result is that the asymmetric unit of the crystals contains half of the L8S8 complex (molecular mass 280 kDa in the asymmetric unit). The activated form of tobacco rubisco is very similar to the activated form of spinach rubisco. The root mean square difference is 0.4 A for 587 equivalent C alpha atoms. Analysis of mutations between tobacco and spinach rubisco revealed that the vast majority of mutations concerned exposed residues. Only 7 buried residues were found to be mutated versus 54 residues at or near the surface of the protein. The crystal structure suggests that the Cys 247-Cys 247 and Cys 449-Cys 459 pairs are linked via disulfide bridges. This pattern of disulfide links differ from the pattern of disulfide links observed in crystals of unactivated tobacco rubisco (Curmi, P.M.G., et al., 1992, J. Biol. Chem. 267, 16980-16989) and is similar to the pattern observed for activated spinach tobacco. PMID:8358296

Schreuder, H. A.; Knight, S.; Curmi, P. M.; Andersson, I.; Cascio, D.; Sweet, R. M.; Branden, C. I.; Eisenberg, D.



Pharmacophore modeling and 3D quantitative structure-activity relationship analysis of febrifugine analogues as potent antimalarial agent  

PubMed Central

Febrifugine and its derivatives are effective against Plasmodium falciparum. Using PHASE algorithm, a five-point pharmacophore model with two hydrogen bond acceptor (A), one positively ionizable (P) and two aromatic rings (R), was developed to derive a predictive ligand-based statistically significant 3D-quantitative structure-activity relationship (QSAR) model (r2 = 0.972, SD = 0.3, F = 173.4, Q2 = 0.712, RMSE = 0.3, Person-R = 0.94, and r2pred = 0.8) to explicate the structural attributes crucial for antimalarial activity. The developed pharmacophore model and 3D QSAR model can be a substantial tool for virtual screening and related antimalarial drug discovery research. PMID:23662282

Sen, Debanjan; Chatterjee, Tapan Kumar



Cheese analogues: a review  

Microsoft Academic Search

Cheese analogues are usually defined as products made by blending individual constituents, including non-dairy fats or proteins, to produce a cheese-like product to meet specific requirements. They are being used increasingly due to their cost-effectiveness, attributable to the simplicity of their manufacture and the replacement of selected milk ingredients by cheaper vegetable products. Sales of cheese analogues are closely linked

Hans-Peter Bachmann



Entanglement verification for quantum key distribution systems with an underlying bipartite qubit-mode structure  

E-print Network

We consider entanglement detection for quantum key distribution systems that use two signal states and continuous variable measurements. This problem can be formulated as a separability problem in a qubit-mode system. To verify entanglement, we introduce an object that combines the covariance matrix of the mode with the density matrix of the qubit. We derive necessary separability criteria for this scenario. These criteria can be readily evaluated using semidefinite programming and we apply them to the specific quantum key distribution protocol.

Johannes Rigas; Otfried Gühne; Norbert Lütkenhaus



Effects of demographic structure on key properties of stochastic density-independent population dynamics  

Microsoft Academic Search

The development of stochastic demography has largely been based on age structured populations, although other types of demographic structure, especially permanent and dynamic heterogeneity, are likely common in natural populations. The combination of stochasticity and demographic structure is a challenge for analyses of population dynamics and extinction risk, because the population structure will fluctuate around the stable structure and the

Yngvild Vindenes; Bernt-Erik Sæther; Steinar Engen


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.



X-ray absorption fine-structure spectroscopy studies of Fe sites in natural human neuromelanin and synthetic analogues.  

PubMed Central

X-ray absorption fine-structure spectroscopy is used to study the local environment of the iron site in natural (human) neuromelanin extracted from substantia nigra tissue and in various synthetic neuromelanins. All the materials show Fe centered in a nearest neighbor sixfold (distorted) oxygen octahedron; the Fe-O distances, while slightly different in the natural and synthetic neuromelanin, are both approximately 2.0 A. Appreciable differences arise, however, in the second (and higher) coordination shells. In this case the synthetic melanin has the four planar oxygens bound to carbon rings with Fe-C distances of approximately 2.82 and 4.13 A; the human sample does not show the 2.82 A link but instead indicates a double shell at approximately 3.45 and 3.78 A. PMID:9826634

Kropf, A J; Bunker, B A; Eisner, M; Moss, S C; Zecca, L; Stroppolo, A; Crippa, P R



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



Structural, Spectroscopic, and Computational Characterization of the Azide Adduct of FeIII(2,6-diacetylpyridinebis(semioxamazide)), a Functional Analogue of Iron Superoxide Dismutase  

PubMed Central

We have prepared and thoroughly characterized, using X-ray crystallographic, spectroscopic, and computational methods, the diazide adduct of [FeIII(dapsox)(H2O)2]1+ [dapsox=2,6-diacetylpyridinebis(semioxamazide)] (1), alow-molecular weight, functional analogue of iron superoxide dismutase (FeSOD). The X-ray crystal structure of the dimeric form of 1, (Na[FeIII(dapsox)(N3)2] DMF)2 (2) shows two axially coordinated, symmetry inequivalent azides with differing Fe–N3 bond lengths and Fe–N–N2 bond angles. This inequivalence of the azide ligands likely reflects the presence of an inter-dimer H-bonding interaction between a dapsox NH group and the coordinated nitrogen of one of the two azide ligands. Resonance Raman (rR) data obtained for frozen aqueous solution and solid-state samples of 2 indicate that the azides remain inequivalent in solution, suggesting that one of the azide ligands of 1 engages in an intermolecular hydrogen bonding interaction with a water molecule. Density functional theory (DFT) and time-dependent DFT calculations have been used to study two different computational models of 1, one using coordinates taken from the X-ray crystal structure of 2, and the other generated via DFT geometry optimization. An evaluation of these models on the basis of electronic absorption, magnetic circular dichroism, and rR data indicates that the crystal structure based model provides a more accurate electronic structure description of 1, providing further support for the proposed intermolecular hydrogen bonding of 1 in the solid state and in solution. An analysis of the experimentally validated DFT results for this model reveals that the azides have both ?- and ?-bonding interactions with the FeIII center and that more negative charge is located on the Fe-bound, rather than on the terminal, nitrogen atom of each azide. These observations are reminiscent of the results previously reported for the azide adduct of FeSOD and provide clues regarding the origin the high catalytic activity of Fe-dapsox for superoxide disproportionation. PMID:23875582

Gutman, Craig T.; Guzei, Ilia A.; Brunold, Thomas C.



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



Regioselective Domino Metathesis of Unsymmetrical 7-Oxanorbornenes with Electron-Rich Vinyl Acetate toward Biologically Active Glutamate Analogues  

PubMed Central

In this article a regioselective domino metathesis reaction of unsymmetrical 7-oxanorbornenes, readily available by a tandem Ugi/Diels–Alder reaction as a key step, promoted by the Hoveyda–Grubbs second-generation catalyst in the presence of electron-rich vinyl acetate as a cross metathesis (CM) substrate is reported. The mechanism for the unusually high regioselectivity observed in the CM reaction was investigated, and a reaction course where a Fischer-type carbene [“Ru”= CH(OAc)] generates a steric interaction is proposed. The metathesis products were further converted to four artificial glutamate analogues whose structures were inspired by naturally derived excitatory glutamate analogues, dysiherbaine and neodysiherbaine. Interestingly, one of the synthetic analogues (28a) induced a cataleptic state in mice. Further electrophysiological studies suggest that 28a might inhibit excitatory synaptic transmission by a yet unknown indirect pathway. PMID:20485531

Oikawa, Masato; Ikoma, Minoru; Sasaki, Makoto; Gill, Martin B.; Swanson, Geoffrey T.; Shimamoto, Keiko; Sakai, Ryuichi



Entanglement verification for quantum-key-distribution systems with an underlying bipartite qubit-mode structure  

Microsoft Academic Search

We consider entanglement detection for quantum-key-distribution systems that use two signal states and continuous-variable measurements. This problem can be formulated as a separability problem in a qubit-mode system. To verify entanglement, we introduce an object that combines the covariance matrix of the mode with the density matrix of the qubit. We derive necessary separability criteria for this scenario. These criteria

Johannes Rigas; Otfried Gühne; Norbert Lütkenhaus



Structural and Functional Insights into Dom34, a Key Component of No-Go mRNA Decay  

Microsoft Academic Search

SUMMARY The yeast protein Dom34 is a key component of no-go decay, by which mRNAs with transla- tional stalls are endonucleolytically cleaved and subsequently degraded. However, the identity of the endoribonuclease is unknown. Homologs of Dom34, called Pelota, are broadly conserved in eukaryotes and archaea. To gain insights into the structure and function of Dom34\\/Pelota, we have determined the struc-

Hyung Ho Lee; Youn-Sung Kim; Kyoung Hoon Kim; Inha Heo; Sang Kyu Kim; Olesya Kim; Hye Kyung Kim; Ji Young Yoon; Hyoun Sook Kim; Do Jin Kim; Sang Jae Lee; Hye Jin Yoon; Soon Jong Kim; Byung Gil Lee; Hyun Kyu Song; V. Narry Kim; Chung-Mo Park; Se Won Suh



Student Value Structures: Key to Interpersonal Interaction in the College Community.  

ERIC Educational Resources Information Center

This study attempts to discover whether personal value structures are present at the personality level of student interaction (1) when there are no specific issues confronting the student, or (2) when issues are present and interaction results in linkage of the student value structure with a particular issue. Based on the results of a differential…

Paulin, Kenneth C.; Bittner, John R.


Structure Activity Relationship of (N)-Methanocarba Phosphonate Analogues of 5’-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor  

PubMed Central

P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis–Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y1 receptor). Two phosphonates, (1’S,2’R,3’S,4’R,5’S)-4’-(6-amino-2-chloropurin-9-yl)-2’,3’-(dihydroxy)-1’-(phosphonomethylene)-bicyclo[3.1.0]hexane 4 and its homologue 9, both 5’-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5’-extended phosphonates, all 2-H analogues, and a CH3-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure. PMID:20192270

Kumar, T. Santhosh; Zhou, Si-Yuan; Joshi, Bhalchandra V.; Balasubramanian, Ramachandran; Yang, Tiehong; Liang, Bruce T.; Jacobson, Kenneth A.



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.



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.



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



Biophysical characterization of recombinant proteins: A key to higher structural genomics success  

PubMed Central

Hundreds of genomes have been successfully sequenced to date, and the data are publicly available. At the same time, the advances in large-scale expression and purification of recombinant proteins have paved the way for structural genomics efforts. Frequently, however, little is known about newly expressed proteins calling for large-scale protein characterization to better understand their biochemical roles and to enable structure–function relationship studies. In the Structural Genomics Consortium (SGC), we have established a platform to characterize large numbers of purified proteins. This includes screening for ligands, enzyme assays, peptide arrays and peptide displacement in a 384-well format. In this review, we describe this platform in more detail and report on how our approach significantly increases the success rate for structure determination. Coupled with high-resolution X-ray crystallography and structure-guided methods, this platform can also be used toward the development of chemical probes through screening families of proteins against a variety of chemical series and focused chemical libraries. PMID:20466062

Vedadi, Masoud; Arrowsmith, Cheryl H.; Allali-Hassani, Abdellah; Senisterra, Guillermo; Wasney, Gregory A.



Orally active prostacyclin analogue for cardiovascular disease.  


Prostacyclin has vasoprotective effects such as vasodilation and antiplatelet aggregatory activity. A relative deficiency of prostacyclin contributes to the pathogenesis of cardiovascular disease including pulmonary artery disease (PAH). Inconvenient intravenous dosing of prostacyclin led to the development of more stable, an orally active analogue: beraprost. It is a chemically stable prostacyclin analogue owing to its cyclo-pentabenzofuranyl structure and produces strong vasodilation and inhibition of platelet aggregation. To date, beraprost has been used in the treatment of PAH and peripheral arterial disease (PAD). Recently, we have shown that beraprost induces neovascularization in ischemic myocardium by enhancement of bone marrow cell mobilization. Interestingly, meta-analysis of clinical studies for PAD has shown that repeated administration of beraprost decreases the number of cardiovascular events. These results suggest that oral administration of beraprost has beneficial effects on cardiovascular disease. Orally active prostacyclin analogues, are promising drugs for the treatment of cardiovascular disease. PMID:20357744

Nagaya, N



Identification of Key Structural Characteristics of Schisandra chinensis Lignans Involved in P-Glycoprotein Inhibition.  


The aim of the present study was to determine the structural requirements for dibenzocyclooctadiene lignans essential for P-glycoprotein inhibition. Altogether 15 structurally related lignans isolated from Schisandra chinensis or prepared by modification of their backbone were investigated, including three pairs of enantiomers. P-Glycoprotein inhibition was quantified using a doxorubicin accumulation assay in human promyelotic leukemia HL60/MDR cells overexpressing P-glycoprotein. A preliminary quantitative structure-activity relationship analysis revealed three main structural features involved in P-glycoprotein inhibition: a 1,2,3-trimethoxy moiety, a 6-acyloxy group, and the absence of a 7-hydroxy group. The most effective inhibitors, (-)-gomisin N (1) and (+)-deoxyschizandrin [(+)-2], were selected for further evaluation of their effects. Both these lignans restored the cytotoxic effect of doxorubicin in HL60/MDR cells and when combined with a subtoxic concentration of this compound increased the proportion of G2/M cells significantly, which is a usual response to treatment with this anticancer drug. PMID:25302569

Slanina, Ji?í; Páchniková, Gabriela; Carnecká, Martina; Porubová Koubíková, Ludmila; Adámková, Lenka; Humpa, Otakar; Smejkal, Karel; Slaninová, Iva



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

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, S.; Gabelli, S; Echeverria, I; Vogel, J; Guan, J; Tan, B; Klee, H; McCarty, D; Amzela, M



Structural insights into maize viviparous14, a key enzyme in the biosynthesis of the phytohormone abscisic acid.  


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)



Analogues of Riemann tensors for the odd metric on supermanifolds  

Microsoft Academic Search

Structure functions constitute the complete set of obstructions to integrability of a G-structure on a manifold. For a Riemannian manifold the structure function is the Riemann tensor. In this work, we compute structure functions for the odd analogue of the metric on supermanifolds and for several related structures. Structure functions take values in Spencer cohomology groups, which we describe by

E. Poletaeva



Longevity and thermo-rheological structure of old lithospheres : key constraints form surface and Moho topography.  

NASA Astrophysics Data System (ADS)

Surface topography and Moho are the most robust observables that have been insufficiently exploited for containing the rheological and thermal structure and hence for understanding the longevity and eventual destruction of cratons and "tectons". Craton longevity has been often explained by their buoyancy and analysed by testing gravitational stability of cratonic mantle "keels" as a function of the hypothesized plate thickness and thermo-rheological structure. Destruction of some cratons (e.g. North China) and data indicating little if no buoyancy of some tectons (e.g., Arabian shield) suggest that buoyancy is not the only factor of their stability, and previous studies show that their mechanical strength is as important as buoyancy. The upper bounds on this strength are provided by flexural studies demonstrating that Te values (equivalent elastic thickness) in cratons are highest in the world and may probably reach 150 km. Yet, the sensitivity of common methods is poor for Te values above 80 km while the lower bounds on the strength and the equivalent elastic thickness of cratons are still matter of debate. How this strength is partitioned between crust and mantle, and which set of rheological parameters pertain, remain major unknowns. We show that smooth low topography and "frozen" heterogeneous crustal structure of cratons represent the missing constraints for understanding of craton longevity. The cratonic crust is characterized by isostatically misbalanced density heterogeneities, suggesting that the lithosphere has to be strong enough to keep them "frozen" through the time without producing major gravitational instabilities and topographic undulations. Hence, to constrain thermo-rheological properties of cratons one should first investigate the stability of their topography and internal structure (constrained from seismic and gravity data). Our thermo-mechanical numerical experiments accounting for free surface boundary condition demonstrate that craton stability cannot be warranted by crustal strength only, and that strong dry olivine mantle rheology and cold thick lithosphere are needed for craton survival. We find fairly robust lower-bound limits on their thermo-rheological structure. In particular, the minimal Te needed for long-term stability of continents (cratons or tectons) is approximately 70 km.

François, Thomas; Burov, Evgueni



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



Quantum Analogue Computing  

E-print Network

We briefly review what a quantum computer is, what it promises to do for us, and why it is so hard to build one. Among the first applications anticipated to bear fruit is quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data is encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data is encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous variable quantum computers (CVQC) becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

Vivien M. Kendon; Kae Nemoto; William J. Munro



Status and key issues of reduced activation ferritic/martensitic steels as the structural material for a DEMO blanket  

SciTech Connect

The status and key issues of reduced activation ferritic/martensitic (RAFM) steels R&D are reviewed as the primary candidate structural material for fusion energy demonstration reactor blankets. This includes manufacturing technology, the as-fabricated and irradiates material database and joining technologies. The review indicated that the manufacturing technology, joining technology and database accumulation including irradiation data are ready for initial design activity, and also identifies various issues that remain to be solved for engineering design activity and qualification of the material for international fusion material irradiation facility (IFMIF) irradiation experiments that will validate the data base.

Tanigawa, Hiroyasu [ORNL; Stoller, Roger E [ORNL; Sokolov, Mikhail A [ORNL; Odette, G.R. [University of California, Santa Barbara; Jitsukawa, Shiro [Japan Atomic Energy Agency (JAEA); Shiba, K. [Japan Atomic Energy Agency (JAEA); Kurtz, Richard [Pacific Northwest National Laboratory (PNNL); Moeslang, A. [Forschungszentrum Karlsruhe, Karlsruhe, Germany; Lindau, R. [Forschungszentrum Karlsruhe, Karlsruhe, Germany



Structural insights into key sites of vulnerability on HIV-1 Env and Influenza HA  

PubMed Central

Summary Human immunodeficiency virus-1 (HIV-1) envelope protein (Env) and influenza hemagglutinin (HA) are the surface glycoproteins responsible for viral entry into host cells, the first step in the virus life cycle necessary to initiate infection. These glycoproteins exhibit a high degree of sequence variability and glycosylation, which are used as strategies to escape host immune responses. Nonetheless, antibodies with broadly neutralizing activity against these viruses have been isolated that have managed to overcome these barriers. Here, we review recent advances in the structural characterization of these antibodies with their viral antigens that defines a few sites of vulnerability on these viral spikes. These broadly neutralizing antibodies tend to focus their recognition on the sites of similar function between the two viruses: the receptor binding site and membrane fusion machinery. However, some sites of recognition are unique to the virus neutralized, such as the dense shield of oligomannose carbohydrates on HIV-1 Env. These observations are discussed in the context of structure-based design strategies to aid in vaccine design or development of antivirals. PMID:23046130

Julien, Jean-Philippe; Lee, Peter S.; Wilson, Ian A.



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-Munoz, Nicolas; Salazar-Quiroz, Natalia; Tischler, Nicole D.



Study of Kaempferol Glycoside as an Insulin Mimic Reveals Glycon To Be the Key Active Structure  

PubMed Central

Diabetes mellitus is increasing in prevalence with patient numbers rising throughout the world. Current treatments for diabetes mellitus focus on control of blood glucose levels. Certain kinds of flavonoids or their glycosides stimulate cells to improve glucose uptake and lower blood glucose levels. We synthesized kaempferol 3-O-neohesperidoside (1), a naturally occurring substance present in Cyathea phalerata Mart., reported to mimic the action of insulin. Synthetic 1 promoted glucose uptake in the cultured cell line, L6. Further studies to determine the core structure responsible for this activity using synthetic compounds revealed neohesperidose to be the primary pharmacophore. These findings support the use of certain saccharides as a potential novel treatment for diabetes mellitus by replacing or supporting insulin. PMID:24900249



Crystal structures of the LsrR proteins complexed with phospho-AI-2 and two signal-interrupting analogues reveal distinct mechanisms for ligand recognition.  


Quorum sensing (QS) is a cell-to-cell communication system responsible for a variety of bacterial phenotypes including virulence and biofilm formation. QS is mediated by small molecules, autoinducers (AIs), including AI-2 that is secreted by both Gram-positive and -negative microbes. LsrR is a key transcriptional regulator that governs the varied downstream processes by perceiving AI-2 signal, but its activation via autoinducer-binding remains poorly understood. Here, we provide detailed regulatory mechanism of LsrR from the crystal structures in complexes with the native signal (phospho-AI-2, D5P) and two quorum quenching antagonists (ribose-5-phosphate, R5P; phospho-isobutyl-AI-2, D8P). Interestingly, the bound D5P and D8P molecules are not the diketone forms but rather hydrated, and the hydrated moiety forms important H-bonds with the carboxylate of D243. The D5P-binding flipped out F124 of the binding pocket, and resulted in the disruption of the dimeric interface-1 by unfolding the ?7 segment. However, the same movement of F124 by the D8P'-binding did not cause the unfolding of the ?7 segment. Although the LsrR-binding affinity of R5P (Kd, ?1 mM) is much lower than that of D5P and D8P (?2.0 and ?0.5 ?M), the ?-anomeric R5P molecule fits into the binding pocket without any structural perturbation, and thus stabilizes the LsrR tetramer. The binding of D5P, not D8P and R5P, disrupted the tetrameric structure and thus is able to activate LsrR. The detailed structural and mechanistic insights from this study could be useful for facilitating design of new antivirulence and antibiofilm agents based on LsrR. PMID:24047255

Ha, Jung-Hye; Eo, Yumi; Grishaev, Alexander; Guo, Min; Smith, Jacqueline A I; Sintim, Herman O; Kim, Eun-Hee; Cheong, Hae-Kap; Bentley, William E; Ryu, Kyoung-Seok



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



Mobilizing communities around HIV prevention for youth: how three coalitions applied key strategies to bring about structural changes.  


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



Crystal structure of Mycobacterium tuberculosis MenB, a key enzyme in vitamin K2 biosynthesis.  


Bacterial enzymes of the menaquinone (Vitamin K2) pathway are potential drug targets because they lack human homologs. MenB, 1,4-dihydroxy-2-naphthoyl-CoA synthase, the fourth enzyme in the biosynthetic pathway leading from chorismate to menaquinone, catalyzes the conversion of O-succinylbenzoyl-CoA (OSB-CoA) to 1,4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA). Based on our interest in developing novel tuberculosis chemotherapeutics, we have solved the structures of MenB from Mycobacterium tuberculosis and its complex with acetoacetyl-coenzyme A at 1.8 and 2.3 A resolution, respectively. Like other members of the crotonase superfamily, MenB folds as an (alpha3)2 hexamer, but its fold is distinct in that the C terminus crosses the trimer-trimer interface, forming a flexible part of the active site within the opposing trimer. The highly conserved active site of MenB contains a deep pocket lined by Asp-192, Tyr-287, and hydrophobic residues. Mutagenesis shows that Asp-192 and Tyr-287 are essential for enzymatic catalysis. We postulate a catalytic mechanism in which MenB enables proton transfer within the substrate to yield an oxyanion as the initial step in catalysis. Knowledge of the active site geometry and characterization of the catalytic mechanism of MenB will aid in identifying new inhibitors for this potential drug target. PMID:12909628

Truglio, James J; Theis, Karsten; Feng, Yuguo; Gajda, Ramona; Machutta, Carl; Tonge, Peter J; Kisker, Caroline



Hidden Tree Structure is a Key to the Emergence of Scaling in the World Wide Web  

NASA Astrophysics Data System (ADS)

Preferential attachment is the most popular explanation for the emergence of scaling behavior in the World Wide Web, but this explanation has been challenged by the global information hypothesis, the existence of linear preference and the emergence of new big internet companies in the real world. We notice that most websites have an obvious feature that their pages are organized as a tree (namely hidden tree) and hence propose a new model that introduces a hidden tree structure into the Erdös—Rényi model by adding a new rule: when one node connects to another, it should also connect to all nodes in the path between these two nodes in the hidden tree. The experimental results show that the degree distribution of the generated graphs would obey power law distributions and have variable high clustering coefficients and variable small average lengths of shortest paths. The proposed model provides an alternative explanation to the emergence of scaling in the World Wide Web without the above-mentioned difficulties, and also explains the “preferential attachment" phenomenon.

Zheng, Bo-Jin; Wang, Jian-Min; Chen, Gui-Sheng; Jiang, Jian; Shen, Xian-Jun



Total Synthesis of Chlorofusin, its Seven Chromophore Diastereomers, and Key Partial Structures  

PubMed Central

Chlorofusin is a recently isolated, naturally occurring inhibitor of p53?MDM2 complex formation whose structure is composed of a densely functionalized azaphilone-derived chromophore linked through the terminal amine of ornithine to a nine residue cyclic peptide. Herein we report the full details of the total synthesis of chlorofusin, resulting in the assignment of the absolute stereochemistry and reassignment of the relative stereochemistry of the complex chromophore. Condensation of each enantiomer of an azaphilone chromophore precursor with the N?-amine of a protected ornithinethreonine dipeptide, followed by a one-step oxidation/spirocyclization of the most reactive olefin provided all eight diastereomers of the fully elaborated chromophore?dipeptide conjugate. Comparison of the spectroscopic properties for these eight compounds and those of simpler models with that reported for the natural product allowed the full assignment of the (4R,8S,9R)-stereochemistry of the chlorofusin chromophore. The natural, but stereochemically reassigned, diastereomer of the dipeptide conjugate was incorporated in a convergent total synthesis of chlorofusin confirming the stereochemical reassignment and establishing its absolute stereochemistry. Similarly and enlisting the late stage convergent point in the total synthesis, the remaining seven diastereomers of the chromophore?dipeptide conjugates were individually incorporated into the 9-residue cyclic peptide of chlorofusin (4 steps each) providing all seven remaining possible chromophore diastereomers of the natural product. PMID:18712872

Clark, Ryan C.; Lee, Sang Yeul; Boger, Dale L.



Identification of a novel vardenafil analogue in herbal product  

Microsoft Academic Search

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

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



Structurally complex habitats provided by Acropora palmata influence ecosystem processes on a reef in the Florida Keys National Marine Sanctuary  

NASA Astrophysics Data System (ADS)

The disappearance of Acropora palmata from reefs in the Florida Keys National Marine Sanctuary (FKNMS) represents a significant loss in the amount of structurally complex habitat available for reef-associated species. The consequences of such a widespread loss of complex structure on ecosystem processes are still unclear. We sought to determine whether the disappearance of complex structure has adversely affected grazing and invertebrate predation rates on a shallow reef in the FKNMS. Surprisingly, we found grazing rates and invertebrate predation rates were lower in the structurally complex A. palmata branches than on the topographically simple degraded reefs. We attribute these results to high densities of aggressively territorial damselfish, Stegastes planifrons, living within A. palmata. Our study suggests the presence of agonistic damselfish can cause the realized spatial patterns of ecosystem processes to deviate from the expected patterns. Reef ecologists must therefore carefully consider the assemblage of associate fish communities when assessing how the mortality of A. palmata has affected coral reef ecosystem processes.

Lemoine, N. P.; Valentine, J. F.



Alkylthioacetic acid (3-thia fatty acids)--a new group of non-beta-oxidizable, peroxisome-inducing fatty acid analogues. I. A study on the structural requirements for proliferation of peroxisomes and mitochondria in rat liver.  


The induction of peroxisome proliferation was examined in rat liver after administration of equal concentrations (1 mmol/kg body weight) of 1,10-bis(carboxymethylthiodecane) (BCMTD), 1-mono(carboxymethylthiotetradecane) (CMTTD), 1-mono(carboxymethylthiooctane) (CMTO), 1-mono(carboxyethylthiotetradecane) (CETTD), palmitic acid and hexadecanedioic acid (HDDA). BCMTD, a non-beta-oxidizable and non-omega-oxidizable sulphur-substituted fatty acid analogue was considerably more potent than CMTTD (only non-beta-oxidizable) in inducing enlargement of the liver and increasing peroxisomal activities (monitored by peroxisomal beta-oxidation, palmitoyl-CoA hydrolase and catalase activities). Morphometric analysis of randomly selected hepatocytes revealed that BCMTD and CMTTD treatment increased the number and size of peroxisomes and the relative volume fraction of the peroxisomes. All these cellular responses were more marked with BCMTD than compared with CMTTD. CMTO, a non-beta-oxidizable fatty acid analogue containing a lower hydrophobic alkyl-end than CMTTD and CETTD (a beta-oxidizable fatty acid analogue), showed a slight increase (1.4-1.8-fold) of peroxisomal beta-oxidation and caused marginally morphological changes of peroxisomes compared with CMTTD and BCMTD. The most striking effect of the alkylthiopropionic acid (CETTD) was an enhancement of the hepatic triacylglycerol level. Palmitic acid and hexadecanedioic acid only marginally affected the peroxisomal activities, but no morphological changes of peroxisomes and fat droplets were observed. The presented data strongly suggest that a minimal structural requirement for a peroxisome proliferator may be (1) a carboxylic acid group linked to (2) a hydrophobic backbone which (3) cannot be beta-oxidized i.e., the fatty acid analogues have a sulphur atom in the beta-position. It is also conceivable that blockage for omega-oxidation may potentiate the peroxisome-proliferating activities in as much as BCMTD was more potent than CMTTD. Two mitochondrial marker enzymes, carnitine palmitoyltransferase and succinate phenazine methosulphate oxidoreductase were differently affected after administration of the investigated compounds. Furthermore, BCMTD and CMTTD as well as HDDA treatments increased the number of mitochondria, but the mitochondria tended to be smaller. The overall results presented here indicate that the structural requirements for proliferation of mitochondria are not identical to those for proliferation of peroxisomes. PMID:2758028

Berge, R K; Aarsland, A; Kryvi, H; Bremer, J; Aarsaether, N



A Strategy for the Late-Stage Divergent Syntheses of Scyphostatin Analogues  

PubMed Central

This account details the synthesis of two scyphostatin analogues exhibiting a reactive polar epoxycyclohexenone core and various amide side chains outfitted for late-stage chemical derivatization into the desirable lipophilic tails. Our efforts highlight a key ipso-dearomatization process and provide new insights regarding the incompatibility and orthogonal reactivity of scyphostatin’s functional groups. We further showcase the utility of resorcinol derived 2,5-cyclohexadienones as synthetic platforms capable of participating in selective chemical reactivity, and we further demonstrate their potential for rapid elaboration into complex structural motifs. PMID:21250721

Cha, Jacob Y.; Burnett, G. Leslie; Huang, Yaodong; Davidson, Jarrod B.; Pettus, Thomas R. R.



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

Eterovic, Vesna A.; Valle-Rodriguez, Angelie Del; Perez, Dinely; Carrasco, Marimee; Khanfar, Mohammad A.; El Sayed, Khalid A.; Ferchmin, Pedro A.



Synthesis of Cholesterol Analogues Bearing BODIPY Fluorophores by Suzuki or Liebeskind-Srogl Cross-Coupling and Evaluation of Their Potential for Visualization of Cholesterol Pools.  


We report a synthetic route to BODIPY-cholesterol conjugates in which the key steps were Suzuki or Liebeskind-Srogl cross-coupling of cholesterol phenyl moieties with structurally diverse BODIPY scaffolds. All conjugates feature single-bonded and hydrophobic linkages between the fluorophore and sterol that are devoid of heteroatoms. Using HeLa cells, we show that these BODIPY-cholesterol analogues can be used simultaneously with the parent BODIPY-cholesterol for cell imaging and flow cytometry. The BODIPY-cholesterol analogues exhibit similar cellular localization in HeLa cells and show similar cholesterol efflux properties from THP-1 cells to HDL acceptors. These results demonstrate that the red-shifted BODIPY-cholesterol analogues behave in a manner similar to unlabeled cholesterol and are useful probes for simultaneous visualization of intracellular cholesterol pools and for monitoring cholesterol efflux from cells to extracellular acceptors. PMID:25154602

Liu, Zheng; Thacker, Seth G; Fernandez-Castillejo, Sara; Neufeld, Edward B; Remaley, Alan T; Bittman, Robert



Structure--activity relationship between the in vivo skin sensitizing potency of analogues of phenyl glycidyl ether and the induction of Nrf2-dependent luciferase activity in the KeratinoSens in vitro assay.  


Because of regulatory constraints and ethical considerations, research on alternatives to animal testing to predict the skin sensitization potential of novel chemicals has become a high priority. Ideally, these alternatives should not only predict the hazard of novel chemicals but also rate the potency of skin sensitizers. Currently, no alternative method gives reliable potency estimations for a wide range of chemicals in differing structural classes. Performing potency estimations within specific structural classes has thus been proposed. Detailed structure-activity studies for the in vivo sensitization capacity of a series of analogues of phenyl glycidyl ether (PGE) were recently published. These studies are part of an investigation regarding the allergenic activity of epoxy-resin monomers. Here we report data on the same chemicals in the KeratinoSens in vitro assay, which is based on a stable transgenic keratinocyte cell line with a luciferase gene under the control of an antioxidant response element. A strong correlation between the EC3 values in the local lymph node assay (LLNA) and both the luciferase-inducing concentrations and the cytotoxicity in the cell-based assay was established for six analogues of PGE. This correlation allowed the potency in the LLNA of two novel structurally closely related derivatives to be predicted by read-across with errors of 1.4- and 2.6-fold. However, the LLNA EC3 values of two structurally different bifunctional monomers were overpredicted on the basis of this data set, indicating that accurate potency estimation by read-across based on in vitro data might be restricted to a relatively narrow applicability domain. PMID:21751775

Delaine, Tamara; Niklasson, Ida B; Emter, Roger; Luthman, Kristina; Karlberg, Ann-Therese; Natsch, Andreas



Comparison of Protein Structures Objective: To give a presentation of about 60 minutes at the end of the week covering the key aspects of the  

E-print Network

Comparison of Protein Structures Objective: To give a presentation of about 60 minutes at the end of the week covering the key aspects of the comparison of protein structures. Comparing homologous objects to evolutionary study. Examples could be networks and structures. These objects are much more complex than

Goldschmidt, Christina


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



Key experimental information on intermediate-range atomic structures in amorphous Ge2Sb2Te5 phase change material  

NASA Astrophysics Data System (ADS)

Laser-induced crystalline-amorphous phase change of Ge-Sb-Te alloys is the key mechanism enabling the fast and stable writing/erasing processes in rewritable optical storage devices, such as digital versatile disk (DVD) or blu-ray disk. Although the structural information in the amorphous phase is essential for clarifying this fast process, as well as long lasting stabilities of both the phases, experimental works were mostly limited to the short-range order by x ray absorption fine structure. Here we show both the short and intermediate-range atomic structures of amorphous DVD material, Ge2Sb2Te5 (GST), investigated by a combination of anomalous x ray scattering and reverse Monte Carlo modeling. From the obtained atomic configurations of amorphous GST, we have found that the Sb atoms and half of the Ge atoms play roles in the fast phase change process of order-disorder transition, while the remaining Ge atoms act for the proper activation energy of barriers between the amorphous and crystalline phases.

Hosokawa, Shinya; Pilgrim, Wolf-Christian; Höhle, Astrid; Szubrin, Daniel; Boudet, Nathalie; Bérar, Jean-François; Maruyama, Kenji



Structural Studies of Cinnamoyl-CoA Reductase and Cinnamyl-Alcohol Dehydrogenase, Key Enzymes of Monolignol Biosynthesis.  


The enzymes cinnamoyl-CoA reductase (CCR) and cinnamyl alcohol dehydrogenase (CAD) catalyze the two key reduction reactions in the conversion of cinnamic acid derivatives into monolignol building blocks for lignin polymers in plant cell walls. Here, we describe detailed functional and structural analyses of CCRs from Medicago truncatula and Petunia hybrida and of an atypical CAD (CAD2) from M. truncatula. These enzymes are closely related members of the short-chain dehydrogenase/reductase (SDR) superfamily. Our structural studies support a reaction mechanism involving a canonical SDR catalytic triad in both CCR and CAD2 and an important role for an auxiliary cysteine unique to CCR. Site-directed mutants of CAD2 (Phe226Ala and Tyr136Phe) that enlarge the phenolic binding site result in a 4- to 10-fold increase in activity with sinapaldehyde, which in comparison to the smaller coumaraldehyde and coniferaldehyde substrates is disfavored by wild-type CAD2. This finding demonstrates the potential exploitation of rationally engineered forms of CCR and CAD2 for the targeted modification of monolignol composition in transgenic plants. Thermal denaturation measurements and structural comparisons of various liganded and unliganded forms of CCR and CAD2 highlight substantial conformational flexibility of these SDR enzymes, which plays an important role in the establishment of catalytically productive complexes of the enzymes with their NADPH and phenolic substrates. PMID:25217505

Pan, Haiyun; Zhou, Rui; Louie, Gordon V; Mühlemann, Joëlle K; Bomati, Erin K; Bowman, Marianne E; Dudareva, Natalia; Dixon, Richard A; Noel, Joseph P; Wang, Xiaoqiang



Preliminary structural design and key technology demonstration of cryogenic assembly in the next-generation infrared space telescope SPICA  

NASA Astrophysics Data System (ADS)

The infrared space telescope SPICA, Space Infrared Telescope for Cosmology and Astrophysics, is a next-generation astronomical project of the Japanese Aerospace Exploration Agency (JAXA), which features a 3m-class and 6K cryogenically- cooled space telescope. This paper outlines the current status for the preliminary structural design of the SPICA payload module. Dedicated studies were conducted for key technologies to enhance the design accuracy of the SPICA cryogenic assembly and mitigate the development risk. One of the results is described in this paper for the concept of the on-orbit truss separation mechanisms, which aim to both reduce the heat load from the main truss assembly and isolate the micro-vibration by changing the natural frequency of the spacecraft.

Mizutani, Tadahito; Yamawaki, Toshihiko; Komatsu, Keiji; Goto, Ken; Takeuchi, Shinsuke; Shinozaki, Keisuke



The investigation of blind continental earthquake sources through analogue and numerical models  

NASA Astrophysics Data System (ADS)

One of the most challenging topic in earthquake geology is to characterize the seismogenic sources, i.e. the potential causative faults of earthquakes. The main seismogenic layer is located in the upper brittle crust. Nevertheless it does not mean that a fault take up the whole schizosphere: i.e. from the brittle-plastic transition to the surface. Indeed, latest damaging earthquakes were generated by blind or "hidden" faults: 23 Oct. 2011, Van earthquake (Mw 7.1, Turkey); 3 Sep 2010, Darfield earthquake (Mw 7.1, New Zealand); 12 January 2010 Haiti earthquake (Mw 7.0); 6 April 2009 L'Aquila earthquake (Mw 6.3, Italy). Therefore understand how a fault grows and develops is a key question to evaluate the seismogenic potential of an area. Analogue model was used to understand kinematics and geometry of the geological structures since the beginning of the modern geology. On the other hand, numerical model develops much more during the last thirty years. Nowadays we can use these two methods working together providing mutual interactions. In the two-three most recent years we tried to use both numerical and analogue models to investigate the long-term and short-term evolution of a blind normal fault. To do this we improved the Analogue Model Laboratory of the University of Pavia with a laser scanner, a stepper motor and other high resolution tools in order to detect the distribution of the deformation mainly induced by blind faults. The goal of this kind of approach is to mimic the effects of the faults movements in a scaled model. We selected two seismogenic source cases: the causative fault of the 1908 Messina earthquake (Mw 7.1) and that of the 2009 L'Aquila earthquake (Mw 6.3). In the first case we investigate the long term evolution of this structure using a set of analogue models and afterwards a numerical model of our sandbox allow us to investigate stress and strain partitioning. In the second case we performed only an analogue model of short-term evolution of the L'Aquila seismogenic source comparing our result with pre-existing numerical models. In both cases we obtain mutual advantages using together experimental results. We believe that the analogue modelling approach coupled with numerical modelling applied to the study of active faults can provide useful insights to investigate the seismic potential of a structure with important appliances also for the seismic risk assessment.

Bonini, L.; Toscani, G.; Seno, S.



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



Geometric Analogue of Holographic Reduced Representation  

E-print Network

Holographic reduced representations (HRR) are based on superpositions of convolution-bound $n$-tuples, but the $n$-tuples cannot be regarded as vectors since the formalism is basis dependent. This is why HRR cannot be associated with geometric structures. Replacing convolutions by geometric products one arrives at reduced representations analogous to HRR but interpretable in terms of geometry. Variable bindings occurring in both HRR and its geometric analogue mathematically correspond to two different representations of $Z_2\\times...\\times Z_2$ (the additive group of binary $n$-tuples with addition modulo 2). As opposed to standard HRR, variable binding performed by means of geometric product allows for computing exact inverses of all nonzero vectors, a procedure even simpler than approximate inverses employed in HRR. The formal structure of the new reduced representation is analogous to cartoon computation, a geometric analogue of quantum computation.

Aerts, Diederik; De Moor, Bart



Geometric Analogue of Holographic Reduced Representation  

E-print Network

Holographic reduced representations (HRR) are based on superpositions of convolution-bound $n$-tuples, but the $n$-tuples cannot be regarded as vectors since the formalism is basis dependent. This is why HRR cannot be associated with geometric structures. Replacing convolutions by geometric products one arrives at reduced representations analogous to HRR but interpretable in terms of geometry. Variable bindings occurring in both HRR and its geometric analogue mathematically correspond to two different representations of $Z_2\\times...\\times Z_2$ (the additive group of binary $n$-tuples with addition modulo 2). As opposed to standard HRR, variable binding performed by means of geometric product allows for computing exact inverses of all nonzero vectors, a procedure even simpler than approximate inverses employed in HRR. The formal structure of the new reduced representation is analogous to cartoon computation, a geometric analogue of quantum computation.

Diederik Aerts; Marek Czachor; Bart De Moor



Synthesis and acetylcholinesterase inhibitory activity of several pyrimidone analogues of huperzine A  

SciTech Connect

Synthesis of four new pyrimidone analogues of the acetyicholinesterase (AChE) inhibitor huperzine A are reported together with the inhibitory potendes of these compounds for foetal bovine calf serum AChE; t3-lactone formation followed by a thermal cycloreversion reaction serves as the key step for introduction of the ethylidene appendage of analogue 12 in the stereochemically correct form.

Kozlkowski, A.P.; Campiani, G.; Saxena, A.; Doctor, S.P.



Microtubule-stabilizing agents based on designed laulimalide analogues  

PubMed Central

Laulimalide is a potent, structurally unique microtubule-stabilizing agent originally isolated from the marine sponge Cacospongia mycofijiensis. Laulimalide exhibits an activity profile different from other microtubule-binding agents, notably including effectiveness against paclitaxel-resistant cells, but it is intrinsically unstable. Five analogues of laulimalide were designed to exhibit enhanced chemical stability yet retain its exceptional biological activities. Evaluations of these analogues showed that all are effective inhibitors of cancer-cell proliferation yet differ substantially in potency with an IC50 range of 0.12–16.5 ?M. Although all of the analogues initiated cellular changes similar to laulimalide, including increased density of interphase microtubules, aberrant mitotic spindles, and ultimately apoptosis, differences among the analogues were apparent. The two most potent analogues, C16-C17-des-epoxy laulimalide and C20-methoxy laulimalide, appear to have a mechanism of action identical to laulimalide. The C16-C17-des-epoxy, C20-methoxy laulimalide derivative, which incorporates both chemical changes of the most potent analogues, was significantly less potent and initiated the formation of unique interphase microtubules unlike the parent compound and other analogues. Two C2-C3-alkynoate derivatives had lower potency, and they initiated abnormal microtubule structures but did not cause micronucleation or extensive G2/M accumulation. Significantly, paclitaxel- and epothilone-resistant cell lines were less resistant to the laulimalide analogues. In summary, analogues of laulimalide designed to minimize or eliminate its intrinsic instability have been synthesized, and some have been found to retain the unique biological activities of laulimalide. PMID:15161976

Mooberry, Susan L.; Randall-Hlubek, Deborah A.; Leal, Rachel M.; Hegde, Sayee G.; Hubbard, Robert D.; Zhang, Lei; Wender, Paul A.



Effects of electrospinning and solution casting protocols on the secondary structure of a genetically engineered dragline spider silk analogue investigated via Fourier transform Raman spectroscopy.  


Micrometer and submicrometer diameter fibers of recombinant dragline spider silk analogues, synthesized via protein engineering strategies, have been electrospun from 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and compared with cast films via Raman spectroscopy in order to assess changes in protein conformation that may result from the electrospinning process. Although the solvent casting process was shown to result in predominantly beta-sheet conformation similar to that observed in the bulk, the electrospinning process causes a major change in conformation from beta-sheet to alpha-helix. A possible mechanism involving electric field-induced stabilization of alpha-helical segments in HFIP solution during the electrospinning process is discussed. PMID:15877359

Stephens, Jean S; Fahnestock, Stephen R; Farmer, Robin S; Kiick, Kristi L; Chase, D Bruce; Rabolt, John F



Structural Re-arrangement and Peroxidase Activation of Cytochrome c by Anionic Analogues of Vitamin E, Tocopherol Succinate and Tocopherol Phosphate.  


Cytochrome c is a multifunctional hemoprotein in the mitochondrial intermembrane space whereby its participation in electron shuttling between respiratory complexes III and IV is alternative to its role in apoptosis as a peroxidase activated by interaction with cardiolipin (CL), and resulting in selective CL peroxidation. The switch from electron transfer to peroxidase function requires partial unfolding of the protein upon binding of CL, whose specific features combine negative charges of the two phosphate groups with four hydrophobic fatty acid residues. Assuming that other endogenous small molecule ligands with a hydrophobic chain and a negatively charged functionality may activate cytochrome c into a peroxidase, we investigated two hydrophobic anionic analogues of vitamin E, ?-tocopherol succinate (?-TOS) and ?-tocopherol phosphate (?-TOP), as potential inducers of peroxidase activity of cytochrome c. NMR studies and computational modeling indicate that they interact with cytochrome c at similar sites previously proposed for CL. Absorption spectroscopy showed that both analogues effectively disrupt the Fe-S(Met(80)) bond associated with unfolding of cytochrome c. We found that ?-TOS and ?-TOP stimulate peroxidase activity of cytochrome c. Enhanced peroxidase activity was also observed in isolated rat liver mitochondria incubated with ?-TOS and tBOOH. A mitochondria-targeted derivative of TOS, triphenylphosphonium-TOS (mito-VES), was more efficient in inducing H2O2-dependent apoptosis in mouse embryonic cytochrome c(+/+) cells than in cytochrome c(-/-) cells. Essential for execution of the apoptotic program peroxidase activation of cytochrome c by ?-TOS may contribute to its known anti-cancer pharmacological activity. PMID:25278024

Yanamala, Naveena; Kapralov, Alexander A; Djukic, Mirjana; Peterson, Jim; Mao, Gaowei; Klein-Seetharaman, Judith; Stoyanovsky, Detcho A; Stursa, Jan; Neuzil, Jiri; Kagan, Valerian E



Synthesis and cytotoxic activity of novel curcumin analogues  

Microsoft Academic Search

Five novel curcumin analogues bearing different substituents at 4-position of phenyl group were synthesized. Their structures were confirmed by NMR and HRMS spectrum. Their cytotoxic activities against six tumor cell lines were tested by the standard MTT assay in vitro. The results indicated that four analogues (1A–1C, 1E) with solubilizing moieties showed selective potent cytotoxicity against HepG2, HeLa and CT26

Qin Zhang; Yao Fu; Hao Wei Wang; Tao Gong; Yong Qin; Zhi Rong Zhang



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.



Identifying transcription factors and microRNAs as key regulators of pathways using Bayesian inference on known pathway structures  

PubMed Central

Background Transcription factors and microRNAs act in concert to regulate gene expression in eukaryotes. Numerous computational methods based on sequence information are available for the prediction of target genes of transcription factors and microRNAs. Although these methods provide a static snapshot of how genes may be regulated, they are not effective for the identification of condition-specific regulators. Results We propose a new method that combines: a) transcription factors and microRNAs that are predicted to target genes in pathways, with b) microarray expression profiles of microRNAs and mRNAs, in conjunction with c) the known structure of molecular pathways. These elements are integrated into a Bayesian network derived from each pathway that, through probability inference, allows for the prediction of the key regulators in the pathway. We demonstrate 1) the steps to discretize the expression data for the computation of conditional probabilities in a Bayesian network, 2) the procedure to construct a Bayesian network using the structure of a known pathway and the transcription factors and microRNAs predicted to target genes in that pathway, and 3) the inference results as potential regulators of three signaling pathways using microarray expression profiles of microRNA and mRNA in estrogen receptor positive and estrogen receptor negative tumors. Conclusions We displayed the ability of our framework to integrate multiple sets of microRNA and mRNA expression data, from two phenotypes, with curated molecular pathway structures by creating Bayesian networks. Moreover, by performing inference on the network using known evidence, e.g., status of differentially expressed genes, or by entering hypotheses to be tested, we obtain a list of potential regulators of the pathways. This, in turn, will help increase our understanding about the regulatory mechanisms relevant to the two phenotypes. PMID:22759573



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.



Analogue Missions on Earth, a New Approach to Prepare Future Missions on the Moon  

NASA Astrophysics Data System (ADS)

Human exploration of the Moon is a target by 2020 with an initial lunar outpost planned in polar regions. Current architectures maintain a capability for sorties to other latitudes for science activities. In the early stages of design of lunar outpost infrastructure and science activity planning, it has been recognized that analogue missions could play a major role in Moon mission design. Analogue missions, as high fidelity simulations of human and robotic surface operations, can help field scientists and engineers develop and test strategies as well as user requirements, as they provide opportunities to groundtruth measurements, and for the team to share understanding of key science needs and key engineering trades. These types of missions also provide direct training in planning science operations, and in team building and communication. The Canadian Space Agency's Exploration Core Program targets the development of technology infrastructure elements in key areas of science, technology and robotics in preparation for its role in the future exploration of the Moon and Mars. Within this Program, Analogue Missions specifically target the operations requirements and lessons learned that will reduce costs and lower the risk of planetary surface missions. Analogue missions are simulations of planetary surface operations that take place at analogue sites on Earth. A terrestrial analogue site resembles in some key way: eg. geomorphologically or geochemically, a surface environment of another planet. An analogue mission can, therefore, be defined as an integrated set of activities that represent (or simulate) entire mission designs or narrowly focus on specific aspects of planned or potential future planetary exploration missions. Within the CSA's Exploration Core Program, Analogue Missions facilitate the maturation of science instruments and mission concepts by integrating ongoing space instrument and technology development programs with science and analogue elements. As well as using analogue missions to meet agency programmatic needs, the Canadian Space Agency encourages scientists and engineers to make use of opportunities presented by analogue missions to further their own research objectives. Specific objectives of Analogue Missions are to (1) foster a multidisciplinary approach to planning, data acquisition, processing and interpretation, calibration of instruments, and telemetry during mission operations; (2) integrate new science with emerging technologies; and (3) develop an expertise on exploration architecture design from projects carried out at terrestrial analogue sites. Within Analogue Missions, teams develop planning tools, use mission-specific software and technology, and communicate results as well as lessons learned during tactical operations. The expertise gained through Analogue Missions will contribute to inform on all aspects of exploration architectures, including planetary mobility requirements and astronaut training.

Lebeuf, Martin


Structural Analysis of the ?-2,3Sialyltransferase Cst-I from Campylobacter jejuni in Apo and Substrate-Analogue Bound Forms † , ‡  

Microsoft Academic Search

Sialic acid is an essential sugar in biology that plays key roles in numerous cellular processes and interactions. The biosynthesis of sialylated glycoconjugates is catalyzed by five distinct families of sialyltransferases. In the last 25 years, there has been much research on the enzymes themselves, their genes, and their reaction products, but we still do not know the precise molecular

Cecilia P. C. Chiu; Luke L. Lairson; Michel Gilbert; Warren W. Wakarchuk; Stephen G. Withers; Natalie C. J. Strynadka



Ab initio quantum mechanical study of the structures and energies for the pseudorotation of 5{prime}-dehydroxy analogues of 2{prime}-deoxyribose and ribose sugars  

SciTech Connect

The authors have used ab initio quantum mechanical (QM) methods to determine the potential energy of pseudorotation for 3,4-dihydroxy-5-methyl-2-(1-pyrollyl)tetrahydrofuran and 4-hydroxy-5-methyl-2-(1-pyrollyl)-tetrahydrofuran, close analogues of 2{prime}-deoxyribose and ribose sugars. The pyrrole is a substitute for the naturally occurring nucleic acid bases: adenine, thymine, guanine, cytosine, and uracil. At the highest calculation level (LMP2/cc-pVTZ(-f)//HF/6-31G**) for 2{prime}-deoxyribose, they find the C2{prime}-endo conformation is the global minimum. The C3{prime}-endo conformation is a local minimum 0.6 kcal/mol higher in energy, and an eastern barrier of 1.6 kcal/mol separates the two minima. Pseudorotation energies of ribose are quite complex and are strongly affected by local orientations of the 2{prime} and 3{prime} hydroxyl groups. When the hydroxyl groups are allowed to assume any conformation, the global minimum remains the C2{prime}-endo conformation. The eastern barrier increases slightly to 1.8 kcal/mol, and the C3{prime}-endo local minimum lies 0.6 kcal/mol above the global minimum. Constraining the torsion angle of the C3{prime} hydroxyl group to {minus}146{degree}, as is found in RNA polymers, results in the C3{prime}-endo conformation becoming the only energy minimum with a C2{prime}-endo conformation 1.9 kcal/mol higher in energy. Bond angles within the pentofuranose ring are correlated to the pseudorotational phase, as is observed by X-ray crystallography and is predicted by pseudorotation theory. Finally, a force field for use in molecular mechanics and dynamics simulations is presented which reproduces the QM potential energies for the 2{prime}-deoxyribose and ribose sugars.

Brameld, K.A.; Goddard, W.A. III



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



Cardiac specific effects of thyroid hormone analogues.  


There is significant interest in development of thyroid hormone analogues to harness specific properties as therapeutic agents for a variety of clinical indications including obesity, hypercholesterolemia, heart failure, and thyrotoxicosis. To date, most analogues have been designed to target liver specific effects, which can promote weight loss and lipid lowering through either tissue specific uptake or thyroid hormone receptor (TR) ? isoform selectivity at the same time minimizing the unwanted cardiac and bone effects. We have developed a molecular biomarker assay to study the induction of the transcription of the cardiac specific ?-myosin heavy chain (MHC) gene as a more sensitive and specific measure of thyroid hormone action on cardiac myocytes. We tested 5 TR? and 1 TR? selective agonists as well as 2 putative TR antagonists in our ?-MHC hnRNA assay. Using reverse transcription and polymerase chain reaction, we measured the induction of the ?-MHC primary transcript in response to administration of drug. The TR? and only 2 of the TR? agonists were highly active, when compared to the effect of T3, at the level of the cardiac myocyte. In addition, our data suggests that the reason that the antagonist NH-3 is not able to block the T3-mediated induction of ?-MHC is that it does not get transported into the cardiac myocyte. Our data suggest that this assay will be useful in preclinical studies of the potential cardiac specific effects of thyroid hormone analogues and that predictions of function based on structure are not necessarily accurate or complete. PMID:22009366

Danzi, S; Klein, I



The influence of pre-existing basement structures on salt tectonics in the Upper Silurian Salina Group, Appalachian Basin, NE Pennsylvania: results from 3D seismic analysis and analogue modelling  

NASA Astrophysics Data System (ADS)

The Upper Silurian Salina Group in Pennsylvania's Appalachian basin consists of several hundred feet of highly deformable and mobile salt that was a significant influence on the tectonic and structural development of the Appalachian Mountains during the late Paleozoic. Understanding how halokinesis and décollement thrusting of the Salina Group has contributed to the present-day structure of the Appalachian Basin is of intense current interest due to the energy resource potential of the overlying Marcellus Shale and underlying Utica Shale. Seismic data suggest that halokinesis of the Salina Group in the Appalachian Basin might be strongly influenced by the presence of preexisting faults in the underlying Neoproterozoic basement, which suggests that these structures may have interacted with the Salina Group or its interior during deformation. We examine these apparent interactions in more detail using high-resolution 3D seismic data from the Appalachian Basin of NE Pennsylvania to identify and characterize salt tectonic-related structures developed above and within the Salina Group during orogenesis, verify their geographic association with major basement faults, and document how reactivation of these preexisting faults might have influenced later deformation within and above the salt units. We also present the results of sandbox modelling of thin-skinned thrusting in a salt-analogue décollement. Multiple runs in the presence and absence of preexisting basement structures provide insight into how the modern structures observed in the seismic data initiated and evolved during progressively more intense orogenesis, and better constrain the physical processes that control the structural linkage through the Salina décollement.

Harding, M. R.; Rowan, C. J.



Answer Keys  

NSDL National Science Digital Library

Answer keys provide acceptable answers to the questions posed in a case. Since these questions are intended to be answered by students and are often graded, keys are password-protected and access limited to registered instructors affiliated with an educational institution.



Total synthesis and antiplasmodial activity of pohlianin C and analogues.  


The first synthesis of the glycine-rich cyclic octapeptide pohlianin C is reported, confirming the structure of this natural product. Screening against Plasmodium falciparum reveals moderate antiplasmodial activity, consistent with data obtained from the natural sample. In addition, the synthesis of three analogues reveals that the antiplasmodial activity of pohlianin C can be preserved or increased with simplified structures. PMID:24813731

Lawer, Aggie; Tai, Jonathan; Jolliffe, Katrina A; Fletcher, Sabine; Avery, Vicky M; Hunter, Luke



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


Abstract--The process required to track cellular structures is a key task in the study of cell migration. This allows the  

E-print Network

migration. This allows the accurate estimation of motility indicators that help in the understanding the development of the quail embryo. I. INTRODUCTION HE study of cell migration is of a great significance]-[3]. In the quantification of the cell migration, the accurate tracking of cellular structures is a key task that determines

Whelan, Paul F.


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



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


Structural studies on the Ebola virus matrix protein VP40 indicate that matrix proteins of enveloped RNA viruses are analogues but not homologues.  


Matrix proteins are the driving force of assembly of enveloped viruses. Their main function is to interact with and polymerize at cellular membranes and link other viral components to the matrix-membrane complex resulting in individual particle shapes and ensuring the integrity of the viral particle. Although matrix proteins of different virus families show functional analogy, they share no sequence or structural homology, Their diversity is also evident in that they use a variety of late domain motifs to commit the cellular vacuolar protein sorting machinery to virus budding. Here, we discuss the structural and functional aspects of teh filovirus matrix protein VP40 and compare them to other known matrix protein structures from vesicular stomatitis virus adn retroviral matrix protein. PMID:15108720

Timmins, Joanna; Ruigrok, Rob W H; Weissenhorn, Winfried



Design and synthesis of paracaseolide A analogues as selective protein tyrosine phosphatase 1B inhibitors.  


A series of structurally related analogues of the natural product paracaseolide A were synthesized and identified as potent PTP1B inhibitors. Among these analogues, compound 10 in particular showed improved PTP1B enzyme inhibitory activity, high selectivity for PTP1B over TC-PTP, and improved cellular effects. PMID:24752625

Yin, Jian-Peng; Tang, Chun-Lan; Gao, Li-Xin; Ma, Wei-Ping; Li, Jing-Ya; Li, Ying; Li, Jia; Nan, Fa-Jun



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



Key Nutrients.  

ERIC Educational Resources Information Center

Lessons written to help trainer agents prepare aides for work with families in the Food and Nutrition Program are presented in this booklet. The key nutrients discussed in the 10 lessons are protein, carbohydrates, fat, calcium, iron, iodine, and Vitamins A, B, C, and D. the format of each lesson is as follows: Purpose, Presentation, Application…

Federal Extension Service (USDA), Washington, DC.


Chemoenzymatic preparation of germacrene analogues.  


A small library of novel germacrenes was generated using a combination of two plant enzymes, germacrene A synthase, and D synthase and modified farnesyl diphosphate (FDP) analogues. This chemoenzymatic approach allows the preparation of potentially valuable volatiles for biological studies. PMID:22914774

Cascón, Oscar; Touchet, Sabrina; Miller, David J; Gonzalez, Veronica; Faraldos, Juan A; Allemann, Rudolf K



New routes towards reutericyclin analogues.  


A range of N-acylpyrrolo[3,4-c]isoxazoles and derived N-acyltetramides has been prepared via a nitrile oxide dipolar cycloaddition approach, as analogues of the acyltetramic acid metabolite reutericyclin, of interest for its antibiotic potential against Gram-positive bacteria including hospital-acquired infections of resistant Clostridium difficile. PMID:24382380

Jones, Raymond C F; Bullous, James P; Law, Carole C M; Elsegood, Mark R J



Ultradeep pyrosequencing and molecular modeling identify key structural features of hepatitis B virus RNase H, a putative target for antiviral intervention.  


Last-generation nucleoside/nucleotide analogues are potent against hepatitis B virus (HBV) and have a high barrier to resistance. However, delayed responses have been observed in patients previously exposed to other drugs of the same class, long-term resistance is possible, and cure of infection cannot be achieved with these therapies, emphasizing the need for alternative therapeutic approaches. The HBV RNase H represents an interesting target because its enzyme activity is essential to the HBV life cycle. The goal of our study was to characterize the structure of the HBV RNase H by computing a 3-dimensional molecular model derived from E. coli RNase H and analyzing 2,326 sequences of all HBV genotypes available in public databases and 958,000 sequences generated by means of ultradeep pyrosequencing of sequences from a homogenous population of 73 treatment-naive patients infected with HBV genotype D. Our data revealed that (i) the putative 4th catalytic residue displays unexpected variability that could be explained by the overlap of the HBx gene and has no apparent impact on HBV replicative capacity and that (ii) the C-helix-containing basic protrusion, which is required to guide the RNA/DNA heteroduplex into the catalytic site, is highly conserved and bears unique structural properties that can be used to target HBV-specific RNase H inhibitors without cross-species activity. The model shows substantial differences from other known RNases H and paves the way for functional and structural studies as a prerequisite to the development of new inhibitors of the HBV cell cycle specifically targeting RNase H activity. PMID:24173223

Hayer, Juliette; Rodriguez, Christophe; Germanidis, Georgios; Deléage, Gilbert; Zoulim, Fabien; Pawlotsky, Jean-Michel; Combet, Christophe



Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B Virus RNase H, a Putative Target for Antiviral Intervention  

PubMed Central

Last-generation nucleoside/nucleotide analogues are potent against hepatitis B virus (HBV) and have a high barrier to resistance. However, delayed responses have been observed in patients previously exposed to other drugs of the same class, long-term resistance is possible, and cure of infection cannot be achieved with these therapies, emphasizing the need for alternative therapeutic approaches. The HBV RNase H represents an interesting target because its enzyme activity is essential to the HBV life cycle. The goal of our study was to characterize the structure of the HBV RNase H by computing a 3-dimensional molecular model derived from E. coli RNase H and analyzing 2,326 sequences of all HBV genotypes available in public databases and 958,000 sequences generated by means of ultradeep pyrosequencing of sequences from a homogenous population of 73 treatment-naive patients infected with HBV genotype D. Our data revealed that (i) the putative 4th catalytic residue displays unexpected variability that could be explained by the overlap of the HBx gene and has no apparent impact on HBV replicative capacity and that (ii) the C-helix-containing basic protrusion, which is required to guide the RNA/DNA heteroduplex into the catalytic site, is highly conserved and bears unique structural properties that can be used to target HBV-specific RNase H inhibitors without cross-species activity. The model shows substantial differences from other known RNases H and paves the way for functional and structural studies as a prerequisite to the development of new inhibitors of the HBV cell cycle specifically targeting RNase H activity. PMID:24173223

Hayer, Juliette; Rodriguez, Christophe; Germanidis, Georgios; Deleage, Gilbert; Zoulim, Fabien; Pawlotsky, Jean-Michel



Models and Analogues  

ERIC Educational Resources Information Center

How do teachers help children understand the difference between the structure of a flower and that of a root? Depending on the time of year this activity is quite easy. Get a bunch of flowers, germinate some chickpeas and raid the kitchen for carrots and beetroots--the children can experience the "real thing". But what if teachers want the…

Maloney, Jane; Curtis, Sheila



The inflamed axis: the interaction between stress, hormones, and the expression of inflammatory-related genes within key structures comprising the hypothalamic-pituitary-adrenal axis.  


Acute stress increases the expression of cytokines and other inflammatory-related factors in the CNS, plasma, and endocrine glands, and activation of inflammatory signaling pathways within the hypothalamic-pituitary-adrenal (HPA) axis may play a key role in later stress sensitization. In addition to providing a summary of stress effects on neuroimmune changes within the CNS, we present a series of experiments that characterize stress effects on members of the interleukin-1? (IL-1) super-family and other inflammatory-related genes in key structures comprising the HPA axis (PVN, pituitary and adrenal glands), followed by a series of experiments examining the impact of exogenous hormone administration (CRH and ACTH) and dexamethasone on the expression of inflammatory-related genes in adult male Sprague-Dawley rats. The results demonstrated robust, time-dependent, and asynchronous expression patterns for IL-1 and IL-1R2 in the PVN, with substantial increases in IL-6 and COX-2 in the adrenal glands emerging as key findings. The effects of exogenous CRH and ACTH were predominantly isolated within the adrenals. Finally, pretreatment with dexamethasone severely blunted neuroimmune changes in the adrenal glands, but not in the PVN. These findings provide novel insight into the relationship between stress, the expression of inflammatory signaling factors within key structures comprising the HPA axis, and their interaction with HPA hormones, and provide a foundation for better understanding the role of cytokines as modulators of hypothalamic, pituitary and adrenal sensitivity. PMID:24184413

Hueston, Cara M; Deak, Terrence



Optical Properties of Titan's Aerosol Analogues  

NASA Astrophysics Data System (ADS)

In the upper Titan's atmosphere its main constituents, CH4 and N2, are photolyzed and radiolyzed by solar photons and magnetospheric electrons. The primary products of these chemical interactions evolve to heavier organic compounds which are likely to associate to form the haze layers observed on Titan's upper atmosphere. Different theories and models have been used to explain the physical, chemical and optical properties of the haze material, but only with limited success. Among the parameters involved in these models, the complex refractive index is one of the most critical due to the influence that chemical composition and structural organization of the solid have on the n and k values. As part of a continued systematical study for the synthesis and characterization of Titan's aerosol analogues initiated in our group, we have subjected mixtures of CH4 in N2 to laser irradiation to produce layer of aerosol analogues. A set of optical properties values directly calculated from the transmission and reflectance curves, as well as a chemical characterization, by tandem mass spectroscopy, of the laboratory analogues will be presented. Our experimental protocol avoids some of the difficulties usually faced on laboratory simulations (over-irradiation, contamination with atmospheric oxygen, accurate ratio of initial gas mixture), porosity influences will also be discussed. The optical values can be used to determine how the chemical and optical properties of these aerosols influence the matching with the observed geometric albedo spectrum and how they participate in the radiative equilibrium processes in Titan's atmosphere. They will certainly help in the interpretation of the observations made by the Huygens descend through Titan's atmosphere last January and in all the new information about Titan generated since then. Financial support from CONACyT (40449) and PROMEP (103.5/03/1134) is acknowledged. SIRJ acknowledges a travel grant from PIFI 3.2.

Ramirez, Sandra I.; Contreras, G.; Agarwal, V.



Naturally occurring crystalline phases: analogues for radioactive waste forms  

SciTech Connect

Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

Haaker, R.F.; Ewing, R.C.



Inheritance of earthquake hazard from suturing: the Himalayas as an analogue for the structural architecture and seismic potential of the Greater Caucasus  

NASA Astrophysics Data System (ADS)

The nascent collision between the Arabian and Eurasian continents has created the second-largest active collisional orogen on Earth and provides a rare opportunity to investigate how structures formed during initial suturing influence and even control the subsequent first-order structural architecture of the evolving orogen. Between the Caspian and Black Seas, the Greater Caucasus Mountains form both the northern margin of the Arabia-Eurasia collision and the main locus of orogen-perpendicular shortening, despite being located some 700 km north of the Bitlis suture. A better understanding of active structures in the range is critical for understanding the mechanics and evolution of this collisional orogen. Developing such a structural model of the Greater Caucasus is also essential for assessing earthquake hazards. Here we begin to address these problems by using geologic maps, digital topographic data, and structural measurements to create preliminary geologic cross sections across the southern flank of the central and western Greater Caucasus. These sections span both a low-elevation foreland fold-thrust belt in the south and the main topographic front of the range ~15-40 km to the north. In addition, we investigate active deformation using topographic surveys of river terraces in the foreland south of the western Greater Caucasus range front near the city of Zugdidi. Based on these observations, we suggest that the neotectonic architecture of the range is broadly analogous to that of the Himalayas, where active deformation is not focused along a range-front-defining fault but instead is localized tens of kilometers to the south, along the south edge of a low-elevation, low-relief foreland fold-thrust belt. We infer that active faults within the fold-thrust belt sole into a shallow (~5-10 km deep), north-dipping basal decollement that roots into a crustal-scale ramp which lies beneath the main topography of the Greater Caucasus. Based on prior work on the regional geology of the range, we hypothesize that this geometry results from the Cenozoic closure of a relict Mesozoic ocean basin within the Arabia-Eurasia collision zone, broadly similar to the eastern Black Sea and South Caspian Basins to which it was connected. A new compilation of earthquake records from local seismic networks shows that the central and eastern Greater Caucasus Mountains are underlain by a northeast-dipping subducted slab, likely resulting from closure of this relict back-arc basin. Himalayan-style tectonism along the northern edge of the Arabia-Eurasia collision could potentially dictate the location, magnitude, and recurrence of seismicity in the Caucasus region, and as such has significant potential for seismic hazard assessment here. Rather than solely occurring on the main thrust within the range, this model suggests that significant earthquakes may occur within the fold-thrust belt and on a basal decollement that connects them to structures within the main range. Much of the region's population, including the Georgian capital city of Tbilisi, is found within or near the foreland fold-thrust belt.

Trexler, C.; Cowgill, E.; Forte, A. M.; Mumladze, T.; Sokhadze, G.; Elashvili, M.; Niemi, N. A.



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



Inhibition of glutamate racemase by substrate-product analogues.  


D-Glutamate is an essential biosynthetic building block of the peptidoglycans that encapsulate the bacterial cell wall. Glutamate racemase catalyzes the reversible formation of D-glutamate from L-glutamate and, hence, the enzyme is a potential therapeutic target. We show that the novel cyclic substrate-product analogue (R,S)-1-hydroxy-1-oxo-4-amino-4-carboxyphosphorinane is a modest, partial noncompetitive inhibitor of glutamate racemase from Fusobacterium nucleatum (FnGR), a pathogen responsible, in part, for periodontal disease and colorectal cancer (Ki=3.1±0.6 mM, cf. Km=1.41±0.06 mM). The cyclic substrate-product analogue (R,S)-4-amino-4-carboxy-1,1-dioxotetrahydro-thiopyran was a weak inhibitor, giving only ?30% inhibition at a concentration of 40 mM. The related cyclic substrate-product analogue 1,1-dioxo-tetrahydrothiopyran-4-one was a cooperative mixed-type inhibitor of FnGR (Ki=18.4±1.2 mM), while linear analogues were only weak inhibitors of the enzyme. For glutamate racemase, mimicking the structure of both enantiomeric substrates (substrate-product analogues) serves as a useful design strategy for developing inhibitors. The new cyclic compounds developed in the present study may serve as potential lead compounds for further development. PMID:24507924

Pal, Mohan; Bearne, Stephen L



Probing human red cone opsin activity with retinal analogues.  


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 an agonist nor an 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



Structural characterization of daptomycin analogues A21978C1-3(d-Asn11) produced by a recombinant Streptomyces roseosporus strain.  


Three daptomycin-related lipopeptides, A21978C1-3(d-Asn11) (2-4), were purified from the fermentation broth of a recombinant Streptomyces roseosporus strain. Their chemical structures were determined by analyses of the biosynthetic pathway, chemical transformations, d,l-amino acid quantitation by enantiomer labeling, tandem LC-MS/MS, and 2D-NMR techniques. Compounds 2-4 exhibited potent antibacterial activity against Staphylococcus aureus with MIC values of 0.6, 0.3, and 0.15 microM, respectively, well correlated to the acyl tail chain length. PMID:17284073

Gu, Jian-Qiao; Nguyen, Kien T; Gandhi, Chhayal; Rajgarhia, Vineet; Baltz, Richard H; Brian, Paul; Chu, Min



Synthesis and crystal structure of new temephos analogues as cholinesterase inhibitor: molecular docking, QSAR study, and hydrogen bonding analysis of solid state.  


A series of temephos (Tem) derivatives were synthesized and characterized by 31P, 13C, and 1H NMR and FT-IR spectral techniques. Also, the crystal structure of compound 9 was investigated. The hydrogen bonding energies (E2) were calculated by NBO analysis of the crystal cluster. The activities and the mixed-type mechanism of Tem derivatives were evaluated using the modified Ellman's and Lineweaver-Burk's methods on cholinesterase (ChE) enzymes. The inhibitory activities of Tem derivatives with a P?S moiety were higher than those with a P?O moiety. Docking analysis disclosed that the hydrogen bonds occurred between the OR (R=CH3 and C2H5) oxygen and N-H nitrogen atoms of the selected compounds and the receptor site (GLN and GLU) of ChEs. PCA-QSAR indicated that the correlation coefficients of the electronic variables were dominant compared to the structural descriptors. MLR-QSAR models clarified that the net charges of nitrogen and phosphorus atoms contribute important electronic function in the inhibition of ChEs. The validity of the QSAR model was confirmed by a LOO cross-validation method with q2=0.965 between the training and testing sets. PMID:24893121

Gholivand, Khodayar; Ebrahimi Valmoozi, Ali Asghar; Bonsaii, Mahyar



Migrastatin analogues target fascin to block tumour metastasis  

SciTech Connect

Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

Chen, L.; Jakoncic, J.; Yang, S.; Zhang, J.; Huang, X.Y.



Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid  

PubMed Central

Summary Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised several structural analogues of TDA and used them in bioactivity tests against Staphylococcus aureus and Vibrio anguillarum for a structure–activity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than the bioactivity of the natural product. The synthesis of this compound and of several analogues is presented and the bioactivity of the synthetic compounds is discussed. PMID:25161739

Rabe, Patrick; Klapschinski, Tim A; Brock, Nelson L; Citron, Christian A; D'Alvise, Paul; Gram, Lone



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.; Muller, Sylke; van Aalten, Daan M. F.; Fairlamb, Alan H.



Farnesyl Diphosphate Analogues with Aryl Moieties are Efficient Alternate Substrates for Protein Farnesyltransferase  

PubMed Central

Farnesylation is an important post-translational modification essential for proper localization and function of many proteins. Transfer of the farnesyl group from farnesyl diphosphate (FPP) to proteins is catalyzed by protein farnesyltransferase (FTase). We employed a library of FPP analogues with a range of aryl groups substituting for individual isoprene moieties to examine some of the structural and electronic properties of analogue transfer to peptide catalyzed by FTase. Analysis of steady-state kinetics for modification of peptide substrates revealed that the multiple turnover activity depends on the analogue structure. Analogues where the first isoprene is replaced by a benzyl group and an analogue where each isoprene is replaced by an aryl group are good substrates. In sharp contrast with the steady-state reaction, the single turnover rate constant for dansyl-GCVLS alkylation was found to be the same for all analogues, despite the increased chemical reactivity of the benzyl analogues and the increased steric bulk of other analogues. However, the single turnover rate constant for alkylation does depend on the Ca1a2X peptide sequence. These results suggest that the isoprenoid transition state conformation is preferred over the inactive E•FPP• Ca1a2X ternary complex conformation. Furthermore, these data suggest that the farnesyl binding site in the exit groove may be significantly more selective for the farnesyl diphosphate substrate than the active site binding pocket and therefore might be a useful site for design of novel inhibitors. PMID:22989235

Subramanian, Thangaiah; Pais, June E.; Liu, Suxia; Troutman, Jerry M.; Suzuki, Yuta; Subramanian, Karunai Leela; Fierke, Carol; Andres, Douglas A.; Spielmann, H. Peter



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



Ligand scaffold optimization of a supramolecular hydrogenation catalyst: Analyzing the influence of key structural subunits on reactivity and selectivity  

PubMed Central

Results are reported for the catalytic asymmetric hydrogenation of two prototypical substrates with a series of more than 150 closely related supramolecular catalysts differing in only their ligand/catalyst scaffold. These modular catalysts are constructed from four subunits and vary widely in their reactivity (no reaction to quantitative yield) and enantioselectivity (racemic to 96% ee). Analysis of the ligand/catalyst scaffold optimization data reveals how each subunit contributes to the effectiveness of the modular supramolecular catalyst. The results suggest that a balance between key elements of rigidity and flexibility is required for the successful catalysts and, moreover, that this balance is required to enable effective fine-tuning via catalyst scaffold optimization. PMID:23525350

Thacker, Nathan C.; Moteki, Shin A.; Takacs, James M.



Synthesis of novel and diverse mollugin analogues and their antibacterial and antioxidant activities.  


Novel and diverse mollugin analogues (1-12) were synthesized using PhB(OH)2/AcOH-mediated electrocyclization reaction as a key step. The newly synthesized compounds were screened for antioxidant and antibacterial activities. Compounds 1, 2, 5, 6, 8, and 10-12 showed high antioxidant activities in DPPH inhibition (IC50=0.52-1.11 ?M) compared with BHT (IC50=9.67 ?M). Compounds 3 exhibited potent antibacterial activity against Staphylococcus aureus (KCTC-1916) bacterial strain at 100 ?g/mL. Structures of newly synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR data and high-resolution mass spectrometry. PMID:24388865

Idhayadhulla, Akber; Xia, Likai; Lee, Yong Rok; Kim, Sung Hong; Wee, Young-Jung; Lee, Chong-Soon



Design, synthesis, and properties of 2',4'-BNA(NC): a bridged nucleic acid analogue.  


The novel bridged nucleic-acid analogue 2',4'-BNA(NC) (2'-O,4'-C-aminomethylene bridged nucleic acid), containing a six-membered bridged structure with an N-O linkage, was designed and synthesized efficiently, demonstrating a one-pot intramolecular NC bond-forming key reaction to construct a perhydro-1,2-oxazine ring (11 and 12). Three monomers of 2',4'-BNA(NC) (2',4'-BNA(NC)[NH], [NMe], and [NBn]) were synthesized and incorporated into oligonucleotides, and their properties were investigated and compared with those of 2',4'-BNA (LNA)-modified oligonucleotides. Compared to 2',4'-BNA (LNA)-modified oligonucleotides, 2',4'-BNA(NC) congeners were found to possess: (i) equal or higher binding affinity against an RNA complement with excellent single-mismatch discriminating power, (ii) much better RNA selective binding, (iii) stronger and more sequence selective triplex-forming characters, and (iv) immensely higher nuclease resistance, even higher than the S(p)-phosphorthioate analogue. 2',4'-BNA(NC)-modified oligonucleotides with these excellent profiles show great promise for applications in antisense and antigene technologies. PMID:18341342

Rahman, S M Abdur; Seki, Sayori; Obika, Satoshi; Yoshikawa, Haruhisa; Miyashita, Kazuyuki; Imanishi, Takeshi



Crystal structure of a key enzyme in the agarolytic pathway, ?-neoagarobiose hydrolase from Saccharophagus degradans 2-40.  


In agarolytic microorganisms, ?-neoagarobiose hydrolase (NABH) is an essential enzyme to metabolize agar because it converts ?-neoagarobiose (O-3,6-anhydro-alpha-l-galactopyranosyl-(1,3)-d-galactose) into fermentable monosaccharides (d-galactose and 3,6-anhydro-l-galactose) in the agarolytic pathway. NABH can be divided into two biological classes by its cellular location. Here, we describe a structure and function of cytosolic NABH from Saccharophagus degradans 2-40 in a native protein and d-galactose complex determined at 2.0 and 1.55 Å, respectively. The overall fold is organized in an N-terminal helical extension and a C-terminal five-bladed ?-propeller catalytic domain. The structure of the enzyme-ligand (d-galactose) complex predicts a +1 subsite in the substrate binding pocket. The structural features may provide insights for the evolution and classification of NABH in agarolytic pathways. PMID:21810409

Ha, Sung Chul; Lee, Saeyoung; Lee, Jonas; Kim, Hee Taek; Ko, Hyeok-Jin; Kim, Kyoung Heon; Choi, In-Geol



Structure of the Cytoplasmic Segment of Histidine Kinase Receptor QseC, a Key Player in Bacterial Virulence†  

PubMed Central

QseC is a histidine kinase (HK) receptor involved in quorum sensing, a mechanism by which bacteria respond to fluctuations in cell population. We conducted a structural study of the cytoplasmic domain of QseC (QseC-CD) using X-ray crystallography. The 2.5 Å structure of the apo-enzyme revealed that the kinase domain of QseC retains the overall fold of the typical HK kinase domain. The construct that we used is inactive in the autokinase reaction and its inactivity is most likely caused by its atypical dimerization interface, as compared to that observed in the T.maritima HK cytoplasmic domain structure. Restoration of the activity may require that the entire dimerization domain be present in the protein construct. QseC, which plays an important role in bacterial pathogenesis, is a promising drug target and the structure of QseCCD provides a platform for developing more potent inhibitors of pathogen virulence. PMID:20594156

Xie, Wei; Dickson, Chris; Kwiatkowski, Witek; Choe, Senyon



Modulation of amyloid precursor protein processing by synthetic ceramide analogues  

Microsoft Academic Search

Previous studies suggest that membrane lipids may regulate proteolytic processing of the amyloid precursor protein (APP) to generate amyloid-beta peptide (Abeta). In the present study, we have assessed the capacity for a series of structurally related synthetic ceramide analogues to modulate APP processing in vitro. The compounds tested are established glucosylceramide synthase (GS) inhibitors based on the d-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) structure.

Hongyun Li; Woojin S. Kim; Gilles J. Guillemin; Andrew F. Hill; Genevieve Evin; Brett Garner



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.



Analogues of estradiol as potential breast tumor imaging agents  

SciTech Connect

The radioiodinated analogue of estradiol, 11..beta..-methoxy-17..cap alpha..-(/sup 125/I)iodovinylestradiol (MIVE/sub 2/), has been shown to be a good candidate for the imaging of estrogen dependent breast tumors. Although there has been no extensive study on the sensitivity of radiotracers of this type, the authors have not observed localization of the radiotracer in metastatic lesions containing less than 20 fmole estrogen receptor/mg protein or in bone metasteses. In order to improve the sensitivity, they have examined several structural analogues of moxestrol (the parent structure for MIVE/sub 2/) for affinity to the ER isolated from immature rat uterus. The 11..beta..-ethyl analogue (EEE/sub 2/) of ethynyl estradiol (EE/sub 2/) exhibits the highest affinity with the 11..beta..-methyl analogue second best. Although the lipophilicity is also very high this compound should not be much more lipophilic than 16-iodoestradiol or MIVE/sub 2/ since the introduction of iodine increases the log P by greater than 1. The distribution of the tritiated derivative of EEE/sub 2/ is under study.

Gibson, R.E.; Rzeszotarski, W.J.; Ferriera, N.L.; Jagoda, E.M.; Reba, R.C.; Eckelman, W.C.



Structure–function studies on the complex iron–sulfur flavoprotein glutamate synthase: the key enzyme of ammonia assimilation  

Microsoft Academic Search

Glutamate synthases are complex iron–sulfur flavoproteins that participate in the essential ammonia assimilation pathway in microorganisms and plants. The recent determination of the 3-dimensional structures of the ? subunit of the NADPH-dependent glutamate synthase form and of the ferredoxin-dependent enzyme of Synechocystis sp. PCC 6803 provides a framework for the interpretation of the functional properties of these enzymes, and highlights

Maria A. Vanoni; Laura Dossena; Bruno Curti



An innovative hydrogel of gemcitabine-loaded lipid nanocapsules: when the drug is a key player of the nanomedicine structure.  


A new method to form a nanoparticle-structured hydrogel is reported; it is based on the drug being loaded into the nanoparticles to form a solid structure. A lipophilic form of gemcitabine (modified lauroyl), an anti-cancer drug, was encapsulated in lipid nanocapsules (LNCs), using a phase-inversion temperature process. A gel was formed spontaneously, depending on the LNC concentration. The drug loading, measured with total entrapment efficiency, and the rheological properties of the gel were assessed. Physical studies (surface tension measurements) showed that modified gemcitabine was localised at the oil-water interface of the LNC, and that the gemcitabine moieties of the prodrug were exposed to the water phase. This particular assembly promoted inter-LNC interactions via hydrogen bonds between gemcitabine moieties that led to an LNC gel structure in water, without a matrix, like a tridimensional pearl necklace. Dilution of the gel produced a gemcitabine-loaded LNC suspension in water, and these nanoparticles presented cytotoxic activity to various cancer cell lines to a greater degree than the native drug. Finally, the syringeability of the formulation was successfully tested and perspectives of its use as a nanomedicine (intratumoural or subcutaneous injection) can be foreseen. PMID:24652455

Moysan, Elodie; González-Fernández, Yolanda; Lautram, Nolwenn; Béjaud, Jérôme; Bastiat, Guillaume; Benoit, Jean-Pierre



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



Synthesis and characterization of mitoQ and idebenone analogues as mediators of oxygen consumption in mitochondria  

Microsoft Academic Search

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone

Damien Y. Duveau; Pablo M. Arce; Robert A. Schoenfeld; Nidhi Raghav; Gino A. Cortopassi; Sidney M. Hecht



Synthesis, biological evaluation and molecular modeling of GW 501516 analogues.  


Eleven analogues of GW 501516 (1) were prepared and subjected to biological testing in a semi-high throughput human skeletal muscle cell assay. The assay testing indicated that all analogues elicited oxidation of oleic acid. Among the most potent agonists, 2e (2-{2-ethyl-4-[(4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl)methylthio]phenoxy}-2-methylpropanoic acid), was also subjected to a luciferase-based transfection assay, which showed that this compound is a potent agonist against PPAR? and a moderate agonist against PPAR?. Docking of compound 2e into PPAR? revealed that it occupied the agonist binding site and exhibited key hydrogen bonding interactions with His323, His449, and Tyr473. PMID:21113965

Ciocoiu, Calin C; Ravna, Aina W; Sylte, Ingebrigt; Hansen, Trond Vidar



Tyrosine 50 at the subunit interface of dimeric human glutathione transferase P1-1 is a structural key residue for modulating protein stability and catalytic function.  


The dimer interface in human GSTP1-1 has been altered by site-directed mutagenesis of Tyr50. It is shown that the effects of some mutations of this single amino acid residue are as detrimental for enzyme function as mutations of Tyr8 in the active site. The dimeric structure is a common feature of the soluble glutathione transferases and the structural lock-and-key motif contributing to the subunit-subunit interface is well conserved in classes alpha, mu, and pi. The key residue Tyr50 in GSTP1-1 was replaced with 5 different amino acids with divergent properties and the mutant proteins expressed and characterized. Mutant Y50F is an improved variant, with higher thermal stability and higher catalytic efficiency than the wild-type enzyme. The other mutants studied are also dimeric proteins, but have lower stabilities and catalytic activities that are reduced by a factor of 10(2)-10(4) from the wild-type value. Mutants Y50L and Y50T are characterized by a markedly increased K(M) value for GSH, while the effect is mainly due to decreased k(cat) values for mutants Y50A and Y50R. In conclusion, residue 50 in the interface governs both structural stability and catalytic function. PMID:10777681

Stenberg, G; Abdalla, A M; Mannervik, B



Solution Structure of the LIM-Homeodomain Transcription Factor Complex Lhx3/Ldb1 and the Effects of a Pituitary Mutation on Key Lhx3 Interactions  

PubMed Central

Lhx3 is a LIM-homeodomain (LIM-HD) transcription factor that regulates neural cell subtype specification and pituitary development in vertebrates, and mutations in this protein cause combined pituitary hormone deficiency syndrome (CPHDS). The recently published structures of Lhx3 in complex with each of two key protein partners, Isl1 and Ldb1, provide an opportunity to understand the effect of mutations and posttranslational modifications on key protein-protein interactions. Here, we use small-angle X-ray scattering of an Ldb1-Lhx3 complex to confirm that in solution the protein is well represented by our previously determined NMR structure as an ensemble of conformers each comprising two well-defined halves (each made up of LIM domain from Lhx3 and the corresponding binding motif in Ldb1) with some flexibility between the two halves. NMR analysis of an Lhx3 mutant that causes CPHDS, Lhx3(Y114C), shows that the mutation does not alter the zinc-ligation properties of Lhx3, but appears to cause a structural rearrangement of the hydrophobic core of the LIM2 domain of Lhx3 that destabilises the domain and/or reduces the affinity of Lhx3 for both Ldb1 and Isl1. Thus the mutation would affect the formation of Lhx3-containing transcription factor complexes, particularly in the pituitary gland where these complexes are required for the production of multiple pituitary cell types and hormones. PMID:22848397

Jeffries, Cy M.; Kwan, Ann; Whitten, Andrew E.; Trewhella, Jill; Mackay, Joel P.; Matthews, Jacqueline M.



Synthesis of photosynthesis-inhibiting nostoclide analogues.  


A series of 34 3-benzyl-5-(arylmethylene)furan-2(5H)-ones, designed using the naturally occurring toxins nostoclides as a lead structure, was synthesized as potential inhibitors of the photosynthetic electron transport. All compounds were fully characterized by IR, NMR (1H and 13C), and MS spectrometry. HMBC and HSQC bidimensional experiments allowed 13C and 1H assignments. Their biological activities were evaluated in vitro as the ability to interfere with light-driven reduction of ferricyanide by isolated spinach chloroplasts. About two-thirds of the compounds exhibited inhibitory properties in the micromolar range against the basal electron flow from water to K3[Fe(CN)6]. The inhibitory potential of these 3-benzyl-5-(arylmethylene)furan-2(5H)-one lactones is higher than that of other nostoclide analogues previously synthesized in the same laboratories. PMID:18338868

Teixeira, Róbson R; Barbosa, Luiz C A; Forlani, Giuseppe; Piló-Veloso, Dorila; Walkimar de Mesquita Carneiro, José



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



Structure analysis of the flavoredoxin from Desulfovibrio vulgaris Miyazaki F reveals key residues that discriminate the functions and properties of the flavin reductase family.  


The crystal structure of flavoredoxin from Desulfovibrio vulgaris Miyazaki F was determined at 1.05 A resolution and its ferric reductase activity was examined. The aim was to elucidate whether flavoredoxin has structural similarity to ferric reductase and ferric reductase activity, based on the sequence similarity to ferric reductase from Archaeoglobus fulgidus. As expected, flavoredoxin shared a common overall structure with A. fulgidus ferric reductase and displayed weak ferric reductase and flavin reductase activities; however, flavoredoxin contains two FMN molecules per dimer, unlike A. fulgidus ferric reductase, which has only one FMN molecule per dimer. Compared with A. fulgidus ferric reductase, flavoredoxin forms three additional hydrogen bonds and has a significantly smaller solvent-accessible surface area. These observations explain the higher affinity of flavoredoxin for FMN. Unexpectedly, an electron-density map indicated the presence of a Mes molecule on the re-side of the isoalloxazine ring of FMN, and that two zinc ions are bound to the two cysteine residues, Cys39 and Cys40, adjacent to FMN. These two cysteine residues are close to one of the putative ferric ion binding sites of ferric reductase. Based on their structural similarities, we conclude that the corresponding site of ferric reductase is the most plausible site for ferric ion binding. Comparing the structures with related flavin proteins revealed key structural features regarding the discrimination of function (ferric ion or flavin reduction) and a unique electron transport system. PMID:19708087

Shibata, Naoki; Ueda, Yasufumi; Takeuchi, Daisuke; Haruyama, Yoshihiro; Kojima, Shuichi; Sato, Junichi; Niimura, Youichi; Kitamura, Masaya; Higuchi, Yoshiki




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...


A First Principles Density-Functional Calculation of the Electronic and Vibrational Structure of the Key Melanin Monomers  

E-print Network

We report first principles density functional calculations for hydroquinone (HQ), indolequinone (IQ) and semiquinone (SQ). These molecules are believed to be the basic building blocks of the eumelanins, a class of bio-macromolecules with important biological functions (including photoprotection) and with potential for certain bioengineering applications. We have used the DeltaSCF (difference of self consistent fields) method to study the energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), Delta_HL. We show that Delta_HL is similar in IQ and SQ but approximately twice as large in HQ. This may have important implications for our understanding of the observed broad band optical absorption of the eumelanins. The possibility of using this difference in Delta_HL to molecularly engineer the electronic properties of eumelanins is discussed. We calculate the infrared and Raman spectra of the three redox forms from first principles. Each of the molecules have significantly different infrared and Raman signatures, and so these spectra could be used in situ to non-destructively identify the monomeric content of macromolecules. It is hoped that this may be a helpful analytical tool in determining the structure of eumelanin macromolecules and hence in helping to determine the structure-property-function relationships that control the behaviour of the eumelanins.

B. J. Powell; T. Baruah; N. Bernstein; K. Brake; Ross H. McKenzie; P. Meredith; M. R. Pederson



Rock Identification Key  

NSDL National Science Digital Library

This identification key has been designed to assist teachers, students, or collectors in the identification of rocks. It consists of a series of "yes/no/then go to" questions that pertain to observations of structure, texture, color, hardness, and other properties of the specimen being examined.

Peck, Don


Antimicrobial Evaluation of Mangiferin Analogues  

PubMed Central

The naturally occurring xanthone glycoside mangiferin has been isolated by column chromatography from the ethanol extract of stem bark of Mangifera indica. Mangiferin was further converted to 5-(N-phenylaminomethyleno)mangiferin, 5-(N-p-chlorophenylaminomethyleno) mangiferin, 5-(N-2-methylphenylaminomethyleno) mangiferin, 5-(N-p-methoxyphenylaminomethyleno) mangiferin, 5-(N, N-diphenylaminomethyleno) mangiferin, 5-(N--napthylaminomethyleno) mangiferin and 5-(N-4-methylphenylaminomethyleno) mangiferin. Mangiferin and its analogues were characterized by melting point and Rf value determination and through spectral technique like UV, IR, and NMR spectral analysis. The synthesized compounds were screened for antimicrobial activity. PMID:20490307

Singh, S. K.; Kumar, Y.; Kumar, S. Sadish; Sharma, V. K.; Dua, K.; Samad, A.



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.; Harps?e, Kasper; Skonberg, Christian; Liljefors, Tommy; Str?mgaard, Kristian



Insight into the binding mode between HIV-1 integrase and pyrimidone analogue inhibitors with MD simulation and 3D-QSAR.  


HIV-1 integrase (HIVIN) plays a key role in the replication of the HIV-1 virus and represents an attractive target for anti-HIV drug design. Experimental observation suggests that pyrimidone analogues have potent anti-HIV activity. Then, we modeled an HIVIN catalytic core domain based on the crystal structure of the prototype foamy virus (PFV) integrase. Molecular docking and molecular dynamics simulations were used to investigate the interaction mechanism between pyrimidone analogues and the HIVIN catalytic core domain. MD results suggest that the most active molecule (6K) has more stable hydrogen bonds and hydrophobic contacts than the FDA approved anti-HIV drug Raltegravir. Furthermore, the analogues and Raltegravir might have similar binding modes with HIVIN. Finally, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to construct three dimensional quantitative structure-activity (3D-QSAR) models. Eleven test set compounds which are not included in the training set were used to evaluate these models. The results suggest that these models are robust and have good prediction abilities. PMID:23210925

Ma, Songyao; Ye, Wei; Ji, Dingjue; Chen, Hai-Feng



Microbial community structure stability, a key parameter in monitoring the development of constructed wetland mesocosms during start-up.  


Constructed wetlands (CWs) are known to be effective for treating waste streams, and pilot-scale CWs are useful for assessing the impact of pollutants and their remediation. However, little is known with respect to the establishment of these mesocosm systems or the parameters which should be monitored in assessing system equilibration, i.e. when they present stabilised physical and biological patterns. The aim of this study was to evaluate the temporal aspects of CW equilibration as a basis for future studies of system response to amendment. Microbial biomass and hydraulic conductivity values were monitored and microbial community fingerprints were obtained using denaturing gradient gel electrophoresis (DGGE). This study showed that microbial community fingerprinting provides a valuable tool for assessing the time scales of equilibration, as it was the last parameter which stabilised during the equilibration period. Hydraulic conductivity was also an important parameter in determining the time scale for initiation of the equilibration process during the study. For a CW of the dimensions used (173 cm long/106 cm large/30 cm depth), community equilibration times demonstrated on the basis of similar microbial community structures were found to be on the order of 100 days. PMID:22027103

Ramond, Jean-Baptiste; Welz, Pamela J; Cowan, Don A; Burton, Stephanie G



Determination of key structure-activity relationships in siRNA delivery with a mixed micelle system.  


Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure-activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions. PMID:24140749

Omedes Pujol, Marta; Coleman, Daniel J L; Allen, Christopher D; Heidenreich, Olaf; Fulton, David A



Determination of key structure-activity relationships in siRNA delivery with a mixed micelle system???  

PubMed Central

Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure–activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions. PMID:24140749

Omedes Pujol, Marta; Coleman, Daniel J.L.; Allen, Christopher D.; Heidenreich, Olaf; Fulton, David A.



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.



Analogue gravity in hyperbolic metamaterials  

E-print Network

Sub-wavelength confinement of light in nonlinear hyperbolic metamaterials due to formation of spatial solitons has attracted much recent attention because of its seemingly counter-intuitive behavior. In order to achieve self-focusing in a hyperbolic wire medium, a nonlinear self-defocusing Kerr medium must be used as a dielectric host. Here we demonstrate that this behavior finds natural explanation in terms of analogue gravity. Wave equation describing propagation of extraordinary light inside hyperbolic metamaterials exhibits 2+1 dimensional Lorentz symmetry. The role of time in the corresponding effective 3D Minkowski spacetime is played by the spatial coordinate aligned with the optical axis of the metamaterial. Nonlinear optical Kerr effect bends this spacetime resulting in effective gravitational force between extraordinary photons. In order for the effective gravitational constant to be positive, negative self-defocusing Kerr medium must be used as a host. If gravitational self-interaction is strong enough, spatial soliton may collapse into a black hole analogue.

Igor I. Smolyaninov



Rational design of ?-helix-stabilized exendin-4 analogues.  


Exendin-4 (Ex4) is a potent glucagon-like peptide-1 receptor agonist, a drug regulating the plasma glucose level of patients suffering from type 2 diabetes. The molecule's poor solubility and its readiness to form aggregates increase the likelihood of unwanted side effects. Therefore, we designed Ex4 analogues with improved structural characteristics and better water solubility. Rational design was started from the parent 20-amino acid, well-folded Trp cage (TC) miniprotein and involved the step-by-step N-terminal elongation of the TC head, resulting in the 39-amino acid Ex4 analogue, E19. Helical propensity coupled to tertiary structure compactness was monitored and quantitatively analyzed by electronic circular dichroism and nuclear magnetic resonance (NMR) spectroscopy for the 14 peptides of different lengths. Both (15)N relaxation- and diffusion-ordered NMR measurements were established to investigate the inherent mobility and self-association propensity of Ex4 and E19. Our designed E19 molecule has the same tertiary structure as Ex4 but is more helical than Ex4 under all studied conditions; it is less prone to oligomerization and has preserved biological activity. These conditions make E19 a perfect lead compound for further drug discovery. We believe that this structural study improves our understanding of the relationship between local molecular features and global physicochemical properties such as water solubility and could help in the development of more potent Ex4 analogues with improved pharmacokinetic properties. PMID:24828921

Rovó, Petra; Farkas, Viktor; Stráner, Pál; Szabó, Mária; Jermendy, Agnes; Hegyi, Orsolya; Tóth, Gábor K; Perczel, András



Anti-angiogenic properties of a sulindac analogue  

PubMed Central

Background and purpose: Angiopoietins (Ang) are crucial for new blood vessel formation and exert their effects by acting on the Tie2 receptor. We have recently described a sulindac analogue 2-((1E,Z)-1-benzylidene-5-bromo-2-methyl-1H-inden-3-yl)acetic acid; termed C-18 from now onwards) that inhibits Tie2 receptor activity in kinase assays in vitro. Here, we have assessed the ability of C-18 to inhibit angiogenesis-related properties of endothelial cells and tested its selectivity for the Tie2 receptor. Experimental approach: For in vitro experiments human umbilical vein endothelial cells (HUVEC) were used. Proliferation was measured using the MTT assay; migration assays were performed in a modified Boyden chamber and tube-like structure formation was determined on matrigel. The effects of C-18 in vivo were evaluated in the chicken chorioallantoic membrane (CAM). Key results: Pre-treatment of HUVEC with C-18 blocked Ang-1-stimulated migration, but also abolished vascular endothelial cell growth factor (VEGF)- and fibroblast growth factor 2-induced responses. Incubation with C-18 inhibited serum-induced proliferation in a concentration-dependent manner; C-18 was, however, without effect on Ang-1-induced survival. In addition, we observed that C-18 did not inhibit ligand-induced receptor phosphorylation of Tie2 or VEGFR2. On the other hand, C-18 blocked activation of members of the mitogen-activated protein kinase family and of the Ser/Thr kinase Akt induced by both VEGF and Ang-1. Furthermore, incubation of CAMs with C-18 led to a dose-dependent inhibition of vascular length. Conclusions and implications: C-18 did not act as a Tie2 inhibitor, as originally thought, but rather inhibited growth factor-stimulated signalling pathways that regulate endothelial cell migration and potently reduces neovascularization in vivo. PMID:17965739

Pyriochou, A; Tsigkos, S; Vassilakopoulos, T; Cottin, T; Zhou, Z; Gourzoulidou, E; Roussos, C; Waldmann, H; Giannis, A; Papapetropoulos, A



Insulin analogues may accelerate progression of diabetic retinopathy after impairment of inner blood-retinal barrier.  


Diabetic retinopathy regresses after spontaneous infarction or surgical ablation of pituitary gland. Growth hormone deficiency seems to be a protective factor for development of diabetic retinopathy in dwarfs. Despite the same glycemic control, development of diabetic retinopathy is significantly higher in pubertal subjects than pre-pubertal subjects. These evidences indicate a strong relationship between growth hormone and progression of diabetic retinopathy. Insulin like growth factor-1 (IGF-1) is the most important mediator of effects of growth hormone (GH). It stimulates IGF-1 receptor. Insulin analogues also stimulate IGF-1 receptor. Therefore insulin analogues may show similar effects like growth hormone and deteriorate diabetic retinopathy. However we suggest that impairment degree of inner blood-retinal barrier should be considered for this claim. We hypothesize that insulin analogues have dual effects (beneficial and worsening) depending on stage of impairment of inner blood-retinal barrier. Insulin analogues protect pericytes and blood-retinal barrier by decreasing blood glucose level. Analogues may pass into the retinal tissue in very low amounts when inner blood-retinal barrier is intact. Therefore, insulin analogues may not deteriorate diabetic retinopathy but also have beneficial effect by protecting blood-retinal barrier at this stage. However, they may pass into the retinal tissue in much more amounts when inner blood-retinal barrier impairs. Analogues may deteriorate cellular composition of retina through stimulation of IGF-1 receptors. A number of different cell types, including glia, retinal pigment epithelial cells and fibroblast-like cells have been identified in diabetic epiretinal tissues. Insulin analogues may cause proliferation in these cells. A type of glial cell named Non-astrocytic Inner Retinal Glia-like (NIRG) cell was identified to be stimulated and proliferate by IGF-1. IGF has been reported to generate traction force in retinal pigment epitelium (RPE) and mullerian cells. Mullerian cells also support inner blood-retinal barrier. Insulin analogues may cause proliferation in glial cells and generate traction force in RPE and mullerian cells by stimulating IGF-1 receptor. These effects of analogues may increase after deterioration of inner blood-retinal barrier and cause structural changes in retinal tissue. Deterioration of cellular structure may contribute to impairment of inner blood-retinal barrier, facilitate anjiogenesis and influence vitreoretinal interface. Therefore we suggest that insulin analogues should be used carefully after impairment of inner blood-retinal barrier. Analogues that bind with lesser affinity to IGF-1 receptor should be chosen after impairment. Pharmacologic agents may be developed to antagonize effect of insulin analogues on IGF-1 receptors. PMID:24090664

Kaya, Abdullah; Kar, Taner; Aksoy, Yakup; Özalper, Veysel; Ba?bu?, Barbaros



Structure of Rhodococcus equi virulence-associated protein B (VapB) reveals an eight-stranded antiparallel ?-barrel consisting of two Greek-key motifs  

PubMed Central

Members of the virulence-associated protein (Vap) family from the pathogen Rhodococcus equi regulate virulence in an unknown manner. They do not share recognizable sequence homology with any protein of known structure. VapB and VapA are normally associated with isolates from pigs and horses, respectively. To contribute to a molecular understanding of Vap function, the crystal structure of a protease-resistant VapB fragment was determined at 1.4?Å resolution. The structure was solved by SAD phasing employing the anomalous signal of one endogenous S atom and two bound Co ions with low occupancy. VapB is an eight-stranded antiparallel ?-barrel with a single helix. Structural similarity to avidins suggests a potential binding function. Unlike other eight- or ten-stranded ?-barrels found in avidins, bacterial outer membrane proteins, fatty-acid-binding proteins and lysozyme inhibitors, Vaps do not have a next-neighbour arrangement but consist of two Greek-key motifs with strand order 41238567, suggesting an unusual or even unique topology. PMID:25005079

Geerds, Christina; Wohlmann, Jens; Haas, Albert; Niemann, Hartmut H.



The fluorite related modulated structures of the Gd{sub 2}(Zr{sub 2-x}Ce{sub x})O{sub 7} solid solution: An analogue for Pu disposition  

SciTech Connect

We present an overview of the Gd{sub 2}(Zr{sub 2-x}Ce{sub x})O{sub 7} 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 Ce{sup 4+} as the dominant species in compositions across this system, remaining analogous to Pu{sup 4+}. - Graphical abstract: Electron diffraction reveals the cation vacancy ordering mechanisms leading to fluorite related superstructures in the Gd{sub 2}(Zr{sub 2-x}Ce{sub x})O{sub 7} solid solution. Highlights: Black-Right-Pointing-Pointer The fluorite related solid solution Gd{sub 2}(Zr{sub 1-x}Ce{sub x})O{sub 7} was prepared by solid state synthesis. Black-Right-Pointing-Pointer Ce L{sub 3} edge XAS and Ce M{sub 4,5} EELS measurements show Ce substitutes as Ce{sup 4+}. Black-Right-Pointing-Pointer Cation and oxygen vacancy ordering results in four fluorite related structures.

Reid, D.P. [Immobilisation Science Laboratory, Department of Materials Science and Engineering, University of Sheffield, Mappin Street, Sheffield S1 3JD (United Kingdom); Stennett, M.C., E-mail: [Immobilisation Science Laboratory, Department of Materials Science and Engineering, University of Sheffield, Mappin Street, Sheffield S1 3JD (United Kingdom); Hyatt, N.C., E-mail: [Immobilisation Science Laboratory, Department of Materials Science and Engineering, University of Sheffield, Mappin Street, Sheffield S1 3JD (United Kingdom)



Discrete analogue computing with rotor-routers  

E-print Network

Discrete analogue computing with rotor-routers James Propp August 18, 2010 Abstract: Rotor a certificate that can itself be computed by the rotor-router network. Rotor- router networks can be viewed processes. Rotor-router networks are discrete analogues of continuous linear systems such as electrical

Propp, James


Topical Prostaglandin Analogue Drugs Inhibit Adipocyte Differentiation  

PubMed Central

Purpose To investigate the effects of topical prostaglandin analogue drugs on the differentiation of adipocytes. Methods Differentiation of 3T3-L1 preadipocytes was induced with isobutylmethylxanthine, dexamethasone, and insulin. 3T3-L1 cells were exposed to 0.008, 0.08, 0.2 µM of latanoprost and travoprost. Reverse transcription polymerase chain reaction for mRNA expression of lipoprotein lipase and peroxisome proliferator-activated receptor ? 2 (PPAR?2), and glycerol-3-phosphate dehydrogenase (G3PDH) assays were performed to examine the effects on early and late differentiation, respectively. Also, glycerol assays were done to evaluate the effect of prostaglandin analogues on lipolysis after differentiation. Results Both prostaglandin analogues inhibited differentiation of preadipocytes. Topical prostaglandin analogues significantly decreased G3PDH activity, a marker of late differentiation. However, topical prostaglandin analogues did not change mRNA expressions of lipoprotein lipase and PPAR?2, markers of early differentiation. The activities of the early markers of differentiation were not changed significantly before and after growth arrest. Compared to latanoprost, travoprost decreased G3PDH activity more significantly (p < 0.05). Both prostaglandin analogues did not affect the lipolysis of differentiated adipocytes (p > 0.05). Conclusions Prostaglandin analogues display an inhibitory effect on the differentiation of adipocytes when the cells start to differentiate especially in the late stage of differentiation. Thus, commercial topical prostaglandin analogues may decrease the fat contents of eyelids. PMID:24882960



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.



Medical therapy of acromegaly: efficacy and safety of somatostatin analogues.  


Acromegaly is a chronic disease with signs and symptoms due to growth hormone (GH) excess. The most frequent cause of acromegaly is a GH-producing pituitary adenoma. Chronic GH excess is accompanied by long-term complications of the locomotor (arthrosis) and cardiovascular (atherosclerosis, cardiomyopathy) systems and is, when untreated, associated with an increased mortality. The aim of treatment of acromegaly is to improve symptoms, to achieve local tumour mass control, and to decrease morbidity and mortality. Treatment options include surgery, medical therapy and radiotherapy. Transsphenoidal surgery is the first choice of treatment when a definitive cure can be achieved, particularly in the case of microadenomas and when decompression of surrounding structures (optic chiasm, ophthalmic motor nerves) is indicated. Primary medical therapy has been increasingly applied in recent years, especially when a priori chances of surgical cure are low (because of adenoma size and localization) and in patients with advanced age and/or serious co-morbidity. In addition, preoperative primary medical therapy may result in tumour shrinkage, facilitating tumour resection, and may reduce perioperative complications due to GH excess. Within the spectrum of medical therapy, long-acting somatostatin analogues (somatostatins) are considered as first-line treatment. Treatment with somatostatin analogues results in GH control in approximately 60% of patients. In addition, somatostatin analogues induce tumour shrinkage in 30-50% of patients, particularly when applied as primary therapy. Prolonged treatment with somatostatin analogues appears to be safe and is usually well tolerated. The currently available somatostatin analogues, octreotide and lanreotide, seem to be equally effective; however, this should still be evaluated in prospective, randomized trials evaluating efficacy with respect to GH control and tumour shrinkage. In patients with an insufficient clinical and biochemical response to somatostatin analogues, combination therapy with dopamine receptor agonists or the GH receptor antagonist pegvisomant usually leads to disease control. New developments in the medical therapy of acromegaly include the universal somatostatin receptor agonist pasireotide, which has a broader affinity for all somatostatin receptor (sst) subtypes compared with the currently available somatostatin analogues with preferential affinity for the sst2 receptor, and chimeric compounds that interact with both somatostatin and dopamine receptors with synergizing effects on GH secretion. PMID:19852525

Feelders, Richard A; Hofland, Leo J; van Aken, Maarten O; Neggers, Sebastian J; Lamberts, Steven W J; de Herder, Wouter W; van der Lely, Aart-Jan



Synthesis and evaluation of substrate analogue inhibitors of trypanothione reductase.  


Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a K(i) = 2 µM. PMID:22085139

Duyzend, Michael H; Clark, Christopher T; Simmons, Shayna L; Johnson, Wade B; Larson, Anna M; Leconte, Aaron M; Wills, Andrew W; Ginder-Vogel, Matthew; Wilhelm, April K; Czechowicz, Josephine A; Alberg, David G



Synthesis and cytotoxicity assay of four ganglioside GM3 analogues.  


A concise and efficient synthetic route for preparation of four ganglioside GM3 analogues was described. The key step is a highly regioselective and stereoselective ?-sialylation from a suitably protected glycoside acceptor with a sialyl xanthate to provide the sialo-oligosaccharide in good yield. The cytotoxic properties of the synthetic gangliosides were evaluated against normal human keratinocytes and human HCT116 and K562 cancer cells. Two of them exhibited good antiproliferative activity and displayed a better cytotoxicity against cancer cell than HaCaT normal cell. PMID:24534540

Qu, Huanhuan; Liu, Jian-Miao; Wdzieczak-Bakala, Joanna; Lu, Dan; He, Xianran; Sun, Wenji; Sollogoub, Matthieu; Zhang, Yongmin



Towards bottom-up nanopatterning of Prussian blue analogues  

PubMed Central

Summary Ordered nanoperforated TiO2 monolayers fabricated through sol–gel chemistry were used to grow isolated particles of Prussian blue analogues (PBA). The elaboration of the TiO2/CoFe PBA nanocomposites involves five steps. The samples were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), infrared spectroscopy and X-ray photoelectron spectroscopy (XPS) all along the synthesis process. Selected physico-chemical parameters have been varied in order to determine the key steps of the synthesis process and to optimize it. This study is an important step towards the full control of the fabrication process. PMID:25383305

Trannoy, Virgile; Faustini, Marco; Grosso, David; Mazerat, Sandra; Brisset, Francois; Dazzi, Alexandre



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.



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



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



CoMFA QSAR models of camptothecin analogues based on the distinctive SAR features of combined ABC, CD and E ring substitutions.  


Quantitative Structure-Activity Relationship (QSAR) paradigm has proved to be useful in understanding the requirements of physicochemical properties of the molecular substituents in many key locations as well as molecules as a whole. The knowledge of Structure-Activity Relationship (SAR), together with the generation of QSAR, constitutes a large body of evidence that may assist in the development of new molecules with excellent biological activity and low toxicity. The camptothecin (CPT) analogues are emerging as a promising group of chemotherapeutic agents. The SAR of these molecules provide insight into the mechanism of topoisomerase I inhibition and help in the synthesis of various CPT analogues by modifying the different rings of the original CPT molecule, giving each analogue a unique property. Here we have demonstrated the Comparative Molecular Force field Analysis (CoMFA) QSAR models for ABC-ring, CD-ring and E-ring substitution of CPT in comparison with the traditional 2D-QSAR model. The 3D-QSAR model gave convincing (standard deviation) r2 values of 0.99, 0.99 and 0.996 as against 2D-QSAR r2 values of 0.83, 0.97 and 0.90 for ABC-Ring, CD-Ring and E-Ring analogues, respectively. In this model special emphasis was given to the contribution of steric and electrostatic force fields in predicting biological activity of CPT derivatives and they were found to improve the QSAR model and make it more precisely predictive. PMID:22840194

Virupaksha, Bastikar; Alpana, Gupte



Key interactions in the immunoglobulin-like structure of apo-neocarzinostatin: Evidence from nuclear magnetic resonance relaxation data and molecular dynamics simulations  

PubMed Central

The three-dimensional structure of apo-neocarzinostatin (apo-NCS, MW: ca.11000, antitumoral chromophore carrier protein) is based on a seven-stranded antiparallel ?-sandwich, very similar to the immunoglobulin folding domain. We investigated the backbone dynamics of apo-NCS by 13C-NMR relaxation measurements and molecular dynamics simulation. Model-free parameters determined from the experimental data are compared with a 1.5-nsec molecular simulation of apo-NCS in aqueous solution. This comparison provides an accurate description of both local and collective movements within the protein. This analysis enabled us to correlate dynamic processes with key interactions of this ?-protein. Local motions that could be relevant for the intermolecular association with the ligand are also described. PMID:11604530

Izadi-Pruneyre, Nadia; Quiniou, Éric; Blouquit, Yves; Perez, Javier; Minard, Philippe; Desmadril, Michel; Mispelter, Joël; Adjadj, Élisabeth



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



Natural analogue studies as supplements to biomineralization research  

SciTech Connect

Chemical reactions can alter the chemistry and crystal structure of solid objects over archeological or geological times, while preserving external physical shapes. The reactions resulting in these structures offer natural analogues to laboratory experiments in biomineralization and to biologically influenced alteration of nuclear waste packages, and thus, they offer the only available way of validating models that purport waste package behavior over archaeological or geological times. Potential uses of such analogues in the construction and validation of hypothetical mechanisms of microbiological corrosion and biomineralization are reviewed. Evidence from such analogues suggests that biofilms can control materials alteration in ways usually overlooked. The newly hypothesized mechanisms involve control by biofilms of the cation flow near the solid surface and offer plausible mechanisms for the formation of mixed-cation minerals under conditions that would lead to dealloying in abiotic experiments; they also account for the formation of unusual minerals [such as posnjakite, Cu{sub 4}SO{sub 4}(OH){sub 6{center_dot}}H{sub 2}O] and mineral morphologies unusual in corrosion [malachite, Cu{sub 2}CO{sub 3}(OH){sub 2}, rarely forms botryoidally under corrosion conditions and its occasional presence on archaeological objects that appear to have undergone microbiological corrosion may be related to biofilm phenomena].

McNeil, M.B. [Nuclear Regulatory Commission, Washington, DC (United States)



Meta-iodobenzylguanidine and analogues: chemistry and biology.  


Meta-iodobenzylguanidine (MIBG) is a structural analogue of the neurotransmitter norepinephrine (NE) and is taken up by cells rich in sympathetic neurons by an active uptake process mediated by the NE transporter, which is referred to as uptake-1. It is a valuable agent in the diagnosis of myocardial abnormalities as well as that of several neuroendocrine tumors such as neuroblastoma, pheochromocytoma and carcinoid tumors. MIBG labeled with (131)I also is used extensively in the therapy of several neuroendocrine tumors. Over the years, a substantial amount of work has been undertaken to improve its clinical utility. Currently, radio-iodinated MIBG used in the clinic is prepared by an exchange radio-iodination method and, thus, is of low specific activity. For possible better targeting and to ward off pharmacological effects, its preparation at a no-carrier-added level both by solution-phase and solid-phase synthesis has been developed. For potential use in the treatment of micrometastatic diseases, synthesis of an analogue labeled with the a emitter (211)At was devised. Development of analogues labeled with positron emitting radionuclides such as (124)I, (18)F, and (76)Br has been reported. Further, efforts have been put in to improve its pharmacokinetic properties by structural modifications. Various aspects of these developments are reviewed herein. PMID:19088690

Vaidyanathan, G



Plant Volatile Analogues Strengthen Attractiveness to Insect  

PubMed Central

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



Analogue transformations in physics and their application to acoustics.  


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



Analogue Transformations in Physics and their Application to Acoustic  

E-print Network

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 an explicit design of a spacetime compressor for acoustic waves and a carpet cloak for a moving aircraft.

C. García-Meca; S. Carloni; C. Barceló; G. Jannes; J. Sánchez-Dehesa; A. Martínez



Analogue Transformations in Physics and their Application to Acoustic  

E-print Network

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 an explicit design of a spacetime compressor for acoustic waves and a carpet cloak for a moving aircraft.

García-Meca, C; Barceló, C; Jannes, G; Sánchez-Dehesa, J; Martínez, A



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



Crystal structure of the ?-hydroxymuconic semialdehyde dehydrogenase from Pseudomonas sp. strainWBC-3, a key enzyme involved in para-Nitrophenol degradation  

PubMed Central

Background para-Nitrophenol (PNP) is a highly toxic compound with threats to mammalian health. The pnpE-encoded ?-hydroxymuconic semialdehyde dehydrogenase catalyzes the reduction of ?-hydroxymuconic semialdehyde to maleylacetate in Pseudomonas sp. strain WBC-3, playing a key role in the catabolism of PNP to Krebs cycle intermediates. However, the catalyzing mechanism by PnpE has not been well understood. Results Here we report the crystal structures of the apo and NAD bound PnpE. In the PnpE-NAD complex structure, NAD is situated in a cleft of PnpE. The cofactor binding site is composed of two pockets. The adenosine and the first ribose group of NAD bind in one pocket and the nicotinamide ring in the other. Conclusions Six amino acids have interactions with the cofactor. They are C281, E247, Q210, W148, I146 and K172. Highly conserved residues C281 and E247 were identified to be critical for its catalytic activity. In addition, flexible docking studies of the enzyme-substrate system were performed to predict the interactions between PnpE and its substrate ?-hydroxymuconic semialdehyde. Amino acids that interact extensively with the substrate and stabilize the substrate in an orientation suitable for enzyme catalysis were identified. The importance of these residues for catalytic activity was confirmed by the relevant site-directed mutagenesis and their biochemical characterization. PMID:24252642



Modern key agreement techniques  

Microsoft Academic Search

Abstract: We present a survey of modern key agreement techniques, and discuss distinguishing characteristics,including identity (entity) authentication, implicit key authentication, key confirmation, andkey freshness.

Rainer A. Rueppel; Paul C. Van Oorschot



Hypoxia-selective antitumor agents. 9. Structure-activity relationships for hypoxia-selective cytotoxicity among analogues of 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide.  


A series of analogues of the novel hypoxia-selective cytotoxin 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (6) have been prepared and evaluated, in a search for compounds which retain high hypoxic selectivity but have increased potency and/or aqueous solubility. Several analogues with ionizable or dipolar carboxamide side chains showed improved solubility but generally had reduced cytotoxic potency and hypoxic selectivity. Modification of the mustard leaving groups or replacement of the carboxamide moiety provided some compounds with superior potency, but only the mixed chloro/mesylate mustard 20 provided a gain in potency relative to solubility while retaining the hypoxic selectivity of 6. These nitrogen mustards did not show the remarkable activity demonstrated by the related aziridine 7 [CB 1954, 5-(N-aziridinyl)- 2,4-dinitrobenzamide] in Walker 256 adenocarcinoma cells and are not efficient substrates for the DT-diaphorase which activates the latter compound by aerobic nitroreduction in Walker cells. Variations in hypoxic selectivity within the dinitrobenzamide mustards appear not to be due to differences in sensitivity to activation by this enzyme. Walker cells showed intermediate sensitivity to the mono(2-chloroethyl) analogue 26 but not to the related half-mustard 27, suggesting that the inhibition of DT-diaphorase activity is due to steric effects in the 5-position. The preferred compound overall with respect to solubility, potency, and in vitro hypoxic cell selectivity was the (dimethylamino)-ethyl derivative 11. DNA elution studies and comparison of the sensitivity of AA8 and UV4 cells to this compound indicated reductive activation to form a DNA cross-linking agent under hypoxia. Radiobiological studies indicated 11 to be equally active against both aerobic and hypoxic cells in KHT tumors. It is not clear whether this reflects efficient killing of aerobic cells as a result of diffusion of reduced metabolites from hypoxic regions or whether cytotoxicity in tumors is independent of hypoxia. PMID:8035424

Palmer, B D; Wilson, W R; Atwell, G J; Schultz, D; Xu, X Z; Denny, W A



The 3.2 ? resolution structure of a Receptor:CheA:CheW signaling complex defines overlapping binding sites and key residue interactions within bacterial chemosensory arrays  

PubMed Central

Bacterial chemosensory arrays are composed of extended networks of chemoreceptors (also known as methyl-accepting chemotaxis proteins, MCPs), the histidine kinase CheA, and the adaptor protein CheW. Models of these arrays have been developed from cryoelectron microscopy, crystal structures of binary and ternary complexes, NMR spectroscopy, mutational data and biochemical studies. A new 3.2 Å resolution crystal structure of a T. maritima MCP protein interaction region in complex with the CheA kinase-regulatory module (P4–P5) and adaptor protein CheW provides sufficient detail to define residue contacts at the interfaces formed among the three proteins. As in a previous 4.5 Å resolution structure, CheA-P5 and CheW interact through conserved hydrophobic surfaces at the ends of their ?-barrels to from pseudo six-fold symmetric rings in which the two proteins alternate around the circumference. The interface between P5 subdomain 1 and CheW subdomain 2 was anticipated from previous studies, whereas the related interface between CheW subdomain 1 and P5 subdomain 2 has only been observed in these ring assemblies. The receptor forms an unexpected structure in that the helical hairpin tip of each subunit has “unzipped” into a continuous ?-helix; four such helices associate into a bundle and the tetramers bridge adjacent P5-CheW rings in the lattice through interactions with both P5 and CheW. P5 and CheW each bind a receptor helix with a groove of conserved hydrophobic residues between subdomains 1 and 2. P5 binds the receptor helix N-terminal to the tip region (lower site), whereas CheW binds the same helix with inverted polarity near the bundle end (upper site). Sequence comparisons among different evolutionary classes of chemotaxis proteins show that the binding partners undergo correlated changes at key residue positions that involve the lower site. Such evolutionary analyses argue that both CheW and P5 bind to the receptor tip at overlapping positions. Computational genomics further reveal that two distinct CheW proteins in Thermotogae utilize the analogous recognition motifs to couple different receptor classes to the same CheA kinase. Important residues for function previously identified by mutagenesis, chemical modification and biophysical approaches also map to these same interfaces. Thus, although the native CheW-receptor interaction is not observed in the present crystal structure, the bioinformatics and previous data predict key features of this interface. The companion study of the P5-receptor interface in native arrays (Piasta et al. (2013) Biochemistry; Companion paper) shows that, despite the non-native receptor fold in the present crystal structure, the local helix-in-groove contacts of the crystallographic P5-receptor interaction are present in native arrays and are essential for receptor regulation of kinase activity. PMID:23668907

Li, Xiaoxiao; Fleetwood, Aaron D.; Bayas, Camille; Bilwes, Alexandrine M.; Ortega, Davi R.; Falke, Joseph J.; Zhulin, Igor B.; Crane, Brian R.



High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues  

PubMed Central

Background and purpose: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. Experimental approach: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (NaV1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (NaV1.2) heterologously expressed in human embryonic kidney cell line 293. Key results: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC50 for block of resting channels at ?150?mV was 2.3, 3.9 and 11.3??M in NaV1.4, respectively, and 29.2??M for 4-chloropropofol in NaV1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81?nM, 312?nM and 227?nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in NaV1.4, and 450?nM for 4-chloropropofol in NaV1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100?Hz). Conclusions and implications: Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. PMID:18574460

Haeseler, G; Karst, M; Foadi, N; Gudehus, S; Roeder, A; Hecker, H; Dengler, R; Leuwer, M



Protonation states of the key active site residues and structural dynamics of glmS riboswitch as reveled by molecular dynamics  

PubMed Central

The glmS catalytic riboswitch is part of the 5'-untranslated region of mRNAs encoding glucosamine-6-phosphate (GlcN6P) synthetase (glmS) in numerous Gram-positive bacteria. Binding of the cofactor GlcN6P induces site-specific self-cleavage of the RNA. However, detailed reaction mechanism as well as protonation state of glmS reactive form remains still elusive. To probe the dominant protonation states of key active site residues, we carried out explicit solvent molecular dynamic simulations involving various protonation states of three crucial active site moieties observed in the available crystal structures: (i) guanine G40 (following the T. tengcongensis numbering), (ii) the GlcN6P amino/ammonium group, and (iii) the GlcN6P phosphate moiety. We found that a deprotonated G40? seems incompatible with the observed glmS active site architecture. Our data suggest that the canonical form of G40 plays a structural role by stabilizing an in-line attack conformation of the cleavage site A-1(2'-OH) nucleophile, rather than a more direct chemical role. In addition, we observe weakened cofactor binding upon protonation of the GlcN6P phosphate moiety, which explains the experimentally observed increase of Km with decreasing pH. Finally, we discuss a possible role of cofactor binding and its interaction with the G65 and G1 purines in structural stabilization of the A-1(2'-OH) in-line attack conformation. Based on the identified dominant protonation state of the reaction precursor, we propose a hypothesis of self-cleavage mechanism, in which A-1(2'-OH) is activated as nucleophile by the G1(pro-Rp) non-bridging oxygen of the scissile phosphate, whereas the ammonium group of GlcN6P acts as the general acid protonating the G1(O5') leaving group. PMID:20536206

Banas, Pavel; Walter, Nils G.



The crystal structure of necrosis- and ethylene-inducing protein 2 from the causal agent of cacao's Witches' Broom disease reveals key elements for its activity.  


The necrosis- and ethylene-inducing peptide 1 (NEP1)-like proteins (NLPs) are proteins secreted from bacteria, fungi and oomycetes, triggering immune responses and cell death in dicotyledonous plants. Genomic-scale studies of Moniliophthora perniciosa, the fungus that causes the Witches' Broom disease in cacao, which is a serious economic concern for South and Central American crops, have identified five members of this family (termed MpNEP1-5). Here, we show by RNA-seq that MpNEP2 is virtually the only NLP expressed during the fungus infection. The quantitative real-time polymerase chain reaction results revealed that MpNEP2 has an expression pattern that positively correlates with the necrotic symptoms, with MpNEP2 reaching its highest level of expression at the advanced necrotic stage. To improve our understanding of MpNEP2's molecular mechanism of action, we determined the crystallographic structure of MpNEP2 at 1.8 Å resolution, unveiling some key structural features. The implications of a cation coordination found in the crystal structure were explored, and we show that MpNEP2, in contrast to another previously described member of the NLP family, NLP(Pya) from Pythium aphanidermatum, does not depend on an ion to accomplish its necrosis- and electrolyte leakage-promoting activities. Results of site-directed mutagenesis experiments confirmed the importance of a negatively charged cavity and an unforeseen hydrophobic ?-hairpin loop for MpNEP2 activity, thus offering a platform for compound design with implications for disease control. Electron paramagnetic resonance and fluorescence assays with MpNEP2 performed in the presence of lipid vesicles of different compositions showed no sign of interaction between the protein and the lipids, implying that MpNEP2 likely requires other anchoring elements from the membrane to promote cytolysis or send death signals. PMID:21999603

Zaparoli, Gustavo; Barsottini, Mario Ramos de Oliveira; de Oliveira, Juliana Ferreira; Dyszy, Fabio; Teixeira, Paulo José Pereira Lima; Barau, Joan Grande; Garcia, Odalys; Costa-Filho, Antonio José; Ambrosio, Andre Luis Berteli; Pereira, Gonçalo Amarante Guimarães; Dias, Sandra Martha Gomes



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.



Synthesis of a tetraazulene porphodimethene analogue.  


Substituted calix[4]azulenes were prepared by reacting 6-alkylazulenes with paraformaldehyde in the presence of florisil. Hydride abstraction of a calix[4]azulene with Ph(3)CPF(6) afforded a tetraazulene analogue of the porphodimethenes. PMID:19908914

Lash, Timothy D; El-Beck, Jessica A; Colby, Denise A



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



A continuous-time hierarchical field programmable analogue array for rapid prototyping and hierarchical approach to analogue systems design  

Microsoft Academic Search

This paper presents our continuous-time Hierarchical Field Programmable Analogue Array (HFPAA) designed as a result of our research efforts to enable rapid prototyping for analogue system design. Here, we present our continuous-time configurable analogue block (CAB) used for our HFPAA, with increased flexibility in facilitating a hierarchical approach to analogue design and also in configuring target applications. This is achieved

David Varghese; J. N. Ross



Synthesis and characterization of mitoQ and idebenone analogues as mediators of oxygen consumption in mitochondria  

PubMed Central

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 6 – 8) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 6 – 8 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate. PMID:20691600

Duveau, Damien Y.; Arce, Pablo M.; Schoenfeld, Robert A.; Raghav, Nidhi; Cortopassi, Gino A.; Hecht, Sidney M.



Synthesis and characterization of mitoQ and idebenone analogues as mediators of oxygen consumption in mitochondria.  


Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2-4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 6-8) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 6-8 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate. PMID:20691600

Duveau, Damien Y; Arce, Pablo M; Schoenfeld, Robert A; Raghav, Nidhi; Cortopassi, Gino A; Hecht, Sidney M



Functional dissection of the major structural protein of bluetongue virus: identification of key residues within VP7 essential for capsid assembly.  


A lattice of VP7 trimers forms the surface of the icosahedral bluetongue virus (BTV) core. To investigate the role of VP7 oligomerization in core assembly, a series of residues for substitution were predicted based on crystal structures of BTV type 10 VP7 molecule targeting the monomer-monomer contacts within the trimer. Seven site-specific substitution mutations of VP7 have been created using cDNA clones and were employed to produce seven recombinant baculoviruses. The effects of these mutations on VP7 solubility, ability to trimerize and formation of core-like particles (CLPs) in the presence of the scaffolding VP3 protein, were investigated. Of the seven VP7 mutants examined, three severely affected the stability of CLP, while two other mutants had lesser effect on CLP stability. Only one mutant had no apparent effect on the formation of the stable capsid. One mutant in which the conserved tyrosine at residue 271 (lower domain helix 6) was replaced by arginine formed insoluble aggregates, implying an effect in the folding of the molecule despite the prediction that such a change would be accommodated. All six soluble VP7 mutants were purified, and their ability to trimerize was examined. All mutants, including those that did not form stable CLPs, assembled into stable trimers, implying that single substitution may not be sufficient to perturb the complex monomer-monomer contacts, although subtle changes within the VP7 trimer could destabilize the core. The study highlights some of the key residues that are crucial for BTV core assembly and illustrates how the structure of VP7 in isolation underrepresents the dynamic nature of the assembly process at the biological level. PMID:10954567

Limn, C K; Staeuber, N; Monastyrskaya, K; Gouet, P; Roy, P



Functional Dissection of the Major Structural Protein of Bluetongue Virus: Identification of Key Residues within VP7 Essential for Capsid Assembly  

PubMed Central

A lattice of VP7 trimers forms the surface of the icosahedral bluetongue virus (BTV) core. To investigate the role of VP7 oligomerization in core assembly, a series of residues for substitution were predicted based on crystal structures of BTV type 10 VP7 molecule targeting the monomer-monomer contacts within the trimer. Seven site-specific substitution mutations of VP7 have been created using cDNA clones and were employed to produce seven recombinant baculoviruses. The effects of these mutations on VP7 solubility, ability to trimerize and formation of core-like particles (CLPs) in the presence of the scaffolding VP3 protein, were investigated. Of the seven VP7 mutants examined, three severely affected the stability of CLP, while two other mutants had lesser effect on CLP stability. Only one mutant had no apparent effect on the formation of the stable capsid. One mutant in which the conserved tyrosine at residue 271 (lower domain helix 6) was replaced by arginine formed insoluble aggregates, implying an effect in the folding of the molecule despite the prediction that such a change would be accommodated. All six soluble VP7 mutants were purified, and their ability to trimerize was examined. All mutants, including those that did not form stable CLPs, assembled into stable trimers, implying that single substitution may not be sufficient to perturb the complex monomer-monomer contacts, although subtle changes within the VP7 trimer could destabilize the core. The study highlights some of the key residues that are crucial for BTV core assembly and illustrates how the structure of VP7 in isolation underrepresents the dynamic nature of the assembly process at the biological level. PMID:10954567

Limn, Chang-Kwang; Staeuber, Norbert; Monastyrskaya, Katherine; Gouet, Patrice; Roy, Polly



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.



Design, synthesis, and pharmacological characterization of novel endomorphin-1 analogues as extremely potent ?-opioid agonists.  


Recently we reported the synthesis and structure-activity study of endomorphin-1 (EM-1) analogues containing novel, unnatural ?-methylene-?-aminopropanoic acids (Map). In the present study, we describe new EM-1 analogues containing Dmt(1), (R/S)-?Pro(2), and (ph)Map(4)/(2-furyl)Map(4). All of the analogues showed a high affinity for the ?-opioid receptor (MOR) and increased stability in mouse brain homogenates. Of the new compounds, Dmt(1)-(R)-?Pro(2)-Trp(3)-(2-furyl)Map(4) (analogue 12) displayed the highest affinity toward MOR, in the picomolar range (Ki(?) = 3.72 pM). Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency, in the subpicomolar range (EC50 = 0.0421 pM, Emax = 99.5%). This compound also displayed stronger in vivo antinociceptive activity after iv administration when compared to morphine in the tail-flick test, which indicates that this analogue was able to cross the blood-brain barrier. PMID:23477419

Liu, Xin; Wang, Yuan; Xing, Yanhong; Yu, Jing; Ji, Hong; Kai, Ming; Wang, Zilong; Wang, Dan; Zhang, Yixin; Zhao, Depeng; Wang, Rui



Stability and bioactivity studies on dipeptidyl peptidase IV resistant glucogan-like peptide-1 analogues.  


Glucagon-like peptide-1 (GLP-1) was once considered as an ideal anti-diabetic candidate for its important role in maintaining glucose homeostasis through the regulation of islet hormone secretion, as well as hepatic and gastric function. However, the major therapeutic obstacle for using native GLP-1 as a therapeutic agent is its very short half-life primarily due to their degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). In this study, GLP-1 analogues with modifications in amino acid site 8, 22 and 23 were synthesized using solid phase peptide synthesis. Resistance of these analogues to DPP-IV cleavage was investigated in vitro by incubation of the peptides with DPP-IV or human plasma. Glucoregulating efficacy of the analogues was evaluated in normal Kunming mice using intraperitoneal glucose tolerance model. Glucose lowering effect of combination therapy (analogue plus Vildagliptin) has also been studied. In vitro studies showed that the modified analogues were much more stable than native GLP-1 (nearly 100% of the peptide keep intact after 4 h incubation). In vivo biological activity evaluation revealed that His8-EEE (the most potent GLP-1 analogues in this study) exhibited significantly improved glycemic control potency (approximately 4.1-fold over saline and 2.5-fold over GLP-1) and longer time of active duration (at least 5 h). Combination therapy also showed the trend of its superiority over mono-therapy. Modified analogues showed increased potency and biological half-time compared with the native GLP-1, which may help to understand the structure-activity relationship of GLP-1 analogues. PMID:21838700

Chen, Wei; Zhou, Yinghong; Zhang, Huibin; Qian, Hai; Huang, Wenlong; Yang, Baowei; Han, Jing; Zhou, Jingpei; Chi, Yushi; Ni, Shuaijian



5,6,7,8-Tetrafluoro-3lambda4delta2,1,2,4-benzothiaselenadiazine, 5,6,7,8-tetrafluoro-1,3lambda4delta2,2,4-benzodithiadiazine, and their hydrocarbon analogues: molecular and crystal structures.  


5,6,7,8-Tetrafluoro-3lambda4delta2,1,2,4-benzothiaselenadiazine (1) is prepared by the intramolecular nucleophilic cyclization of C6F5SeN=S=NSiMe3 (2) mediated by CsF. According to an X-ray diffraction analysis, the heterocycle of 1 is bent along the Se(1)...N4 line by 6.0(2) degrees in the crystal. Despite the obvious similarities between 1 and its 1,3-dithia analogue (7) with respect to molecular composition and shape, the crystal packing of 1 is substantially different from that of 7. An interesting consequence of this is the inclusion of atmospheric N2 in the crystal lattice of the selenium derivative 1. The molecular structure and bonding of 1 have been investigated using quantum-chemical calculations at the DFT/B3LYP/6-311+G level of theory, and the results have been compared to those of 5,6,7,8-tetrafluoro-1,3lambda4delta2,2,4-benzodithiadiazine (7) and their hydrocarbon analogues (5 and 8). PMID:16499387

Makarov, Alexander Yu; Tersago, Karla; Nivesanond, Kanda; Blockhuys, Frank; Van Alsenoy, Christian; Kovalev, Mikhail K; Bagryanskaya, Irina Yu; Gatilov, Yuri V; Shakirov, Makhmut M; Zibarev, Andrey V



Design and NMR characterization of active analogues of compstatin containing non-natural amino acids.  


We present new findings in our drug discovery effort to develop an anticomplement therapeutic. We have designed several active analogues of compstatin by altering its amino acid composition at positions 4 and 9. The most effective analogues have tryptophan or fused-ring non-natural amino acids at position 4 and alanine or an unbranched single-methyl amino acid at position 9. Twenty-one of these analogues have 2-99-fold higher activities compared to the parent peptide compstatin. The analogue Ac-V4(2Nal)/H9A-NH(2) has the highest inhibitory activity with IC(50) 500 nM. NMR data, through NOE and chemical shift analysis, suggest the presence of interconverting conformers spanning the extended and helical regions of the Ramachandran plot, and they detect a predominant averaged conformer with coil structure and at least one flexible beta-turn, of type I. The fused-ring non-natural amino acids at position 4 contribute to the formation of the hydrophobic cluster of compstatin, which has been previously proposed, together with the beta-turn and a disulfide bridge, to be essential for binding to the target of compstatin, complement component C3. We propose that additional mechanisms may contribute to the structural stability of the analogues and to binding to C3, involving intra- and intermolecular electrostatic interactions of the pi-electron system of side chain aromatic rings. The presence of pi-pi interactions for Trp4-Trp7 was confirmed with a molecular dynamics simulation for the most active analogue with natural amino acids, Ac-V4W/H9A-NH(2). Alanine or aminobutyric acid at position 9 contribute to the weak propensity for helical structure of the residue segment 4-10 of the analogues, which may also play a role in increased activity. PMID:15634022

Mallik, Buddhadeb; Katragadda, Madan; Spruce, Lynn A; Carafides, Caterina; Tsokos, Christos G; Morikis, Dimitrios; Lambris, John D



Protonation states of the key active site residues and structural dynamics of the glmS riboswitch as revealed by molecular dynamics.  


The glmS catalytic riboswitch is part of the 5'-untranslated region of mRNAs encoding glucosamine-6-phosphate (GlcN6P) synthetase (glmS) in numerous gram-positive bacteria. Binding of the cofactor GlcN6P induces site-specific self-cleavage of the RNA. However, the detailed reaction mechanism as well as the protonation state of the glmS reactive form still remains elusive. To probe the dominant protonation states of key active site residues, we carried out explicit solvent molecular dynamic simulations involving various protonation states of three crucial active site moieties observed in the available crystal structures: (i) guanine G40 (following the Thermoanaerobacter tengcongensis numbering), (ii) the GlcN6P amino/ammonium group, and (iii) the GlcN6P phosphate moiety. We found that a deprotonated G40(-) seems incompatible with the observed glmS active site architecture. Our data suggest that the canonical form of G40 plays a structural role by stabilizing an in-line attack conformation of the cleavage site A-1(2'-OH) nucleophile, rather than a more direct chemical role. In addition, we observe weakened cofactor binding upon protonation of the GlcN6P phosphate moiety, which explains the experimentally observed increase in K(m) with decreasing pH. Finally, we discuss a possible role of cofactor binding and its interaction with the G65 and G1 purines in structural stabilization of the A-1(2'-OH) in-line attack conformation. On the basis of the identified dominant protonation state of the reaction precursor, we propose a hypothesis of the self-cleavage mechanism in which A-1(2'-OH) is activated as a nucleophile by the G1(pro-R(p)) nonbridging oxygen of the scissile phosphate, whereas the ammonium group of GlcN6P acts as the general acid protonating the G1(O5') leaving group. PMID:20536206

Banás, Pavel; Walter, Nils G; Sponer, Jirí; Otyepka, Michal



Synthetic chondramide A analogues stabilize filamentous actin and block invasion by Toxoplasma gondii.  


Apicomplexan parasites such as Toxoplasma gondii rely on actin-based motility to cross biological barriers and invade host cells. Key structural and biochemical differences in host and parasite actins make this an attractive target for small-molecule inhibitors. Here we took advantage of recent advances in the synthesis of cyclic depsipeptide compounds that stabilize filamentous actin to test the ability of chondramides to disrupt growth of T. gondii in vitro. Structural modeling of chondramide A (2) binding to an actin filament model revealed variations in the binding site between host and parasite actins. A series of 10 previously synthesized analogues (2b-k) with substitutions in the ?-tyrosine moiety blocked parasite growth on host cell monolayers with EC?? values that ranged from 0.3 to 1.3 ?M. In vitro polymerization assays using highly purified recombinant actin from T. gondii verified that synthetic and natural product chondramides target the actin cytoskeleton. Consistent with this, chondramide treatment blocked parasite invasion into host cells and was more rapidly effective than pyrimethamine, a standard therapeutic agent. Although the current compounds lack specificity for parasite vs host actin, these studies provide a platform for the future design and synthesis of synthetic cyclic peptide inhibitors that selectively disrupt actin dynamics in parasites. PMID:24020843

Ma, Christopher I; Diraviyam, Karthikeyan; Maier, Martin E; Sept, David; Sibley, L David



Seamount subduction to the Nankai accretionary wedge and its impact on methane hydrate accumulation: insights from analogue and numerical models  

NASA Astrophysics Data System (ADS)

Seamount sudbuction is a common feature at convergent plate margins and several examples can also be seen at the Nankai wedge, but its impact on methane hydrate accumulation has not fully described. In order to understand the accumulation mechanism of methane hydrate, the key issue would be the fluid flow within the sediments. The fluid flow can be classified into two types; the diffusive flow by intergranular porosity and the focused flow along faults (Baba and Yamada, 2004). The diffusive flow can be modeled by conventional reservoir simulator type of approaches, but the focused flow along faults may be difficult. One possible scenario was suggested by Sibson (1995) that fluid may migrate along a fault surface when it slipped (breakage of seal). Following the idea, the focused fluid flow can be evaluated by fault activity that can be modeled and examined by analogue experiments and numerical simulations (Yamada et al., submitted). This research employed analogue experiments that used granular materials (dry sand and glass beads) and numerical simulations that approximate the geologic body as particles (distinct element method). The analogue model results are further analyzed by optical image correlation technique, PIV, to extract faulting events in detail. By using the same tectonic model of sea mount subduction to an accretionary prism, we examined the deformation process particularly the faulting by these two techniques. The results of the analogue experiments and numerical simulations are basically the same, apart from the reproducibility of small structures influenced by the particle size. The models suggest that a sea mount subduction causes segmentation of wedge formation. The segmentation of wedge also produces two types of fault systems; one formed before sea mount subduction and the other afterward. The geometry of these faults illustrates that the fluid from the deeper segment of the sedimentary pile may focus on the faults that formed after sudbuction. These models can provide some ideas to interpret seismic profiles at subduction margins to evaluate the focused fluid flow along the faults at the Nankai accretionary wedge. By combining geochemical and well-log data from the Nankai area, we are gong to construct the next stage model of methane migration at the Nankai wedge.

Yamada, Y.; Nagamura, N.; Baba, K.; Matsuoka, T.



Imperial College London EEE 1L1 Autumn 2009 E2.2 Analogue Electronics E2.2 Analogue Electronics  

E-print Network

Imperial College London ­ EEE 1L1 Autumn 2009 E2.2 Analogue Electronics E2.2 Analogue Electronics Autumn 2009 E2.2 Analogue Electronics What analogue electronics is · Engineering, i.e. the analysis ­ EEE 3L1 Autumn 2009 E2.2 Analogue Electronics analogue electronics is not only · CMOS integrated

Papavassiliou, Christos



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


New cytotoxic guttiferone analogues from Garcinia virgata from New Caledonia.  


There are thirteen endemic species belonging to the genus Garcinia in New Caledonia. Among them, G. virgata is an evergreen tree mainly growing in the rain forests of this island. Fractionation of the cyclohexane extract of the stem bark of this plant produced the known benzophenones guttiferone E and xanthochymol, together with two new guttiferone analogues, namely guttiferones I and J. The structures of these benzophenones were mainly elucidated using 1D and 2D NMR spectroscopy. Compounds and were weakly cytotoxic on the KB cell line with IC50 values of 4.70 and 5.0 microg/mL respectively. PMID:16450306

Merza, Joumaa; Mallet, Sabine; Litaudon, Marc; Dumontet, Vincent; Séraphin, Denis; Richomme, Pascal



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.



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



Planetary Analogues of Volcanic Systems  

NASA Astrophysics Data System (ADS)

Terrestrial volcanoes studies are being used to develop techniques for interpretation of the styles of volcanic processes and the evolution of volcanic systems on Mars. Detailed characterizations of terrestrial flow fields provide critical evaluation of flow field emplacement on planetary surfaces, namely at vent fissure type features associated to volcanic shields eruptions that help to develop techniques for analyses of planetary flow fields origin and emplacement. For the purpose of this work, field observations, using differential Global Positioning System (dGPS) measurements, and remote sensing analyses, using the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) of some satellitic low shields on the east rift zone of Kilauea Volcano, Hawaii, were collected to allow detailed characterization of the textural and morphologic variability of flow field surfaces as well as provide a means to generate surface unit maps that represent local flow emplacement processes and constrain flow field development. The field characteristics were compared with remote sensing data, including visible and near-infrared spectra. These characteristics were then compared to what is observed on satellitic shield volcanoes on Mars, at the same wavelengths. On Mars, the emplacement of extensive lava flows associated to eruptive vent features in the surroundings of low shield volcanoes occur in two particular regions on Mars; in Syria Planum and at the Tharsis Montes. Their studies have been recently carried out (e.g. Baptista et al., 2008, 2009; Bleacher et al., 2007) using datasets with high spatial and/or spectral resolution, such as with HRSC or HiRISE, namely in what concerns the rheological properties of the flows, the relation and duration of several eruptive periods, and also the depth of the magma chambers. Satellitic shield eruptions on Kilauea contribute significantly to the growth of the volcano and they are closely associated with lava tube systems and long duration eruptions (Rowland and Munro, 1992). Of the 15 satellitic shields on Kilauea (Holcomb, 1987) three formed in post-contact times: Mauna Iki in 1919-1920; Mauna Ulu in 1969-1974; and Kupanaiaba in 1986-1992. The relationship between activity at the summit of Kilauea and downrift provides important support for the connections (hydraulic or not) between the summit and rift zones of Kilauea, as well as information concerning the depth of the magma chambers. This work investigates the textures of surface emplaced lavas to be used to examine flow field growth, development and local flow stratigraphy on Mauna Iki, establishing relations with the other Kilauea satellitic shield volcanoes. Also, in order to characterize regions within flow fields dominated by networks of lava toes and lobes, measurements of toe length, width, thickness, and orientation were done for both Martian and terrestrial analogues. We concluded that the volcanic systems in Syria Planum, Mars and the Kilauea and its satellitic system are analogous concerning their development. Their relation with the regional faulting pattern and morphological features distribution help us to interpret the origin and longstanding evolution of these volcanic provinces.

Baptista, A. R.; Craddock, R. A.; Zimbelman, J. R.



Transition States, Analogues and Drug Development  

PubMed Central

Enzymes achieve their transition states by dynamic conformational searches on the fsec to psec timescale. Mimics of reactants at enzymatic transition states bind tightly to enzymes by stabilizing the conformation optimized through evolution for transition state formation. Instead of forming the transient transition state geometry, transition state analogues convert the short-lived transition state to a stable thermodynamic state. Enzymatic transition states are understood by combining kinetic isotope effects and computational chemistry. Analogues of the transition state can bind millions of times tighter than substrates and show promise for drug development for several targets. PMID:23259601

Schramm, Vern L.



Synthesis of sphingomyelin carbon analogues as sphingomyelinase inhibitors.  


The highly efficient and stereocontrolled syntheses of sphingomyelin carbon analogues 1 and 2 were achieved by effectively utilizing Hofmann rearrangement of enantiomerically pure beta-hydroxyamide 7, which was prepared by an asymmetric hydrogenation of alpha-acyl-gamma-butyrolactone 9 and ring opening with NH(3). Intermediary isocyanate 6 was selectively trapped with the vicinal hydroxy group in an intramolecular fashion to produce an oxazolidinone derivative, 5. In the synthesis of a quite polar compound such as 1, a convenient one-pot procedure of the introduction of a benzyloxycarbonyl group into the hydroxy group resulting from the oxazolidinone ring opening is another key point, because, in addition to the efficiency, this protecting group was easily removable by a simple procedure and workup at the final step. Both synthesized compounds 1 and 2 showed moderate inhibitory activity toward sphingomyelinase from B. cereus. PMID:12098296

Hakogi, Toshikazu; Monden, Yoshiko; Taichi, Misako; Iwama, Seiji; Fujii, Shinobu; Ikeda, Kiyoshi; Katsumura, Shigeo



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:



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.



The Preparation of Metallocarborane and Iodinated Carborane Amjno Acid Analogues for Molecular Imaging and Therapy  

Microsoft Academic Search

This thesis demonstrates the versatility of the carborane cage by qsing a known carborane containing analogue of the amino acid phenylalanine, carborananylalanine (Car5) as a novel platform for radio labelling targeting vectors with both 99mTc and 125I. Initial racemic synthesis of Car was undertaken based on a literature procedure. Optimization of the procedure yielded all key intermediates leading to closo-carboranylalanine

Teri Janet Gullon



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

Microsoft Academic Search

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

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



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



Instructional Influences on Analogue Functional Analysis Outcomes  

ERIC Educational Resources Information Center

Analogue assessments were conducted with a common contingency (escape from tasks) that varied only by three different instructions describing the contingency. In one condition, the contingency was described as "taking a break," in another condition it was described as "time-out," and no description of the contingency was provided in a third…

Northup, John; Kodak, Tiffany; Lee, Jennifer; Coyne, Amanda



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



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



Analogue modelling of the initiation of subduction  

Microsoft Academic Search

We report the results of experiments on the initiation of subduction, using stratified analogue models in a large centrifuge, where the experiments are driven only by the enhanced gravity of the centrifuge without the effect of external lateral stresses. The scaled density of the stratified components resembles that of the asthenosphere and the continental and oceanic lithospheres. The experiments demonstrate

Yossi Mart; Einat Aharonov; Genene Mulugeta; William Ryan; Tatiana Tentler; Liran Goren



Dumb holes: analogues for black holes.  


The use of sonic analogues to black and white holes, called dumb or deaf holes, to understand the particle production by black holes is reviewed. The results suggest that the black hole particle production is a low-frequency and low-wavenumber process. PMID:18534934

Unruh, W G



Synthesis of gemcitabine and it's tetrafluorinated analogues.  

E-print Network

??A novel synthesis of the 2-deoxy-2,2-difluorocytidine nucleoside analogue gemcitabine has been achieved. Starting from the known 3,5-O-dibenzoyl-2- deoxy-2,2-difluororibose, the nucleobase moiety is constructed in a… (more)

Brown, Kylie J.



Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring  

PubMed Central

Summary We report the synthesis of a novel analogue of Alogliptin via condensation of two key intermediates one of which is an aminopiperidine derivative bearing a spirocyclic ring on the piperidine moiety. Preparation of the aminopiperidine intermediate was carried out by constructing the cyclopropyl ring prior to assembling the piperidine ring. PMID:20703380

Kodimuthali, Arumugam; Prasunamba, Padala Lakshmi



Key Stakeholders' Perceptions of Effective School Leadership  

Microsoft Academic Search

There has been limited research on how teachers, parents and students perceive effective school leadership in practice. The purpose of this article is to present some of the findings derived from a study of key stakeholders’ perceptions of effective school leadership. Key stakeholders were identified as teachers, students and parents. Data were gathered through semi-structured interviews with key stakeholders from

George Odhiambo; Amy Hii



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



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



Ruthenium Derivatives of NiS2N2 Complexes as Analogues of Bioorganometallic Reaction Centers  

E-print Network

, respectively, to give [Cp*Ru(NiS2N2)(2- E2)]+ (E ) O, S), which were characterized spectroscopicallyRuthenium Derivatives of NiS2N2 Complexes as Analogues of Bioorganometallic Reaction Centers Recent results from structural biology demonstrate the catalytic significance of Ni(SR)2L2 centers

Rauchfuss, Thomas B.


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


Escape configuration lattice near the nematic-isotropic transition: Tilt analogue of blue phases  

E-print Network

We predict the possible existence of a new phase of liquid crystals near the nematic-isotropic ($ NI $) transition. This phase is an achiral, tilt-analogue of the blue phase and is composed of a lattice of {\\em double-tilt}, escape-configuration cylinders. We discuss the structure and the stability of this phase and provide an estimate of the lattice parameter.

Buddhapriya Chakrabarti; Yashodhan Hatwalne; N. V. Madhusudana



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



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.



E22 Analogue Electronics PS3 Answers p 1/4 E2.2 Analogue electronics  

E-print Network

E22 Analogue Electronics PS3 Answers p 1/4 E2.2 Analogue electronics Problem sheet 3 (Week 5) Q1 inZ j j = + + = + - + R2 R1 R1 R2 Vcc Vin Vout #12;E22 Analogue Electronics PS3 Answers p 222 Analogue Electronics PS3 Answers p 3/4 inverting amplifier, the open loop gain of the amplifier

Papavassiliou, Christos


Synthesis and Biochemical Evaluation of Thiochromanone Thiosemicarbazone Analogues as Inhibitors of Cathepsin L  

PubMed Central

A series of 36 thiosemicarbazone analogues containing the thiochromanone molecular scaffold functionalized primarily at the C-6 position were prepared by chemical synthesis and evaluated as inhibitors of cathepsins L and B. The most promising inhibitors from this group are selective for cathepsin L and demonstrate IC50 values in the low nanomolar range. In nearly all cases, the thiochromanone sulfide analogues show superior inhibition of cathepsin L as compared to their corresponding thiochromanone sulfone derivatives. Without exception, the compounds evaluated were inactive (IC50 > 10000 nM) against cathepsin B. The most potent inhibitor (IC50 = 46 nM) of cathepsin L proved to be the 6,7-difluoro analogue 4. This small library of compounds significantly expands the structure–activity relationship known for small molecule, nonpeptidic inhibitors of cathepsin L. PMID:24900494



Late Pleniglacial vegetation in eastern-central Europe: are there modern analogues in Siberia?  

NASA Astrophysics Data System (ADS)

To characterize Late Pleniglacial (LPG: 26.5-15 ka cal BP) and particularly Last Glacial Maximum (LGM: 21 ± 2 ka cal BP) vegetation and climate, fossil pollen assemblages are often compared with modern pollen assemblages. Given the non-analogue climate of the LPG, a key question is how glacial pollen assemblages and thereby vegetation compare with modern vegetation. In this paper we present three LPG pollen records from the Carpathian Basin and the adjoining Carpathian Mountains to address this question and provide a concise compositional characterization of the LPG vegetation. Fossil pollen assemblages were compared with surface pollen spectra from the Altai-Sayan Mountains in southern Siberia. This area shows many similarities with the LPG vegetation of eastern-central Europe, and has long been considered as its best modern analogue. Ordination and analogue matching were used to characterize vegetation composition and find the best analogues. Our results show that few LPG pollen assemblages have statistically significant analogues in southern Siberia. When analogue pairings occur they suggest the predominance of wet and mesic grasslands and dry steppe in the studied region. Wooded vegetation types (continental and suboceanic hemiboreal forest, continental taiga) appear as significant analogues only in a few cases during the LGM and more frequently after 16 ka cal BP. These results suggest that the LPG landscape of the Carpathian Basin was dominated by dry steppe that occurred outside the river floodplains, while wet and mesic grasslands occurred in the floodplains and on other sites influenced by ground water. Woody vegetation mainly occurred in river valleys, on wet north-facing hillsides, and scattered trees were likely also present on the loess plateaus. The dominant woody species were Larix, Pinus sylvestris, Pinus mugo, Pinus cembra, Picea abies, Betula pendula/pubescens, Betula nana, Juniperus, Hippophaë rhamnoides, Populus, Salix and Alnus. The pollen records suggest uninterrupted presence of mesophilous temperate trees (Quercus, Ulmus, Corylus, Fagus and Fraxinus excelsior) in the Eastern Carpathian Mountains throughout the LPG. We demonstrate that the LPG vegetation in this area was characterized by increasing grass cover and high frequency of wildfires. We conclude that pollen spectra over represent trees in the forest-steppe landscape of the LPG, furthermore pollen-based quantitative climate reconstructions for the LPG are challenging in this area due to the scarcity of modern analogues.

Magyari, Enik? Katalin; Kuneš, Petr; Jakab, Gusztáv; Sümegi, Pál; Pelánková, Barbora; Schäbitz, Frank; Braun, Mihály; Chytrý, Milan



The structure of Pyrococcus furiosus glutamate dehydrogenase reveals a key role for ion-pair networks in maintaining enzyme stability at extreme temperatures  

Microsoft Academic Search

Background: The hyperthermophile Pyrococcus furiosus is one of the most thermostable organisms known, with an optimum growth temperature of 100°C. The proteins from this organism display extreme thermostability. We have undertaken the structure determination of glutamate dehydrogenase from P. furiosus in order to gain further insights into the relationship between molecular structure and thermal stability.Results The structure of P. furiosus

KSP Yip; TJ Stillman; KL Britton; PJ Artymiuk; PJ Baker; SE Sedelnikova; PC Engel; A Pasquo; R Chiaraluce; V Consalvi; R Scandurra; DW Rice



Terrestrial research in Mars analogue environments  

NASA Astrophysics Data System (ADS)

Fatty acids (FA) content was measured by GC-MS SIM technique in Sulfide ores of present day (Mid-Atlantic Ridge and others) and ancient (Ural Paleocene, Russia) black smokers; Early Proterozoic kerites of Volyn; Siberian, Canadian and Antarctic permafrosts and also in rocks of East-European platform Achaean crystalline basement. Analysis was shown presence those and only those fatty acids which are specific to microorganisms. FA with 12 up 19 of carbon atoms are thought to be a bacterial biomass sign. 3-Hydroxy fatty acids also found in samples and are strong specific markers of gram-negative bacteria. Cultivation yield living bacteria in some cases. The East-European platform Achaean crystalline basement rocks opened by Vorotilov Deep Well (VDW) drilled through Puchezh-Katunski impact structure were studied within depths 2575 - 2805 m. 34 microbial lipid markers were detected by GC-MS and 22 species were identified. Bacteria of g. Bacillus reached 6,8 % in subsurface communities. However, members of gg. Clostridium (37,1 - 33,2 %) and Rhodococcus (27,6 - 33,7 %) were absolute dominants within studied depth interval. Some lipid patterns of kerite samples could be assessed to definite genera or, in special cases, to species of contemporary microorganisms. For instance, 2-hydroxylauric acid is specific to Pseudomonas putida group or Acinetobacter spp., and hydroxymyristic together with hydroxypalmitic are specific to P.cepacea and cyanobacteria. 3-hydroxystearic acid was known as component of Acetobacter diazothrophycus and Gloebacter violaceous cyanobacterium. 10-hydroxystearic acid associated with Nocardia spp., which oxidizes oleic acid in organic substrates. 10-methylhexadecanoic (10Me16) acid together with 10Me14, 10Me15 and 10Me17 analogues are markers of actinomycetes. Significant part of Black Smokers organic matter is probably biogenic. Fatty acid features strongly assigns it to bacterial, microeucariotic and planta cells. Par example 3-hydroxy acids are strictly referred to bacteria, and 2-hydroxyacids to bacteria and eukaryotes. Branched fatty acids (iso-, anteiso-acids, 10-Me-isomers) also could be bacterial. Hydrocarbons, terpenoids, alcohols could be both of bacterial and vegetable origin. Fatty acids' composition and profiles are similar, and confirm the similarity of microbial communities of the environments. The data confirm chemicals are well conserved in sulphide ores and fatty acid composition of contemporary microorganisms could be applied to identification and calculation composition of ancient microbial communities (as well as Martian ones).

Osipov, G.


Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition.  


Epoxyeicosatrienoic acids (EETs) contribute to haemodynamics, electrolyte homoeostasis and blood pressure regulation, leading to the concept that EETs can be therapeutically targeted for hypertension. In the present study, multiple structural EET analogues were synthesized based on the EET pharmacophore and vasodilator structure-activity studies. Four EET analogues with 91-119% vasodilatory activity in the isolated bovine coronary artery (EC50: 0.18-1.6 ?M) were identified and studied for blood-pressure-lowering in hypertension. Two EET analogues in which the COOH group at carbon 1 of the EET pharmacophore was replaced with either an aspartic acid (EET-A) or a heterocyclic surrogate (EET-X) were administered for 14 days [10 mg/kg per day intraperitoneally (i.p.)]. Both EET-A and EET-X lowered blood pressure in spontaneously hypertensive rats (SHRs) and in angiotensin II (AngII) hypertension. On day 14, the mean arterial pressures in EET analogue-treated AngII-hypertensive and SHRs were 30-50 mmHg (EET-A) and 15-20 mmHg (EET-X) lower than those in vehicle-treated controls. These EET analogues (10 mg/kg per day) were further tested in AngII hypertension by administering orally in drinking water for 14 days and EET-A lowered blood pressure. Additional experiments demonstrated that EET-A inhibits epithelial sodium channel (ENaC) activity in cultured cortical collecting duct cells and reduced renal expression of ENaC subunits in AngII hypertension. In conclusion, we have characterized EET-A as an orally active antihypertensive EET analogue that protects vascular endothelial function and has ENaC inhibitory activity in AngII hypertension. PMID:24707975

Hye Khan, Md Abdul; Pavlov, Tengis S; Christain, Sarah V; Necká?, Jan; Staruschenko, Alexander; Gauthier, Kathryn M; Capdevila, Jorge H; Falck, John R; Campbell, William B; Imig, John D



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



Megabits secure key rate quantum key distribution  

E-print Network

Quantum cryptography (QC) can provide unconditional secure communication between two authorized parties based on the basic principles of quantum mechanics. However, imperfect practical conditions limit its transmission distance and communication speed. Here we implemented the differential phase shift (DPS) quantum key distribution (QKD) with up-conversion assisted hybrid photon detector (HPD) and achieved 1.3 M bits per second secure key rate over a 10-km fiber, which is tolerant against the photon number splitting (PNS) attack, general collective attacks on individual photons, and any other known sequential unambiguous state discrimination (USD) attacks.

Zhang, Q; Honjo, T; Wen, K; Hirohata, T; Suyama, M; Takiguchi, Y; Kamada, H; Tokura, Y; Tadanaga, O; Nishida, Y; Asobe, M; Yamamoto, Y



Megabits secure key rate quantum key distribution  

E-print Network

Quantum cryptography (QC) can provide unconditional secure communication between two authorized parties based on the basic principles of quantum mechanics. However, imperfect practical conditions limit its transmission distance and communication speed. Here we implemented the differential phase shift (DPS) quantum key distribution (QKD) with up-conversion assisted hybrid photon detector (HPD) and achieved 1.3 M bits per second secure key rate over a 10-km fiber, which is tolerant against the photon number splitting (PNS) attack, general collective attacks on individual photons, and any other known sequential unambiguous state discrimination (USD) attacks.

Q. Zhang; H. Takesue; T. Honjo; K. Wen; T. Hirohata; M. Suyama; Y. Takiguchi; H. Kamada; Y. Tokura; O. Tadanaga; Y. Nishida; M. Asobe; Y. Yamamoto



Thermal conductivity determination of cometary and asteroid material analogues  

NASA Astrophysics Data System (ADS)

Measurements of physical properties of surface and subsurface layers of planetary bodies often provide important information about the structure of the medium and processes that occur there Thermal properties of cometary nuclues subsurface material are crucial in determining the heat and gas transport Similarly asteroid s regolith is a buffering zone in heat transfer from to surface to from interior of a body There are space experiments planned to perform temperature and thermal conductivity measurements on a comet ROSETTA and one can easily foresee such measurements carried out by future robotic missions on Mars planetary satellites and asteroids In the paper we present the results of measurements carried out with a new type of thermal sensors The elementary cylindrical sensor is made of platinum wire resistance thermometer and isotan wire heating element that can operate independently By choosing these materials the problems of temperature measurement calibration and constant heating power are resolved We confront the results of measurements made for a number of sensors combined into a long cylinder in delrin basalt ice-dust mixture comet analogue and regolith-like material with models and show that agreement is very good Therefore we can recommend both the sensors and the method of data interpretation for the thermal conductivity determination as very useful tools in future space missions and in laboratory experiments on cometary and asteroid material analogues

Banaszkiewicz, M.; Seweryn, K.; Wawrzaszek, R.


Key Characteristics: Support limited for pursuits outside the program  

E-print Network

of structure Follow instructions Key Characteristics: Classroom based Learning in a group Key Student Competencies: Use existing resources and fill in Work well with the group Acceptance and peers Key Characteristics: Focuses on the individual's learning process Experience subject

Haller, Gary L.


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 still in the realm of *gedanken-experiments*, but there are plausible candidate models that should lead to laboratory experiments in the not too distant future.

Matt Visser; Carlos Barcelo; Stefano Liberati