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Sample records for acyl-coa synthetic activity

  1. High fat fed heart failure animals have enhanced mitochondrial function and acyl-coa dehydrogenase activities

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have previously shown that administration of high fat in heart failure (HF) increased mitochondrial respiration and did not alter left ventricular (LV) function. PPARalpha is a nuclear transcription factor that activates expression of genes involved in fatty acid uptake and utilization. We hypoth...

  2. Active synthetic soil

    NASA Technical Reports Server (NTRS)

    Ming, Douglas W. (Inventor); Henninger, Donald L. (Inventor); Allen, Earl R. (Inventor); Golden, Dadigamuwage C. (Inventor)

    1995-01-01

    A synthetic soil/fertilizer for horticultural application having all the agronutrients essential for plant growth is disclosed. The soil comprises a synthetic apatite fertilizer having sulfur, magnesium and micronutrients dispersed in a calcium phosphate matrix, a zeolite cation exchange medium saturated with a charge of potassium and nitrogen cations, and an optional pH buffer. Moisture dissolves the apatite and mobilizes the nutrient elements from the apatite matrix and the zeolite charge sites.

  3. Active synthetic soil

    NASA Technical Reports Server (NTRS)

    Ming, Douglas W. (Inventor); Henninger, Donald L. (Inventor); Allen, Earl R. (Inventor); Golden, Dadigamuwage C. (Inventor)

    1995-01-01

    A synthetic soil/fertilizer for horticultural application having all the agronutrients essential for plant growth is disclosed. The soil comprises a synthetic apatite fertilizer having sulfur, magnesium, and micronutrients dispersed in a calcium phosphate matrix, a zeolite cation exchange medium saturated with a charge of potassium and nitrogen cations, and an optional pH buffer. Moisture dissolves the apatite and mobilizes the nutrient elements from the apatite matrix and the zeolite charge sites.

  4. Light-activated communication in synthetic tissues.

    PubMed

    Booth, Michael J; Schild, Vanessa Restrepo; Graham, Alexander D; Olof, Sam N; Bayley, Hagan

    2016-04-01

    We have previously used three-dimensional (3D) printing to prepare tissue-like materials in which picoliter aqueous compartments are separated by lipid bilayers. These printed droplets are elaborated into synthetic cells by using a tightly regulated in vitro transcription/translation system. A light-activated DNA promoter has been developed that can be used to turn on the expression of any gene within the synthetic cells. We used light activation to express protein pores in 3D-printed patterns within synthetic tissues. The pores are incorporated into specific bilayer interfaces and thereby mediate rapid, directional electrical communication between subsets of cells. Accordingly, we have developed a functional mimic of neuronal transmission that can be controlled in a precise way. PMID:27051884

  5. Light-activated communication in synthetic tissues

    PubMed Central

    Booth, Michael J.; Schild, Vanessa Restrepo; Graham, Alexander D.; Olof, Sam N.; Bayley, Hagan

    2016-01-01

    We have previously used three-dimensional (3D) printing to prepare tissue-like materials in which picoliter aqueous compartments are separated by lipid bilayers. These printed droplets are elaborated into synthetic cells by using a tightly regulated in vitro transcription/translation system. A light-activated DNA promoter has been developed that can be used to turn on the expression of any gene within the synthetic cells. We used light activation to express protein pores in 3D-printed patterns within synthetic tissues. The pores are incorporated into specific bilayer interfaces and thereby mediate rapid, directional electrical communication between subsets of cells. Accordingly, we have developed a functional mimic of neuronal transmission that can be controlled in a precise way. PMID:27051884

  6. Natural and synthetic peptides with antifungal activity.

    PubMed

    Ciociola, Tecla; Giovati, Laura; Conti, Stefania; Magliani, Walter; Santinoli, Claudia; Polonelli, Luciano

    2016-08-01

    In recent years, the increase of invasive fungal infections and the emergence of antifungal resistance stressed the need for new antifungal drugs. Peptides have shown to be good candidates for the development of alternative antimicrobial agents through high-throughput screening, and subsequent optimization according to a rational approach. This review presents a brief overview on antifungal natural peptides of different sources (animals, plants, micro-organisms), peptide fragments derived by proteolytic cleavage of precursor physiological proteins (cryptides), synthetic unnatural peptides and peptide derivatives. Antifungal peptides are schematically reported based on their structure, antifungal spectrum and reported effects. Natural or synthetic peptides and their modified derivatives may represent the basis for new compounds active against fungal infections. PMID:27502155

  7. Synthetic modulators of TRP channel activity.

    PubMed

    Harteneck, Christian; Klose, Chihab; Krautwurst, Dietmar

    2011-01-01

    In humans, 27 TRP channels from 6 related families contribute to a broad spectrum of cellular functions, such as thermo-, pressure-, volume-, pain- and chemosensation. Pain and inflammation-inducing compounds represent potent plant and animal defense mechanisms explaining the great variety of the naturally occurring, TRPV1-, TRPM8-, and TRPA1-activating ligands. The discovery of the first vanilloid receptor (TRPV1) and its involvement in nociception triggered the euphoria and the hope in novel therapeutic strategies treating pain, and this clear-cut indication inspired the development of TRPV1-selective ligands. On the other hand the nescience in the physiological role and putative clinical indication hampered the development of a selective drug in the case of the other TRP channels. Therefore, currently only a handful of mostly un-selective blocker is available to target TRP channels. Nevertheless, there is an ongoing quest for new, natural or synthetic ligands and modulators. In this chapter, we will give an overview on available broad-range blocker, as well as first TRP channel-selective compounds. PMID:21290290

  8. CCN activation of ambient and "synthetic ambient" urban aerosol

    NASA Astrophysics Data System (ADS)

    Burkart, Julia; Reischl, Georg; Steiner, Gerhard; Bauer, Heidi; Leder, Klaus; Kistler, Magda; Puxbaum, Hans; Hitzenberger, R.

    2013-05-01

    In this study, the Cloud Condensation Nuclei (CCN) activation properties of the urban aerosol in Vienna, Austria, were investigated in a long term (11 month) field study. Filter samples of the aerosol below 100 nm were taken in parallel to these measurements, and later used to generate "synthetic ambient" aerosols. Activation parameters of this "synthetic ambient" aerosol were also obtained. Hygroscopicity parameters κ [1] were calculated both for the urban and the "synthetic ambient" aerosol and also from the chemical composition. Average κ for the "synthetic ambient" aerosol ranged from 0.20 to 0.30 with an average value of 0.24, while the κ from the chemical composition of this "synthetic ambient" aerosol was significantly higher (average 0.43). The full results of the study are given elsewhere [2,3].

  9. Immunobiological activities of synthetic lipid A analogs with low endotoxicity.

    PubMed Central

    Kotani, S; Takada, H; Takahashi, I; Ogawa, T; Tsujimoto, M; Shimauchi, H; Ikeda, T; Okamura, H; Tamura, T; Harada, K

    1986-01-01

    Synthetic lipid A analogs, beta(1-6)glucosamine disaccharide 1,4'-bisphosphates, which possesses four tetradecanoyl groups at the 2- and 2'-amino, and 3- and 3'-hydroxyl groups (LA-17-PP), and each two of the (R)-3-hydroxytetradecanoyl and tetradecanoyl groups at the 2- and 2'-amino and 3- and 3'-hydroxyl groups, respectively (LA-18-PP), were far less endotoxic than synthetic (506, LA-15-PP) and bacterial Escherichia coli type lipid A's; neither compound showed any detectable lethal toxicity in chicken embryos or preparatory activity for the local Shwartzman reaction in rabbits. Also both compounds were only weakly pyrogenic and comparably less lethally toxic in galactosamine-loaded mice than the reference synthetic and bacterial lipid A's and a synthetic counterpart to biosynthetic lipid A precursor Ia (406, LA-14-PP). Nevertheless, LA-17-PP and LA-18-PP exhibited definite in vivo immunoadjuvant activity in mice, and the ability to induce a possible tumor necrosis factor and alpha/beta interferon in Mycobacterium bovis BCG and Propionibacterium acnes-primed mice, respectively, although these activities were weaker than those of the reference lipid A's. 4'-Monophosphate analogs of the above two test compounds exhibited neither endotoxic nor beneficial activities, but they showed remarkable in vitro bioactivities comparable to those of the corresponding bisphosphate compounds; the ability to activate the human complement system and the clotting enzyme cascade of horseshoe crab amoebocyte lysate, stimulatory effects on guinea pig and murine peritoneal macrophages, and murine splenocytes. PMID:3781622

  10. Evaluation of antibacterial activity of synthetic aliphatic and aromatic monoacylglycerols.

    PubMed

    Batovska, Daniela; Todorova, Iva; Parushev, Stoyan; Tsvetkova, Iva; Najdenski, Hristo; Ubukata, Makoto

    2008-01-01

    The antibacterial activity of synthetic aliphatic and aromatic monoacylglycerols (MAGs) was studied against two human pathogens: Staphylococcus aureus and Escherichia coli. The active compounds inhibited selectively S. aureus. The most active compounds amongst them were those with medium size aliphatic chain and aromatic MAGs with electron withdrawing substituents at the aryl ring. The introduction of one or two-carbon spacer between the aryl ring and the carboxylic function did not influence antibacterial effectiveness. PMID:19004249

  11. Light activated cell migration in synthetic extracellular matrices.

    PubMed

    Guo, Qiongyu; Wang, Xiaobo; Tibbitt, Mark W; Anseth, Kristi S; Montell, Denise J; Elisseeff, Jennifer H

    2012-11-01

    Synthetic extracellular matrices provide a framework in which cells can be exposed to defined physical and biological cues. However no method exists to manipulate single cells within these matrices. It is desirable to develop such methods in order to understand fundamental principles of cell migration and define conditions that support or inhibit cell movement within these matrices. Here, we present a strategy for manipulating individual mammalian stem cells in defined synthetic hydrogels through selective optical activation of Rac, which is an intracellular signaling protein that plays a key role in cell migration. Photoactivated cell migration in synthetic hydrogels depended on mechanical and biological cues in the biomaterial. Real-time hydrogel photodegradation was employed to create geometrically defined channels and spaces in which cells could be photoactivated to migrate. Cell migration speed was significantly higher in the photo-etched channels and cells could easily change direction of movement compared to the bulk hydrogels.

  12. Antimicrobial activity of new porphyrins of synthetic and natural origin

    NASA Astrophysics Data System (ADS)

    Gyulkhandanyan, Grigor V.; Ghazaryan, Robert K.; Paronyan, Marina H.; Ulikhanyan, Ghukas I.; Gyulkhandanyan, Aram G.; Sahakyan, Lida A.

    2012-03-01

    Antimicrobial photodynamic inactivation has been successfully used against Gram (+) microorganisms, but most of the photosensitizers (PSs) on Gram (-) bacteria acts weakly. PSs are the natural or synthetic origin dyes, mainly porphyrins. We have synthesized more than 100 new cationic porphyrins and metalloporphyrins with different functional groups (hydroxyethyl, butyl, allyl, methallyl) and metals (cobalt, iron, copper, zinc, silver and other); from the nettle have also been purified pheophytin (a+b) and pheophytin (a) and have synthesized their Ag-and Zn-metalloporphyrins. It was found that in the dark (cytotoxic) mode, the most highly efficiency against microorganisms showed Agmetalloporphyrins of both types of porphyrins (synthetic and natural). Metalloporphyrin of natural origin Ag-pheophytin (a + b) is a strong antibacterial agent and causes 100% death as the Gram (+) microorganisms (St. aureus and MRSA) and the Gram (-) microorganisms (E.coli and Salmonella). It is established that for the destruction of Gram (+) and Gram (-) microorganisms in photodynamic mode cationic water-soluble synthetic metalloporphyrins, especially Zn-TBut4PyP, many times more effective than pheophytins. In vivo conditions on mice established that the best therapeutic activity against various strains of the microorganism St. aureus has the synthetic metalloporphyrin Ag-TBut4PyP. It is significantly more efficient than known drug "Chlorophyllipt" (2.5-3 times) and leads the survival rate of animals up to 50-60%.

  13. Synthetic galactomannans with potent anti-HIV activity.

    PubMed

    Budragchaa, Davaanyam; Bai, Shiming; Kanamoto, Taisei; Nakashima, Hideki; Han, Shuqin; Yoshida, Takashi

    2015-10-01

    Ring-opening polymerization of a new 1,6-anhydro disaccharide monomer, 1, 6-anhydro-2, 3-di-O-benzyl-4-O-(2', 3', 4', 6'-tetra-O-benzyl-α-d-galactopyranosyl)-α-d-mannopyranose, was carried out using PF5 as a catalyst under high vacuum at -60°C to give galactose branched mannopyranan (synthetic galactomannan), 4-O-α-d-galactopyranosyl-(1→6)-α-d-mannopyranan, after debenzylation with Na in liquid NH3. The ring-opening copolymerization with 1, 6-anhydro-tri-O-benzyl-α-d-mannopyranose in various feeds was also performed to give synthetic galactomannans with various proportions of galactose branches. After sulfation, sulfated synthetic galactomannans were found to have anti-HIV activity and cytotoxicity as high and low as those of standard curdlan and dextran sulfates, respectively, which are potent anti-HIV sulfated polysaccharides with low cytotoxicity. The anti-HIV mechanism of sulfated synthetic galactomannans used by poly-l-lysine as a model peptide of the HIV surface protein was estimated by using SPR, DSL, and zeta potential measurements, revealing the electrostatic interaction between negatively charged sulfate groups and positively charged amino groups.

  14. Synthetic galactomannans with potent anti-HIV activity.

    PubMed

    Budragchaa, Davaanyam; Bai, Shiming; Kanamoto, Taisei; Nakashima, Hideki; Han, Shuqin; Yoshida, Takashi

    2015-10-01

    Ring-opening polymerization of a new 1,6-anhydro disaccharide monomer, 1, 6-anhydro-2, 3-di-O-benzyl-4-O-(2', 3', 4', 6'-tetra-O-benzyl-α-d-galactopyranosyl)-α-d-mannopyranose, was carried out using PF5 as a catalyst under high vacuum at -60°C to give galactose branched mannopyranan (synthetic galactomannan), 4-O-α-d-galactopyranosyl-(1→6)-α-d-mannopyranan, after debenzylation with Na in liquid NH3. The ring-opening copolymerization with 1, 6-anhydro-tri-O-benzyl-α-d-mannopyranose in various feeds was also performed to give synthetic galactomannans with various proportions of galactose branches. After sulfation, sulfated synthetic galactomannans were found to have anti-HIV activity and cytotoxicity as high and low as those of standard curdlan and dextran sulfates, respectively, which are potent anti-HIV sulfated polysaccharides with low cytotoxicity. The anti-HIV mechanism of sulfated synthetic galactomannans used by poly-l-lysine as a model peptide of the HIV surface protein was estimated by using SPR, DSL, and zeta potential measurements, revealing the electrostatic interaction between negatively charged sulfate groups and positively charged amino groups. PMID:26076622

  15. Antiproliferative activity of synthetic fatty acid amides from renewable resources.

    PubMed

    dos Santos, Daiane S; Piovesan, Luciana A; D'Oca, Caroline R Montes; Hack, Carolina R Lopes; Treptow, Tamara G M; Rodrigues, Marieli O; Vendramini-Costa, Débora B; Ruiz, Ana Lucia T G; de Carvalho, João Ernesto; D'Oca, Marcelo G Montes

    2015-01-15

    In the work, the in vitro antiproliferative activity of a series of synthetic fatty acid amides were investigated in seven cancer cell lines. The study revealed that most of the compounds showed antiproliferative activity against tested tumor cell lines, mainly on human glioma cells (U251) and human ovarian cancer cells with a multiple drug-resistant phenotype (NCI-ADR/RES). In addition, the fatty methyl benzylamide derived from ricinoleic acid (with the fatty acid obtained from castor oil, a renewable resource) showed a high selectivity with potent growth inhibition and cell death for the glioma cell line-the most aggressive CNS cancer.

  16. Synthetic muscle promoters: activities exceeding naturally occurring regulatory sequences

    NASA Technical Reports Server (NTRS)

    Li, X.; Eastman, E. M.; Schwartz, R. J.; Draghia-Akli, R.

    1999-01-01

    Relatively low levels of expression from naturally occurring promoters have limited the use of muscle as a gene therapy target. Myogenic restricted gene promoters display complex organization usually involving combinations of several myogenic regulatory elements. By random assembly of E-box, MEF-2, TEF-1, and SRE sites into synthetic promoter recombinant libraries, and screening of hundreds of individual clones for transcriptional activity in vitro and in vivo, several artificial promoters were isolated whose transcriptional potencies greatly exceed those of natural myogenic and viral gene promoters.

  17. Libraries of Synthetic TALE-Activated Promoters: Methods and Applications.

    PubMed

    Schreiber, T; Tissier, A

    2016-01-01

    The discovery of proteins with programmable DNA-binding specificities triggered a whole array of applications in synthetic biology, including genome editing, regulation of transcription, and epigenetic modifications. Among those, transcription activator-like effectors (TALEs) due to their natural function as transcription regulators, are especially well-suited for the development of orthogonal systems for the control of gene expression. We describe here the construction and testing of libraries of synthetic TALE-activated promoters which are under the control of a single TALE with a given DNA-binding specificity. These libraries consist of a fixed DNA-binding element for the TALE, a TATA box, and variable sequences of 19 bases upstream and 43 bases downstream of the DNA-binding element. These libraries were cloned using a Golden Gate cloning strategy making them usable as standard parts in a modular cloning system. The broad range of promoter activities detected and the versatility of these promoter libraries make them valuable tools for applications in the fine-tuning of expression in metabolic engineering projects or in the design and implementation of regulatory circuits.

  18. Libraries of Synthetic TALE-Activated Promoters: Methods and Applications.

    PubMed

    Schreiber, T; Tissier, A

    2016-01-01

    The discovery of proteins with programmable DNA-binding specificities triggered a whole array of applications in synthetic biology, including genome editing, regulation of transcription, and epigenetic modifications. Among those, transcription activator-like effectors (TALEs) due to their natural function as transcription regulators, are especially well-suited for the development of orthogonal systems for the control of gene expression. We describe here the construction and testing of libraries of synthetic TALE-activated promoters which are under the control of a single TALE with a given DNA-binding specificity. These libraries consist of a fixed DNA-binding element for the TALE, a TATA box, and variable sequences of 19 bases upstream and 43 bases downstream of the DNA-binding element. These libraries were cloned using a Golden Gate cloning strategy making them usable as standard parts in a modular cloning system. The broad range of promoter activities detected and the versatility of these promoter libraries make them valuable tools for applications in the fine-tuning of expression in metabolic engineering projects or in the design and implementation of regulatory circuits. PMID:27480693

  19. Advances in synthetic approach to and antifungal activity of triazoles

    PubMed Central

    Kumar, Nitin; Drabu, Sushma; Sharma, Pramod Kumar

    2011-01-01

    Summary Several five membered ring systems, e.g., triazole, oxadiazole dithiazole and thiadiazole with three heteroatoms at symmetrical or asymmetrical positions have been studied because of their interesting pharmacological properties. In this article our emphasis is on synthetic development and pharmacological activity of the triazole moiety which exhibit a broad spectrum of pharmacological activity such as antifungal, antibacterial, anti-inflammatory and anticancer etc. Triazoles have increased our ability to treat many fungal infections, for example, candidiasis, cryptococcal meningitis, aspergillosis etc. However, mortality due to these infections even with antifungal therapy is still unacceptably high. Therefore, the development of new antifungal agents targeting specific fungal structures or functions is being actively pursued. Rapid developments in molecular mycology have led to a concentrated search for more target antifungals. Although we are entering a new era of antifungal therapy in which we will continue to be challenged by systemic fungal diseases, the options for treatment will have greatly expanded. PMID:21804864

  20. Synthetic Methods, Chemistry, and the Anticonvulsant Activity of Thiadiazoles

    PubMed Central

    Sharma, Bhawna; Verma, Amita; Prajapati, Sunil; Sharma, Upendra Kumar

    2013-01-01

    The chemistry of heterocyclic compounds has been an interesting field of study for a long time. Heterocyclic nucleus 1,3,4-thiadiazole constitutes an important class of compounds for new drug development. The synthesis of novel thiadiazole derivatives and investigation of their chemical and biological behavior have gained more importance in recent decades. The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an active area of intensive investigation in medicinal chemistry. During the recent years, there has been intense investigation of different classes of thiadiazole compounds, many of which possess extensive pharmacological activities, namely, antimicrobial activity, anticonvulsant, antifungal antidiabetic, anti-inflammatory, antioxidant, and antituberculosis activities, and so forth. The resistance towards available drugs is rapidly becoming a major worldwide problem. The need to design new compounds to deal with this resistance has become one of the most important areas of research today. Thiadiazole is a versatile moiety that exhibits a wide variety of biological activities. Thiadiazole moiety acts as “hydrogen binding domain” and “two-electron donor system.” It also acts as a constrained pharmacophore. On the basis of the reported literature, we study here thiadiazole compounds and their synthetic methods chemistry and anticonvulsant activity. PMID:25405032

  1. Immunomodulatory effects of endogenous and synthetic peptides activating opioid receptors.

    PubMed

    Pomorska, Dorota K; Gach, Katarzyna; Janecka, Anna

    2014-01-01

    The main role of endogenous opioid peptides is the modulation of pain. Opioid peptides exert their analgesic activity by binding to the opioid receptors distributed widely in the central nervous system (CNS). However, opioid receptors are also found on tissues and organs outside the CNS, including the cells of the immune system, indicating that opioids are capable of exerting additional effects in periphery. Morphine, which is a gold standard in the treatment of chronic pain, is well-known for its immunosuppressive effects. Much less is known about the immunomodulatory effects exerted by endogenous (enkephalins, endorphins, dynorphins and endomorphins) and synthetic peptides activating opioid receptors. In this review we tried to summarize opioid peptide-mediated modulation of immune cell functions which can be stimulatory as well as inhibitory. PMID:25553430

  2. The latest developments in synthetic peptides with immunoregulatory activities.

    PubMed

    Zhou, Chun-lei; Lu, Rong; Lin, Gang; Yao, Zhi

    2011-02-01

    In the past few years, many researches have provided us with much data demonstrating the abilities of synthetic peptides to impact immune response in vitro and in vivo. These peptides were designed according to the structure of some important protein molecules which play a key role in immune response, so they act with specific targets. The class I and II MHC-derived peptides inhibit the TCR recognition of antigen peptide-MHC complex. Rationally designed CD80 and CD154-binding peptides block the interaction between cell surface costimulatory molecules on antigen-presenting cells (APCs) and T cells. Some peptides were designed to inhibit the activities of cell signal proteins, including JNK, NF-κB and NFAT. Some peptide antagonists competitively bind to important cytokines and inhibit their activities, such as TNF-α, TGF-β and IL-1β inhibitory peptides. Adhesion molecule ICAM-1 derived peptides block the T cell adhesion and activation. These immunoregulatory peptides showed therapeutic effect in several animal models, including collagen-induced arthritis (CIA), autoimmune cystitis model, murine skin transplant model and cardiac allograft model. These results give us important implications for the development of a novel therapy for immune mediated diseases. PMID:20979984

  3. Antifouling activity of synthetic alkylpyridinium polymers using the barnacle model.

    PubMed

    Piazza, Veronica; Dragić, Ivanka; Sepčić, Kristina; Faimali, Marco; Garaventa, Francesca; Turk, Tom; Berne, Sabina

    2014-04-01

    Polymeric alkylpyridinium salts (poly-APS) isolated from the Mediterranean marine sponge, Haliclona (Rhizoniera) sarai, effectively inhibit barnacle larva settlement and natural marine biofilm formation through a non-toxic and reversible mechanism. Potential use of poly-APS-like compounds as antifouling agents led to the chemical synthesis of monomeric and oligomeric 3-alkylpyridinium analogues. However, these are less efficient in settlement assays and have greater toxicity than the natural polymers. Recently, a new chemical synthesis method enabled the production of poly-APS analogues with antibacterial, antifungal and anti-acetylcholinesterase activities. The present study examines the antifouling properties and toxicity of six of these synthetic poly-APS using the barnacle (Amphibalanus amphitrite) as a model (cyprids and II stage nauplii larvae) in settlement, acute and sub-acute toxicity assays. Two compounds, APS8 and APS12-3, show antifouling effects very similar to natural poly-APS, with an anti-settlement effective concentration that inhibits 50% of the cyprid population settlement (EC₅₀) after 24 h of 0.32 mg/L and 0.89 mg/L, respectively. The toxicity of APS8 is negligible, while APS12-3 is three-fold more toxic (24-h LC₅₀: nauplii, 11.60 mg/L; cyprids, 61.13 mg/L) than natural poly-APS. This toxicity of APS12-3 towards nauplii is, however, 60-fold and 1200-fold lower than that of the common co-biocides, Zn- and Cu-pyrithione, respectively. Additionally, exposure to APS12-3 for 24 and 48 h inhibits the naupliar swimming ability with respective IC₅₀ of 4.83 and 1.86 mg/L. PMID:24699112

  4. Dynamic properties of biologically active synthetic heparin-like hexasaccharides.

    PubMed

    Angulo, Jesús; Hricovíni, Milos; Gairi, Margarida; Guerrini, Marco; de Paz, José Luis; Ojeda, Rafael; Martín-Lomas, Manuel; Nieto, Pedro M

    2005-10-01

    A complete study of the dynamics of two synthetic heparin-like hexasaccharides, D-GlcNHSO3-6-SO4-alpha-(1-->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHSO3-6-SO4-alpha-(1-->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHSO3-6-SO4-alpha-(1-->4)-L-IdoA-2-SO4-alpha-1-->iPr (1) and -->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHAc-6-SO4-alpha-(1-->4)-L-IdoA-alpha-(1-->4)-D-GlcNHSO3-alpha-(1-->4)-L-IdoA-2-SO4-alpha-1-->iPr (2), has been performed using 13C-nuclear magnetic resonance (NMR) relaxation parameters, T1, T2, and heteronuclear nuclear Overhauser effect (NOEs). Compound 1 is constituted from sequences corresponding to the major polysaccharide heparin region, while compound 2 contains a sequence never found in natural heparin. They differ from each other only in sulphation patterns, and are capable of stimulating fibroblast growth factors (FGFs)-1 induced mitogenesis. Both oligosaccharides exhibit a remarkable anisotropic overall motion in solution as revealed by their anisotropic ratios (tau /tau||), 4.0 and 3.0 respectively. This is a characteristic behaviour of natural glycosaminoglycans (GAG) which has also been observed for the antithrombin (AT) binding pentasaccharide D-GlcNHSO3-6-SO4-alpha-(1-->4)-D-GlcA-beta-(1-->4)-D-GlcNHSO3-(3,6-SO4)-alpha-(1-->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHSO3-6-SO4-alpha-1-->Me (3) (Hricovíni, M., Guerrini, M., Torri, G., Piani, S., and Ungarelli, F. (1995) Conformational analysis of heparin epoxide in aqueous solution. An NMR relaxation study. Carbohydr. Res., 277, 11-23). The motional properties observed for 1 and 2 provide additional support to the suitability of these compounds as heparin models in agreement with previous structural (de Paz, J.L., Angulo, J., Lassaletta, J.M., Nieto, P.M., Redondo-Horcajo, M., Lozano, R.M., Jiménez-Gallego, G., and Martín-Lomas, M. (2001) The activation of fibroblast growth factors by heparin: synthesis, structure and biological activity of heparin-like oligosaccharides. Chembiochem, 2, 673-685; Ojeda, R

  5. Dynamic properties of biologically active synthetic heparin-like hexasaccharides.

    PubMed

    Angulo, Jesús; Hricovíni, Milos; Gairi, Margarida; Guerrini, Marco; de Paz, José Luis; Ojeda, Rafael; Martín-Lomas, Manuel; Nieto, Pedro M

    2005-10-01

    A complete study of the dynamics of two synthetic heparin-like hexasaccharides, D-GlcNHSO3-6-SO4-alpha-(1-->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHSO3-6-SO4-alpha-(1-->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHSO3-6-SO4-alpha-(1-->4)-L-IdoA-2-SO4-alpha-1-->iPr (1) and -->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHAc-6-SO4-alpha-(1-->4)-L-IdoA-alpha-(1-->4)-D-GlcNHSO3-alpha-(1-->4)-L-IdoA-2-SO4-alpha-1-->iPr (2), has been performed using 13C-nuclear magnetic resonance (NMR) relaxation parameters, T1, T2, and heteronuclear nuclear Overhauser effect (NOEs). Compound 1 is constituted from sequences corresponding to the major polysaccharide heparin region, while compound 2 contains a sequence never found in natural heparin. They differ from each other only in sulphation patterns, and are capable of stimulating fibroblast growth factors (FGFs)-1 induced mitogenesis. Both oligosaccharides exhibit a remarkable anisotropic overall motion in solution as revealed by their anisotropic ratios (tau /tau||), 4.0 and 3.0 respectively. This is a characteristic behaviour of natural glycosaminoglycans (GAG) which has also been observed for the antithrombin (AT) binding pentasaccharide D-GlcNHSO3-6-SO4-alpha-(1-->4)-D-GlcA-beta-(1-->4)-D-GlcNHSO3-(3,6-SO4)-alpha-(1-->4)-L-IdoA-2-SO4-alpha-(1-->4)-D-GlcNHSO3-6-SO4-alpha-1-->Me (3) (Hricovíni, M., Guerrini, M., Torri, G., Piani, S., and Ungarelli, F. (1995) Conformational analysis of heparin epoxide in aqueous solution. An NMR relaxation study. Carbohydr. Res., 277, 11-23). The motional properties observed for 1 and 2 provide additional support to the suitability of these compounds as heparin models in agreement with previous structural (de Paz, J.L., Angulo, J., Lassaletta, J.M., Nieto, P.M., Redondo-Horcajo, M., Lozano, R.M., Jiménez-Gallego, G., and Martín-Lomas, M. (2001) The activation of fibroblast growth factors by heparin: synthesis, structure and biological activity of heparin-like oligosaccharides. Chembiochem, 2, 673-685; Ojeda, R

  6. Short and efficient synthetic route to methyl α-trioxacarcinoside B and anomerically activated derivatives.

    PubMed

    Magauer, Thomas; Myers, Andrew G

    2011-10-21

    A 9-step synthetic route to the complex carbohydrate methyl α-trioxacarcinoside B from 2-acetylfuran is described. Anomerically activated forms, including 1-phenylthio, 1-O-(4'-pentenyl), 1-fluoro, and 1-O-acetyl derivatives are also prepared.

  7. Antimicrobial peptides: natural templates for synthetic membrane-active compounds.

    PubMed

    Giuliani, A; Pirri, G; Bozzi, A; Di Giulio, A; Aschi, M; Rinaldi, A C

    2008-08-01

    The innate immunity of multicellular organisms relies in large part on the action of antimicrobial peptides (AMPs) to resist microbial invasion. Crafted by evolution into an extremely diversified array of sequences and folds, AMPs do share a common amphiphilic 3-D arrangement. This feature is directly linked with a common mechanism of action that predominantly (although not exclusively) develops upon interaction of peptides with cell membranes of target cells. This minireview reports on current understanding of the modes of interaction of AMPs with biological and model membranes, especially focusing on recent insights into the folding and oligomerization requirements of peptides to bind and insert into lipid membranes and exert their antibiotic effects. Given the potential of AMPs to be developed into a new class of anti-infective agents, emphasis is placed on how the information on peptide-membrane interactions could direct the design and selection of improved biomimetic synthetic peptides with antibiotic properties.

  8. Synthetic Training Data Generation for Activity Monitoring and Behavior Analysis

    NASA Astrophysics Data System (ADS)

    Monekosso, Dorothy; Remagnino, Paolo

    This paper describes a data generator that produces synthetic data to simulate observations from an array of environment monitoring sensors. The overall goal of our work is to monitor the well-being of one occupant in a home. Sensors are embedded in a smart home to unobtrusively record environmental parameters. Based on the sensor observations, behavior analysis and modeling are performed. However behavior analysis and modeling require large data sets to be collected over long periods of time to achieve the level of accuracy expected. A data generator - was developed based on initial data i.e. data collected over periods lasting weeks to facilitate concurrent data collection and development of algorithms. The data generator is based on statistical inference techniques. Variation is introduced into the data using perturbation models.

  9. Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity.

    PubMed

    Guzman, Juan David

    2014-11-25

    Antimicrobial natural preparations involving cinnamon, storax and propolis have been long used topically for treating infections. Cinnamic acids and related molecules are partly responsible for the therapeutic effects observed in these preparations. Most of the cinnamic acids, their esters, amides, aldehydes and alcohols, show significant growth inhibition against one or several bacterial and fungal species. Of particular interest is the potent antitubercular activity observed for some of these cinnamic derivatives, which may be amenable as future drugs for treating tuberculosis. This review intends to summarize the literature data on the antimicrobial activity of the natural cinnamic acids and related derivatives. In addition, selected hybrids between cinnamic acids and biologically active scaffolds with antimicrobial activity were also included. A comprehensive literature search was performed collating the minimum inhibitory concentration (MIC) of each cinnamic acid or derivative against the reported microorganisms. The MIC data allows the relative comparison between series of molecules and the derivation of structure-activity relationships.

  10. Activity of Novel Synthetic Peptides against Candida albicans.

    PubMed

    Lum, Kah Yean; Tay, Sun Tee; Le, Cheng Foh; Lee, Vannajan Sanghiran; Sabri, Nadia Hanim; Velayuthan, Rukumani Devi; Hassan, Hamimah; Sekaran, Shamala Devi

    2015-01-01

    Candida spp. are the most common causes of fungal infections worldwide. Among the Candida species, Candida albicans remains the predominant species that causes invasive candidiasis in most countries. In this study, we used two peptides, KABT-AMP and uperin 3.6 as templates to develop novel antifungal peptides. Their anticandidal activity was assessed using a combination of MIC, time-killing assay and biofilm reduction assay. Hybrid peptides, KU2 and KU3 containing a mixed backbone of KABT-AMP and Uperin 3.6 demonstrated the most potent anticandidal activity with MIC values ranging from 8-16 mg/L. The number of Trp residues and the amphipathic structure of peptides probably enhanced the anticandidal activity of peptides. Increasing the cationicity of the uperin 3.6 analogues resulted in reduced MIC from the range of 64-128 mg/L to 16-64 mg/L and this was also correlated with the antibiofilm activity and killing kinetics of the peptides. Peptides showed synergistic effects when used in combination with conventional antifungals. Peptides demonstrated low haemolytic activity but significant toxicity on two normal human epithelial cell lines. This study provides us with a better understanding on the structure-activity relationship and the balance between cationicity and hydrophobicity of the peptides although the therapeutic application of the peptides is limited. PMID:25965506

  11. A synthetic segment of surfactant protein A: structure, in vitro surface activity, and in vivo efficacy.

    PubMed

    Walther, F J; David-Cu, R; Leung, C; Bruni, R; Hernández-Juviel, J; Gordon, L M; Waring, A J

    1996-06-01

    Surfactant protein A (SP-A) is a 248-residue, water-soluble, lipid-associating protein found in lung surfactant. Analysis of the amino acid sequence using the Eisenberg hydrophobic moment algorithm predicts that the SP-A segment spanning residues 114-144 has high hydrophobic moments, typical of lipid-associating amphipathic domains. The secondary structure, in vitro surface activity and in vivo lung activity of this SP-A sequence were studied with a 31-residue synthetic peptide analog (A114-144). Analysis of the secondary structure using circular dichroism and Fourier transform infrared spectroscopy indicated association with lipid dispersions and a dominant helical content. Surface activity measurements of A114-144 with surfactant lipid dispersions and the hydrophobic surfactant proteins B and C (SP-B/C) showed that A114-144 enhances surface activity under conditions of dynamic compression and respreading on a Langmuir/Wilhelmy surface balance. Synthetic surfactant dispersions containing A114-144 improved lung compliance in spontaneously breathing, 28-d premature rabbits to a greater degree than surfactant dispersions with synthetic SP-B/C and synthetic surfactant lipids alone. These observations indicate that inclusion of A114-144 may improve synthetic preparations currently used for surfactant replacement therapy.

  12. Synthetic Physical Interactions Map Kinetochore-Checkpoint Activation Regions

    PubMed Central

    Ólafsson, Guðjón; Thorpe, Peter H.

    2016-01-01

    The spindle assembly checkpoint (SAC) is a key mechanism to regulate the timing of mitosis and ensure that chromosomes are correctly segregated to daughter cells. The recruitment of the Mad1 and Mad2 proteins to the kinetochore is normally necessary for SAC activation. This recruitment is coordinated by the SAC kinase Mps1, which phosphorylates residues at the kinetochore to facilitate binding of Bub1, Bub3, Mad1, and Mad2. There is evidence that the essential function of Mps1 is to direct recruitment of Mad1/2. To test this model, we have systematically recruited Mad1, Mad2, and Mps1 to most proteins in the yeast kinetochore, and find that, while Mps1 is sufficient for checkpoint activation, recruitment of either Mad1 or Mad2 is not. These data indicate an important role for Mps1 phosphorylation in SAC activation, beyond the direct recruitment of Mad1 and Mad2. PMID:27280788

  13. Leishmanicidal Activities of Novel Synthetic Furoxan and Benzofuroxan Derivatives

    PubMed Central

    Dutra, Luiz Antônio; de Almeida, Letícia; Passalacqua, Thais G.; Reis, Juliana Santana; Torres, Fabio A. E.; Martinez, Isabel; Peccinini, Rosangela Gonçalves; Chin, Chung Man; Chegaev, Konstantin; Guglielmo, Stefano; Fruttero, Roberta

    2014-01-01

    A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (compounds 3, 4a and -b, 13a and -b, and 14a to -f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (compounds 7 and 8a to -c) derivatives were synthesized, characterized, and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited the ability to generate nitric oxide at different levels (7.8% to 27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in medium supernatant from murine macrophages infected with L. amazonensis at 0.75 mM after 48 h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a and -b, and 14d exerted selective leishmanicidal activities superior to those of amphotericin B and pentamidine. In vitro studies at pH 5.4 reveal that compound 8a is stable until 8 h and that compound 14a behaves as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis. PMID:24913171

  14. Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes.

    PubMed

    Ashino, Takashi; Hakukawa, Kanae; Itoh, Yuka; Numazawa, Satoshi

    2014-01-01

    Synthetic cannabinoids developed by chemical modification are believed to bind to cannabinoid receptors and cause neurological effects similar to cannabis; however, their effects on drug metabolizing enzymes are unknown. This study aimed to elucidate the effect of synthetic cannabinoids on cytochrome P450 1A activity. Naphthoylindole, a basic structure of the major synthetic cannabinoids, strongly inhibited CYP1A activity in a competitive manner; the apparent Ki value was 0.40 μM. The N-Alkylated derivatives of naphthoylindole, MAM-2201 and JWH-019, also inhibited CYP1A activity in a concentration-dependent manner; however, their inhibitory effects were weaker than naphthoylindole. An adamantylamidoindole derivative, STS-135, showed inhibition of CYP1A activity in a concentrationdependent manner, but the adamantoylindole derivatives, AB-001 and AM-1248, did not. A tetramethylcyclopropanoylindole derivative, UR-144, showed a weak inhibition of CYP1A activity at high concentrations. These results suggest that synthetic cannabinoids and their basic molecules are capable of inhibiting CYP1A enzymatic activity.

  15. Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes.

    PubMed

    Ashino, Takashi; Hakukawa, Kanae; Itoh, Yuka; Numazawa, Satoshi

    2014-01-01

    Synthetic cannabinoids developed by chemical modification are believed to bind to cannabinoid receptors and cause neurological effects similar to cannabis; however, their effects on drug metabolizing enzymes are unknown. This study aimed to elucidate the effect of synthetic cannabinoids on cytochrome P450 1A activity. Naphthoylindole, a basic structure of the major synthetic cannabinoids, strongly inhibited CYP1A activity in a competitive manner; the apparent Ki value was 0.40 μM. The N-Alkylated derivatives of naphthoylindole, MAM-2201 and JWH-019, also inhibited CYP1A activity in a concentration-dependent manner; however, their inhibitory effects were weaker than naphthoylindole. An adamantylamidoindole derivative, STS-135, showed inhibition of CYP1A activity in a concentrationdependent manner, but the adamantoylindole derivatives, AB-001 and AM-1248, did not. A tetramethylcyclopropanoylindole derivative, UR-144, showed a weak inhibition of CYP1A activity at high concentrations. These results suggest that synthetic cannabinoids and their basic molecules are capable of inhibiting CYP1A enzymatic activity. PMID:25374372

  16. Fine-tuning of macrophage activation using synthetic rocaglate derivatives

    PubMed Central

    Bhattacharya, Bidisha; Chatterjee, Sujoy; Devine, William G.; Kobzik, Lester; Beeler, Aaron B.; Porco, John A.; Kramnik, Igor

    2016-01-01

    Drug-resistant bacteria represent a significant global threat. Given the dearth of new antibiotics, host-directed therapies (HDTs) are especially desirable. As IFN-gamma (IFNγ) plays a central role in host resistance to intracellular bacteria, including Mycobacterium tuberculosis, we searched for small molecules to augment the IFNγ response in macrophages. Using an interferon-inducible nuclear protein Ipr1 as a biomarker of macrophage activation, we performed a high-throughput screen and identified molecules that synergized with low concentration of IFNγ. Several active compounds belonged to the flavagline (rocaglate) family. In primary macrophages a subset of rocaglates 1) synergized with low concentrations of IFNγ in stimulating expression of a subset of IFN-inducible genes, including a key regulator of the IFNγ network, Irf1; 2) suppressed the expression of inducible nitric oxide synthase and type I IFN and 3) induced autophagy. These compounds may represent a basis for macrophage-directed therapies that fine-tune macrophage effector functions to combat intracellular pathogens and reduce inflammatory tissue damage. These therapies would be especially relevant to fighting drug-resistant pathogens, where improving host immunity may prove to be the ultimate resource. PMID:27086720

  17. A Short and Efficient Synthetic Route to Methyl α-Trioxacarcinoside B and Anomerically Activated Derivatives

    PubMed Central

    Magauer, Thomas; Myers, Andrew G.

    2011-01-01

    A 9-step synthetic route to the complex carbohydrate methyl α-trioxacarcinoside B from 2-acetylfuran is described. Anomerically activated forms, including 1-phenylthio, 1-O-(4’f-pentenyl), 1-fluoro, and 1-O-acetyl derivatives are also prepared. PMID:21958151

  18. Potent antiprotozoal activity of a novel semi-synthetic berberine derivative.

    PubMed

    Bahar, Mark; Deng, Ye; Zhu, Xiaohua; He, Shanshan; Pandharkar, Trupti; Drew, Mark E; Navarro-Vázquez, Armando; Anklin, Clemens; Gil, Roberto R; Doskotch, Raymond W; Werbovetz, Karl A; Kinghorn, A Douglas

    2011-05-01

    Treatment of diseases such as African sleeping sickness and leishmaniasis often depends on relatively expensive or toxic drugs, and resistance to current chemotherapeutics is an issue in treating these diseases and malaria. In this study, a new semi-synthetic berberine analogue, 5,6-didehydro-8,8-diethyl-13-oxodihydroberberine chloride (1), showed nanomolar level potency against in vitro models of leishmaniasis, malaria, and trypanosomiasis as well as activity in an in vivo visceral leishmaniasis model. Since the synthetic starting material, berberine hemisulfate, is inexpensive, 8,8-dialkyl-substituted analogues of berberine may lead to a new class of affordable antiprotozoal compounds.

  19. Phytotoxic Potential and Biological Activity of Three Synthetic Coumarin Derivatives as New Natural-Like Herbicides.

    PubMed

    Araniti, Fabrizio; Mancuso, Raffaella; Lupini, Antonio; Giofrè, Salvatore V; Sunseri, Francesco; Gabriele, Bartolo; Abenavoli, Maria Rosa

    2015-01-01

    Coumarin is a natural compound well known for its phytotoxic potential. In the search for new herbicidal compounds to manage weeds, three synthetic derivatives bearing the coumarin scaffold (1-3), synthesized by a carbonylative organometallic approach, were in vitro assayed on germination and root growth of two noxious weeds, Amaranthus retroflexus and Echinochloa crus-galli. Moreover, the synthetic coumarins 1-3 were also in vitro assayed on seedlings growth of the model species Arabidopsis thaliana to identify the possible physiological targets. All molecules strongly affected seed germination and root growth of both weeds. Interestingly, the effects of synthetic coumarins on weed germination were higher than template natural coumarin, pointing out ED50 values ranging from 50-115 µM. Moreover, all synthetic coumarins showed a strong phytotoxic potential on both Arabidopsis shoot and root growth, causing a strong reduction in shoot fresh weight (ED50 values ≤ 60 µM), accompanied by leaf development and a decrease in pigment content. Furthermore, they caused a strong alteration in root growth (ED50 values ≤ 170 µM) and morphology with evident alterations in root tip anatomy. Taken together, our results highlight the promising potential herbicidal activity of these compounds.

  20. Phytotoxic Potential and Biological Activity of Three Synthetic Coumarin Derivatives as New Natural-Like Herbicides.

    PubMed

    Araniti, Fabrizio; Mancuso, Raffaella; Lupini, Antonio; Giofrè, Salvatore V; Sunseri, Francesco; Gabriele, Bartolo; Abenavoli, Maria Rosa

    2015-01-01

    Coumarin is a natural compound well known for its phytotoxic potential. In the search for new herbicidal compounds to manage weeds, three synthetic derivatives bearing the coumarin scaffold (1-3), synthesized by a carbonylative organometallic approach, were in vitro assayed on germination and root growth of two noxious weeds, Amaranthus retroflexus and Echinochloa crus-galli. Moreover, the synthetic coumarins 1-3 were also in vitro assayed on seedlings growth of the model species Arabidopsis thaliana to identify the possible physiological targets. All molecules strongly affected seed germination and root growth of both weeds. Interestingly, the effects of synthetic coumarins on weed germination were higher than template natural coumarin, pointing out ED50 values ranging from 50-115 µM. Moreover, all synthetic coumarins showed a strong phytotoxic potential on both Arabidopsis shoot and root growth, causing a strong reduction in shoot fresh weight (ED50 values ≤ 60 µM), accompanied by leaf development and a decrease in pigment content. Furthermore, they caused a strong alteration in root growth (ED50 values ≤ 170 µM) and morphology with evident alterations in root tip anatomy. Taken together, our results highlight the promising potential herbicidal activity of these compounds. PMID:26426002

  1. Synthetic mRNA splicing modulator compounds with in vivo antitumor activity.

    PubMed

    Lagisetti, Chandraiah; Pourpak, Alan; Goronga, Tinopiwa; Jiang, Qin; Cui, Xiaoli; Hyle, Judith; Lahti, Jill M; Morris, Stephan W; Webb, Thomas R

    2009-11-26

    We report our progress on the development of new synthetic anticancer lead compounds that modulate the splicing of mRNA. We also report the synthesis and evaluation of new biologically active ester and carbamate analogues. Further, we describe initial animal studies demonstrating the antitumor efficacy of compound 5 in vivo. Additionally, we report the enantioselective and diastereospecific synthesis of a new 1,3-dioxane series of active analogues. We confirm that compound 5 inhibits the splicing of mRNA in cell-free nuclear extracts and in a cell-based dual-reporter mRNA splicing assay. In summary, we have developed totally synthetic novel spliceosome modulators as therapeutic lead compounds for a number of highly aggressive cancers. Future efforts will be directed toward the more complete optimization of these compounds as potential human therapeutics.

  2. A Synthetic Transcriptional Activator of Genes Associated with the Retina in Human Dermal Fibroblasts.

    PubMed

    Syed, Junetha; Chandran, Anandhakumar; Pandian, Ganesh N; Taniguchi, Junichi; Sato, Shinsuke; Hashiya, Kaori; Kashiwazaki, Gengo; Bando, Toshikazu; Sugiyama, Hiroshi

    2015-07-01

    Small molecules capable of modulating epigenetic signatures can activate the transcription of tissue-restricted genes in a totally unrelated cell type and have potential use in epigenetic therapy. To provide an example for an initial approach, we report here on one synthetic small-molecule compound-termed "SAHA-PIP X"-from our library of conjugates. This compound triggered histone acetylation accompanied by the transcription of retinal-tissue-related genes in human dermal fibroblasts (HDFs).

  3. Design and biological evaluation of synthetic retinoids: probing length vs. stability vs. activity.

    PubMed

    Clemens, Graeme; Flower, Kevin R; Gardner, Peter; Henderson, Andrew P; Knowles, Jonathan P; Marder, Todd B; Whiting, Andrew; Przyborski, Stefan

    2013-12-01

    All trans-retinoic acid (ATRA) is widely used to direct the differentiation of cultured stem cells. When exposed to the pluripotent human embryonal carcinoma (EC) stem cell line, TERA2.cl.SP12, ATRA induces ectoderm differentiation and the formation of neuronal cell types. We report in this study that novel polyene chain length analogues of ATRA require a specific chain length to elicit a biological responses of the EC cells TERA2.cl.SP12, with synthetic retinoid AH61 being particularly active, and indeed more so than ATRA. The impacts of both the synthetic retinoid AH61 and natural ATRA on the TERA2.cl.SP12 cells were directly compared using both RT-PCR and Fourier Transform Infrared Micro-Spectroscopy (FT-IRMS) coupled with multivariate analysis. Analytical results produced from this study also confirmed that the synthetic retinoid AH61 had biological activity comparable or greater than that of ATRA. In addition to this, AH61 has the added advantage of greater compound stability than ATRA, therefore, avoiding issues of oxidation or decomposition during use with embryonic stem cells. PMID:24108350

  4. Enhanced fuel efficiency on tractor-trailers using synthetic jet-based active flow control

    NASA Astrophysics Data System (ADS)

    Amitay, Michael; Menicovich, David; Gallardo, Daniele

    2016-04-01

    The application of piezo-electrically-driven synthetic-jet-based active flow control to reduce drag on tractor-trailers was explored experimentally in wind tunnel testing as well as full-scale road tests. Aerodynamic drag accounts for more than 50% of the usable energy at highway speeds, a problem that applies primarily to trailer trucks. Therefore, a reduction in aerodynamic drag results in large saving of fuel and reduction in CO2 emissions. The active flow control technique that is being used relies on a modular system comprised of distributed, small, highly efficient actuators. These actuators, called synthetic jets, are jets that are synthesized at the edge of an orifice by a periodic motion of a piezoelectric diaphragm(s) mounted on one (or more) walls of a sealed cavity. The synthetic jet is zero net mass flux (ZNMF), but it allows momentum transfer to flow. It is typically driven near diaphragm and/or cavity resonance, and therefore, small electric input [O(10W)] is required. Another advantage of this actuator is that no plumbing is required. The system doesn't require changes to the body of the truck, can be easily reconfigured to various types of vehicles, and consumes small amounts of electrical power from the existing electrical system of the truck. Preliminary wind tunnel results showed up to 18% reduction in fuel consumption, whereas road tests also showed very promising results.

  5. Synthetic analogues of the microtubule-stabilizing agent (+)-discodermolide: preparation and biological activity.

    PubMed

    Gunasekera, Sarath P; Mickel, Stuart J; Daeffler, Robert; Niederer, Daniel; Wright, Amy E; Linley, Patricia; Pitts, Tara

    2004-05-01

    A series of seven synthetic discodermolide analogues 2-8, which are minor side products generated during the final stages in the synthesis of (+)-discodermolide (1), have been purified and evaluated for in vitro cytotoxicity against A549, P388, MFC-7, NCI/ADR, PANC-1, and VERO cell lines. These synthetic analogues showed a significant variation of cytotoxicity and confirmed the importance of the C-7 hydroxy through C-17 hydroxy molecular fragment for potency. Specifically, these analogues suggested the relevance of the C-11 hydroxyl group, the C-13 double bond, and the C-16 (S) stereochemistry for the potency of (+)-discodermolide. The preparation, purification, structure elucidation, and biological activity of these new analogues are described.

  6. Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids.

    PubMed

    Wiley, Jenny L; Marusich, Julie A; Huffman, John W

    2014-02-27

    Originally synthesized for research purposes, indole- and pyrrole-derived synthetic cannabinoids are the most common psychoactive compounds contained in abused products marketed as "spice" or "herbal incense." While CB1 and CB2 receptor affinities are available for most of these research chemicals, in vivo pharmacological data are sparse. In mice, cannabinoids produce a characteristic profile of dose-dependent effects: antinociception, hypothermia, catalepsy and suppression of locomotion. In combination with receptor binding data, this tetrad battery has been useful in evaluation of the relationship between the structural features of synthetic cannabinoids and their in vivo cannabimimetic activity. Here, published tetrad studies are reviewed and additional in vivo data on synthetic cannabinoids are presented. Overall, the best predictor of likely cannabimimetic effects in the tetrad tests was good CB1 receptor affinity. Further, retention of good CB1 affinity and in vivo activity was observed across a wide array of structural manipulations of substituents of the prototypic aminoalkylindole molecule WIN55,212-2, including substitution of an alkyl for the morpholino group, replacement of an indole core with a pyrrole or phenylpyrrole, substitution of a phenylacetyl or tetramethylcyclopropyl group for JWH-018's naphthoyl, and halogenation of the naphthoyl group. This flexibility of cannabinoid ligand-receptor interactions has been a particular challenge for forensic scientists who have struggled to identify and regulate each new compound as it has appeared on the drug market. One of the most pressing future research needs is determination of the extent to which the pharmacology of these synthetic cannabinoids may differ from those of classical cannabinoids.

  7. Moving around the molecule: Relationship between chemical structure and in vivo activity of synthetic cannabinoids

    PubMed Central

    Wiley, Jenny L.; Marusich, Julie A.; Huffman, John W.

    2013-01-01

    Originally synthesized for research purposes, indole- and pyrrole-derived synthetic cannabinoids are the most common psychoactive compounds contained in abused products marketed as “spice” or “herbal incense.” While CB1 and CB2 receptor affinities are available for most of these research chemicals, in vivo pharmacological data are sparse. In mice, cannabinoids produce a characteristic profile of dose-dependent effects: antinociception, hypothermia, catalepsy and suppression of locomotion. In combination with receptor binding data, this tetrad battery has been useful in evaluation of the relationship between the structural features of synthetic cannabinoids and their in vivo cannabimimetic activity. Here, published tetrad studies are reviewed and additional in vivo data on synthetic cannabinoids are presented. Overall, the best predictor of likely cannabimimetic effects in the tetrad tests was good CB1 receptor affinity. Further, retention of good CB1 affinity and in vivo activity was observed across a wide array of structural manipulations of substituents of the prototypic aminoalkylindole molecule WIN55,212-2, including substitution of an alkyl for the morpholino group, replacement of an indole core with a pyrrole or phenylpyrrole, substitution of a phenylacetyl or tetramethylcyclopropyl group for JWH-018’s naphthoyl, and halogenation of the naphthoyl group. This flexibility of cannabinoid ligand-receptor interactions has been a particular challenge for forensic scientists who have struggled to identify and regulate each new compound as it has appeared on the drug market. One of the most pressing future research needs is determination of the extent to which the pharmacology of these synthetic cannabinoids may differ from those of classical cannabinoids. PMID:24071522

  8. Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities

    PubMed Central

    Sanjiv, Kumar; Hagenkort, Anna; Calderón-Montaño, José Manuel; Koolmeister, Tobias; Reaper, Philip M.; Mortusewicz, Oliver; Jacques, Sylvain A.; Kuiper, Raoul V.; Schultz, Niklas; Scobie, Martin; Charlton, Peter A.; Pollard, John R.; Berglund, Ulrika Warpman; Altun, Mikael; Helleday, Thomas

    2015-01-01

    Summary ATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy. PMID:26748709

  9. iNOS Activity Modulates Inflammation, Angiogenesis, and Tissue Fibrosis in Polyether-Polyurethane Synthetic Implants

    PubMed Central

    Cassini-Vieira, Puebla; Araújo, Fernanda Assis; da Costa Dias, Filipi Leles; Russo, Remo Castro; Andrade, Silvia Passos; Teixeira, Mauro Martins; Barcelos, Luciola Silva

    2015-01-01

    There is considerable interest in implantation techniques and scaffolds for tissue engineering and, for safety and biocompatibility reasons, inflammation, angiogenesis, and fibrosis need to be determined. The contribution of inducible nitric oxide synthase (iNOS) in the regulation of the foreign body reaction induced by subcutaneous implantation of a synthetic matrix was never investigated. Here, we examined the role of iNOS in angiogenesis, inflammation, and collagen deposition induced by polyether-polyurethane synthetic implants, using mice with targeted disruption of the iNOS gene (iNOS−/−) and wild-type (WT) mice. The hemoglobin content and number of vessels were decreased in the implants of iNOS−/− mice compared to WT mice 14 days after implantation. VEGF levels were also reduced in the implants of iNOS−/− mice. In contrast, the iNOS−/− implants exhibited an increased neutrophil and macrophage infiltration. However, no alterations were observed in levels of CXCL1 and CCL2, chemokines related to neutrophil and macrophage migration, respectively. Furthermore, the implants of iNOS−/− mice showed boosted collagen deposition. These data suggest that iNOS activity controls inflammation, angiogenesis, and fibrogenesis in polyether-polyurethane synthetic implants and that lack of iNOS expression increases foreign body reaction to implants in mice. PMID:26106257

  10. iNOS Activity Modulates Inflammation, Angiogenesis, and Tissue Fibrosis in Polyether-Polyurethane Synthetic Implants.

    PubMed

    Cassini-Vieira, Puebla; Araújo, Fernanda Assis; da Costa Dias, Filipi Leles; Russo, Remo Castro; Andrade, Silvia Passos; Teixeira, Mauro Martins; Barcelos, Luciola Silva

    2015-01-01

    There is considerable interest in implantation techniques and scaffolds for tissue engineering and, for safety and biocompatibility reasons, inflammation, angiogenesis, and fibrosis need to be determined. The contribution of inducible nitric oxide synthase (iNOS) in the regulation of the foreign body reaction induced by subcutaneous implantation of a synthetic matrix was never investigated. Here, we examined the role of iNOS in angiogenesis, inflammation, and collagen deposition induced by polyether-polyurethane synthetic implants, using mice with targeted disruption of the iNOS gene (iNOS(-/-)) and wild-type (WT) mice. The hemoglobin content and number of vessels were decreased in the implants of iNOS(-/-) mice compared to WT mice 14 days after implantation. VEGF levels were also reduced in the implants of iNOS(-/-) mice. In contrast, the iNOS(-/-) implants exhibited an increased neutrophil and macrophage infiltration. However, no alterations were observed in levels of CXCL1 and CCL2, chemokines related to neutrophil and macrophage migration, respectively. Furthermore, the implants of iNOS(-/-) mice showed boosted collagen deposition. These data suggest that iNOS activity controls inflammation, angiogenesis, and fibrogenesis in polyether-polyurethane synthetic implants and that lack of iNOS expression increases foreign body reaction to implants in mice.

  11. Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities.

    PubMed

    Sanjiv, Kumar; Hagenkort, Anna; Calderón-Montaño, José Manuel; Koolmeister, Tobias; Reaper, Philip M; Mortusewicz, Oliver; Jacques, Sylvain A; Kuiper, Raoul V; Schultz, Niklas; Scobie, Martin; Charlton, Peter A; Pollard, John R; Berglund, Ulrika Warpman; Altun, Mikael; Helleday, Thomas

    2016-01-12

    ATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy. PMID:26748709

  12. Activation of epitope-specific memory cytotoxic T lymphocyte responses by synthetic peptides.

    PubMed

    Reali, E; Guerrini, R; Giori, B; Borghi, M; Marastoni, M; Tomatis, R; Traniello, S; Masucci, M G; Gavioli, R

    1996-08-01

    Cytotoxic T lymphocytes (CTL) recognize antigens as short peptides selected for presentation by their ability to bind to MHC class I molecules. Polyclonal Epstein-Barr virus (EBV)-specific memory CTL responses, reactivated from blood lymphocytes of HLA-A11-positive individuals by stimulation with the autologous EBV-transformed lymphoblastoid cell line (LCL), are often dominated by reactivites directed to the peptide epitope IVTDFSVIK (IVT), corresponding to amino acids 416-424 of EBV nuclear antigen-4 (EBNA4). We now report the selective activation of IVT-specific CTL by stimulation of lymphocytes with the corresponding synthetic peptide. A more than 10-fold increase in frequency of CTL clones with this specificity (from 8% to 96%) was obtained when the peptide was presented by HLA-A11-transfected T2 cells (T2/A11). Titration of synthetic peptide in cytotoxic assay demonstrated that clones activated under these conditions are as efficient as clones activated by conventional LCL stimulations. Induction of memory CTL responses required low surface density of MHC: peptide complexes, since reactivation was achieved by stimulation with T2/A11 cells pulsed with concentrations of peptide that are suboptimal for induction of target cell lysis. This protocol of activation revealed the presence of IVT-specific CTL precursors in a donor that failed to mount an IVT-specific response upon stimulation with the autologous B95.8 virus-transformed LCL. The results suggest that stimulation with synthetic peptide epitopes can be efficiently used for induction of memory CTL responses, and may be particularly helpful for the selective expansion of subdominant CTL specificities.

  13. Geographic Variability and Anti-Staphylococcal Activity of the Chrysophaentins and Their Synthetic Fragments

    PubMed Central

    Keffer, Jessica L.; Hammill, Jared T.; Lloyd, John R.; Plaza, Alberto; Wipf, Peter; Bewley, Carole A.

    2012-01-01

    Drug-resistant Staphylococcus aureus is a continuing public health concern, both in the hospital and community settings. Antibacterial compounds that possess novel structural scaffolds and are effective against multiple S. aureus strains, including current drug-resistant ones, are needed. Previously, we have described the chrysophaentins, a family of bisdiarylbutene macrocycles from the chrysophyte alga Chrysophaeum taylori that inhibit the growth of S. aureus and methicillin-resistant S. aureus (MRSA). In this study we have analyzed the geographic variability of chrysophaentin production in C. taylori located at different sites on the island of St. John, U.S. Virgin Islands, and identified two new linear chrysophaentin analogs, E2 and E3. In addition, we have expanded the structure activity relationship through synthesis of fragments comprising conserved portions of the chrysophaentins, and determined the antimicrobial activity of natural chrysophaentins and their synthetic analogs against five diverse S. aureus strains. We find that the chrysophaentins show similar activity against all S. aureus strains, regardless of their drug sensitivity profiles. The synthetic chrysophaentin fragments indeed mimic the natural compounds in their spectrum of antibacterial activity, and therefore represent logical starting points for future medicinal chemistry studies of the natural products and their analogs. PMID:22822360

  14. Immunostimulation by Synthetic Lipopeptide-Based Vaccine Candidates: Structure-Activity Relationships

    PubMed Central

    Zaman, Mehfuz; Toth, Istvan

    2013-01-01

    Peptide-based vaccines offer several advantages over conventional whole organism or protein approaches by offering improved purity and specificity in inducing immune response. However, peptides alone are generally non-immunogenic. Concerns remain about the toxicity of adjuvants which are critical for immunogenicity of synthetic peptides. The use of lipopeptides in peptide vaccines is currently under intensive investigation because potent immune responses can be generated without the use of adjuvant (thus are self-adjuvanting). Several lipopeptides derived from microbial origin, and their synthetic versions or simpler fatty acid moieties impart this self-adjuvanting activity by signaling via Toll-like receptor 2 (TLR2). Engagement of this innate immune receptor on antigen-presenting cell leads to the initiation and development of potent immune responses. Therefore optimization of lipopeptides to enhance TLR2-mediated activation is a promising strategy for vaccine development. Considerable structure-activity relationships that determine TLR2 binding and consequent stimulation of innate immune responses have been investigated for a range of lipopeptides. In this mini review we address the development of lipopeptide vaccines, mechanism of TLR2 recognition, and immune activation. An overview is provided of the best studied lipopeptide vaccine systems. PMID:24130558

  15. Topical Anti-inflammatory Activity of New Hybrid Molecules of Terpenes and Synthetic Drugs.

    PubMed

    Theoduloz, Cristina; Delporte, Carla; Valenzuela-Barra, Gabriela; Silva, Ximena; Cádiz, Solange; Bustamante, Fernanda; Pertino, Mariano Walter; Schmeda-Hirschmann, Guillermo

    2015-06-18

    The aim of the study was to assess changes in the activity of anti-inflammatory terpenes from Chilean medicinal plants after the formation of derivatives incorporating synthetic anti-inflammatory agents. Ten new hybrid molecules were synthesized combining terpenes (ferruginol (1), imbricatolic acid (2) and oleanolic acid (3)) with ibuprofen (4) or naproxen (5). The topical anti-inflammatory activity of the compounds was assessed in mice by the arachidonic acid (AA) and 12-O-tetradecanoyl phorbol 13-acetate (TPA) induced ear edema assays. Basal cytotoxicity was determined towards human lung fibroblasts, gastric epithelial cells and hepatocytes. At 1.4 µmol/mouse, a strong anti-inflammatory effect in the TPA assay was observed for oleanoyl ibuprofenate 12 (79.9%) and oleanoyl ibuprofenate methyl ester 15 (80.0%). In the AA assay, the best activity was observed for 12 at 3.2 µmol/mouse, with 56.8% reduction of inflammation, in the same range as nimesulide (48.9%). All the terpenyl-synthetic anti-inflammatory hybrids showed better effects in the TPA assay, with best activity for 6, 12 and 15. The cytotoxicity of the compounds 8 and 10 with a free COOH, was higher than that of 2. The derivatives from 3 were less toxic than the triterpene. Several of the new compounds presented better anti-inflammatory effect and lower cytotoxicity than the parent terpenes.

  16. Topical Anti-inflammatory Activity of New Hybrid Molecules of Terpenes and Synthetic Drugs.

    PubMed

    Theoduloz, Cristina; Delporte, Carla; Valenzuela-Barra, Gabriela; Silva, Ximena; Cádiz, Solange; Bustamante, Fernanda; Pertino, Mariano Walter; Schmeda-Hirschmann, Guillermo

    2015-01-01

    The aim of the study was to assess changes in the activity of anti-inflammatory terpenes from Chilean medicinal plants after the formation of derivatives incorporating synthetic anti-inflammatory agents. Ten new hybrid molecules were synthesized combining terpenes (ferruginol (1), imbricatolic acid (2) and oleanolic acid (3)) with ibuprofen (4) or naproxen (5). The topical anti-inflammatory activity of the compounds was assessed in mice by the arachidonic acid (AA) and 12-O-tetradecanoyl phorbol 13-acetate (TPA) induced ear edema assays. Basal cytotoxicity was determined towards human lung fibroblasts, gastric epithelial cells and hepatocytes. At 1.4 µmol/mouse, a strong anti-inflammatory effect in the TPA assay was observed for oleanoyl ibuprofenate 12 (79.9%) and oleanoyl ibuprofenate methyl ester 15 (80.0%). In the AA assay, the best activity was observed for 12 at 3.2 µmol/mouse, with 56.8% reduction of inflammation, in the same range as nimesulide (48.9%). All the terpenyl-synthetic anti-inflammatory hybrids showed better effects in the TPA assay, with best activity for 6, 12 and 15. The cytotoxicity of the compounds 8 and 10 with a free COOH, was higher than that of 2. The derivatives from 3 were less toxic than the triterpene. Several of the new compounds presented better anti-inflammatory effect and lower cytotoxicity than the parent terpenes. PMID:26096431

  17. Correction: Enhanced photocatalytic activity of a self-stabilized synthetic flavin anchored on a TiO2 surface.

    PubMed

    Pandiri, Manjula; Shaham-Waldmann, Nurit; Hossain, Mohammad S; Foss, Frank W; Rajeshwar, Krishnan; Paz, Yaron

    2016-09-14

    Correction for 'Enhanced photocatalytic activity of a self-stabilized synthetic flavin anchored on a TiO2 surface' by Manjula Pandiri et al., Phys. Chem. Chem. Phys., 2016, 18, 18575-18583. PMID:27509005

  18. Molecular shuttles based on motor proteins: active transport in synthetic environments.

    PubMed

    Hess, H; Vogel, V

    2001-11-01

    Active transport in cells, utilizing molecular motors like kinesin and myosin, provides the inspiration for the integration of active transport into synthetic devices. Hybrid devices, employing motor proteins in a synthetic environment, are the first prototypes of molecular shuttles. Here the basic characteristics of motor proteins are discussed from an engineering point of view, and the experiments aimed at incorporating motor proteins, such as myosins and kinesins, into devices are reviewed. The key problems for the construction of a molecular shuttle are: guiding the direction of motion, controlling the speed, and loading and unloading of cargo. Various techniques, relying on surface topography and chemistry as well as flow fields and electric fields, have been developed to guide the movement of molecular shuttles on surfaces. The control of ATP concentration, acting as a fuel supply, can serve as a means to control the speed of movement. The loading process requires the coupling of cargo to the shuttle, ideally by a strong and specific link. Applications of molecular shuttles can be envisioned, e.g. in the field of nano-electro-mechanical systems (NEMS), where scaling laws favor active transport over fluid flow, and in the bottom-up assembly of novel materials.

  19. Lipid-lowering Activity of Natural and Semi-Synthetic Sterols and Stanols.

    PubMed

    Taha, Dhiaa A; Wasan, Ellen K; Wasan, Kishor M; Gershkovich, Pavel

    2015-01-01

    Consumption of plant sterols/ stanols has long been demonstrated to reduce plasma cholesterol levels. The objective of this review is to demonstrate the lipid-lowering activity and anti-atherogenic effects of natural and semi-synthetic plant sterols/ stanols based on evidence from cell-culture studies, animal studies and clinical trials. Additionally, this review highlights certain molecular mechanisms by which plant sterols/ stanols lower plasma cholesterol levels with a special emphasis on factors that affect the cholesterol-lowering activity of plant sterols/stanols. The crystalline nature and the poor oil solubility of these natural products could be important factors that limit their cholesterol-lowering efficiency. Several attempts have been made to improve the cholesterol-lowering activity by enhancing the bioavailability of crystalline sterols and stanols. Approaches involved reduction of the crystal size and/or esterification with fatty acids from vegetable or fish oils. However, the most promising approach in this context is the chemical modification of plant sterols /stanols into water soluble disodium ascorbyl phytostanyl phosphates analogue by esterification with ascorbic acid. This novel semi-synthetic stanol derivative has improved efficacy over natural plant sterols/ stanols and can provide additional benefits by combining the cholesterol-lowering properties of plant stanols with the antioxidant potential of ascorbic acid. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID:26626241

  20. Latent luciferase activity in the fruit fly revealed by a synthetic luciferin

    PubMed Central

    Mofford, David M.; Reddy, Gadarla Randheer; Miller, Stephen C.

    2014-01-01

    Beetle luciferases are thought to have evolved from fatty acyl-CoA synthetases present in all insects. Both classes of enzymes activate fatty acids with ATP to form acyl-adenylate intermediates, but only luciferases can activate and oxidize d-luciferin to emit light. Here we show that the Drosophila fatty acyl-CoA synthetase CG6178, which cannot use d-luciferin as a substrate, is able to catalyze light emission from the synthetic luciferin analog CycLuc2. Bioluminescence can be detected from the purified protein, live Drosophila Schneider 2 cells, and from mammalian cells transfected with CG6178. Thus, the nonluminescent fruit fly possesses an inherent capacity for bioluminescence that is only revealed upon treatment with a xenobiotic molecule. This result expands the scope of bioluminescence and demonstrates that the introduction of a new substrate can unmask latent enzymatic activity that differs significantly from an enzyme’s normal function without requiring mutation. PMID:24616520

  1. Synthetic 3D modeling of active regions and simulation of their multi-wavelength emission

    NASA Astrophysics Data System (ADS)

    Nita, Gelu M.; Fleishman, Gregory; Kuznetsov, Alexey A.; Loukitcheva, Maria A.; Viall, Nicholeen M.; Klimchuk, James A.; Gary, Dale E.

    2015-04-01

    To facilitate the study of solar active regions, we have created a synthetic modeling framework that combines 3D magnetic structures obtained from magnetic extrapolations with simplified 1D thermal models of the chromosphere, transition region, and corona. To handle, visualize, and use such synthetic data cubes to compute multi-wavelength emission maps and compare them with observations, we have undertaken a major enhancement of our simulation tools, GX_Simulator (ftp://sohoftp.nascom.nasa.gov/solarsoft/packages/gx_simulator/), developed earlier for modeling emission from flaring loops. The greatly enhanced, object-based architecture, which now runs on Windows, Mac, and UNIX platform, offers important new capabilities that include the ability to either import 3D density and temperature distribution models, or to assign to each individual voxel numerically defined coronal or chromospheric temperature and densities, or coronal Differential Emission Measure distributions. Due to these new capabilities, the GX_Simulator can now apply parametric heating models involving average properties of the magnetic field lines crossing a given voxel volume, as well as compute and investigate the spatial and spectral properties of radio (to be compared with VLA or EOVSA data), (sub-)millimeter (ALMA), EUV (AIA/SDO), and X-ray (RHESSI) emission calculated from the model. The application integrates shared-object libraries containing fast free-free, gyrosynchrotron, and gyroresonance emission codes developed in FORTRAN and C++, and soft and hard X-ray and EUV codes developed in IDL. We use this tool to model and analyze an active region and compare the synthetic emission maps obtained in different wavelengths with observations.This work was partially supported by NSF grants AGS-1250374, AGS-1262772, NASA grant NNX14AC87G, the Marie Curie International Research Staff Exchange Scheme "Radiosun" (PEOPLE-2011-IRSES-295272), RFBR grants 14-02-91157, 15-02-01089, 15-02-03717, 15

  2. Anti-endotoxin activity of a novel synthetic lipid A analog.

    PubMed

    Kawata, T; Bristol, J R; Rose, J R; Rossignol, D P; Christ, W J; Asano, O; Dubuc, G R; Gavin, W E; Hawkins, L D; Kishi, Y

    1995-01-01

    Lipid As from non-toxic bacteria such as Rhodobacter capsulatus and Rhodobacter sphaeroides have been shown to antagonize the immunostimulatory effects of lipid A and LPS from pathogenic bacteria. We have biologically characterized a series of synthetic LPS antagonists including the proposed structures of the lipid A and R. sphaeroides containing fatty acid side chains ester-linked to the disaccharide backbone, as well as an analog of R. capsulatus lipid A containing ether-linked alkyloxy side chains (E5531). In vitro assays utilizing LPS-stimulated human monocytes or whole blood demonstrated that low nanomolar concentrations of E5531 inhibited cellular activation as indicated by decreased release of the cytokines TNF-a, and interleukins-1, 6, and 8. E5531 also inhibited LPS-induced release of cytokines and nitric oxide from murine macrophages. Synthetic antagonists at up to 100 microM were devoid of agonistic activity in murine and human in vitro systems. In vivo, E5531 blocked induction of TNF-a by LPS and reduced LPS-induced lethality in mice. These in vitro and in vivo results indicate that E5531 may have clinical therapeutic utility as an antagonist of endotoxin-mediated morbidity and mortality.

  3. Infrasound Interferometry for Active and Passive Sources: A Synthetic Example for Waves Refracted in the Stratosphere

    NASA Astrophysics Data System (ADS)

    Fricke, J.; Ruigrok, E. N.; Evers, L. G.; El Allouche, N.; Simons, D.; Wapenaar, C. A.

    2012-12-01

    The travel time of infrasound through the stratosphere depends on the temperature profile and the wind speed. These atmospheric conditions can be estimated by determining the travel times between different receivers (microbarometers). Therefore the determination of the travel time of infrasound between different receivers becomes more and more important. An approach to determine the travel time is infrasound interferometry. In this work, the infrasound interferometry is applied to synthetic data of active and passive sources refracted by the stratosphere is tested. The synthetic data were generated with a raytracing model. The inputs of the raytracing model are the atmospheric conditions and a source wavelet. As source wavelet we used blast waves and microbaroms. With the atmospheric conditions and the source wavelet the raytracing model calculates the raypath and the travel time of the infrasound. In order to simulate the measurement of a receiver the rays which reach the receiver need to be found. The rays which propagate from a source to the receiver are called eigen rays. The simulation of the receiver measurements takes into account the travel time along the eigen rays, the attenuation of the different atmospheric layers, the spreading of the rays and the influence of caustics. The simulated measurements of the different receivers are combined to synthetic barograms. Two synthetic experiments were performed with the described model. In the first experiment the interferometry was applied to barograms of active sources like blast waves. The second experiment with microbaroms tests the applicability of interferometry to barograms of passive sources. In the next step infrasound interferometry will be applied to measured barograms. These barograms are measured with the 'Large Aperture Infrasound Array' (LAIA). LAIA is being installed by the Royal Netherlands Meteorological Institute (KNMI) in the framework of the radio-astronomical 'Low Frequency Array' (LOFAR

  4. Antioxidant and antidepressant-like activities of semi-synthetic α-phenylseleno citronellal.

    PubMed

    Victoria, Francine Novack; Anversa, Roberta; Penteado, Filipe; Castro, Micheli; Lenardão, Eder João; Savegnago, Lucielli

    2014-11-01

    In this study, the antioxidant and antidepressant-like activities of the semi-synthetic compound α-phenylseleno citronellal (PhSeCIT) and the natural terpenoid R-citronellal (CIT) were evaluated. The biological potential of PhSeCIT and CIT was evaluated by antioxidant in vitro assays, such as 1,1-diphenyl-2-picryl-hydrazyl (DPPH), 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS), ferric ion reducing antioxidant power (FRAP) and linoleic acid oxidation. The compounds were also assessed by ex vivo tests to determine the acute toxicity, levels of thiobarbituric acid reactive species (TBARS), δ-aminolevulinate dehydratase (δ-Ala-D) and Na(+)/K(+) ATPase activities. The antidepressant-like activity of compounds in the tail suspension test (TST) and forced swimming test (FST) was also investigated. The results demonstrated that the addition of an organoselenium group to (R)-citronellal increased its antioxidant properties, since PhSeCIT showed better activity than CIT. The treatment of mice with both compounds did not cause death of any animals. The levels of TBARS were significantly reduced by PhSeCIT in liver and cortex of animals, whereas CIT did not alter these parameters. In the TST and FST, PhSeCIT showed promising antidepressant-like activity, while CIT was not active in this test. Taken together, these data demonstrate the role of selenium in the antioxidant and antidepressant-like activities of (R)-citronellal.

  5. Identification of Synthetic Host Defense Peptide Mimics That Exert Dual Antimicrobial and Anti-Inflammatory Activities

    PubMed Central

    Som, Abhigyan; Navasa, Nicolás; Percher, Avital; Scott, Richard W.

    2012-01-01

    A group of synthetic antimicrobial oligomers, inspired by naturally occurring antimicrobial peptides, were analyzed for the ability to modulate innate immune responses to Toll-like receptor (TLR) ligands. These synthetic mimics of antimicrobial peptides (SMAMPs) specifically reduced cytokine production in response to Staphylococcus aureus and the S. aureus component lipoteichoic acid (LTA), a TLR2 agonist. Anti-inflammatory SMAMPs prevented the induction of tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-10 in response to S. aureus or LTA, but no other TLR2 ligands. We show that these SMAMPs bind specifically to LTA in vitro and prevent its interaction with TLR2. Importantly, the SMAMP greatly reduced the induction of TNF and IL-6 in vivo in mice acutely infected with S. aureus while simultaneously reducing bacterial loads dramatically (4 log10). Thus, these SMAMPs can eliminate the damage induced by pathogen-associated molecular patterns (PAMPs) while simultaneously eliminating infection in vivo. They are the first known SMAMPs to demonstrate anti-inflammatory and antibacterial activities in vivo. PMID:22956655

  6. Cargo-towing synthetic nanomachines: towards active transport in microchip devices.

    PubMed

    Wang, Joseph

    2012-05-01

    This review article discusses the use of synthetic catalytic nano motors for cargo manipulations and for developing miniaturized lab-on-chip systems based on autonomous transport. The ability of using chemically-powered artificial nanomotors to capture, transport and release therapeutic payloads or nanostructured biomaterials represents one of the next major prospects for nanomotor development. The increased cargo-towing force of such self-propelled nanomotors, along with their precise motion control within microchannel networks, versatility and facile functionalization, pave the way to new integrated functional lab-on-a-chip powered by active transport and perform a series of tasks. Such use of cargo-towing artificial nanomotors has been inspired by on-chip kinesin molecular shuttles. Functionalized nano/microscale motors can thus be used to pick a selected nano/microscale chemical or biological payload target at the right place, transport and deliver them to a target location in a timely manner. Key challenges for using synthetic nanomachines for driving transport processes along microchannel networks are discussed, including loading and unloading of cargo and precise motion control, along with recent examples of related cargo manipulation processes and guided transport in lab-on-a-chip formats. The exciting research area of cargo-carrying catalytic man-made nanomachines is expected to grow rapidly, to lead to new lab-on-a-chip formats and to provide a wide range of future microchip opportunities.

  7. Activation of "synthetic ambient" aerosols - Relation to chemical composition of particles <100 nm

    NASA Astrophysics Data System (ADS)

    Burkart, J.; Hitzenberger, R.; Reischl, G.; Bauer, H.; Leder, K.; Puxbaum, H.

    2012-07-01

    Cloud condensation nuclei (CCN) are an important fraction of atmospheric aerosols because of their role in cloud formation. Experimental studies focus either on direct field measurements of complex ambient aerosols or laboratory investigations on well defined aerosols produced from single substances or substance mixtures. In this study, we focussed on the ultrafine aerosol because in terms of number concentration, the majority of the CCN are expected to have sizes in this range. A field study was performed from July 2007 to October 2008 to investigate the activation behaviour of the atmospheric aerosol in Vienna (Burkart et al., 2011). Filter samples of the aerosol <0.1 μm aerodynamic equivalent diameter were collected, elutriated and used to generate "synthetic ambient" aerosol in a nebulizer. Chemical analyses of the ultrafine water soluble material were also performed. The CCN properties of the "synthetic ambient" aerosol were obtained using the University of Vienna CCN counter (Giebl et al., 2002; Dusek et al., 2006b) at a nominal supersaturation (SS) of 0.5%. Activation diameters dact ranged from 54.5 nm to 66 nm, were larger than dact of typical single inorganic salts and showed no seasonal pattern in contrast to the fraction of water soluble organic carbon (WSOC), which ranged from 44% in spring to 15% in winter. The average hygroscopicity parameter κ (Petters and Kreidenweis, 2007) obtained from the activation curves ranged from 0.20 to 0.30 (average 0.24), which was significantly lower than κchem calculated from the chemical composition (0.43 ± 0.07).

  8. Antimicrobial and antibiofilm activity of cathelicidins and short, synthetic peptides against Francisella.

    PubMed

    Amer, Lilian S; Bishop, Barney M; van Hoek, Monique L

    2010-05-28

    Francisella infects the lungs causing pneumonic tularemia. Focusing on the lung's host defense, we have examined antimicrobial peptides as part of the innate immune response to Francisella infection. Interest in antimicrobial peptides, such as the cathelicidins, has grown due their potential therapeutic applications and the increasing problem of bacterial resistance to commonly used antibiotics. Only one human cathelicidin, LL-37, has been characterized. Helical cathelicidins have also been discovered in snakes including the Chinese King Cobra, Naja atra (NA-CATH). Four synthetic 11-residue peptides (ATRA-1, -2, -1A and -1P) containing variations of a repeated motif within NA-CATH were designed. We hypothesized that these smaller synthetic peptides could have excellent antimicrobial effectiveness with shorter length (and less cost), making them strong potential candidates for development into broad-spectrum antimicrobial compounds. We tested the susceptibility of F. novicida to four ATRA peptides, LL-37, and NA-CATH. Two of the ATRA peptides had high antimicrobial activity (microM), while the two proline-containing ATRA peptides had low activity. The ATRA peptides did not show significant hemolytic activity even at high peptide concentration, indicating low cytotoxicity against host cells. NA-CATH killed Francisella bacteria more quickly than LL-37. However, LL-37 was the most effective peptide against F. novicida (EC50=50 nM). LL-37 mRNA was induced in A549 cells by Francisella infection. We recently demonstrated that F. novicida forms in vitro biofilms. LL-37 inhibited F. novicida biofilm formation at sub-antimicrobial concentrations. Understanding the properties of these peptides, and their endogenous expression in the lung could lead to potential future therapeutic interventions for this lung infection. PMID:20399752

  9. Enhancement of the aspartame precursor synthetic activity of an organic solvent-stable protease.

    PubMed

    Ogino, Hiroyasu; Tsuchiyama, Shotaro; Yasuda, Masahiro; Doukyu, Noriyuki

    2010-03-01

    The PST-01 protease is highly stable and catalyzes the synthesis of the aspartame precursor with high reaction yields in the presence of organic solvents. However, the synthesis rate using the PST-01 protease was slower than that observed when thermolysin was used. Structural comparison of both enzymes showed particular amino acid differences near the active center. These few residue differences in the PST-01 protease were mutated to match those amino acid types found in thermolysin. The mutated PST-01 proteases at the 114th residue from tyrosine to phenylalanine showed enhancement of synthetic activity. This activity was found to be similar to thermolysin. In addition, mutating the residue in the PST-01 protease with arginine and serine showed more improvement of the activity. The mutant PST-01 protease should be more useful than thermolysin for the synthesis of the aspartame precursor, because this enzyme has higher stability and activity in the presence of organic solvents. The results show the potential of organic solvent-stable enzymes as industrial catalysts.

  10. Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro

    NASA Astrophysics Data System (ADS)

    Dechristopher, Brian A.; Loy, Brian A.; Marsden, Matthew D.; Schrier, Adam J.; Zack, Jerome A.; Wender, Paul A.

    2012-09-01

    Bryostatin is a unique lead in the development of potentially transformative therapies for cancer, Alzheimer's disease and the eradication of HIV/AIDS. However, the clinical use of bryostatin has been hampered by its limited supply, difficulties in accessing clinically relevant derivatives, and side effects. Here, we address these problems through the step-economical syntheses of seven members of a new family of designed bryostatin analogues using a highly convergent Prins-macrocyclization strategy. We also demonstrate for the first time that such analogues effectively induce latent HIV activation in vitro with potencies similar to or better than bryostatin. Significantly, these analogues are up to 1,000-fold more potent in inducing latent HIV expression than prostratin, the current clinical candidate for latent virus induction. This study provides the first demonstration that designed, synthetically accessible bryostatin analogues could serve as superior candidates for the eradication of HIV/AIDS through induction of latent viral reservoirs in conjunction with current antiretroviral therapy.

  11. Larvicidal activity of synthetic disinfectants and antibacterial soaps against mosquito, Culex quinquefasciatus (Diptera: Culicidae).

    PubMed

    Xue, Rui-De; Qualls, Whitney A

    2013-01-01

    Seven commercial synthetic disinfectant and antibacterial soap products were evaluated as mosquito larvicides against Culex quinquefasciatus Say in the laboratory. Three aerosol disinfectant products, at 0.01% concentration resulted in 58-76% mortality of laboratory-reared fourth instar mosquito larvae at 24 h posttreatment. Four antibacterial soap products at 0.0001% concentration resulted in 88-100% larval mortality at 24 h posttreatment. The active ingredient of the antibacterial soap products, triclosan (0.1%) resulted in 74% larval mortality. One of the antibacterial soap products, Equate caused the highest mosquito larval mortality in the laboratory. Equate antibacterial soap at the application rate of 0.000053 ppm resulted in 90% mortality of the introduced fourth instar larvae of Cx. quinquesfasicatus in the outdoor pools. In laboratory and field bioassays, the antibacterial soap resulted in significant larval mosquito mortality.

  12. Larvicidal activity of synthetic disinfectants and antibacterial soaps against mosquito, Culex quinquefasciatus (Diptera: Culicidae).

    PubMed

    Xue, Rui-De; Qualls, Whitney A

    2013-01-01

    Seven commercial synthetic disinfectant and antibacterial soap products were evaluated as mosquito larvicides against Culex quinquefasciatus Say in the laboratory. Three aerosol disinfectant products, at 0.01% concentration resulted in 58-76% mortality of laboratory-reared fourth instar mosquito larvae at 24 h posttreatment. Four antibacterial soap products at 0.0001% concentration resulted in 88-100% larval mortality at 24 h posttreatment. The active ingredient of the antibacterial soap products, triclosan (0.1%) resulted in 74% larval mortality. One of the antibacterial soap products, Equate caused the highest mosquito larval mortality in the laboratory. Equate antibacterial soap at the application rate of 0.000053 ppm resulted in 90% mortality of the introduced fourth instar larvae of Cx. quinquesfasicatus in the outdoor pools. In laboratory and field bioassays, the antibacterial soap resulted in significant larval mosquito mortality. PMID:23427662

  13. Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity

    PubMed Central

    Marr, A. K.; Cen, S.; Hancock, R. E. W.

    2016-01-01

    Leishmania parasites are a major public health problem worldwide. Effective treatment of leishmaniasis is hampered by the high incidence of adverse effects to traditional drug therapy and the emergence of resistance to current therapeutics. A vaccine is currently not available. Host defense peptides have been investigated as novel therapeutic agents against a wide range of pathogens. Here we demonstrate that the antimicrobial peptide LL-37 and the three synthetic peptides E6, L-1018, and RI-1018 exhibit leishmanicidal activity against promastigotes and intramacrophage amastigotes of Leishmania donovani and Leishmania major. We also report that the Leishmania protease/virulence factor GP63 confers protection to Leishmania from the cytolytic properties of all l-form peptides (E6, L-1018, and LL-37) but not the d-form peptide RI-1018. The results suggest that RI-1018, E6, and LL-37 are promising peptides to develop further into components for antileishmanial therapy. PMID:26883699

  14. Preliminary study for active monitoring of the plate boundary using ACROSS: Synthetic and observed seismic records

    NASA Astrophysics Data System (ADS)

    Tsuruga, K.; Kasahara, J.; Hasada, Y.; Kunitomo, T.; Ikuta, R.; Watanabe, T.; Yamaoka, K.; Fujii, N.; Kumazawa, M.; Nagao, H.; Nakajima, T.; Saiga, A.; Satomura, M.

    2005-12-01

    ACROSS (Accurately-Controlled Routinely-Operated Signal System) has been developed for active monitoring of a dynamic state in the Earth's structure (Kumazawa et al., 2000). Since November 2004, we have conducted an array observation of ACROSS signals in Tokai area, central Japan, to identify any seismic reflection (and hopefully its temporal change) from the lower crust and/or subducting Philippine Sea plate (Kasahara et al., 2004). In this report, we show the recent results and discuss the relevance of several arrivals of wave groups to underground structures using the theoretical travel times and synthetic waveforms. The frequency-modulated ACROSS signals (10-20 Hz) have been continuously transmitted from the sources located in Toki city, central Japan (Kunitomo et al., 2005) and received at 22 temporal seismic stations at the offset distance of 40-75 km from the source. We define the transfer function between a source and a receiver as a nine-element second-order tensor, Hjk, where j and k denote directional components of the observed displacement and the excitation force, and r, t and v represent the radial, transverse and vertical components, respectively. We recognized the significant wave groups within the travel time ranges of 10-18 and of 15-23 seconds at 54-74 km offset distance through stacking the data for about 60 days. Such wave groups also appear on the records of a Hi-net station at 57.4km by stacking for 30 days (Yoshida et al., 2004). A 2-D velocity structure model was made for our observation area using seismic exploration records across the central Japan (Iidaka et al., 2003). We calculated both travel times by ray tracing method (Fujie et al., 2000; Kubota et al., 2005), and synthetic seismograms by FDM simulation (Larsen and Schultz, 1995). Comparing the observed time series of Hrr and Hzr to the theoretical travel times and synthetic seismograms, we noticed that the wave groups observed at 61-73 km are well corresponding to the theoretical

  15. Synthetic aperture microwave imaging with active probing for fusion plasma diagnostics

    SciTech Connect

    Shevchenko, Vladimir F.; Freethy, Simon J.; Huang, Billy K.

    2014-08-21

    A Synthetic Aperture Microwave Imaging (SAMI) system has been designed and built to obtain 2-D images at several frequencies from fusion plasmas. SAMI uses a phased array of linearly polarised antennas. The array configuration has been optimised to achieve maximum synthetic aperture beam efficiency. The signals received by antennas are down-converted to the intermediate frequency range and then recorded in a full vector form. Full vector signals allow beam focusing and image reconstruction in both real time and a post-processing mode. SAMI can scan over 16 pre-programmed frequencies in the range of 10-35GHz with a switching time of 300ns. The system operates in 2 different modes simultaneously: both a 'passive' imaging of plasma emission and also an 'active' imaging of the back-scattered signal of the radiation launched by one of the antennas from the same array. This second mode is similar to so-called Doppler backscattering (DBS) reflectometry with 2-D resolution of the propagation velocity of turbulent structures. Both modes of operation show good performance in fusion plasma experiments on Mega Amp Spherical Tokamak (MAST). We have obtained the first ever 2-D images of BXO mode conversion windows. With active probing, first ever turbulence velocity maps have been obtained. We present an overview of the diagnostic and discuss recent results. In contrast to quasi-optical microwave imaging systems SAMI requires neither big aperture viewing ports nor large 2-D detector arrays to achieve the desired imaging resolution. The number of effective 'pixels' of the synthesized image is proportional to the number of receiving antennas squared. Thus only a small number of optimised antennas is sufficient for the majority of applications. Possible implementation of SAMI on ITERand DEMO is discussed.

  16. Prediction of Antimicrobial Activity of Synthetic Peptides by a Decision Tree Model

    PubMed Central

    Lira, Felipe; Perez, Pedro S.; Baranauskas, José A.

    2013-01-01

    Antimicrobial resistance is a persistent problem in the public health sphere. However, recent attempts to find effective substitutes to combat infections have been directed at identifying natural antimicrobial peptides in order to circumvent resistance to commercial antibiotics. This study describes the development of synthetic peptides with antimicrobial activity, created in silico by site-directed mutation modeling using wild-type peptides as scaffolds for these mutations. Fragments of antimicrobial peptides were used for modeling with molecular modeling computational tools. To analyze these peptides, a decision tree model, which indicated the action range of peptides on the types of microorganisms on which they can exercise biological activity, was created. The decision tree model was processed using physicochemistry properties from known antimicrobial peptides available at the Antimicrobial Peptide Database (APD). The two most promising peptides were synthesized, and antimicrobial assays showed inhibitory activity against Gram-positive and Gram-negative bacteria. Colossomin C and colossomin D were the most inhibitory peptides at 5 μg/ml against Staphylococcus aureus and Escherichia coli. The methods described in this work and the results obtained are useful for the identification and development of new compounds with antimicrobial activity through the use of computational tools. PMID:23455341

  17. Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents

    PubMed Central

    Carreño, Leandro J; Saavedra-Ávila, Noemí A; Porcelli, Steven A

    2016-01-01

    Certain types of glycolipids have been found to have remarkable immunomodulatory properties as a result of their ability to activate specific T lymphocyte populations with an extremely wide range of immune effector properties. The most extensively studied glycolipid reactive T cells are known as invariant natural killer T (iNKT) cells. The antigen receptors of these cells specifically recognize certain glycolipids, most notably glycosphingolipids with α-anomeric monosaccharides, presented by the major histocompatibility complex class I-like molecule CD1d. Once activated, iNKT cells can secrete a very diverse array of pro- and anti-inflammatory cytokines to modulate innate and adaptive immune responses. Thus, glycolipid-mediated activation of iNKT cells has been explored for immunotherapy in a variety of disease states, including cancer and a range of infections. In this review, we discuss the design of synthetic glycolipid activators for iNKT cells, their impact on adaptive immune responses and their use to modulate iNKT cell responses to improve immunity against infections and cancer. Current challenges in translating results from preclinical animal studies to humans are also discussed. PMID:27195112

  18. Natural and Synthetic Flavonoids: Structure-Activity Relationship and Chemotherapeutic Potential for the Treatment of Leukemia.

    PubMed

    Menezes, José C J M D S; Orlikova, Barbora; Morceau, Franck; Diederich, Marc

    2016-07-29

    Flavonoids and their derivatives are polyphenolic secondary metabolites with an extensive spectrum of pharmacological activities, including antioxidants, antitumor, anti-inflammatory, and antiviral activities. These flavonoids can also act as chemopreventive agents by their interaction with different proteins and can play a vital role in chemotherapy, suggesting a positive correlation between a lower risk of cancer and a flavonoid-rich diet. These agents interfere with the main hallmarks of cancer by various individual mechanisms, such as inhibition of cell growth and proliferation by arresting the cell cycle, induction of apoptosis and differentiation, or a combination of these mechanisms. This review is an effort to highlight the therapeutic potential of natural and synthetic flavonoids as anticancer agents in leukemia treatment with respect to the structure-activity relationship (SAR) and their molecular mechanisms. Induction of cell death mechanisms, production of reactive oxygen species, and drug resistance mechanisms, including p-glycoprotein efflux, are among the best-described effects triggered by the flavonoid polyphenol family. PMID:26463658

  19. In vitro activity of synthetic tetrahydroindeno[2,1-c]quinolines on Leishmania mexicana.

    PubMed

    Hernández-Chinea, Concepción; Carbajo, Erika; Sojo, Felipe; Arvelo, Francisco; Kouznetsov, Vladimir V; Romero-Bohórquez, Arnold R; Romero, Pedro J

    2015-12-01

    New synthetic compounds based on tetrahydroindenoquinoline structure were evaluated for their in vitro antileishmanial activities. The seven compounds assayed have antiproliferative activities against promastigotes of Leishmania mexicana. Compound 1 and 3 were the most active (IC50 1.0 μg/ml) and showed high selectivity towards the parasite. These compounds were selected to evaluate their effect on promastigote morphology and mitochondrial transmembrane potential as well as on the amastigote capability to survive into macrophages J774 cell line. Whereas compound 1 affected the promastigote cell cycle, compound 3 induced morphological changes and the total collapse of the mitochondrial transmembrane potential, a hallmark of apoptosis. Both compounds also affected the amastigote form of the parasite, decreasing their survival rate in J774 macrophages. Due to the greatest selectivity index, the apparent effect as apoptotic inducer and its sustained inhibition on intracellular amastigote replication, compound 3 is the best candidate to be tested in vivo. This compound is worth considering for the development of new antileishmanial drugs.

  20. Structure-activity relationship of synthetic branched-chain distearoylglycerol (distearin) as protein kinase C activators

    SciTech Connect

    Zhou, Qingzhong; Raynor, R.L.; Wood, M.G. Jr.; Menger, F.M.; Kuo, J.F. )

    1988-09-20

    Several representative branched-chain analogues of distearin (DS) were synthesized and tested for their abilities to activate protein kinase C (PKC) and to compete for the binding of ({sup 3}H)phorbol 12,13-dibutyrate (PDBu) to the enzyme. Substitutions of stearoyl moieties at sn-1 and sn-2 with 8-methylstearate decreased activities on these parameters, relative to those of the parental diacylglycerol DS, a weak PKC activator. Substitutions with 8-butyl, 4-butyl, or 8-phenyl derivatives, on the other hand, increased activities of the resulting analogues to levels comparable to those seen for diolein (DO), a diacylglycerol prototype shown to be a potent PKC activator. Kinetic analysis indicated that 8-methyldistearin (8-MeDS) acted by decreasing, whereas 8-butyldistearin (8-BuDS) and 8-phenyldistearin (8-PhDS) acted by increasing, the affinities of PKC for phosphatidylserine (PS, a phospholipid cofactor) and Ca{sup 2+} compared to the values seen in the absence or presence of DS. The stimulatory effect of 8-BuDS and 8-PhDS on PKC, as DO, was additive to that of 1,2-(8-butyl)distearoylphosphatidylcholine (1,2(8-Bu)DSPC) and, moreover, they abolished the marked inhibition of the enzyme activity caused by high concentrations of 1,2(8-Bu)DSPC. The present findings demonstrated a structure-activity relationship of the branched-chain DS analogues in the regulation of PKC, perhaps related to their abilities to specifically modify interactions of PKC with PS and/or Ca{sup 2+} critically involved in enzyme activation/inactivation.

  1. Regulation of AMP-activated protein kinase by natural and synthetic activators

    PubMed Central

    Grahame Hardie, David

    2015-01-01

    The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is almost universally expressed in eukaryotic cells. While it appears to have evolved in single-celled eukaryotes to regulate energy balance in a cell-autonomous manner, during the evolution of multicellular animals its role has become adapted so that it also regulates energy balance at the whole body level, by responding to hormones that act primarily on the hypothalamus. AMPK monitors energy balance at the cellular level by sensing the ratios of AMP/ATP and ADP/ATP, and recent structural analyses of the AMPK heterotrimer that have provided insight into the complex mechanisms for these effects will be discussed. Given the central importance of energy balance in diseases that are major causes of morbidity or death in humans, such as type 2 diabetes, cancer and inflammatory disorders, there has been a major drive to develop pharmacological activators of AMPK. Many such activators have been described, and the various mechanisms by which these activate AMPK will be discussed. A particularly large class of AMPK activators are natural products of plants derived from traditional herbal medicines. While the mechanism by which most of these activate AMPK has not yet been addressed, I will argue that many of them may be defensive compounds produced by plants to deter infection by pathogens or grazing by insects or herbivores, and that many of them will turn out to be inhibitors of mitochondrial function. PMID:26904394

  2. Regulation of AMP-activated protein kinase by natural and synthetic activators.

    PubMed

    Grahame Hardie, David

    2016-01-01

    The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is almost universally expressed in eukaryotic cells. While it appears to have evolved in single-celled eukaryotes to regulate energy balance in a cell-autonomous manner, during the evolution of multicellular animals its role has become adapted so that it also regulates energy balance at the whole body level, by responding to hormones that act primarily on the hypothalamus. AMPK monitors energy balance at the cellular level by sensing the ratios of AMP/ATP and ADP/ATP, and recent structural analyses of the AMPK heterotrimer that have provided insight into the complex mechanisms for these effects will be discussed. Given the central importance of energy balance in diseases that are major causes of morbidity or death in humans, such as type 2 diabetes, cancer and inflammatory disorders, there has been a major drive to develop pharmacological activators of AMPK. Many such activators have been described, and the various mechanisms by which these activate AMPK will be discussed. A particularly large class of AMPK activators are natural products of plants derived from traditional herbal medicines. While the mechanism by which most of these activate AMPK has not yet been addressed, I will argue that many of them may be defensive compounds produced by plants to deter infection by pathogens or grazing by insects or herbivores, and that many of them will turn out to be inhibitors of mitochondrial function. PMID:26904394

  3. RTA 408, A Novel Synthetic Triterpenoid with Broad Anticancer and Anti-Inflammatory Activity.

    PubMed

    Probst, Brandon L; Trevino, Isaac; McCauley, Lyndsey; Bumeister, Ron; Dulubova, Irina; Wigley, W Christian; Ferguson, Deborah A

    2015-01-01

    Semi-synthetic triterpenoids are antioxidant inflammation modulator (AIM) compounds that inhibit tumor cell growth and metastasis. Compounds in the AIM class bind to Keap1 and attenuate Nrf2 degradation. In the nucleus, Nrf2 increases antioxidant gene expression and reduces pro-inflammatory gene expression. By increasing Nrf2 activity, AIMs reduce reactive oxygen species and inflammation in the tumor microenvironment, which reverses tumor-mediated immune evasion and inhibits tumor growth and metastasis. AIMs also directly inhibit tumor cell growth by modulating oncogenic signaling pathways, such as IKKβ/NF-κB. Here, we characterized the in vitro antioxidant, anti-inflammatory, and anticancer activities of RTA 408, a novel AIM that is currently being evaluated in patients with advanced malignancies. At low concentrations (≤ 25 nM), RTA 408 activated Nrf2 and suppressed nitric oxide and pro-inflammatory cytokine levels in interferon-γ-stimulated RAW 264.7 macrophage cells. At higher concentrations, RTA 408 inhibited tumor cell growth (GI50 = 260 ± 74 nM) and increased caspase activity in tumor cell lines, but not in normal primary human cells. Consistent with the direct effect of AIMs on IKKβ, RTA 408 inhibited NF-κB signaling and decreased cyclin D1 levels at the same concentrations that inhibited cell growth and induced apoptosis. RTA 408 also increased CDKN1A (p21) levels and JNK phosphorylation. The in vitro activity profile of RTA 408 is similar to that of bardoxolone methyl, which was well-tolerated by patients at doses that demonstrated target engagement. Taken together, these data support clinical evaluation of RTA 408 for cancer treatment.

  4. Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

    PubMed Central

    Walther, Frans J.; Waring, Alan J.; Hernandez-Juviel, Jose M.; Gordon, Larry M.; Schwan, Adrian L.; Jung, Chun-Ling; Chang, Yusuo; Wang, Zhengdong; Notter, Robert H.

    2007-01-01

    Background This study examines the surface activity and resistance to phospholipase degradation of a fully-synthetic lung surfactant containing a novel diether phosphonolipid (DEPN-8) plus a 34 amino acid peptide (Mini-B) related to native surfactant protein (SP)-B. Activity studies used adsorption, pulsating bubble, and captive bubble methods to assess a range of surface behaviors, supplemented by molecular studies using Fourier transform infrared (FTIR) spectroscopy, circular dichroism (CD), and plasmon resonance. Calf lung surfactant extract (CLSE) was used as a positive control. Results DEPN-8+1.5% (by wt.) Mini-B was fully resistant to degradation by phospholipase A2 (PLA2) in vitro, while CLSE was severely degraded by this enzyme. Mini-B interacted with DEPN-8 at the molecular level based on FTIR spectroscopy, and had significant plasmon resonance binding affinity for DEPN-8. DEPN-8+1.5% Mini-B had greatly increased adsorption compared to DEPN-8 alone, but did not fully equal the very high adsorption of CLSE. In pulsating bubble studies at a low phospholipid concentration of 0.5 mg/ml, DEPN-8+1.5% Mini-B and CLSE both reached minimum surface tensions <1 mN/m after 10 min of cycling. DEPN-8 (2.5 mg/ml)+1.5% Mini-B and CLSE (2.5 mg/ml) also reached minimum surface tensions <1 mN/m at 10 min of pulsation in the presence of serum albumin (3 mg/ml) on the pulsating bubble. In captive bubble studies, DEPN-8+1.5% Mini-B and CLSE both generated minimum surface tensions <1 mN/m on 10 successive cycles of compression/expansion at quasi-static and dynamic rates. Conclusions These results show that DEPN-8 and 1.5% Mini-B form an interactive binary molecular mixture with very high surface activity and the ability to resist degradation by phospholipases in inflammatory lung injury. These characteristics are promising for the development of related fully-synthetic lipid/peptide exogenous surfactants for treating diseases of surfactant deficiency or dysfunction. PMID

  5. Current Challenges for Modeling Enzyme Active Sites by Biomimetic Synthetic Diiron Complexes

    PubMed Central

    Friedle, Simone; Reisner, Erwin; Lippard, Stephen J.

    2010-01-01

    This tutorial review describes recent progress in modeling the active sites of carboxylate-rich non-heme diiron enzymes that activate dioxygen to carry out several key reactions in nature. The chemistry of soluble methane monooxygenase, which catalyzes the selective oxidation of methane to methanol, is of particular interest for (bio)technological applications. Novel synthetic diiron complexes that mimic structural, and, to a lesser extent, functional features of these diiron enzymes are discussed. The chemistry of the enzymes is also briefly summarized. A particular focus of this review is on models that mimic characteristics of the diiron systems that were previously not emphasized, including systems that contain (i) aqua ligands, (ii) different substrates tethered to the ligand framework, (iii) dendrimers attached to carboxylates to mimic the protein environment, (iv) two N-donors in a syn-orientation with respect to the iron-iron vector, and (v) a N-rich ligand environment capable of accessing oxygenated high-valent diiron intermediates. PMID:20485834

  6. Synthetic models of the active site of catechol oxidase: mechanistic studies.

    PubMed

    Koval, Iryna A; Gamez, Patrick; Belle, Catherine; Selmeczi, Katalin; Reedijk, Jan

    2006-09-01

    The ability of copper proteins to process dioxygen at ambient conditions has inspired numerous research groups to study their structural, spectroscopic and catalytic properties. Catechol oxidase is a type-3 copper enzyme usually encountered in plant tissues and in some insects and crustaceans. It catalyzes the conversion of a large number of catechols into the respective o-benzoquinones, which subsequently auto-polymerize, resulting in the formation of melanin, a dark pigment thought to protect a damaged tissue from pathogens. After the report of the X-ray crystal structure of catechol oxidase a few years earlier, a large number of publications devoted to the biomimetic modeling of its active site appeared in the literature. This critical review (citing 114 references) extensively discusses the synthetic models of this enzyme, with a particular emphasis on the different approaches used in the literature to study the mechanism of the catalytic oxidation of the substrate (catechol) by these compounds. These are the studies on the substrate binding to the model complexes, the structure-activity relationship, the kinetic studies of the catalytic oxidation of the substrate and finally the substrate interaction with (per)oxo-dicopper adducts. The general overview of the recognized types of copper proteins and the detailed description of the crystal structure of catechol oxidase, as well as the proposed mechanisms of the enzymatic cycle are also presented. PMID:16936929

  7. In Vitro Neuroprotective and Anti-Inflammatory Activities of Natural and Semi-Synthetic Spirosteroid Analogues.

    PubMed

    García-Pupo, Laura; Zaldo-Castro, Armando; Exarchou, Vassiliki; Tacoronte-Morales, Juan Enrique; Pieters, Luc; Vanden Berghe, Wim; Nuñez-Figueredo, Yanier; Delgado-Hernández, René

    2016-01-01

    Two spirosteroid analogues were synthesized and evaluated for their in vitro neuroprotective activities in PC12 cells, against glutamate-induced excitotoxicity and mitochondrial damage in glucose deprivation conditions, as well as their anti-inflammatory potential in LPS/IFNγ-stimulated microglia primary cultures. We also evaluated the in vitro anti-excitotoxic and anti-inflammatory activities of natural and endogenous steroids. Our results show that the plant-derived steroid solasodine decreased PC12 glutamate-induced excitotoxicity, but not the cell death induced by mitochondrial damage and glucose deprivation. Among the two synthetic spirosteroid analogues, only the (25R)-5α-spirostan-3,6-one (S15) protected PC12 against ischemia-related in vitro models and inhibited NO production, as well as the release of IL-1β by stimulated primary microglia. These findings provide further insights into the role of specific modifications of the A and B rings of sapogenins for their neuroprotective potential. PMID:27483221

  8. Anti-proliferation activity of synthetic ajoene analogues on cancer cell-lines.

    PubMed

    Kaschula, Catherine H; Hunter, Roger; Hassan, Hassan T; Stellenboom, Nashia; Cotton, Jonathan; Zhai, Xiao Q; Parker, M Iqbal

    2011-03-01

    The ability of garlic preparations to inhibit cancer cell-growth has been attributed to a group of structurally-related organosulfur compounds found in the crushed clove. Historically, interest has centred on three such compounds as allicin, diallyl disulfide and diallyl trisulfide, with less interest on E- and Z-ajoene. A recently developed synthetic route from our laboratory for preparing ajoene analogues allows access to derivatives containing the sulfoxide / vinyl disulfide core whilst varying the terminal end-group functionality. A small library has been synthesized and an advanced lead with p-methoxybenzyl end groups (8) identified. Data on the in vitro anti-proliferation activity of compound (8) is presented here against six cancer cell-lines in comparison with that of Z- and E-ajoene to reveal an enhancement in activity of up to twelvefold. In addition, a modest selectivity is observed for tumour over normal cell-lines of up to threefold. Data on ajoene and its derivatives is presented in the context of chemosensitization in drug-resistance, and ideas on ajoene's mode of action at the molecular level are presented and discussed.

  9. Biological treatment of synthetic wastewater containing 2,4 dichlorophenol (DCP) in an activated sludge unit.

    PubMed

    Kargi, Fikret; Eker, Serkan; Uygur, Ahmet

    2005-08-01

    Chlorophenol compounds present in many chemical industry wastewaters are resistant to biological degradation because of the toxic effects of such compounds on microorganisms. Synthetic wastewater containing different concentrations of 2,4 dichlorophenol (DCP) was subjected to biological treatment in an activated sludge unit. Effects of feed DCP concentration on COD, DCP, and toxicity removals and on sludge volume index were investigated at a constant sludge age of 10 days and hydraulic residence time (HRT) of 25 h. The Resazurin method based on dehydrogenase activity was used for assessment of toxicity for the feed and effluent wastewater. Percent COD, DCP, and toxicity removals decreased and the effluent COD, DCP, and toxicity levels increased with increasing feed DCP concentrations above 150 mgl(-1) because of inhibitory effects of DCP. Biomass concentration in the aeration tank decreased and the sludge volume index (SVI) increased with feed DCP concentrations above 150 mgl(-1) resulting in lower COD and DCP removal rates. The system should be operated at feed DCP concentrations of less than 150 mgl(-1) in order to obtain high COD, DCP, and toxicity removals.

  10. Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B.

    PubMed

    Gallardo-Godoy, Alejandra; Muldoon, Craig; Becker, Bernd; Elliott, Alysha G; Lash, Lawrence H; Huang, Johnny X; Butler, Mark S; Pelingon, Ruby; Kavanagh, Angela M; Ramu, Soumya; Phetsang, Wanida; Blaskovich, Mark A T; Cooper, Matthew A

    2016-02-11

    The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity-toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure-activity and structure-toxicity studies set the stage for further improvements to the polymyxin class of antibiotics.

  11. Synthetic Peptides as cGMP-Independent Activators of cGMP-Dependent Protein Kinase Iα.

    PubMed

    Moon, Thomas M; Tykocki, Nathan R; Sheehe, Jessica L; Osborne, Brent W; Tegge, Werner; Brayden, Joseph E; Dostmann, Wolfgang R

    2015-12-17

    PKG is a multifaceted signaling molecule and potential pharmaceutical target due to its role in smooth muscle function. A helix identified in the structure of the regulatory domain of PKG Iα suggests a novel architecture of the holoenzyme. In this study, a set of synthetic peptides (S-tides), derived from this helix, was found to bind to and activate PKG Iα in a cyclic guanosine monophosphate (cGMP)-independent manner. The most potent S-tide derivative (S1.5) increased the open probability of the potassium channel KCa1.1 to levels equivalent to saturating cGMP. Introduction of S1.5 to smooth muscle cells in isolated, endothelium-denuded cerebral arteries through a modified reversible permeabilization procedure inhibited myogenic constriction. In contrast, in endothelium-intact vessels S1.5 had no effect on myogenic tone. This suggests that PKG Iα activation by S1.5 in vascular smooth muscle would be sufficient to inhibit augmented arterial contractility that frequently occurs following endothelial damage associated with cardiovascular disease. PMID:26687482

  12. Pilot performance and eye movement activity with varying levels of display integration in a synthetic vision cockpit

    NASA Astrophysics Data System (ADS)

    Stark, Julie Michele

    The primary goal of the present study was to investigate the effects of display integration in a simulated commercial aircraft cockpit equipped with a synthetic vision display. Combinations of display integration level (low/high), display view (synthetic vision view/traditional display), and workload (low/high) were presented to each participant. Sixteen commercial pilots flew multiple approaches under IMC conditions in a moderate fidelity fixed-base part-task simulator. Pilot performance data, visual activity, mental workload, and self-report situation awareness were measured. Congruent with the Proximity Compatibility Principle, the more integrated display facilitated superior performance on integrative tasks (lateral and vertical path maintenance), whereas a less integrated display elicited better focus task performance (airspeed maintenance). The synthetic vision displays facilitated superior path maintenance performance under low workload, but these performance gains were not as evident during high workload. The majority of the eye movement findings identified differences in visual acquisition of the airspeed indicator, the glideslope indicator, the localizer, and the altimeter as a function of display integration level or display view. There were more fixations on the airspeed indicator with the more integrated display layout and during high workload trials. There were also more fixations on the glideslope indicator with the more integrated display layout. However, there were more fixations on the localizer with the less integrated display layout. There were more fixations on the altimeter with the more integrated display and with the traditional view. Only a few eye movement differences were produced by the synthetic vision displays; pilots looked at the glideslope indicator and the altimeter less with the synthetic vision view. This supports the notion that utilizing a synthetic vision display should not adversely impact visual acquisition of data. Self

  13. Synthetic Astrobiology

    NASA Technical Reports Server (NTRS)

    Rothschild, Lynn J.

    2015-01-01

    Synthetic biology - the design and construction of new biological parts and systems and the redesign of existing ones for useful purposes - has the potential to transform fields from pharmaceuticals to fuels. Our lab has focused on the potential of synthetic biology to revolutionize all three major parts of astrobiology: Where do we come from? Where are we going? and Are we alone? For the first and third, synthetic biology is allowing us to answer whether the evolutionary narrative that has played out on planet earth is likely to have been unique or universal. For example, in our lab we are re-evolving the biosynthetic pathways of amino acids in order to understand potential capabilities of an early organism with a limited repertoire of amino acids and developing techniques for the recovery of metals from spent electronics on other planetary bodies. In the future synthetic biology will play an increasing role in human activities both on earth, in fields as diverse as human health and the industrial production of novel bio-composites. Beyond earth, we will rely increasingly on biologically-provided life support, as we have throughout our evolutionary history. In order to do this, the field will build on two of the great contributions of astrobiology: studies of the origin of life and life in extreme environments.

  14. Synthetic Astrobiology

    NASA Technical Reports Server (NTRS)

    Rothschild, Lynn J.

    2016-01-01

    Synthetic biology - the design and construction of new biological parts and systems and the redesign of existing ones for useful purposes - has the potential to transform fields from pharmaceuticals to fuels. Our lab has focused on the potential of synthetic biology to revolutionize all three major parts of astrobiology: Where do we come from? Where are we going? and Are we alone? For the first and third, synthetic biology is allowing us to answer whether the evolutionary narrative that has played out on planet earth is likely to have been unique or universal. For example, in our lab we are re-evolving the biosynthetic pathways of amino acids in order to understand potential capabilities of an early organism with a limited repertoire of amino acids and developing techniques for the recovery of metals from spent electronics on other planetary bodies. And what about the limits for life? Can we create organisms that expand the envelope for life? In the future synthetic biology will play an increasing role in human activities both on earth, in fields as diverse as human health and the industrial production of novel bio-composites. Beyond earth, we will rely increasingly on biologically-provided life support, as we have throughout our evolutionary history. In order to do this, the field will build on two of the great contributions of astrobiology: studies of the origin of life and life in extreme environments.

  15. Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B

    PubMed Central

    2016-01-01

    The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity–toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure–activity and structure–toxicity studies set the stage for further improvements to the polymyxin class of antibiotics. PMID:26734854

  16. Light activation of genotoxic components in natural and synthetic crude oils

    SciTech Connect

    Strniste, G.

    1982-01-01

    Undefined components in natural and synthetically-produced petroleums elicit a genotoxic response in cultured mammalian cells after exposure to light. The NUV component of the solar spectrum is the radiation responsible for photochemical transformation. The type(s) of lesion(s) induced in DNA by the photoactivation process is mimetic of FUV light-induced genotoxic lesions (bulky adduct-like) due to the similar sensitizing abilities of either insult in cells deficient in excision repair. Because of their intimate contact with the oil in the various stages associated with the production of shale oil, process waters contain significant quantities of uv-absorbing organic materials. Chemical fractionation of a process water has been achieved using an acid/base extraction scheme and reverse-phase HPLC. Resulting fractions have been assessed for photo-induced genotoxicity using a modification of the Ames/Salmonella bioassay in which NUV light is the source of activation in place of metabolic enzymes. Chemical identification of components in a photoactive peak fraction is in progress employing an additional class fractionation scheme and GC/MS methods.

  17. Simple synthetic method toward solid supported c60 visible light-activated photocatalysts.

    PubMed

    Moor, Kyle J; Kim, Jae-Hong

    2014-01-01

    Solid supported fullerene materials are prepared in aims of creating a fullerene-based photocatalyst that is capable of producing (1)O2 in the aqueous phase. Past studies of using fullerene as a photocatalyst in water have exclusively focused on using water soluble fullerene derivatives and employed sophisticated chemistry to create immobilized fullerene materials. The method presented herein is much less synthetically complex and utilizes pristine fullerene, providing a drastically simpler route to supported fullerene materials and furthering their potential for use in environmental applications. Covalent immobilization was achieved through the nucleophilic addition of a terminal amine (located on a solid support) across a [6,6] fullerene double bond, resulting in attachment directly to C60's cage. Immobilization allowed supported fullerene moieties to produce (1)O2 in water under various illumination conditions and inactivate MS2 bacteriophages. In a water with natural organic matter, supported fullerene materials produced (1)O2 under visible light irradiation without exhibiting significant loss of photocatalytic activity after successive cycling.

  18. Active Vibration Control of an S809 Wind Turbine Blade Using Synthetic Jet Actuators

    NASA Astrophysics Data System (ADS)

    Maldonado, Victor; Boucher, Matthew; Ostman, Rebecca; Amitay, Michael

    2009-11-01

    Active flow control via synthetic jet actuators was implemented to improve the aeroelastic performance of a small scale S809 airfoil wind turbine blade model in a wind tunnel. Blade vibration performance was explored for a range of steady post-stall angles of attack, as well as various unsteady pitching motions for a chord based Reynolds number range of 1.29x10^5 to 3.69x10^5. Blade tip deflection was measured using a pair of calibrated strain gauges mounted at the root of the model. Using flow control, significant vibration reduction was observed for some steady post-stall angles of attack, while for dynamic pitching motions, vibration reduction was more pronounced (for a given angle of attack) on the pitch up motion compared to the pitch down motion of the blade cycle. This effect was attributed to the phenomenon known as dynamic stall, where the shedding of a leading edge vortex during the pitch up motion contributes to elevated values of lift (compared to static angles of attack) and lower values of lift when the blade is pitched down. This effect was also quantified through the use of Particle Image Velocimetry.

  19. Antiparasitic activity of natural and semi-synthetic tirucallane triterpenoids from Schinus terebinthifolius (Anacardiaceae): structure/activity relationships.

    PubMed

    Morais, Thiago R; da Costa-Silva, Thais A; Tempone, Andre G; Borborema, Samanta Etel T; Scotti, Marcus T; de Sousa, Raquel Maria F; Araujo, Ana Carolina C; de Oliveira, Alberto; de Morais, Sérgio Antônio L; Sartorelli, Patricia; Lago, João Henrique G

    2014-05-05

    Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi-synthetic derivatives were investigated against Leishmania (L.) infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC50 values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC50 values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR) data as well as electrospray ionization mass spectrometry (ESI-MS). Additionally, structure-activity relationships were performed using Decision Trees.

  20. Synthetic Active Site Model of the [NiFeSe] Hydrogenase

    PubMed Central

    Wombwell, Claire; Reisner, Erwin

    2015-01-01

    A dinuclear synthetic model of the [NiFeSe] hydrogenase active site and a structural, spectroscopic and electrochemical analysis of this complex is reported. [NiFe(‘S2Se2’)(CO)3] (H2‘S2Se2’=1,2-bis(2-thiabutyl-3,3-dimethyl-4-selenol)benzene) has been synthesized by reacting the nickel selenolate complex [Ni(‘S2Se2’)] with [Fe(CO)3bda] (bda=benzylideneacetone). X-ray crystal structure analysis confirms that [NiFe(‘S2Se2’)(CO)3] mimics the key structural features of the enzyme active site, including a doubly bridged heterobimetallic nickel and iron center with a selenolate terminally coordinated to the nickel center. Comparison of [NiFe(‘S2Se2’)(CO)3] with the previously reported thiolate analogue [NiFe(‘S4’)(CO)3] (H2‘S4’=H2xbsms=1,2-bis(4-mercapto-3,3-dimethyl-2-thiabutyl)benzene) showed that the selenolate groups in [NiFe(‘S2Se2’)(CO)3] give lower carbonyl stretching frequencies in the IR spectrum. Electrochemical studies of [NiFe(‘S2Se2’)(CO)3] and [NiFe(‘S4’)(CO)3] demonstrated that both complexes do not operate as homogenous H2 evolution catalysts, but are precursors to a solid deposit on an electrode surface for H2 evolution catalysis in organic and aqueous solution. PMID:25847470

  1. Anti-Angiogenic and Anti-Metastatic Activity of Synthetic Phosphoethanolamine

    PubMed Central

    Ferreira, Adilson Kleber; Freitas, Vanessa Morais; Levy, Débora; Ruiz, Jorge Luiz Mária; Bydlowski, Sergio Paulo; Rici, Rose Eli Grassi; Filho, Otaviano Mendonça R.; Chierice, Gilberto Orivaldo; Maria, Durvanei Augusto

    2013-01-01

    Background Renal cell carcinoma (RCC) is the most common type of kidney cancer, and represents the third most common urological malignancy. Despite the advent of targeted therapies for RCC and the improvement of the lifespan of patients, its cost-effectiveness restricted the therapeutic efficacy. In a recent report, we showed that synthetic phosphoethanolamine (Pho-s) has a broad antitumor activity on a variety of tumor cells and showed potent inhibitor effects on tumor progress in vivo. Methodology/Principal Findings We show that murine renal carcinoma (Renca) is more sensitive to Pho-s when compared to normal immortalized rat proximal tubule cells (IRPTC) and human umbilical vein endothelial cells (HUVEC). In vitro anti-angiogenic activity assays show that Pho-s inhibits endothelial cell proliferation, migration and tube formation. In addition, Pho-s has anti-proliferative effects on HUVEC by inducing a cell cycle arrest at the G2/M phase. It causes a decrease in cyclin D1 mRNA, VEGFR1 gene transcription and VEGFR1 receptor expression. Pho-s also induces nuclear fragmentation and affects the organization of the cytoskeleton through the disruption of actin filaments. Additionally, Pho-s induces apoptosis through the mitochondrial pathway. The putative therapeutic potential of Pho-s was validated in a renal carcinoma model, on which our remarkable in vivo results show that Pho-s potentially inhibits lung metastasis in nude mice, with a superior efficacy when compared to Sunitinib. Conclusions/Significance Taken together, our findings provide evidence that Pho-s is a compound that potently inhibits lung metastasis, suggesting that it is a promising novel candidate drug for future developments. PMID:23516420

  2. Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

    SciTech Connect

    Soisson, Stephen M.; Parthasarathy, Gopalakrishnan; Adams, Alan D.; Sahoo, Soumya; Sitlani, Ayesha; Sparrow, Carl; Cui, Jisong; Becker, Joseph W.

    2008-07-08

    The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-{angstrom} resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.

  3. Substrate activity of synthetic formyl phosphate in the reaction catalyzed by formyltetrahydrofolate synthetase

    SciTech Connect

    Smithers, G.W.; Jahansouz, H.; Kofron, J.L.; Himes, R.H.; Reed, G.H.

    1987-06-30

    Formyl phosphate, a putative enzyme-bound intermediate in the reaction catalyzed by formyltetrahydrofolate synthetase (EC 6.3.4.3), was synthesized from formyl fluoride and inorganic phosphate, and the product was characterized by /sup 31/P, /sup 1/H, and /sup 13/C nuclear magnetic resonance (NMR). Measurement of hydrolysis rates by /sup 31/P NMR indicates that formyl phosphate is particularly labile, with a half-life of 48 min in a buffered neutral solution at 20 /sup 0/C. At pH 7, hydrolysis occurs with P-O bond cleavage, as demonstrated by /sup 18/O incorporation from H/sub 2//sup 18/O into P/sub i/, while at pH 1 and pH 13 hydrolysis occurs with C-O bond cleavage. The substrate activity of formyl phosphate was tested in the reaction catalyzed by formyltetrahydrofolate synthetase isolated from Clostridium cylindrosporum. Formyl phosphate supports the reaction in both the forward and reverse directions. Thus, N/sup 10/-formyltetrahydrofolate is produced from tetrahydrofolate and formyl phosphate in a reaction mixture that contains enzyme, Mg(II), and ADP, and ATP is produced from formyl phosphate and ADP with enzyme, Mg(II), and tetrahydrofolate present. The requirements for ADP and for tetrahydrofolate as cofactors in these reactions are consistent with previous steady-state kinetic and isotope exchange studies, which demonstrated that all substrate subsites must be occupied prior to catalysis. The k/sub cat/ values for both the forward and reverse directions, with formyl phosphate as the substrate, are much lower than those for the normal forward and reverse reactions. Kinetic analysis of the formyl phosphate supported reactions indicates that the low steady-state rates observed for the synthetic intermediate are most likely due to the sequential nature of the normal reaction.

  4. Synthetic fuel oil effects on microbial activity and nitrogen transformations in soil

    SciTech Connect

    Ward, M.H.; Saylor, G.S.; Luxmoore, R.J.

    1984-12-01

    The effects of a solvent refined coal oil (SRC-II) on microbial processes in a Captina silt loam soil were examined. The soil samples were maintained under environmental conditions favorable for most aerobic microbial activities. Soil was treated with four oil concentrations ranging from 0.2 to 8.6% (wt/wt). Oxygen uptake rates, total viable cell counts, numbers of nitrifying bacteria, and inorganic nitrogen concentrations were monitored before oil addition and at regular intervals for three months thereafter. Organic carbon, total nitrogen, and soil pH were also measured before and after application of the oil. The SRC-II coal oil effected soil processes at all treatment levels. The lowest oil concentration (0.2%) decreased numbers of nitrifying bacteria while increasing total viable cell numbers and net nitrogen mineralization. The higher oil concentrations reduced oxygen uptake rates and total viable cells as well as nitrifier numbers. Soil treated with a 1.7% oil concentration showed significant increases in respiration rates and cell densities after two months, while no significant increases were observed at oil levels of 3.4 and 8.6%. The application of the coal oil to soil samples raised the carbon to nitrogen ratio of the soil. The sum of nitrate and ammonium nitrogen in the oil-treated soils was never significantly lower than the control soil levels, indicating that nitrogen was not limiting to decomposition. However, the toxicity of the oil toward the nitrifying bacteria resulted in an accumulation of ammonium in treated soils. This may affect plant establishment on soils contaminated with a synthetic fuel oil. 104 references, 7 figures, 15 tables.

  5. Multifunctional activities of KSLW synthetic antimicrobial decapeptide: Implications for wound healing

    NASA Astrophysics Data System (ADS)

    Williams, Richard Leroy

    Wound healing is a complex process leading to the maintenance of skin integrity. Stress is known to increase susceptibility to bacterial infection, alter proinflammatory cytokine expression, and delay wound closure. Recently, antimicrobial peptides have generated interest due to their prokaryotic selectivity, decreased microbial resistance and multifunctional roles in wound healing, including fibroblast stimulation, keratinocyte migration and leukocyte migration. The objective of this dissertation project was to evaluate the effect of a synthetic antimicrobial decapeptide (KSLW) on bacterial clearance inflammation, and wound closure during stress-impaired healing. SKH-1 mice were randomly assigned to either control or restraint-stressed (RST) groups. Punch biopsy wounds (3.5 mm in diameter) were created bilaterally on the dorsal skin. Wounds were injected with 50 microL of empty carriers or KSLW prepared in Pluronic-F68, phospholipid micelles, or saline. Bacterial assays of harvested wounds were conducted on BHI agar. Wound closure was determined by photoplanimetry. Cytokine and growth factor mRNA expression was assessed with real-time RT-PCR. Human neutrophil migration assays and checkerboard analyses were performed using Transweli plates, and counting on hemacytometer. Oxidative burst activity was measured by spectrophotometric analysis of 2,7-dichlorofluorescein oxidation. KSLW-treatment resulted in significant reductions in bacterial load among RST mice, with no difference from control after 24h. The effect was sustained 5 days post-wounding, in RST mice treated with KSLW-F68. Temporal analysis of gene induction revealed reversals of stress-induced altered expression of growth factors, proinflammatory cytokines, and chemokines essential for favorable wound healing, at various time points. KSLW-treatment in RST mice demonstrated faster wound closure throughout the stress period. KSLW, at micromolar concentrations, demonstrated a significant effect on neutrophil

  6. A synthetic ecology perspective: How well does behavior of model organisms in the laboratory predict microbial activities in natural habitats?

    DOE PAGES

    Yu, Zheng; Krause, Sascha M. B.; Beck, David A. C.; Chistoserdova, Ludmila

    2016-06-15

    In this perspective article, we question how well model organisms, the ones that are easy to cultivate in the laboratory and that show robust growth and biomass accumulation, reflect the dynamics and interactions of microbial communities observed in nature. Today's -omics toolbox allows assessing the genomic potential of microbes in natural environments in a high-throughput fashion and at a strain-level resolution. However, understanding of the details of microbial activities and of the mechanistic bases of community function still requires experimental validation in simplified and fully controlled systems such as synthetic communities. We have studied methane utilization in Lake Washington sedimentmore » for a few decades and have identified a number of species genetically equipped for this activity. We have also identified cooccurring satellite species that appear to form functional communities together with the methanotrophs. Here, we compare experimental findings from manipulation of natural communities involved in metabolism of methane in this niche with findings from manipulation of synthetic communities assembled in the laboratory of species originating from the same study site, from very simple (two-species) to rather complex (50-species) synthetic communities. We observe some common trends in community dynamics between the two types of communities, toward representation of specific functional guilds. However, we also identify strong discrepancies between the dominant methane oxidizers in synthetic communities compared to natural communities, under similar incubation conditions. Furthermore, these findings highlight the challenges that exist in using the synthetic community approach to modeling dynamics and species interactions in natural communities.« less

  7. A Synthetic Ecology Perspective: How Well Does Behavior of Model Organisms in the Laboratory Predict Microbial Activities in Natural Habitats?

    PubMed Central

    Yu, Zheng; Krause, Sascha M. B.; Beck, David A. C.; Chistoserdova, Ludmila

    2016-01-01

    In this perspective article, we question how well model organisms, the ones that are easy to cultivate in the laboratory and that show robust growth and biomass accumulation, reflect the dynamics and interactions of microbial communities observed in nature. Today’s -omics toolbox allows assessing the genomic potential of microbes in natural environments in a high-throughput fashion and at a strain-level resolution. However, understanding of the details of microbial activities and of the mechanistic bases of community function still requires experimental validation in simplified and fully controlled systems such as synthetic communities. We have studied methane utilization in Lake Washington sediment for a few decades and have identified a number of species genetically equipped for this activity. We have also identified co-occurring satellite species that appear to form functional communities together with the methanotrophs. Here, we compare experimental findings from manipulation of natural communities involved in metabolism of methane in this niche with findings from manipulation of synthetic communities assembled in the laboratory of species originating from the same study site, from very simple (two-species) to rather complex (50-species) synthetic communities. We observe some common trends in community dynamics between the two types of communities, toward representation of specific functional guilds. However, we also identify strong discrepancies between the dominant methane oxidizers in synthetic communities compared to natural communities, under similar incubation conditions. These findings highlight the challenges that exist in using the synthetic community approach to modeling dynamics and species interactions in natural communities. PMID:27379075

  8. Synthetic Molecular Machines for Active Self-Assembly: Prototype Algorithms, Designs, and Experimental Study

    NASA Astrophysics Data System (ADS)

    Dabby, Nadine L.

    behaviors. This class of behaviors includes any behavior where a passive physical system simply does not have enough physical energy to perform the specified tasks in the requisite amount of time. As we will demonstrate and prove, a sufficiently expressive implementation of an "active" molecular self-assembly approach can achieve these behaviors. Using an external source of fuel solves part of the problem, so the system is not "energetically incomplete." But the programmable system also needs to have sufficient expressive power to achieve the specified behaviors. Perhaps surprisingly, some of these systems do not even require Turing completeness to be sufficiently expressive. Building on a large variety of work by other scientists in the fields of DNA nanotechnology, chemistry and reconfigurable robotics, this thesis introduces several research contributions in the context of active self-assembly. We show that simple primitives such as insertion and deletion are able to generate complex and interesting results such as the growth of a linear polymer in logarithmic time and the ability of a linear polymer to treadmill. To this end we developed a formal model for active-self assembly that is directly implementable with DNA molecules. We show that this model is computationally equivalent to a machine capable of producing strings that are stronger than regular languages and, at most, as strong as context-free grammars. This is a great advance in the theory of active self-assembly as prior models were either entirely theoretical or only implementable in the context of macro-scale robotics. We developed a chain reaction method for the autonomous exponential growth of a linear DNA polymer. Our method is based on the insertion of molecules into the assembly, which generates two new insertion sites for every initial one employed. The building of a line in logarithmic time is a first step toward building a shape in logarithmic time. We demonstrate the first construction of a synthetic

  9. Short, Synthetic Cationic Peptides Have Antibacterial Activity against Mycobacterium smegmatis by Forming Pores in Membrane and Synergizing with Antibiotics

    PubMed Central

    Gupta, Kajal; Singh, Sameer; van Hoek, Monique L.

    2015-01-01

    Multicellular organisms are constantly exposed to a multitude of pathogenic microbes. Infection is inhibited in vivo by the innate and adaptive immune system. Mycobacterium species have emerged that are resistant to most antibiotics. We identified several naturally occurring cationic antimicrobial peptides that were active at low micromolar concentrations against Mycobacterium smegmatis. Human-derived cathelicidin LL-37 is well characterized and studied against M. smegmatis; we compared LL-37 with Chinese cobra-derived cathelicidin NA-CATH and mouse cathelicidin (mCRAMP). Two synthetic 11-residue peptides (ATRA-1A and ATRA-2) containing variations of a repeated motif within NA-CATH were tested for their activity against M. smegmatis along with a short synthetic peptide derivative from the human beta-defensin hBD3 (hBD3-Pep4). We hypothesized that these smaller synthetic peptides may demonstrate antimicrobial effectiveness with shorter length (and at less cost), making them strong potential candidates for development into broad-spectrum antimicrobial compounds or use in combination with antibiotics. These peptides have antimicrobial activity with EC50 ranging from 0.05 to 1.88 μg/mL against Mycobacterium smegmatis. The ATRA-1A short peptide was found to be the most effective antimicrobial peptide (AMP) (EC50 = 0.05 μg/mL). High bactericidal activity correlated with bacterial membrane depolarization and permeabilization activities. The efficacy of the peptides was further analyzed through Minimal Inhibitory Concentration (MIC) assays. The MICs were determined by the microdilution method. The peptide mCRAMP showed the best MIC activity at 15.6 μg/mL. Neither of the effective short synthetic peptides demonstrated synergy with the antibiotic rifampicin, although both demonstrated synergy with the cyclic peptide antibiotic polymyxin B. The peptides LL-37 and mCRAMP displayed synergism with rifampicin in MIC assays, whereas antibiotic polymyxin B displayed synergism

  10. Unbiased identification of signal-activated transcription factors by barcoded synthetic tandem repeat promoter screening (BC-STAR-PROM)

    PubMed Central

    Gosselin, Pauline; Rando, Gianpaolo; Fleury-Olela, Fabienne; Schibler, Ueli

    2016-01-01

    The discovery of transcription factors (TFs) controlling pathways in health and disease is of paramount interest. We designed a widely applicable method, dubbed barcorded synthetic tandem repeat promoter screening (BC-STAR-PROM), to identify signal-activated TFs without any a priori knowledge about their properties. The BC-STAR-PROM library consists of ∼3000 luciferase expression vectors, each harboring a promoter (composed of six tandem repeats of synthetic random DNA) and an associated barcode of 20 base pairs (bp) within the 3′ untranslated mRNA region. Together, the promoter sequences encompass >400,000 bp of random DNA, a sequence complexity sufficient to capture most TFs. Cells transfected with the library are exposed to a signal, and the mRNAs that it encodes are counted by next-generation sequencing of the barcodes. This allows the simultaneous activity tracking of each of the ∼3000 synthetic promoters in a single experiment. Here we establish proof of concept for BC-STAR-PROM by applying it to the identification of TFs induced by drugs affecting actin and tubulin cytoskeleton dynamics. BC-STAR-PROM revealed that serum response factor (SRF) is the only immediate early TF induced by both actin polymerization and microtubule depolymerization. Such changes in cytoskeleton dynamics are known to occur during the cell division cycle, and real-time bioluminescence microscopy indeed revealed cell-autonomous SRF–myocardin-related TF (MRTF) activity bouts in proliferating cells. PMID:27601530

  11. Probing the Biomimetic Ice Nucleation Inhibition Activity of Poly(vinyl alcohol) and Comparison to Synthetic and Biological Polymers

    PubMed Central

    2015-01-01

    Nature has evolved many elegant solutions to enable life to flourish at low temperatures by either allowing (tolerance) or preventing (avoidance) ice formation. These processes are typically controlled by ice nucleating proteins or antifreeze proteins, which act to either promote nucleation, prevent nucleation or inhibit ice growth depending on the specific need, respectively. These proteins can be expensive and their mechanisms of action are not understood, limiting their translation, especially into biomedical cryopreservation applications. Here well-defined poly(vinyl alcohol), synthesized by RAFT/MADIX polymerization, is investigated for its ice nucleation inhibition (INI) activity, in contrast to its established ice growth inhibitory properties and compared to other synthetic polymers. It is shown that ice nucleation inhibition activity of PVA has a strong molecular weight dependence; polymers with a degree of polymerization below 200 being an effective inhibitor at just 1 mg.mL–1. Other synthetic and natural polymers, both with and without hydroxyl-functional side chains, showed negligible activity, highlighting the unique ice/water interacting properties of PVA. These findings both aid our understanding of ice nucleation but demonstrate the potential of engineering synthetic polymers as new biomimetics to control ice formation/growth processes PMID:26258729

  12. Unbiased identification of signal-activated transcription factors by barcoded synthetic tandem repeat promoter screening (BC-STAR-PROM).

    PubMed

    Gosselin, Pauline; Rando, Gianpaolo; Fleury-Olela, Fabienne; Schibler, Ueli

    2016-08-15

    The discovery of transcription factors (TFs) controlling pathways in health and disease is of paramount interest. We designed a widely applicable method, dubbed barcorded synthetic tandem repeat promoter screening (BC-STAR-PROM), to identify signal-activated TFs without any a priori knowledge about their properties. The BC-STAR-PROM library consists of ∼3000 luciferase expression vectors, each harboring a promoter (composed of six tandem repeats of synthetic random DNA) and an associated barcode of 20 base pairs (bp) within the 3' untranslated mRNA region. Together, the promoter sequences encompass >400,000 bp of random DNA, a sequence complexity sufficient to capture most TFs. Cells transfected with the library are exposed to a signal, and the mRNAs that it encodes are counted by next-generation sequencing of the barcodes. This allows the simultaneous activity tracking of each of the ∼3000 synthetic promoters in a single experiment. Here we establish proof of concept for BC-STAR-PROM by applying it to the identification of TFs induced by drugs affecting actin and tubulin cytoskeleton dynamics. BC-STAR-PROM revealed that serum response factor (SRF) is the only immediate early TF induced by both actin polymerization and microtubule depolymerization. Such changes in cytoskeleton dynamics are known to occur during the cell division cycle, and real-time bioluminescence microscopy indeed revealed cell-autonomous SRF-myocardin-related TF (MRTF) activity bouts in proliferating cells. PMID:27601530

  13. Probing the Biomimetic Ice Nucleation Inhibition Activity of Poly(vinyl alcohol) and Comparison to Synthetic and Biological Polymers.

    PubMed

    Congdon, Thomas; Dean, Bethany T; Kasperczak-Wright, James; Biggs, Caroline I; Notman, Rebecca; Gibson, Matthew I

    2015-09-14

    Nature has evolved many elegant solutions to enable life to flourish at low temperatures by either allowing (tolerance) or preventing (avoidance) ice formation. These processes are typically controlled by ice nucleating proteins or antifreeze proteins, which act to either promote nucleation, prevent nucleation or inhibit ice growth depending on the specific need, respectively. These proteins can be expensive and their mechanisms of action are not understood, limiting their translation, especially into biomedical cryopreservation applications. Here well-defined poly(vinyl alcohol), synthesized by RAFT/MADIX polymerization, is investigated for its ice nucleation inhibition (INI) activity, in contrast to its established ice growth inhibitory properties and compared to other synthetic polymers. It is shown that ice nucleation inhibition activity of PVA has a strong molecular weight dependence; polymers with a degree of polymerization below 200 being an effective inhibitor at just 1 mg.mL(-1). Other synthetic and natural polymers, both with and without hydroxyl-functional side chains, showed negligible activity, highlighting the unique ice/water interacting properties of PVA. These findings both aid our understanding of ice nucleation but demonstrate the potential of engineering synthetic polymers as new biomimetics to control ice formation/growth processes.

  14. Probing the Biomimetic Ice Nucleation Inhibition Activity of Poly(vinyl alcohol) and Comparison to Synthetic and Biological Polymers.

    PubMed

    Congdon, Thomas; Dean, Bethany T; Kasperczak-Wright, James; Biggs, Caroline I; Notman, Rebecca; Gibson, Matthew I

    2015-09-14

    Nature has evolved many elegant solutions to enable life to flourish at low temperatures by either allowing (tolerance) or preventing (avoidance) ice formation. These processes are typically controlled by ice nucleating proteins or antifreeze proteins, which act to either promote nucleation, prevent nucleation or inhibit ice growth depending on the specific need, respectively. These proteins can be expensive and their mechanisms of action are not understood, limiting their translation, especially into biomedical cryopreservation applications. Here well-defined poly(vinyl alcohol), synthesized by RAFT/MADIX polymerization, is investigated for its ice nucleation inhibition (INI) activity, in contrast to its established ice growth inhibitory properties and compared to other synthetic polymers. It is shown that ice nucleation inhibition activity of PVA has a strong molecular weight dependence; polymers with a degree of polymerization below 200 being an effective inhibitor at just 1 mg.mL(-1). Other synthetic and natural polymers, both with and without hydroxyl-functional side chains, showed negligible activity, highlighting the unique ice/water interacting properties of PVA. These findings both aid our understanding of ice nucleation but demonstrate the potential of engineering synthetic polymers as new biomimetics to control ice formation/growth processes. PMID:26258729

  15. Unbiased identification of signal-activated transcription factors by barcoded synthetic tandem repeat promoter screening (BC-STAR-PROM).

    PubMed

    Gosselin, Pauline; Rando, Gianpaolo; Fleury-Olela, Fabienne; Schibler, Ueli

    2016-08-15

    The discovery of transcription factors (TFs) controlling pathways in health and disease is of paramount interest. We designed a widely applicable method, dubbed barcorded synthetic tandem repeat promoter screening (BC-STAR-PROM), to identify signal-activated TFs without any a priori knowledge about their properties. The BC-STAR-PROM library consists of ∼3000 luciferase expression vectors, each harboring a promoter (composed of six tandem repeats of synthetic random DNA) and an associated barcode of 20 base pairs (bp) within the 3' untranslated mRNA region. Together, the promoter sequences encompass >400,000 bp of random DNA, a sequence complexity sufficient to capture most TFs. Cells transfected with the library are exposed to a signal, and the mRNAs that it encodes are counted by next-generation sequencing of the barcodes. This allows the simultaneous activity tracking of each of the ∼3000 synthetic promoters in a single experiment. Here we establish proof of concept for BC-STAR-PROM by applying it to the identification of TFs induced by drugs affecting actin and tubulin cytoskeleton dynamics. BC-STAR-PROM revealed that serum response factor (SRF) is the only immediate early TF induced by both actin polymerization and microtubule depolymerization. Such changes in cytoskeleton dynamics are known to occur during the cell division cycle, and real-time bioluminescence microscopy indeed revealed cell-autonomous SRF-myocardin-related TF (MRTF) activity bouts in proliferating cells.

  16. Synthetic feeding stimulants enhance insecticide activity against western corn rootworm larvae, Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In behavioral bioassays, the addition of a synthetic feeding stimulant blend improved the efficacy of the insecticide thiamethoxam against neonate western corn rootworm, Diabrotica virgifera virgifera LeConte, larvae. In 4-h bioassays, the concentration of thiamethoxam required for 50% mortality (LC...

  17. An Experimental Study on Active Flow Control Using Synthetic Jet Actuators over S809 Airfoil

    NASA Astrophysics Data System (ADS)

    Gul, M.; Uzol, O.; Akmandor, I. S.

    2014-06-01

    This study investigates the effect of periodic excitation from individually controlled synthetic jet actuators on the dynamics of the flow within the separation and re-attachment regions of the boundary layer over the suction surface of a 2D model wing that has S809 airfoil profile. Experiments are performed in METUWIND's C3 open-loop suction type wind tunnel that has a 1 m × 1 m cross-section test section. The synthetic jet array on the wing consists of three individually controlled actuators driven by piezoelectric diaphragms located at 28% chord location near the mid-span of the wing. In the first part of the study, surface pressure, Constant Temperature Anemometry (CTA) and Particle Image Velocimetry (PIV) measurements are performed over the suction surface of the airfoil to determine the size and characteristics of the separated shear layer and the re-attachment region, i.e. the laminar separation bubble, at 2.3x105 Reynolds number at zero angle of attack and with no flow control as a baseline case. For the controlled case, CTA measurements are carried out under the same inlet conditions at various streamwise locations along the suction surface of the airfoil to investigate the effect of the synthetic jet on the boundary layer properties. During the controlled case experiments, the synthetic jet actuators are driven with a sinusoidal frequency of 1.45 kHz and 300Vp-p. Results of this study show that periodic excitation from the synthetic jet actuators eliminates the laminar separation bubble formed over the suction surface of the airfoil at 2.3x105 Reynolds number at zero angle of attack.

  18. Synthetic cannabinoids: In silico prediction of the cannabinoid receptor 1 affinity by a quantitative structure-activity relationship model.

    PubMed

    Paulke, Alexander; Proschak, Ewgenij; Sommer, Kai; Achenbach, Janosch; Wunder, Cora; Toennes, Stefan W

    2016-03-14

    The number of new synthetic psychoactive compounds increase steadily. Among the group of these psychoactive compounds, the synthetic cannabinoids (SCBs) are most popular and serve as a substitute of herbal cannabis. More than 600 of these substances already exist. For some SCBs the in vitro cannabinoid receptor 1 (CB1) affinity is known, but for the majority it is unknown. A quantitative structure-activity relationship (QSAR) model was developed, which allows the determination of the SCBs affinity to CB1 (expressed as binding constant (Ki)) without reference substances. The chemically advance template search descriptor was used for vector representation of the compound structures. The similarity between two molecules was calculated using the Feature-Pair Distribution Similarity. The Ki values were calculated using the Inverse Distance Weighting method. The prediction model was validated using a cross validation procedure. The predicted Ki values of some new SCBs were in a range between 20 (considerably higher affinity to CB1 than THC) to 468 (considerably lower affinity to CB1 than THC). The present QSAR model can serve as a simple, fast and cheap tool to get a first hint of the biological activity of new synthetic cannabinoids or of other new psychoactive compounds.

  19. Sub-lethal activity of small molecules from natural sources and their synthetic derivatives against biofilm forming nosocomial pathogens.

    PubMed

    Villa, Federica; Villa, Stefania; Gelain, Arianna; Cappitelli, Francesca

    2013-01-01

    Nowadays, the patient safety is seriously jeopardized by the emergence and spread of nosocomial pathogens in the form of biofilm that is resistant to traditional and affordable antimicrobials. Although advances in organic synthesis have extended the lifetime of classic antibiotics through synthetic modifications, the search of innovative antibiofilm compounds from natural sources can provide new templates, novel targets and unique mechanisms that should have advantages over known antimicrobial agents. Testing sub-lethal concentrations of crude extracts and/or isolated compounds from plants and microorganisms is critical to acting on mechanisms subtler than the killing activity, e.g. those influencing the multicellular behavior, offering an elegant way to develop novel antimicrobial-free antibiofilm strategies. Herein we discussed the search and biological activity of small molecules from natural sources and their synthetic derivatives able to modulate biofilm genesis of nosocomial pathogens through non-microbicidal mechanisms (sub-lethal concentrations). The present work offers an overview about the approaches applied to the discovery of lead small molecules including a) conventional drug design methods like screening of chemical compounds obtained from nature and b) computer- aided drug design approaches. Finally, a classification (not exhaustive but representative) based on the natural origin of small molecules and their synthetic derivatives was reported. The information presented in this review should be of interest to a broad range of disciplines and represents an effort to summarize experimental research and advances in this field. PMID:24200356

  20. Aminopyrrolic synthetic receptors for monosaccharides: a class of carbohydrate-binding agents endowed with antibiotic activity versus pathogenic yeasts.

    PubMed

    Nativi, Cristina; Francesconi, Oscar; Gabrielli, Gabriele; De Simone, Irene; Turchetti, Benedetta; Mello, Tommaso; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Buzzini, Pietro; Roelens, Stefano

    2012-04-16

    The biological activity of a set of structurally related aminopyrrolic synthetic receptors for monosaccharides has been tested versus yeast and yeast-like microorganisms and compared to their binding affinity toward mannosides. Antibiotic activity comparable to that of well-known polyene (amphotericin B) or azole (ketoconazole) drugs has been found for some members of the family, along with a general correlation with binding abilities. A systematic structure-activity-affinity investigation shed light on the structural and functional requirements necessary for antibiotic activity and identified the tripodal compound 1 as the most potent compound of the set. Together with toxicity tests and inhibitor localization experiments performed through fluorescence microscopy, these studies led to the characterization of a new class of carbohydrate binding agents possessing antibiotic activity, in which pyrrolic groups precisely structured on a tripodal architecture appear to be responsible for permeability through the cell wall of pathogens, as well as for antibiotic activity inside the cytoplasm.

  1. Quantitative Analysis of Cis-Regulatory Element Activity Using Synthetic Promoters in Transgenic Plants.

    PubMed

    Benn, Geoffrey; Dehesh, Katayoon

    2016-01-01

    Synthetic promoters, introduced stably or transiently into plants, are an invaluable tool for the identification of functional regulatory elements and the corresponding transcription factor(s) that regulate the amplitude, spatial distribution, and temporal patterns of gene expression. Here, we present a protocol describing the steps required to identify and characterize putative cis-regulatory elements. These steps include application of computational tools to identify putative elements, construction of a synthetic promoter upstream of luciferase, identification of transcription factors that regulate the element, testing the functionality of the element introduced transiently and/or stably into the species of interest followed by high-throughput luciferase screening assays, and subsequent data processing and statistical analysis. PMID:27557758

  2. Copper complexes of glycyl-histidyl-lysine and two of its synthetic analogues: chemical behaviour and biological activity.

    PubMed

    Conato, C; Gavioli, R; Guerrini, R; Kozlowski, H; Mlynarz, P; Pasti, C; Pulidori, F; Remelli, M

    2001-05-01

    Copper complex formation equilibria of glycyl-L-histidyl-L-lysine (Gly-His-Lys, GHK) and of two synthetic analogues, where the histidine residue was replaced with a synthetic amino acid (L-spinacine or L-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid), have been carefully investigated using different experimental techniques: potentiometry, solution calorimetry, UV-VIS spectrophotometry, circular dichroism and electron paramagnetic resonance spectroscopies. All the ligands formed complexes having different stoichiometries and stabilities; evidence for the formation of binuclear species is also shown. The structures of the main complexes are discussed. It is suggested that the lateral lysine amino group participates in complex formation, but only at alkaline pH values: at physiological pH this group is protonated and available for possible interactions with cellular receptors. The above tripeptides have been tested for their enzymatic stability in human serum: the synthetic compounds showed no significant degradation for at least 3 h. Finally, their activity as growth factor has been studied in vitro. The two synthetic analogues showed an activity comparable to or even higher than that of GHK, thus suggesting their possible use as additives in cell culture media, even in the presence of serum. Relevant information on the GHK action mechanism as cell growth factor has been obtained: the formation of copper complexes, driven by the first (Gly) residue, appears necessary while the second residue (His) does not appear to play a specific role; the presence of the free side chain of the third residue (Lys) appears to be of fundamental importance. PMID:11325542

  3. Targeting EZH2 methyltransferase activity in ARID1A mutated cancer cells is synthetic lethal

    PubMed Central

    Biter, Benjamin G.; Aird, Katherine M.; Garipov, Azat; Li, Hua; Amatangelo, Michael; Kossenkov, Andrew V.; Schultz, David C.; Liu, Qin; Shih, Ie-Ming; Conejo-Garcia, Jose R.; Speicher, David W.; Zhang, Rugang

    2015-01-01

    ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently has no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated ovarian cancer cells. ARID1A mutational status correlates with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct ARID1A/EZH2 target, which is upregulated by EZH2 inhibition and contributes to the observed synthetic lethality by inhibiting PI3K/AKT signaling. Significantly, EZH2 inhibition causes regression of ARID1A mutated ovarian tumors in vivo. Together, these data demonstrate for the first time a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers. PMID:25686104

  4. Synthetic Molecular Machines for Active Self-Assembly: Prototype Algorithms, Designs, and Experimental Study

    NASA Astrophysics Data System (ADS)

    Dabby, Nadine L.

    behaviors. This class of behaviors includes any behavior where a passive physical system simply does not have enough physical energy to perform the specified tasks in the requisite amount of time. As we will demonstrate and prove, a sufficiently expressive implementation of an "active" molecular self-assembly approach can achieve these behaviors. Using an external source of fuel solves part of the problem, so the system is not "energetically incomplete." But the programmable system also needs to have sufficient expressive power to achieve the specified behaviors. Perhaps surprisingly, some of these systems do not even require Turing completeness to be sufficiently expressive. Building on a large variety of work by other scientists in the fields of DNA nanotechnology, chemistry and reconfigurable robotics, this thesis introduces several research contributions in the context of active self-assembly. We show that simple primitives such as insertion and deletion are able to generate complex and interesting results such as the growth of a linear polymer in logarithmic time and the ability of a linear polymer to treadmill. To this end we developed a formal model for active-self assembly that is directly implementable with DNA molecules. We show that this model is computationally equivalent to a machine capable of producing strings that are stronger than regular languages and, at most, as strong as context-free grammars. This is a great advance in the theory of active self-assembly as prior models were either entirely theoretical or only implementable in the context of macro-scale robotics. We developed a chain reaction method for the autonomous exponential growth of a linear DNA polymer. Our method is based on the insertion of molecules into the assembly, which generates two new insertion sites for every initial one employed. The building of a line in logarithmic time is a first step toward building a shape in logarithmic time. We demonstrate the first construction of a synthetic

  5. [Repellent activity against Aedes aegypti (L.) of formulas based on natural vegetable extracts or synthetic active agents].

    PubMed

    Girgenti, P; Suss, L

    2002-01-01

    A comparison of 5 commercial mosquito repellents was made on adult male and female volunteers in laboratory trials. The products tested in forms of cream or lotion included 4 natural oil formulations (containing citronella, clover, eucalyptus, geranium, lavender, peppermint, sandalwood, thyme, etc.) and 1 synthetic chemical repellent containing 10% KBR 3023). Natural oil products showed essentially poor or no repellency against Ae, aegypti: the protection times were less than or equal to 1 hour. Only the synthetic repellent based on KBR 3023 provided satisfactory defence to human volunteers. PMID:12162118

  6. [Repellent activity against Aedes aegypti (L.) of formulas based on natural vegetable extracts or synthetic active agents].

    PubMed

    Girgenti, P; Suss, L

    2002-01-01

    A comparison of 5 commercial mosquito repellents was made on adult male and female volunteers in laboratory trials. The products tested in forms of cream or lotion included 4 natural oil formulations (containing citronella, clover, eucalyptus, geranium, lavender, peppermint, sandalwood, thyme, etc.) and 1 synthetic chemical repellent containing 10% KBR 3023). Natural oil products showed essentially poor or no repellency against Ae, aegypti: the protection times were less than or equal to 1 hour. Only the synthetic repellent based on KBR 3023 provided satisfactory defence to human volunteers.

  7. Antiviral Activity of Synthetic Aminopyrrolic Carbohydrate Binding Agents: Targeting the Glycans of Viral gp120 to Inhibit HIV Entry.

    PubMed

    Francesconi, Oscar; Nativi, Cristina; Gabrielli, Gabriele; De Simone, Irene; Noppen, Sam; Balzarini, Jan; Liekens, Sandra; Roelens, Stefano

    2015-07-01

    The binding abilities of a set of structurally related aminopyrrolic synthetic receptors for mannosides, endowed with antimycotic activity against yeast and yeast-like pathogens bearing mannoproteins on their cell surface, have been investigated towards the highly mannosylated gp120 and gp41 glycoproteins of the HIV envelope. A pronounced binding interaction with both glycoproteins was observed by SPR for most of the investigated compounds. Comparison of their binding properties towards the glycoproteins with their binding affinities toward mannosides revealed a direct correlation, supporting their role as carbohydrate binding agents (CBAs). Cytostatic activity studies revealed antiproliferative activity dependent on the nature and the structure of compounds. Antiviral activity studies against a broad panel of DNA and RNA viruses showed inhibitory effect against HIV infection of the T-lymphocyte CEM cell line for two compounds, suggesting antiviral activity similar to other CBAs, such as the nonpeptidic pradimicin antibiotics.

  8. Multitasking water-soluble synthetic G-quartets: from preferential RNA-quadruplex interaction to biocatalytic activity.

    PubMed

    Haudecoeur, Romain; Stefan, Loic; Monchaud, David

    2013-09-16

    Natural G-quartets, a cyclic and coplanar array of four guanine residues held together through a Watson-Crick/Hoogsteen hydrogen-bond network, have received recently much attention due to their involvement in G-quadruplex DNA, an alternative higher-order DNA structure strongly suspected to play important roles in key cellular events. Besides this, synthetic G-quartets (SQ), which artificially mimic native G-quartets, have also been widely studied for their involvement in nanotechnological applications (i.e., nanowires, artificial ion channels, etc.). In contrast, intramolecular synthetic G-quartets (iSQ), also named template-assembled synthetic G-quartets (TASQ), have been more sparingly investigated, despite a technological potential just as interesting. Herein, we report on a particular iSQ named (PNA) DOTASQ, which demonstrates very interesting properties in terms of DNA and RNA interaction (notably its selective recognition of quadruplexes according to a bioinspired process) and catalytic activities, through its ability to perform peroxidase-like hemin-mediated oxidations either in an autonomous fashion (i.e., as pre-catalyst for TASQzyme reactions) or in conjunction with quadruplex DNA (i.e., as enhancing agents for DNAzyme processes). These results provide a solid scientific basis for TASQ to be used as multitasking tools for bionanotechnological applications.

  9. Total synthesis of cordatanine, structural reassignment of drymaritin, and anti-inflammatory activity of synthetic precursors.

    PubMed

    Fang, Hsin Wei; Liao, Yu-Ren; Hwang, Tsong-Long; Shieh, Po-Chuen; Lee, Kuo-Hsiung; Hung, Hsin-Yi; Wu, Tian-Shung

    2015-09-15

    In this study, cordatanine, with a canthin-6-one skeleton, was totally synthesized in four steps via a Pictet-Spengler reaction using tryptamine and methyl glyoxylate with a total yield of 8%. The NMR spectra of synthesized cordatanine compared well with those of drymaritin isolated by Hsieh et al., confirming the need to revise the original structural assignment. In addition, kumujian A, a synthetic intermediate, showed significant anti-inflammatory effects, inhibiting both superoxide anion generation (IC50 4.87 μg/mL) and elastase release (IC50 6.29 μg/mL). PMID:26248804

  10. Role of Amphiphilicity in the Design of Synthetic Mimics of Antimicrobial Peptides with Gram-Negative Activity

    PubMed Central

    2013-01-01

    Two new series of aryl SMAMPs (synthetic mimics of antimicrobial peptides) with facially amphiphilic (FA) and disrupted amphiphilic (DA) topologies were designed and synthesized to directly assess the role of amphiphilicity on their antimicrobial activity against Gram-positive and Gram-negative bacteria in closely related structures. The FA SMAMPs displayed broad spectrum antimicrobial activity against both Gram-positive S. aureus and Gram-negative E. coli, whereas the DA SMAMPs, which contained a polar amide bond in between the hydrophobic moieties, only exhibited activity toward S. aureus with increasing hydrophobicity. The integy moment (IW) was used to quantify the amphiphilicity of the SMAMPs and confirmed that it is critical for the design of SMAMPs with Gram-negative activity. PMID:23814644

  11. Correct disulfide pairing is required for the biological activity of crustacean androgenic gland hormone (AGH): synthetic studies of AGH.

    PubMed

    Katayama, Hidekazu; Hojo, Hironobu; Ohira, Tsuyoshi; Ishii, Akira; Nozaki, Takamichi; Goto, Kiyomi; Nakahara, Yuko; Takahashi, Tetsuo; Hasegawa, Yuriko; Nagasawa, Hiromichi; Nakahara, Yoshiaki

    2010-03-01

    Androgenic gland hormone (AGH) of the woodlouse, Armadillidium vulgare, is a heterodimeric glycopeptide. In this study, we synthesized AGH with a homogeneous N-linked glycan using the expressed protein ligation method. Unexpectedly, disulfide bridge arrangement of a semisynthetic peptide differed from that of a recombinant peptide prepared in a baculovirus expression system, and the semisynthetic peptide showed no biological activity in vivo. To confirm that the loss of biological activity resulted from disulfide bond isomerization, AGH with a GlcNAc moiety was chemically synthesized by the selective disulfide formation. This synthetic AGH showed biological activity in vivo. These results indicate that the native conformation of AGH is not the most thermodynamically stable form, and correct disulfide linkages are important for conferring AGH activity. PMID:20092253

  12. Correct disulfide pairing is required for the biological activity of crustacean androgenic gland hormone (AGH): synthetic studies of AGH.

    PubMed

    Katayama, Hidekazu; Hojo, Hironobu; Ohira, Tsuyoshi; Ishii, Akira; Nozaki, Takamichi; Goto, Kiyomi; Nakahara, Yuko; Takahashi, Tetsuo; Hasegawa, Yuriko; Nagasawa, Hiromichi; Nakahara, Yoshiaki

    2010-03-01

    Androgenic gland hormone (AGH) of the woodlouse, Armadillidium vulgare, is a heterodimeric glycopeptide. In this study, we synthesized AGH with a homogeneous N-linked glycan using the expressed protein ligation method. Unexpectedly, disulfide bridge arrangement of a semisynthetic peptide differed from that of a recombinant peptide prepared in a baculovirus expression system, and the semisynthetic peptide showed no biological activity in vivo. To confirm that the loss of biological activity resulted from disulfide bond isomerization, AGH with a GlcNAc moiety was chemically synthesized by the selective disulfide formation. This synthetic AGH showed biological activity in vivo. These results indicate that the native conformation of AGH is not the most thermodynamically stable form, and correct disulfide linkages are important for conferring AGH activity.

  13. The synthetic cationic lipid diC14 activates a sector of the Arabidopsis defence network requiring endogenous signalling components.

    PubMed

    Cambiagno, Damián Alejandro; Lonez, Caroline; Ruysschaert, Jean-Marie; Alvarez, María Elena

    2015-12-01

    Natural and synthetic elicitors have contributed significantly to the study of plant immunity. Pathogen-derived proteins and carbohydrates that bind to immune receptors, allow the fine dissection of certain defence pathways. Lipids of a different nature that act as defence elicitors, have also been studied, but their specific effects have been less well characterized, and their receptors have not been identified. In animal cells, nanoliposomes of the synthetic cationic lipid 3-tetradecylamino-tert-butyl-N-tetradecylpropionamidine (diC14) activate the TLR4-dependent immune cascade. Here, we have investigated whether this lipid induces Arabidopsis defence responses. At the local level, diC14 activated early and late defence gene markers (FRK1, WRKY29, ICS1 and PR1), acting in a dose-dependent manner. This lipid induced the salicylic acid (SA)-dependent, but not jasmonic acid (JA)-dependent, pathway and protected plants against Pseudomonas syringae pv. tomato (Pst), but not Botrytis cinerea. diC14 was not toxic to plant or pathogen, and potentiated pathogen-induced callose deposition. At the systemic level, diC14 induced PR1 expression and conferred resistance against Pst. diC14-induced defence responses required the signalling protein EDS1, but not NDR1. Curiously, the lipid-induced defence gene expression was lower in the fls2/efr/cerk1 triple mutant, but still unchanged in the single mutants. The amidine headgroup and chain length were important for its activity. Given the robustness of the responses triggered by diC14, its specific action on a defence pathway and the requirement for well-known defence components, this synthetic lipid is emerging as a useful tool to investigate the initial events involved in plant innate immunity.

  14. Anti-NF-κB and Anti-inflammatory Activities of Synthetic Isothiocyanates: effect of chemical structures and cellular signaling

    PubMed Central

    Prawan, Auemduan; Saw, Constance Lay Lay; Khor, Tin Oo; Keum, Young-Sam; Yu, Siwang; Hu, Longqin; Kong, Ah-Ng

    2009-01-01

    Many cancer chemopreventive agents have been associated with lower cancer risk by suppressing nuclear factor-κB (NF-κB) signaling pathways, which subsequently leads to attenuated pro-inflammatory mediators and activities. Of the natural compounds, the isothiocyanates (ITCs) found in cruciferous vegetables have received particular attention because of their potential anti-cancer effects. However, limited studies regarding the influence of ITCs structure on NF-κB transactivation and anti-inflammatory action are reported. In the present study, the anti-inflammatory potential of ten structurally divergent synthetic ITCs were evaluated in HT-29-N9 human colon cancer cells and RAW 264.7 murine macrophages. The effect of ITCs on the basal transcriptional activation of NF-κB and the inflammatory response to bacterial lipopolysaccharide (LPS) were assessed. The synthetic ITC analogs suppressed NF-κB-mediated pro-inflammatory gene transcription. Among the ITC analogs, tetrahydrofurfuryl isothiocyanate, methyl-3-isothiocyanatopropionate, 3-morpholinopropyl isothiocyanate and 3,4-methyelendioxybenzyl isothiocyanate showed stronger NF-κB inhibition as compared to the parent compound, phenylethyl isothiocyanate (PEITC). Molecular analysis revealed that several of the pro-inflammatory mediators and cytokines (iNOS, COX-2, IL-1β , IL-6 and TNF-α ,) were reduced by ITCs, and correlated with the downregulation of NF-κB signaling pathways. Immunoblotting showed that ITCs suppressed LPS-induced phosphorylation and degradation of IκBα and decreased nuclear translocation of p65. In parallel, ITCs suppressed the phosphorylation of IκB kinase α /β (IKKα /β ). Taken together, our findings provide the possibility that synthetic ITC analogs might have promising cancer chemopreventive potential, based on their stronger anti-NF-κB and anti-inflammatory activities, than the natural ITCs. PMID:19159619

  15. Nanoparticles That Sense Thrombin Activity As Synthetic Urinary Biomarkers of Thrombosis

    PubMed Central

    2013-01-01

    Thrombin is a serine protease and regulator of hemostasis that plays a critical role in the formation of obstructive blood clots, or thrombosis, that is a life-threatening condition associated with numerous diseases such as atherosclerosis and stroke. To detect thrombi in living animals, we design and conjugate thrombin-sensitive peptide substrates to the surface of nanoparticles. Following intravenous infusion, these “synthetic biomarkers” survey the host vasculature for coagulation and, in response to substrate cleavage by thrombin, release ligand-encoded reporters into the host urine. To detect the urinary reporters, we develop a companion 96-well immunoassay that utilizes antibodies to bind specifically to the ligands, thus capturing the reporters for quantification. Using a thromboplastin-induced mouse model of pulmonary embolism, we show that urinary biomarker levels differentiate between healthy and thrombotic states and correlate closely with the aggregate burden of clots formed in the lungs. Our results demonstrate that synthetic biomarkers can be engineered to sense vascular diseases remotely from the urine and may allow applications in point-of-care diagnostics. PMID:24015809

  16. Active Control of Separation on a Low Reynolds Number Airfoil Using Synthetic Jet Actuation

    NASA Astrophysics Data System (ADS)

    Feero, Mark

    Wind tunnel experiments were used to study the effect of excitation amplitude and frequency on flow separation using synthetic jet actuation. A synthetic jet actuator was located near the leading edge of a NACA0025 airfoil at a chord-based Reynolds number of 100,000 and angle-of-attack of 10°. Under these flow conditions, the boundary layer separated from the suction surface and failed to reattach. Low-frequency excitation was used to target flow instabilities, while high-frequency excitation was performed at time scales an order of magnitude smaller. Low-frequency excitation at the separated shear layer frequency was found to be the most effective technique for flow reattachment and drag reduction. The results suggested that flow reattachment depended on exceeding a threshold momentum coefficient that varied with excitation frequency. Furthermore, a local minimum in drag independent of excitation frequency was achieved when the momentum coefficient corresponded to an average jet velocity that matched the freestream velocity.

  17. Active flow control of subsonic flow in an adverse pressure gradient using synthetic jets and passive micro flow control devices

    NASA Astrophysics Data System (ADS)

    Denn, Michael E.

    Several recent studies have shown the advantages of active and/or passive flow control devices for boundary layer flow modification. Many current and future proposed air vehicles have very short or offset diffusers in order to save vehicle weight and create more optimal vehicle/engine integration. Such short coupled diffusers generally result in boundary layer separation and loss of pressure recovery which reduces engine performance and in some cases may cause engine stall. Deployment of flow control devices can alleviate this problem to a large extent; however, almost all active flow control devices have some energy penalty associated with their inclusion. One potential low penalty approach for enhancing the diffuser performance is to combine the passive flow control elements such as micro-ramps with active flow control devices such as synthetic jets to achieve higher control authority. The goal of this dissertation is twofold. The first objective is to assess the ability of CFD with URANS turbulence models to accurately capture the effects of the synthetic jets and micro-ramps on boundary layer flow. This is accomplished by performing numerical simulations replicating several experimental test cases conducted at Georgia Institute of Technology under the NASA funded Inlet Flow Control and Prediction Technologies Program, and comparing the simulation results with experimental data. The second objective is to run an expanded CFD matrix of numerical simulations by varying various geometric and other flow control parameters of micro-ramps and synthetic jets to determine how passive and active control devices interact with each other in increasing and/or decreasing the control authority and determine their influence on modification of boundary layer flow. The boundary layer shape factor is used as a figure of merit for determining the boundary layer flow quality/modification and its tendency towards separation. It is found by a large number of numerical experiments and

  18. In vitro activity of CD4+ and CD8+ T lymphocytes from mice immunized with a synthetic malaria peptide.

    PubMed Central

    Rénia, L; Marussig, M S; Grillot, D; Pied, S; Corradin, G; Miltgen, F; Del Giudice, G; Mazier, D

    1991-01-01

    In previous work, a T-helper epitope was mapped within the circumsporozoite protein of the murine malaria parasite Plasmodium yoelii. A 21-mer synthetic peptide corresponding to this epitope (amino acid positions 59-79; referred to as Py1) induced a specific T-cell proliferation in BALB/c and C57BL/6 mice and provided help for the production of antibodies to peptides from the repetitive region, (Gln-Gly-Pro-Gly-Ala-Pro)n, of the P. yoelii circumsporozoite protein when mice were immunized with the Py1 peptide conjugated to the repetitive peptide. Experiments were then designed to study the in vitro antiparasite efficacy of T cells elicited in vivo by peptide immunization. T-cell activity was evaluated on cultured hepatic stages of P. yoelii. Peptide immunizations led to the preferential activation of CD8+ T cells in BALB/c mice and of both CD4+ and CD8+ T cells in C57BL/6 mice. Parasite elimination was mediated directly by these cells and did not seem to be dependent on lymphokine secretion. These data suggest that peptide-primed CD4+ T cells as well as CD8+ T cells could be cytolytic for the hepatic phase of malaria parasites. The fact that the same peptide could activate different lymphocyte populations, depending on the strain of mouse, highlights the importance of a better understanding of the fine mechanisms behind the immune responses to synthetic peptides being tested for malaria vaccine development. Images PMID:1680235

  19. A library of synthetic transcription activator-like effector-activated promoters for coordinated orthogonal gene expression in plants

    PubMed Central

    Brückner, Kathleen; Schäfer, Petra; Weber, Ernst; Grützner, Ramona; Marillonnet, Sylvestre; Tissier, Alain

    2015-01-01

    A library of synthetic promoters containing the binding site of a single designer transcription activator-like effector (dTALE) was constructed. The promoters contain a constant sequence, consisting of an 18-base long dTALE-binding site and a TATA box, flanked by degenerate sequences of 49 bases downstream and 19 bases upstream. Forty-three of these promoters were sequenced and tested in transient assays in Nicotiana benthamiana using a GUS reporter gene. The strength of expression of the promoters ranged from around 5% to almost 100% of the viral 35S promoter activity. We then demonstrated the utility of these promoters for metabolic engineering by transiently expressing three genes for the production of a plant diterpenoid in N. benthamiana. The simplicity of the promoter structure shows great promise for the development of genetic circuits, with wide potential applications in plant synthetic biology and metabolic engineering. PMID:25846505

  20. Cytolytic and antibacterial activity of synthetic peptides derived from amoebapore, the pore-forming peptide of Entamoeba histolytica.

    PubMed Central

    Leippe, M; Andrä, J; Müller-Eberhard, H J

    1994-01-01

    The pore-forming peptide amoebapore is considered part of the cytolytic armament of pathogenic Entamoeba histolytica. Amoebapore is composed of 77 amino acid residues arranged in four alpha-helical domains. For structure-function analysis, synthetic peptides were constructed corresponding to these four domains: H1 (residues 1-22), H2 (25-39), H3 (40-64), and H4 (67-77). The peptides H1 and H3, representing two highly amphipathic alpha-helical regions of amoebapore, possessed pore-forming activity. Peptide H3 displayed cytolytic and antibacterial functions similar to those of natural amoebapore. The most potent antibacterial activity and the broadest activity spectrum were expressed by H1-Mel, a hybrid molecule composed of the N-terminal alpha-helix of amoebapore and the C-terminal hexapeptide of melittin from the venom of Apis mellifera. Images PMID:8146160

  1. Forward Modeling of Synthetic EUV/SXR Emission from Solar Coronal Active Regions: Case of AR 11117

    NASA Astrophysics Data System (ADS)

    Airapetian, V. S.; Allred, J.

    2015-01-01

    Recent progress in obtaining high spatial resolution images of the solar corona in the extreme-ultraviolet (EUV) with Hinode, TRACE, SDO and recent Hi-C missions and soft X-ray (SXR) bands opened a new avenue in understanding the solar coronal heating, the major goal of solar physics. The data from EUV/SXR missions suggest that solar corona is a non-uniform environment structured into active regions (AR) represented by bundles magnetic loops heated to temperatures exceeding 5 MK. Any viable coronal heating model should be capable of reproducing EUV and SXR emission from coronal active regions well as dynamic activity. Measurements of emission measures (EM) for ARs provide clues to time dependence of the heating mechanism: static versus impulsive. While static equilibrium coronal loop models are successful in reproducing SXR emission within an AR, they cannot adequately predict the bright EUV loops. Meantime, impulsive heating is capable in reproducing both EUV and SXR loop emission. The major goal of this paper is to construct realistic synthetic EM images of specific solar corona active region, AR 11117 by using our 1D fully non-linear time-dependent single-fluid hydrodynamic code. We first construct a magnetic skeleton for the entire active region using the HMI/SDO magnetogram for AR 11117 and populate magnetic field lines with plasma. We then parametrically specify impulsive heating of individual strands (flux tubes) comprising coronal loops. Next, we simulated the response of the entire active region (with LOS projection effects) to the heating function (volumetric heating rate) scaled with magnetic field and spatial scale parameters and find the best match between synthetic and actual (reconstructed) DEMs obtained by SDO.

  2. Synthetic Polymers Active against Clostridium difficile Vegetative Cell Growth and Spore Outgrowth

    PubMed Central

    2015-01-01

    Nylon-3 polymers (poly-β-peptides) have been investigated as synthetic mimics of host-defense peptides in recent years. These polymers are attractive because they are much easier to synthesize than are the peptides themselves, and the polymers resist proteolysis. Here we describe in vitro analysis of selected nylon-3 copolymers against Clostridium difficile, an important nosocomial pathogen that causes highly infectious diarrheal disease. The best polymers match the human host-defense peptide LL-37 in blocking vegetative cell growth and inhibiting spore outgrowth. The polymers and LL-37 were effective against both the epidemic 027 ribotype and the 012 ribotype. In contrast, neither vancomycin nor nisin inhibited outgrowth for the 012 ribotype. The best polymer was less hemolytic than LL-37. Overall, these findings suggest that nylon-3 copolymers may be useful for combatting C. difficle. PMID:25279431

  3. Cardiomyocytes In Vitro Adhesion Is Actively Influenced by Biomimetic Synthetic Peptides for Cardiac Tissue Engineering

    PubMed Central

    Huerta-Cantillo, Rocio; Comisso, Marina; Danesin, Roberta; Ghezzo, Francesca; Naso, Filippo; Gastaldello, Alessandra; Schittullo, Eleonora; Buratto, Edward; Spina, Michele; Gerosa, Gino; Dettin, Monica

    2012-01-01

    Scaffolds for tissue engineering must be designed to direct desired events such as cell attachment, growth, and differentiation. The incorporation of extracellular matrix-derived peptides into biomaterials has been proposed to mimic biochemical signals. In this study, three synthetic fragments of fibronectin, vitronectin, and stromal-derived factor-1 were investigated for the first time as potential adhesive sequences for cardiomyocytes (CMs) compared to smooth muscle cells. CMs are responsive to all peptides to differing degrees, demonstrating the existence of diverse adhesion mechanisms. The pretreatment of nontissue culture well surfaces with the (Arginine-Glycine-Aspartic Acid) RGD sequence anticipated the appearance of CMs' contractility compared to the control (fibronectin-coated well) and doubled the length of cell viability. Future prospects are the inclusion of these sequences into biomaterial formulation with the improvement in cell adhesion that could play an important role in cell retention during dynamic cell seeding. PMID:22011064

  4. Facile and novel synthetic method to prepare nano molybdenum and its catalytic activity.

    PubMed

    Sam Jaikumar, Sugumaran; Yuvakkumar, Rathinam; Suriya Prabha, Rangaraj; Karunakaran, Gopalu; Rajendran, Venkatachalam; Hong, Sun Ig

    2015-08-01

    This study reports on a facile and economical synthetic method to prepare nano molybdenum by solid-state reaction technique. Metallic nano molybdenum was synthesised from molybdenum trioxide, molybdenum IV oxide and molybdenum VI oxide through thermal decomposition technique. Metallic nano molybdenum prepared from molybdenum IV oxide was used to study the catalytic effect of molybdenum nanoparticles on the growth of Anabaena sp. The increase in concentration of nano molybdenum from 0.1 to 100% in BG11 (N⁻ Mo⁻ + nano Mo) medium increases heterocyst frequency. The chlorophyll and protein content in Anabaena sp. was found to improve when compared with bulk molybdenum particles and showed a positive influence to be used as a nano nutrient for Anabaena sp. PMID:26224349

  5. Facile and novel synthetic method to prepare nano molybdenum and its catalytic activity.

    PubMed

    Sam Jaikumar, Sugumaran; Yuvakkumar, Rathinam; Suriya Prabha, Rangaraj; Karunakaran, Gopalu; Rajendran, Venkatachalam; Hong, Sun Ig

    2015-08-01

    This study reports on a facile and economical synthetic method to prepare nano molybdenum by solid-state reaction technique. Metallic nano molybdenum was synthesised from molybdenum trioxide, molybdenum IV oxide and molybdenum VI oxide through thermal decomposition technique. Metallic nano molybdenum prepared from molybdenum IV oxide was used to study the catalytic effect of molybdenum nanoparticles on the growth of Anabaena sp. The increase in concentration of nano molybdenum from 0.1 to 100% in BG11 (N⁻ Mo⁻ + nano Mo) medium increases heterocyst frequency. The chlorophyll and protein content in Anabaena sp. was found to improve when compared with bulk molybdenum particles and showed a positive influence to be used as a nano nutrient for Anabaena sp.

  6. Synthetic polymers active against Clostridium difficile vegetative cell growth and spore outgrowth.

    PubMed

    Liu, Runhui; Suárez, Jose M; Weisblum, Bernard; Gellman, Samuel H; McBride, Shonna M

    2014-10-15

    Nylon-3 polymers (poly-β-peptides) have been investigated as synthetic mimics of host-defense peptides in recent years. These polymers are attractive because they are much easier to synthesize than are the peptides themselves, and the polymers resist proteolysis. Here we describe in vitro analysis of selected nylon-3 copolymers against Clostridium difficile, an important nosocomial pathogen that causes highly infectious diarrheal disease. The best polymers match the human host-defense peptide LL-37 in blocking vegetative cell growth and inhibiting spore outgrowth. The polymers and LL-37 were effective against both the epidemic 027 ribotype and the 012 ribotype. In contrast, neither vancomycin nor nisin inhibited outgrowth for the 012 ribotype. The best polymer was less hemolytic than LL-37. Overall, these findings suggest that nylon-3 copolymers may be useful for combatting C. difficle. PMID:25279431

  7. Neutralization of the haemorrhagic activities of viperine snake venoms and venom metalloproteinases using synthetic peptide inhibitors and chelators.

    PubMed

    Howes, J-M; Theakston, R D G; Laing, G D

    2007-04-01

    Envenoming by the West African saw-scaled viper, Echis ocellatus resembles that of most vipers, in that it results in local blistering, necrosis and sometimes life-threatening systemic haemorrhage. While effective against systemic envenoming, current antivenoms have little or no effect against local tissue damage. The major mediators of local venom pathology are the zinc-dependant snake venom metalloproteinases (SVMPs). The high degree of structural and functional homology between SVMPs and their mammalian relatives the matrix metalloproteinases (MMPs) suggests that substrate/inhibitor interactions between these subfamilies are likely to be analogous. In this study, four recently developed MMP inhibitors (MMPIs) (Marimastat, AG-3340, CGS-270 23A and Bay-12 9566) are evaluated in addition to three metal ion chelators (EDTA, TPEN and BAPTA) for their ability to inhibit the haemorrhagic activities of the medically important E. ocellatus venom and one of its haemorrhagic SVMPs, EoVMP2. As expected, the metal ion chelators significantly inhibited the haemorrhagic activities of both whole E. ocellatus venom and EoVMP2, while the synthetic MMPIs show more variation in their efficacies. These variations suggest that individual MMPIs show specificity towards SVMPs and that their application to the neutralization of local haemorrhage may require a synthetic MMPI mixture, ensuring that a close structural component for each SVMP is represented. PMID:17196631

  8. Three novel synthetic retinoids, Re 80, Am 580 and Am 80, all exhibit anti-angiogenic activity in vivo.

    PubMed

    Oikawa, T; Okayasu, I; Ashino, H; Morita, I; Murota, S; Shudo, K

    1993-11-01

    In a previous study, we demonstrated that retinoic acid or a synthetic retinoid, Ch 55 ((E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid), significantly affects in vivo angiogenesis, on the basis of our working hypothesis that a cell differentiation modulator could also exhibit anti-angiogenic activity. In the present study, three novel synthetic retinoids, Re 80 (4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl- 2- naphthalenyl)-1-propenyl]benzoic acid), Am 580 (4-[(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid) and Am 80 (4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl] benzoic acid), whose cell differentiation-modulating effects are roughly comparable to or more potent than that of Ch 55, which was the most effective angiostatic retinoid identified previously, were examined. Their anti-angiogenic effects were tested in an in vivo assay system involving chorioallantoic membranes of growing chick embryos. They were all found to exert dose-dependent anti-angiogenic effects in the picomolar range. Their rank order for inhibitory potency was Re 80 > Am 580 > Am 80, the ID50 values being 6.3, 23 and 28 pmol/egg, respectively. These results indicate that treatment involving these three novel synthetic retinoids might have potential therapeutic efficacy in various angiogenesis-dependent disorders, including solid tumors, psoriasis, rheumatoid arthritis and diabetic retinopathy.

  9. DBAASP v.2: an enhanced database of structure and antimicrobial/cytotoxic activity of natural and synthetic peptides

    PubMed Central

    Pirtskhalava, Malak; Gabrielian, Andrei; Cruz, Phillip; Griggs, Hannah L.; Squires, R. Burke; Hurt, Darrell E.; Grigolava, Maia; Chubinidze, Mindia; Gogoladze, George; Vishnepolsky, Boris; Alekseev, Vsevolod; Rosenthal, Alex; Tartakovsky, Michael

    2016-01-01

    Antimicrobial peptides (AMPs) are anti-infectives that may represent a novel and untapped class of biotherapeutics. Increasing interest in AMPs means that new peptides (natural and synthetic) are discovered faster than ever before. We describe herein a new version of the Database of Antimicrobial Activity and Structure of Peptides (DBAASPv.2, which is freely accessible at http://dbaasp.org). This iteration of the database reports chemical structures and empirically-determined activities (MICs, IC50, etc.) against more than 4200 specific target microbes for more than 2000 ribosomal, 80 non-ribosomal and 5700 synthetic peptides. Of these, the vast majority are monomeric, but nearly 200 of these peptides are found as homo- or heterodimers. More than 6100 of the peptides are linear, but about 515 are cyclic and more than 1300 have other intra-chain covalent bonds. More than half of the entries in the database were added after the resource was initially described, which reflects the recent sharp uptick of interest in AMPs. New features of DBAASPv.2 include: (i) user-friendly utilities and reporting functions, (ii) a ‘Ranking Search’ function to query the database by target species and return a ranked list of peptides with activity against that target and (iii) structural descriptions of the peptides derived from empirical data or calculated by molecular dynamics (MD) simulations. The three-dimensional structural data are critical components for understanding structure–activity relationships and for design of new antimicrobial drugs. We created more than 300 high-throughput MD simulations specifically for inclusion in DBAASP. The resulting structures are described in the database by novel trajectory analysis plots and movies. Another 200+ DBAASP entries have links to the Protein DataBank. All of the structures are easily visualized directly in the web browser. PMID:26578581

  10. DBAASP v.2: an enhanced database of structure and antimicrobial/cytotoxic activity of natural and synthetic peptides.

    PubMed

    Pirtskhalava, Malak; Gabrielian, Andrei; Cruz, Phillip; Griggs, Hannah L; Squires, R Burke; Hurt, Darrell E; Grigolava, Maia; Chubinidze, Mindia; Gogoladze, George; Vishnepolsky, Boris; Alekseev, Vsevolod; Rosenthal, Alex; Tartakovsky, Michael

    2016-01-01

    Antimicrobial peptides (AMPs) are anti-infectives that may represent a novel and untapped class of biotherapeutics. Increasing interest in AMPs means that new peptides (natural and synthetic) are discovered faster than ever before. We describe herein a new version of the Database of Antimicrobial Activity and Structure of Peptides (DBAASPv.2, which is freely accessible at http://dbaasp.org). This iteration of the database reports chemical structures and empirically-determined activities (MICs, IC50, etc.) against more than 4200 specific target microbes for more than 2000 ribosomal, 80 non-ribosomal and 5700 synthetic peptides. Of these, the vast majority are monomeric, but nearly 200 of these peptides are found as homo- or heterodimers. More than 6100 of the peptides are linear, but about 515 are cyclic and more than 1300 have other intra-chain covalent bonds. More than half of the entries in the database were added after the resource was initially described, which reflects the recent sharp uptick of interest in AMPs. New features of DBAASPv.2 include: (i) user-friendly utilities and reporting functions, (ii) a 'Ranking Search' function to query the database by target species and return a ranked list of peptides with activity against that target and (iii) structural descriptions of the peptides derived from empirical data or calculated by molecular dynamics (MD) simulations. The three-dimensional structural data are critical components for understanding structure-activity relationships and for design of new antimicrobial drugs. We created more than 300 high-throughput MD simulations specifically for inclusion in DBAASP. The resulting structures are described in the database by novel trajectory analysis plots and movies. Another 200+ DBAASP entries have links to the Protein DataBank. All of the structures are easily visualized directly in the web browser. PMID:26578581

  11. Effect of the tripeptide glycyl-L-histidyl-L-lysine on the proliferation and synthetic activity of chick embryo chondrocytes.

    PubMed

    Pesáková, V; Novotná, J; Adam, M

    1995-08-01

    Under certain conditions chondrocytes form lattices with cartilage collagens, which may serve as cartilage implants. It is necessary to find the optimal conditions for culturing chondrocytes. Three different supports are compared: (a) plastic; (b) cartilage collagens; and (c) insoluble skin collagen solubilized under denaturing conditions (ISC-40). The effect of culture medium supplementation with the tripeptide (Gly-His-Lys)2.Cu.2H2O.2NaCl (GHK) on chondrocyte proliferation and synthetic activity is studied, with particular attention paid to collagen types I, II and III. The collagen supports stimulated chondrocyte proliferation, but on the ISC-40 support they started to dedifferentiate rather early. In the primary culture, chondrocytes on all three supports synthesized mainly collagen type II, and only small amounts of types I and III. In the first passage the synthesis of these two collagen types increased, relative to collagen type II, at least on the cartilage collagen support. Supplementation of culture medium with GHK stimulated chondrocyte proliferation in the primary structure mostly on the ISC-40 support. On the other two types of supports the stimulatory effect of GHK was expressed mostly in the first passages. The collagen synthetic rate was increased by GHK on both of the collagen supports; on the cartilage collagen support collagen type II was synthesized predominantly and on the ISC-40 support types I and III were mostly formed. It is suggested that supplementation of culture medium with GHK may be useful in the preparation of cartilage implants. PMID:8562779

  12. Larvicidal activity and structure activity relationship of cinnamoyl amides from Zanthoxylum armatum and their synthetic analogues against diamondback moth, Plutella xylostella

    PubMed Central

    Kumar, Vishal; Reddy, S. G. Eswara; Bhardwaj, Anuja; Dolma, Shudh Kirti; Kumar, Neeraj

    2016-01-01

    Cinnamoyl amides isolated from Zanthoxylum armatum (Rutaceae) and their synthetic analogues were tested for their insecticidal activity against the second instar larvae of diamondback moth, Plutella xylostella (L.) (Lepidoptera: Yponomeutidae) to determine the promising structures with insecticidal activity. Most of the test compounds showed promising activity against larvae of P. xylostella. However, the activities of different compounds varied depending on the presence of different substituents at various positions of both the aromatic rings A and B. Among the tested compounds, 8, N-(3-bromo-4-methoxyphenethyl)cinnamamide showed best larvicidal activity with an LC50 = 62.13 mg/L followed by 6, N-(3׳-bromophenethyl)cinnamamide (LC50=128.49 mg/L) and 2 N-(4׳-methoxyphenylethyl)cinnamamide (LC50 = 225.65 mg/L). PMID:27231477

  13. Growth-inhibitory activity of natural and synthetic isothiocyanates against representative human microbial pathogens

    PubMed Central

    Kurepina, Natalia; Kreiswirth, Barry N.; Mustaev, Arkady

    2013-01-01

    Aims The aim of this study was to test the growth inhibition activity of isothiocyanates (ITC), defense compounds of plants, against common human microbial pathogens. Methods and Results In this study we have tested the growth inhibitory activity of a diverse collection of new and previously known representative ITC of various structural classes against pathogenic bacteria, fungi and molds by a serial dilution method. Generally, the compounds were more active against Gram-positive bacteria and fungi exhibiting species-specific bacteriostatic or bactericidal effect. The most active compounds inhibited the growth of both drug-susceptible and multi drug resistant (MDR) pathogens at micromolar concentrations. In the case of Mycobacterium tuberculosis some compounds were more active against MDR, rather than against susceptible strains. The average anti-microbial activity for some of new derivatives was significantly higher than previously reported for the most active ITC compounds. The structure-activity relationship (SAR) established for various classes of ITC with Bacillus cereus (model organism for B. anthracis) followed a distinct pattern, thereby enabling prediction of new more efficient inhibitors. Remarkably, tested bacteria failed to develop resistance to ITC. While effectively inhibiting microbial growth, ITCs displayed moderate toxicity towards eukaryotic cells. Conclusions High antimicrobial activity coupled with moderate toxicity grants further thorough studies of the ITC compounds aimed at elucidation of their cellular targets and inhibitory mechanism. Significance and impact of the study This systematic study identified new ITC compounds highly active against common human microbial pathogens at the concentrations comparable with those for currently used antimicrobial drugs (e.g. rifampicin, fluconazole). Tested representative pathogens do not develop resistance to the inhibitors. These properties justify further evaluation of ITC compounds as potential

  14. Annexation of a high-activity enzyme in a synthetic three-enzyme complex greatly decreases the degree of substrate channeling.

    PubMed

    You, Chun; Zhang, Y-H Percival

    2014-06-20

    The self-assembled three-enzyme complex containing triosephosphate isomerase (TIM), aldolase (ALD), and fructose 1,6-biphosphatase (FBP) was constructed via a mini-scaffoldin containing three different cohesins and the three dockerin-containing enzymes. This enzyme complex exhibited 1 order of magnitude higher initial reaction rates than the mixture of noncomplexed three enzymes. In this enzyme cascade reactions, the reaction mediated by ALD was the rate-limiting step. To understand the in-depth role of the rate-limiting enzyme ALD in influencing the substrate channeling effect of synthetic enzyme complexes, low-activity ALD from Thermotoga maritima was replaced with a similar-size ALD isolated from Thermus thermophilus, where the latter had more than 5 times specific activity of the former. The synthetic three-enzyme complexes annexed with either low-activity or high-activity ALDs exhibited higher initial reaction rates than the mixtures of the two-enzyme complex (TIM-FBP) and the nonbound low-activity or high activity ALD at the same enzyme concentration. It was also found that the annexation of more high-activity ALD in the synthetic enzyme complexes drastically decreased the degree of substrate channeling from 7.5 to 1.5. These results suggested that the degree of substrate channeling in synthetic enzyme complexes depended on the enzyme choice. This study implied that the construction of synthetic enzyme enzymes in synthetic cascade pathways could be a very important tool to accrelerate rate-limiting steps controlled by low-activity enzymes.

  15. Structural and Functional Studies of Aspergillus oryzae Cutinase: Enhanced Thermostability and Hydrolytic Activity of Synthetic Ester and Polyester Degradation

    SciTech Connect

    Liu, Z.; Gosser, Y; Baker, P; Ravee, Y; Li, H; Butterfoss, G; Kong, X; Gross, R; Montclare, J; et al.

    2009-01-01

    Cutinases are responsible for hydrolysis of the protective cutin lipid polyester matrix in plants and thus have been exploited for hydrolysis of small molecule esters and polyesters. Here we explore the reactivity, stability, and structure of Aspergillus oryzae cutinase and compare it to the well-studied enzyme from Fusarium solani. Two critical differences are highlighted in the crystallographic analysis of the A. oryzae structure: (i) an additional disulfide bond and (ii) a topologically favored catalytic triad with a continuous and deep groove. These structural features of A. oryzae cutinase are proposed to result in an improved hydrolytic activity and altered substrate specificity profile, enhanced thermostability, and remarkable reactivity toward the degradation of the synthetic polyester polycaprolactone. The results presented here provide insight into engineering new cutinase-inspired biocatalysts with tailor-made properties.

  16. Antinociceptive and antitumor activity of novel synthetic mononuclear Ruthenium (II) compounds

    PubMed Central

    Sunder A, Shyam; Dhulipala, Satyavati; Thota, Sreekanth; Yerra, Rajeshwar; Balzarini, Jan; De Clercq, Erik

    2013-01-01

    Background: From the thousands of years, metal compounds have been used in medicine for treatment of various diseases including various types of cancers. Ruthenium was seen as a promising metal due to its similar kinetics to platinum and its lower toxicity. Therefore, we aimed to evaluate the newer mononuclear ruthenium (II) compounds for antinociceptive and antitumor activities. Materials and Methods: Ruthenium (II) compounds were evaluated for antinociceptive and antitumor activity using the various in vitro and in vivo models. The compounds were injected to mice at concentrations of 1 and 2 mg kg-1 intraperitoneally and were screened for antinociceptive activity, and the antiproliferative effect was evaluated against murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) using MTT assay. Results: The results for antitumor activity clearly indicated that compound R1 was potent cytotoxic agent than R2 with IC50 values ranging from 4-6 μM for R1, whereas IC50 values for compound R2 ranging from 65-103 μM. The compounds have shown a significant anti-inflammatory effect in carrageenan and dextran models but do not having the central analgesic activity, this indicating that the antinociceptive activity is related to the peripheral nervous system. The results for 5-Lipoxygenase (5-LOX) activity showed that both R1 and R2 compounds were found to be significant 5-LOX inhibitory activity with IC50 values of 14.35 μg ml-1 and 29.24 μg ml-1 respectively. Conclusion: These findings concluded that the new ruthenium compounds might be the promising antiproliferative agents as these compounds showing significant 5-LOX inhibitory activity and potential agents in the management of pain related disorders. PMID:23930118

  17. Comparative assessment of synthetic strategies toward active platinum-rhodium-tin electrocatalysts for efficient ethanol electro-oxidation

    NASA Astrophysics Data System (ADS)

    Erini, Nina; Krause, Paul; Gliech, Manuel; Yang, Ruizhi; Huang, Yunhui; Strasser, Peter

    2015-10-01

    The present work explores the effect of autoclave-based autogenous-pressure vs. ambient pressure conditions on the synthesis and properties of carbon-supported Pt-Rh-Sn nanoparticle electrocatalysts. The Pt-Rh-Sn nanoparticles were characterized by X-ray spectroscopy, electron microscopy and mass spectroscopy and deployed as catalysts for the electrocatalytic ethanol oxidation reaction. Pt-Rh-Sn catalysts precipitated with carbon already present showed narrow particle size distribution around 7 nm, while catalysts supported on carbon after particle formation showed broader size distribution ranging from 8 to 16 nm, similar metal loadings between 40 and 48 wt.% and similar atomic ratios of Pt:Rh:Sn of 30:10:60. The highest ethanol oxidation activity at low overpotentials associated with exceptionally early ethanol oxidation onset potential was observed for ambient-pressure catalysts with the active ternary alloy phase formed in presence of the carbon supports. In contrast, catalysts prepared under ambient pressure in a two-step approach, involving alloy particle formation followed by particle separation and subsequent deposition on the carbon support, yielded the highest overall mass activities. Based on the observed synthesis-activity correlations, a comparative assessment is provided of the synthetic techniques at high vs. low pressures, and in presence and absence of carbon support. Plausible hypotheses in terms of particle dispersion and interparticle distance accounting for these observed differences are discussed.

  18. Apoptosis Activation in Human Lung Cancer Cell Lines by a Novel Synthetic Peptide Derived from Conus californicus Venom

    PubMed Central

    Oroz-Parra, Irasema; Navarro, Mario; Cervantes-Luevano, Karla E.; Álvarez-Delgado, Carolina; Salvesen, Guy; Sanchez-Campos, Liliana N.; Licea-Navarro, Alexei F.

    2016-01-01

    Lung cancer is one of the most common types of cancer in men and women and a leading cause of death worldwide resulting in more than one million deaths per year. The venom of marine snails Conus contains up to 200 pharmacologically active compounds that target several receptors in the cell membrane. Due to their diversity and specific binding properties, Conus toxins hold great potential as source of new drugs against cancer. We analyzed the cytotoxic effect of a 17-amino acid synthetic peptide (s-cal14.1a) that is based on a native toxin (cal14.1a) isolated from the sea snail Conus californicus. Cytotoxicity studies in four lung cancer cell lines were complemented with measurement of gene expression of apoptosis-related proteins Bcl-2, BAX and the pro-survival proteins NFκB-1 and COX-2, as well as quantification of caspase activity. Our results showed that H1299 and H1437 cell lines treated with s-call4.1a had decreased cell viability, activated caspases, and reduced expression of the pro-survival protein NFκB-1. To our knowledge, this is the first report describing activation of apoptosis in human lung cancer cell lines by s-cal14.1a and we offer insight into the possible mechanism of action. PMID:26861394

  19. Anticancer activity of a synthetic peptide derived from harmoniasin, an antibacterial peptide from the ladybug Harmonia axyridis.

    PubMed

    Kim, In-Woo; Lee, Joon Ha; Kwon, Young-Nam; Yun, Eun-Young; Nam, Sung-Hee; Ahn, Mi-Young; Kang, Dong-Chul; Hwang, Jae Sam

    2013-08-01

    Harmoniasin is a defensin-like antimicrobial peptide identified from the ladybug Harmonia axyridis. Among the synthetic homodimer peptide analogues derived from harmoniasin, HaA4 has been found to have antibacterial activity without hemolytic activity. In this study, we investigated whether HaA4 has anticancer activity against human leukemia cell lines such as U937 and Jurkat cells. HaA4 manifested cytotoxicity and decreased the cell viability of U937 and Jurkat cells in MTS assay and LDH release assay. We found that HaA4 induced apoptotic and necrotic cell death of the leukemia cells using flow cytometric analysis, acridine orange/ethidium bromide staining and nucleosomal fragmentation of genomic DNA. Activation of caspase-7 and -9 and fragmentation of poly (ADP-ribose) polymerase was detected in the HaA4-treated leukemia cells, suggesting induction of a caspase-dependent apoptosis pathway by HaA4. Caspase-dependent apoptosis was further confirmed by reversal of the HaA4-induced viability reduction by treatment of Z-VAD-FMK, a pan-caspase inhibitor. In conclusion, HaA4 caused necrosis and caspase-dependent apoptosis in both U937 and Jurkat leukemia cells, which suggests potential utility of HaA4 as a cancer therapeutic agent. PMID:23732481

  20. TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS

    PubMed Central

    Wang, Ying; Su, Lijing; Morin, Matthew D.; Jones, Brian T.; Whitby, Landon R.; Surakattula, Murali M. R. P.; Huang, Hua; Shi, Hexin; Choi, Jin Huk; Wang, Kuan-wen; Moresco, Eva Marie Y.; Berger, Michael; Zhan, Xiaoming; Zhang, Hong; Boger, Dale L.; Beutler, Bruce

    2016-01-01

    Structurally disparate molecules reportedly engage and activate Toll-like receptor (TLR) 4 and other TLRs, yet the interactions that mediate binding and activation by dissimilar ligands remain unknown. We describe Neoseptins, chemically synthesized peptidomimetics that bear no structural similarity to the established TLR4 ligand, lipopolysaccharide (LPS), but productively engage the mouse TLR4 (mTLR4)/myeloid differentiation factor 2 (MD-2) complex. Neoseptin-3 activates mTLR4/MD-2 independently of CD14 and triggers canonical myeloid differentiation primary response gene 88 (MyD88)- and Toll-interleukin 1 receptor (TIR) domain-containing adaptor inducing IFN-beta (TRIF)-dependent signaling. The crystal structure mTLR4/MD-2/Neoseptin-3 at 2.57-Å resolution reveals that Neoseptin-3 binds as an asymmetrical dimer within the hydrophobic pocket of MD-2, inducing an active receptor complex similar to that induced by lipid A. However, Neoseptin-3 and lipid A form dissimilar molecular contacts to achieve receptor activation; hence strong TLR4/MD-2 agonists need not mimic LPS. PMID:26831104

  1. High Throughput Screening Methods for Assessing Antibiofilm and Immunomodulatory Activities of Synthetic Peptides

    PubMed Central

    Haney, Evan F.; Mansour, Sarah; Hilchie, Ashley L.; de la Fuente-Núñez, César; Hancock, Robert E.W.

    2015-01-01

    The recent observation that certain cationic peptides possess potent antibiofilm activity demonstrated that small peptides could be used to treat biofilm-associated infections. Other so-called innate defense regulator peptides possess potent immunomodulatory properties such as leukocyte recruitment and suppression of harmful inflammation. A peptide that directly targets biofilm cells while favourably modulating the immune response would be particularly advantageous for treating serious skin infections caused by S. aureus. In the present work, using SPOT-synthesized peptide arrays on cellulose membranes, we outline a strategy for systematically assessing the antibiofilm activity of hundreds of IDR-1002 (VQRWLIVWRIRK-NH2) and IDR-HH2 (VQLRIRVAVIRA-NH2) peptide variants against MRSA biofilms. In addition, the ability of these peptides to stimulate production of a monocyte chemoattractant protein (MCP-1) and suppress LPS-induced interleukin (IL)-1β production in human peripheral blood mononuclear cells (PBMCs) was evaluated. These results informed the synthesis of second-generation peptides resulting in a new peptide, IDR-2009 (KWRLLIRWRIQK-NH2), with enhanced MCP-1 stimulatory activity, favourable IL-1β suppression characteristics and strong antibiofilm activity against MRSA and Pseudomonas aeruginosa biofilms. This work provides a proof-of-concept that multiple peptide activities can be optimized simultaneously to generate novel sequences that possess a variety of biological properties. PMID:25836992

  2. Synthetic method and biological activities of cis-fused alpha-methylene gamma-lactones.

    PubMed

    Higuchi, Yohsuke; Shimoma, Fumito; Ando, Masayoshi

    2003-06-01

    A reliable method was developed for the synthesis of cis-fused alpha-methylene gamma-lactones via alpha-methyl gamma-lactones. Bromination of alpha-methyl gamma-lactones with LDA/CBr(4) or TMSOTf/PTAB and successive dehydrobromination with DBU or TBAF of the resulting alpha-bromo-alpha-methyl gamma-lactones gave the desired alpha-methylene gamma-lactones in high yield. This method was successfully applied to the synthesis of biologically active compounds. alpha-Methylene gamma-lactone derivatives 1c, 2c, 4c, and 17 showed cell growth inhibitory activity to P388 lymphocytic leukemia. They also showed significant activities to crop diseases. Thus, alpha-methylene gamma-lactone 1c showed preventive activity in controlling scab of apple caused by Venturia inaequalis. alpha-Methylene gamma-lactones 2c, 4c, 17, and 18 also showed significant preventive activities in controlling damping off of cucumber caused by Pythium aphanidermatum.

  3. Antimicrobial activity of the synthetic peptide scolopendrasin ii from the centipede Scolopendra subspinipes mutilans.

    PubMed

    Kwon, Young-Nam; Lee, Joon Ha; Kim, In-Woo; Kim, Sang-Hee; Yun, Eun-Young; Nam, Sung-Hee; Ahn, Mi-Young; Jeong, Mihye; Kang, Dong-Chul; Lee, In Hee; Hwang, Jae Sam

    2013-10-28

    The centipede Scolopendra subpinipes mutilans is a medicinally important arthropod species. However, its transcriptome is not currently available and transcriptome analysis would be useful in providing insight into a molecular level approach. Hence, we performed de novo RNA sequencing of S. subpinipes mutilans using next-generation sequencing. We generated a novel peptide (scolopendrasin II) based on a SVM algorithm, and biochemically evaluated the in vitro antimicrobial activity of scolopendrasin II against various microbes. Scolopendrasin II showed antibacterial activities against gram-positive and -negative bacterial strains, including the yeast Candida albicans and antibiotic-resistant gram-negative bacteria, as determined by a radial diffusion assay and colony count assay without hemolytic activity. In addition, we confirmed that scolopendrasin II bound to the surface of bacteria through a specific interaction with lipoteichoic acid and a lipopolysaccharide, which was one of the bacterial cell-wall components. In conclusion, our results suggest that scolopendrasin II may be useful for developing peptide antibiotics.

  4. Examination of growth inhibitory properties of synthetic chalcones for which antibacterial activity was predicted.

    PubMed

    Batovska, Daniela; Parushev, Stoyan; Stamboliyska, Bistra; Tsvetkova, Iva; Ninova, Mariana; Najdenski, Hristo

    2009-05-01

    A large series of chalcones were synthesized and studied against Staphylococcus aureus and Escherichia coli. Chalcones were either unsubstituted in ring A or possessed 4'-chloro or 3',4',5'-trimethoxy groups. Their other ring B was variously substituted. It was found that the anti-staphylococcal activity of chalcones was related to the energy difference between the two highest occupied molecular orbitals (HOMO and HOMO-1). Presence of hydroxyl group in ring B was not a determinant factor for the anti-staphylococcal activity, but the lipophilicity of ring A of the hydroxyl chalcones was of importance. PMID:18584918

  5. Harmful Effects of Synthetic Surface-Active Detergents against Atopic Dermatitis

    PubMed Central

    Deguchi, Hajime; Aoyama, Riho; Takahashi, Hideaki; Isobe, Yoshinari; Tsutsumi, Yutaka

    2015-01-01

    We report herein two cases of intractable atopic dermatitis successfully treated by simply avoiding the contact with surface-active detergents in the daily life and living. The detergents were closely related to the exacerbation and remission of the disease. Steroid ointment was no longer used. We discuss that the removal of horny layer lipids by surface-active detergents accelerates the transepidermal water loss and disturbs the barrier function of the epidermis and thus is intimately involved in the pathogenesis of atopic dermatitis. PMID:25648414

  6. Adsorption uptake of synthetic organic chemicals by carbon nanotubes and activated carbons.

    PubMed

    Brooks, A J; Lim, Hyung-nam; Kilduff, James E

    2012-07-27

    Carbon nanotubes (CNTs) have shown great promise as high performance materials for adsorbing priority pollutants from water and wastewater. This study compared uptake of two contaminants of interest in drinking water treatment (atrazine and trichloroethylene) by nine different types of carbonaceous adsorbents: three different types of single walled carbon nanotubes (SWNTs), three different sized multi-walled nanotubes (MWNTs), two granular activated carbons (GACs) and a powdered activated carbon (PAC). On a mass basis, the activated carbons exhibited the highest uptake, followed by SWNTs and MWNTs. However, metallic impurities in SWNTs and multiple walls in MWNTs contribute to adsorbent mass but do not contribute commensurate adsorption sites. Therefore, when uptake was normalized by purity (carbon content) and surface area (instead of mass), the isotherms collapsed and much of the CNT data was comparable to the activated carbons, indicating that these two characteristics drive much of the observed differences between activated carbons and CNT materials. For the limited data set here, the Raman D:G ratio as a measure of disordered non-nanotube graphitic components was not a good predictor of adsorption from solution. Uptake of atrazine by MWNTs having a range of lengths and diameters was comparable and their Freundlich isotherms were statistically similar, and we found no impact of solution pH on the adsorption of either atrazine or trichloroethylene in the range of naturally occurring surface water (pH = 5.7-8.3). Experiments were performed using a suite of model aromatic compounds having a range of π-electron energy to investigate the role of π-π electron donor-acceptor interactions on organic compound uptake by SWNTs. For the compounds studied, hydrophobic interactions were the dominant mechanism in the uptake by both SWNTs and activated carbon. However, comparing the uptake of naphthalene and phenanthrene by activated carbon and SWNTs, size exclusion effects

  7. Adsorption uptake of synthetic organic chemicals by carbon nanotubes and activated carbons

    NASA Astrophysics Data System (ADS)

    Brooks, A. J.; Lim, Hyung-nam; Kilduff, James E.

    2012-07-01

    Carbon nanotubes (CNTs) have shown great promise as high performance materials for adsorbing priority pollutants from water and wastewater. This study compared uptake of two contaminants of interest in drinking water treatment (atrazine and trichloroethylene) by nine different types of carbonaceous adsorbents: three different types of single walled carbon nanotubes (SWNTs), three different sized multi-walled nanotubes (MWNTs), two granular activated carbons (GACs) and a powdered activated carbon (PAC). On a mass basis, the activated carbons exhibited the highest uptake, followed by SWNTs and MWNTs. However, metallic impurities in SWNTs and multiple walls in MWNTs contribute to adsorbent mass but do not contribute commensurate adsorption sites. Therefore, when uptake was normalized by purity (carbon content) and surface area (instead of mass), the isotherms collapsed and much of the CNT data was comparable to the activated carbons, indicating that these two characteristics drive much of the observed differences between activated carbons and CNT materials. For the limited data set here, the Raman D:G ratio as a measure of disordered non-nanotube graphitic components was not a good predictor of adsorption from solution. Uptake of atrazine by MWNTs having a range of lengths and diameters was comparable and their Freundlich isotherms were statistically similar, and we found no impact of solution pH on the adsorption of either atrazine or trichloroethylene in the range of naturally occurring surface water (pH = 5.7-8.3). Experiments were performed using a suite of model aromatic compounds having a range of π-electron energy to investigate the role of π-π electron donor-acceptor interactions on organic compound uptake by SWNTs. For the compounds studied, hydrophobic interactions were the dominant mechanism in the uptake by both SWNTs and activated carbon. However, comparing the uptake of naphthalene and phenanthrene by activated carbon and SWNTs, size exclusion effects

  8. Adsorption uptake of synthetic organic chemicals by carbon nanotubes and activated carbons.

    PubMed

    Brooks, A J; Lim, Hyung-nam; Kilduff, James E

    2012-07-27

    Carbon nanotubes (CNTs) have shown great promise as high performance materials for adsorbing priority pollutants from water and wastewater. This study compared uptake of two contaminants of interest in drinking water treatment (atrazine and trichloroethylene) by nine different types of carbonaceous adsorbents: three different types of single walled carbon nanotubes (SWNTs), three different sized multi-walled nanotubes (MWNTs), two granular activated carbons (GACs) and a powdered activated carbon (PAC). On a mass basis, the activated carbons exhibited the highest uptake, followed by SWNTs and MWNTs. However, metallic impurities in SWNTs and multiple walls in MWNTs contribute to adsorbent mass but do not contribute commensurate adsorption sites. Therefore, when uptake was normalized by purity (carbon content) and surface area (instead of mass), the isotherms collapsed and much of the CNT data was comparable to the activated carbons, indicating that these two characteristics drive much of the observed differences between activated carbons and CNT materials. For the limited data set here, the Raman D:G ratio as a measure of disordered non-nanotube graphitic components was not a good predictor of adsorption from solution. Uptake of atrazine by MWNTs having a range of lengths and diameters was comparable and their Freundlich isotherms were statistically similar, and we found no impact of solution pH on the adsorption of either atrazine or trichloroethylene in the range of naturally occurring surface water (pH = 5.7-8.3). Experiments were performed using a suite of model aromatic compounds having a range of π-electron energy to investigate the role of π-π electron donor-acceptor interactions on organic compound uptake by SWNTs. For the compounds studied, hydrophobic interactions were the dominant mechanism in the uptake by both SWNTs and activated carbon. However, comparing the uptake of naphthalene and phenanthrene by activated carbon and SWNTs, size exclusion effects

  9. Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities

    PubMed Central

    Sobarzo-Sánchez, Eduardo; Bilbao-Ramos, Pablo; Dea-Ayuela, Maria; González-Díaz, Humberto; Yañez, Matilde; Uriarte, Eugenio; Santana, Lourdes; Martínez-Sernández, Victoria; Bolás-Fernández, Francisco; Ubeira, Florencio M.

    2013-01-01

    Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S). PMID:24204870

  10. Immunoregulatory activities of human immunodeficiency virus (HIV) proteins: Effect of HIV recombinant and synthetic peptides on immunoglobulin synthesis and proliferative responses by normal lymphocytes

    SciTech Connect

    Nair, M.P.N.; Pottathil, R.; Heimer, E.P.; Schwartz, S.A.

    1988-09-01

    Recombinant and synthetic peptides corresponding to envelope proteins of the human immunodeficiency virus (HIV) were examined for their effects on the activities of lymphocytes from normal donors in vitro. Although lymphocytes cultured with env-gag peptides produced significant amounts of IgG, addition of env-gag peptides to a pokeweed mitogen-induced B-cell activation system resulted in suppression of immunoglobulin synthesis by normal lymphocytes. Recombinant antigens, env-gag and env-80 dihydrofolate reductase (DHFR), produced a substantial proliferative response by peripheral blood mononuclear cells (PBMC) as determined by (/sup 3/H)thymidine incorporation. PBMC precultured with HIV synthetic peptide env 578-608 also manifested significant proliferative responses as compared to control cultures. CD3/sup +/ lymphocytes precultured with recombinant HIV antigens, env-gag and env-80 DHFR, and synthetic HIV peptide, env 487-511, showed moderate but significant proliferative responses. Both recombinant antigens and synthetic peptides also produced a dose-dependent stimulatory effect on proliferation by CD3/sup /minus// lymphocytes. These studies demonstrate that recombinant and synthetic peptides of the HIV genome express immunoregulatory T- and B-cell epitopes. Identification of unique HIV epitopes with immunogenic and immunoregulatory activities is necessary for the development of an effective vaccine against HIV infection.

  11. Antibacterial Activity of Synthetic Peptides Derived from Lactoferricin against Escherichia coli ATCC 25922 and Enterococcus faecalis ATCC 29212

    PubMed Central

    León-Calvijo, María A.; Leal-Castro, Aura L.; Almanzar-Reina, Giovanni A.; Rosas-Pérez, Jaiver E.; García-Castañeda, Javier E.; Rivera-Monroy, Zuly J.

    2015-01-01

    Peptides derived from human and bovine lactoferricin were designed, synthesized, purified, and characterized using RP-HPLC and MALDI-TOF-MS. Specific changes in the sequences were designed as (i) the incorporation of unnatural amino acids in the sequence, the (ii) reduction or (iii) elongation of the peptide chain length, and (iv) synthesis of molecules with different number of branches containing the same sequence. For each peptide, the antibacterial activity against Escherichia coli ATCC 25922 and Enterococcus faecalis ATCC 29212 was evaluated. Our results showed that Peptides I.2 (RWQWRWQWR) and I.4 ((RRWQWR)4K2Ahx2C2) exhibit bigger or similar activity against E. coli (MIC 4–33 μM) and E. faecalis (MIC 10–33 μM) when they were compared with lactoferricin protein (LF) and some of its derivate peptides as II.1 (FKCRRWQWRMKKLGA) and IV.1 (FKCRRWQWRMKKLGAPSITCVRRAE). It should be pointed out that Peptides I.2 and I.4, containing the RWQWR motif, are short and easy to synthesize; our results demonstrate that it is possible to design and obtain synthetic peptides that exhibit enhanced antibacterial activity using a methodology that is fast and low-cost and that allows obtaining products with a high degree of purity and high yield. PMID:25815317

  12. Synthesis and protein tyrosine phosphatase 1B inhibition activities of two new synthetic bromophenols and their methoxy derivatives

    NASA Astrophysics Data System (ADS)

    Cui, Yongchao; Shi, Dayong; Hu, Zhiqiang

    2011-11-01

    3-bromo-4,5-bis(2,3-dibromo-4,5-dihydroxybenzyl)-1,2-benzenediol ( 1) is a natural bromophenol isolated from the red algae Rhodomela confervoides that exhibits significant inhibition against protein tyrosine phosphatase 1B (PTP1B). Based on its activity, we synthesized two new synthetic bromophenols and their methoxy derivatives from vanillin using the structure of natural bromophenol 1 as a scaffold. The structures of these bromophenols were elucidated from 1H NMR, 13C NMR, and high resolution electron ionization mass spectrometry as 2,3-dibromo-1-(2'-bromo-6'-(3″,4″-dimethoxybenzyl)-3',4'-dimethoxybenzyl)-4,5-dimethoxybenzene ( 2), 2,3-dibromo-1-(2'-bromo-6'-(2″-bromo-4″,5″-dimethoxybenzyl)-3',4'-dimethoxybenzyl)-4,5-dimethoxybenzene ( 3), 3,4-dibromo-5-(2'-bromo-6'-(2″-bromo-4″,5″-dihydroxybenzyl)-3',4'-dihydroxybenzyl)pyrocatechol ( 4) and 3,4-dibromo-5-(2'-bromo-6'-(3″,4″-dihydroxybenzyl)-3',4'-dihydroxybenzyl)pyrocatechol ( 5). PTP1B inhibition activities of these compounds were evaluated using a colorimetric assay, and compounds 3 and 4 demonstrated interesting activity against PTP1B.

  13. Synthetically Tuning the 2-Position of Halogenated Quinolines: Optimizing Antibacterial and Biofilm Eradication Activities via Alkylation and Reductive Amination Pathways.

    PubMed

    Basak, Akash; Abouelhassan, Yasmeen; Norwood, Verrill M; Bai, Fang; Nguyen, Minh Thu; Jin, Shouguang; Huigens, Robert W

    2016-06-27

    Agents capable of eradicating bacterial biofilms are of great importance to human health as biofilm-associated infections are tolerant to our current antibiotic therapies. We have recently discovered that halogenated quinoline (HQ) small molecules are: 1) capable of eradicating methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE) and vancomycin-resistant Enterococcus faecium (VRE) biofilms, and 2) synthetic tuning of the 2-position of the HQ scaffold has a significant impact on antibacterial and antibiofilm activities. Here, we report the chemical synthesis and biological evaluation of 39 HQ analogues that have a high degree of structural diversity at the 2-position. We identified diverse analogues that are alkylated and aminated at the 2-position of the HQ scaffold and demonstrate potent antibacterial (MIC≤0.39 μm) and biofilm eradication (MBEC 1.0-93.8 μm) activities against drug-resistant Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium strains while demonstrating <5 % haemolysis activity against human red blood cells (RBCs) at 200 μm. In addition, these HQs demonstrated low cytotoxicity against HeLa cells. Halogenated quinolines are a promising class of antibiofilm agents against Gram-positive pathogens that could lead to useful treatments against persistent bacterial infections. PMID:27245927

  14. Antitumor triptycene bisquinones: a novel synthetic class of dual inhibitors of DNA topoisomerase I and II activities.

    PubMed

    Wang, Buna; Perchellet, Elisabeth M; Wang, Yang; Tamura, Masafumi; Hua, Duy H; Perchellet, Jean-Pierre H

    2003-08-01

    Synthetic triptycene analogs (TT code number) mimic the antitumor effects of daunorubicin in the nanomolar range in vitro, but have the advantage of blocking nucleoside transport and retaining their efficacy in multidrug-resistant (MDR) tumor cells. Since TT bisquinones induce poly(ADP-ribose) polymerase-1 cleavage at 6 h and internucleosomal DNA fragmentation at 24 h, which are, respectively, early and late markers of apoptosis, these lead antitumor drugs were tested for their ability to trigger the DNA topoisomerase (Topo) inhibitions responsible for the initial and massive high-molecular-weight cleavage of DNA required for tumor cells to commit apoptosis. Interestingly, antitumor TTs have the unusual ability to inhibit, in a concentration-dependent manner, the relaxation of supercoiled plasmid DNA catalyzed by both purified human Topo I and II enzymes. However, if there is a relationship between the ability of TT analogs to inhibit Topo activities and their quinone functionality and cytotoxicity, it is far from perfect, suggesting that other molecular targets may be involved in the mechanism of action of these antitumor drugs. Moreover, one of the most cytotoxic TT bisquinone, 6-bromo-7-methoxy- or 7-bromo-6-methoxy-2-N-methylamino-1 H,4 H,5 H,8H-9,10-dihydro-9,10-[1',2']benzenoanthracene-1,4,5,8-tetraone (TT24), inhibits Topo II activity more effectively than amsacrine (m-AMSA) and matches the Topo I inhibitory effect of camptothecin (CPT). The dual inhibitory activity of TT24 is substantiated by the findings that TT24 mimics the action of m-AMSA in the Topo II assay, where the Topo I inhibitor CPT is ineffective, and also mimics the action of CPT in the Topo I assay, where the Topo II inhibitor etoposide is ineffective. Because of their ability to target nucleoside transport and topoisomerase activities, synthetic TT bisquinones might represent a novel class of bifunctional drugs valuable to develop new means of polychemotherapy and circumvent MDR. PMID

  15. Versatile synthesis of oxime-containing acyclic nucleoside phosphonates--synthetic solutions and antiviral activity.

    PubMed

    Solyev, Pavel N; Jasko, Maxim V; Kleymenova, Alla A; Kukhanova, Marina K; Kochetkov, Sergey N

    2015-11-28

    New oxime-containing acyclic nucleoside phosphonates 9-{2-[(phosphonomethyl)oximino]ethyl}adenine (1), -guanine (2) and 9-{2-[(phosphonomethyl)oximino]propyl}adenine (3) with wide spectrum activity against different types of viruses were synthesized. The key intermediate, diethyl aminooxymethylphosphonate, was obtained by the Mitsunobu reaction. Modified conditions for the by-product separation (without chromatography and distillation) allowed us to obtain 85% yield of the aminooxy intermediate. The impact of DBU and Cs2CO3 on the N(9)/N(7) product ratio for adenine and guanine alkylation was studied. A convenient procedure for aminooxy group detection was found. The synthesized phosphonates were tested and they appeared to display moderate activity against different types of viruses (HIV, herpes viruses in cell cultures, and hepatitis C virus in the replicon system) without toxicity up to 1000 μM. PMID:26383895

  16. Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound.

    PubMed

    Deodato, Davide; Maccari, Giorgio; De Luca, Filomena; Sanfilippo, Stefania; Casian, Alexandru; Martini, Riccardo; D'Arezzo, Silvia; Bonchi, Carlo; Bugli, Francesca; Posteraro, Brunella; Vandeputte, Patrick; Sanglard, Dominique; Docquier, Jean-Denis; Sanguinetti, Maurizio; Visca, Paolo; Botta, Maurizio

    2016-04-28

    We recently identified a novel family of macrocyclic amidinoureas showing potent antifungal activity against Candida spp. In this study, we demonstrate the fungicidal effect of these compounds as well as their killing activity in a dose-dependent manner. Transcriptional analysis data indicate that our molecules induce a significant change in the transcriptome involving ATP binding cassette (ABC) transporter genes. Notably, experiments against Candida albicans mutants lacking those genes showed resistance to the compound, suggesting the involvement of ABC transporters in the uptake or intracellular accumulation of the molecule. To probe the mode of action, we performed fluorescence microscopy experiments on fungal cells treated with an ad-hoc synthesized fluorescent derivative. Fluorescence microscopy images confirm the ability of the compound to cross the membrane and show a consistent accumulation within the cytoplasm. Finally, we provide data supporting the in vivo efficacy in a systemic infection murine model setup with a drug-resistant strain of C. albicans. PMID:27045868

  17. Synthetic oils

    NASA Technical Reports Server (NTRS)

    Hatton, R. E.

    1973-01-01

    Synthetic lubricants are discussed by chemical class and their general strengths and weaknesses in terms of lubrication properties are analyzed. Comparative ratings are given for 14 chemical classes and are used as a guide for lubricant selection. The effects of chemical structure on the properties of the lubricant are described with special emphasis on thermal stability. The diversity of synthetic lubricants which is provided by the wide range of properties permits many applications, some of which are reported.

  18. Caatinga plants: Natural and semi-synthetic compounds potentially active against Trichomonas vaginalis.

    PubMed

    Vieira, Patrícia de Brum; Silva, Nícolas Luiz Feijó; da Silva, Gloria Narjara Santos; Silva, Denise Brentan; Lopes, Norberto Peporine; Gnoatto, Simone Cristina Baggio; da Silva, Márcia Vanusa; Macedo, Alexandre José; Bastida, Jaume; Tasca, Tiana

    2016-05-01

    Trichomonas vaginalis causes trichomoniasis; the most common but overlooked non-viral sexually transmitted disease worldwide. The treatment is based at 5'-nitroimidazoles, however, failure are related to resistance of T. vaginalis to chemotherapy. Caatinga is a uniquely Brazilian region representing a biome with type desert vegetation and plants present diverse biological activity, however, with few studies. The aim of this study was to investigate the activity against T. vaginalis of different plants from Caatinga and identify the compounds responsible by the activity. A bioguided fractionation of Manilkara rufula was performed and four major compounds were identified: caproate of α-amyrin (1b), acetate of β-amyrin (2a), caproate of β-amyrin (2b), and acetate of lupeol (3a). In addition, six derivatives of α-amyrin (1), β-amyrin (2) and lupeol (3) were synthesized and tested against the parasite. Ursolic acid (5) reduced about 98% of parasite viability after 2h of incubation and drastic ultrastructural alterations were observed by scanning electron microscopy. Moreover, 5 presented high cytotoxicity to HMVII and HeLa cell line and low cytotoxicity against Vero line at 50 μM (MIC against the parasite). Metronidazole effect against T. vaginalis resistant isolate was improved when in association with 5. PMID:27020521

  19. Caatinga plants: Natural and semi-synthetic compounds potentially active against Trichomonas vaginalis.

    PubMed

    Vieira, Patrícia de Brum; Silva, Nícolas Luiz Feijó; da Silva, Gloria Narjara Santos; Silva, Denise Brentan; Lopes, Norberto Peporine; Gnoatto, Simone Cristina Baggio; da Silva, Márcia Vanusa; Macedo, Alexandre José; Bastida, Jaume; Tasca, Tiana

    2016-05-01

    Trichomonas vaginalis causes trichomoniasis; the most common but overlooked non-viral sexually transmitted disease worldwide. The treatment is based at 5'-nitroimidazoles, however, failure are related to resistance of T. vaginalis to chemotherapy. Caatinga is a uniquely Brazilian region representing a biome with type desert vegetation and plants present diverse biological activity, however, with few studies. The aim of this study was to investigate the activity against T. vaginalis of different plants from Caatinga and identify the compounds responsible by the activity. A bioguided fractionation of Manilkara rufula was performed and four major compounds were identified: caproate of α-amyrin (1b), acetate of β-amyrin (2a), caproate of β-amyrin (2b), and acetate of lupeol (3a). In addition, six derivatives of α-amyrin (1), β-amyrin (2) and lupeol (3) were synthesized and tested against the parasite. Ursolic acid (5) reduced about 98% of parasite viability after 2h of incubation and drastic ultrastructural alterations were observed by scanning electron microscopy. Moreover, 5 presented high cytotoxicity to HMVII and HeLa cell line and low cytotoxicity against Vero line at 50 μM (MIC against the parasite). Metronidazole effect against T. vaginalis resistant isolate was improved when in association with 5.

  20. Anorganic bovine bone and a silicate-based synthetic bone activate different microRNAs.

    PubMed

    Annalisa, Palmieri; Furio, Pezzetti; Ilaria, Zollino; Anna, Avantaggiato; Luca, Scapoli; Marcella, Martinelli; Marzia, Arlotti; Elena, Masiero; Carinci, Francesco

    2008-09-01

    Bio-Oss (BO), composed of anorganic bovine bone, is widely used in several bone regeneration procedures in oral surgery. PerioGlas (PG) is an alloplastic material that has been used for grafting of periodontal osseous defects since the 1990s. However, how these biomaterials alter osteoblast activity to promote bone formation is poorly understood. We attempted to address this question by using microRNA microarray techniques to investigate differences in translational regulation in osteoblasts exposed to BO and PG. By using miRNA microarrays containing 329 probes designed from human miRNA sequences, we investigated miRNAs whose expression was significantly modified in an osteoblast-like cell line (MG-63) cultured with BO vs PG. Three up-regulated miRNAs (mir-337, mir-200b, mir-377) and 4 down-regulated miRNAs (mir-130a, mir-214, mir-27a, mir-93) were identified. Our results indicated that BO and PG act on different miRNAs. Globally, PG causes activation of bone-forming signaling, whereas BO also activates cartilage-related pathways.

  1. A synthetic isoflavone, DCMF, promotes human keratinocyte migration by activating Src/FAK signaling pathway.

    PubMed

    Sophors, Phorl; Kim, Young Mee; Seo, Ga Young; Huh, Jung-Sik; Lim, Yoongho; Koh, Dong Soo; Cho, Moonjae

    2016-04-01

    Flavonoids are plant secondary compounds with various pharmacological properties. We previously showed that one flavonoid, trimethoxyisoflavone (TMF), could promote wound healing by inducing keratinocyte migration. Here, we screened TMF derivatives for enhanced activity and identified one compound, 2',6 Dichloro-7-methoxyisoflavone (DCMF), as most effective at promoting migration in a scratch wound assay. Using the HaCaT keratinocyte cell line, we found DCMF treatment induced phosphorylation of both FAK and Src, and increased keratinocyte migration. DCMF-induced Src kinase could promote activation of ERK, AKT, and p38 signaling pathways, and DCMF-induced secretion of matrix metalloproteinase (MMP)-2 and MMP-9 and partial epithelial-mesenchymal transition (EMT), whereas Src inhibition abolished DCMF-induced EMT. Using an in vivo excisional wound model, we observed improved wound closure and re-epithelialization in DCMF-treated mice, as compared to controls. Collectively, our data demonstrate that DCMF induces cell migration and promotes wound healing through activation of Src/FAK, ERK, AKT, and p38 MAPK signaling. PMID:26923073

  2. Effect of the synthetic method on the catalytic activity of alumina: Epoxidation of cyclohexene

    SciTech Connect

    Valderruten, N.E.; Peña, W.F.; Ramírez, A.E.; Rodríguez-Páez, J.E.

    2015-02-15

    Graphical abstract: Temperature influence on percent conversion and selectivity in the epoxidation of cyclohexene using commercial alumina as a catalyst. - Highlights: • Aluminum oxide was synthesized using Pechini method. • The alumina obtained showed a mix of boehmite and γ-alumina phases. • We research an economically feasible method to obtain alumina for use as a catalyst. • Alumina obtained by Pechini showed high percent conversion and/or selectivity. • The best results were 78% conversion and 78% selectivity to epoxidation reactions. - Abstract: Al{sub 2}O{sub 3} was prepared from different inorganic precursors via the Pechini method and compared with Al{sub 2}O{sub 3} prepared by the sol–gel method. Structural characterization of these materials was carried out by FTIR, X-ray diffraction (XRD), N{sub 2} adsorption at −196 °C and transmission electron microscopy (TEM). The solids were tested in the epoxidation of cyclohexene and a difference in their catalytic activities was observed. The characterization results indicate that the samples prepared by Pechini have a mixture of γ-alumina and boehmite, a condition favoring catalytic activity, whereas the sol–gel sample is less crystalline due to higher boehmite content. These results indicate that both the nature of the precursor and the method of synthesis strongly affect the catalytic activity of Al{sub 2}O{sub 3}.

  3. Antimicrobial activity of the synthetic peptide scolopendrasin ii from the centipede Scolopendra subspinipes mutilans.

    PubMed

    Kwon, Young-Nam; Lee, Joon Ha; Kim, In-Woo; Kim, Sang-Hee; Yun, Eun-Young; Nam, Sung-Hee; Ahn, Mi-Young; Jeong, Mihye; Kang, Dong-Chul; Lee, In Hee; Hwang, Jae Sam

    2013-10-28

    The centipede Scolopendra subpinipes mutilans is a medicinally important arthropod species. However, its transcriptome is not currently available and transcriptome analysis would be useful in providing insight into a molecular level approach. Hence, we performed de novo RNA sequencing of S. subpinipes mutilans using next-generation sequencing. We generated a novel peptide (scolopendrasin II) based on a SVM algorithm, and biochemically evaluated the in vitro antimicrobial activity of scolopendrasin II against various microbes. Scolopendrasin II showed antibacterial activities against gram-positive and -negative bacterial strains, including the yeast Candida albicans and antibiotic-resistant gram-negative bacteria, as determined by a radial diffusion assay and colony count assay without hemolytic activity. In addition, we confirmed that scolopendrasin II bound to the surface of bacteria through a specific interaction with lipoteichoic acid and a lipopolysaccharide, which was one of the bacterial cell-wall components. In conclusion, our results suggest that scolopendrasin II may be useful for developing peptide antibiotics. PMID:23801249

  4. Water oxidation chemistry of a synthetic dinuclear ruthenium complex containing redox-active quinone ligands.

    PubMed

    Isobe, Hiroshi; Tanaka, Koji; Shen, Jian-Ren; Yamaguchi, Kizashi

    2014-04-21

    We investigated theoretically the catalytic mechanism of electrochemical water oxidation in aqueous solution by a dinuclear ruthenium complex containing redox-active quinone ligands, [Ru2(X)(Y)(3,6-tBu2Q)2(btpyan)](m+) [X, Y = H2O, OH, O, O2; 3,6-tBu2Q = 3,6-di-tert-butyl-1,2-benzoquinone; btpyan =1,8-bis(2,2':6',2″-terpyrid-4'-yl)anthracene] (m = 2, 3, 4) (1). The reaction involves a series of electron and proton transfers to achieve redox leveling, with intervening chemical transformations in a mesh scheme, and the entire molecular structure and motion of the catalyst 1 work together to drive the catalytic cycle for water oxidation. Two substrate water molecules can bind to 1 with simultaneous loss of one or two proton(s), which allows pH-dependent variability in the proportion of substrate-bound structures and following pathways for oxidative activation of the aqua/hydroxo ligands at low thermodynamic and kinetic costs. The resulting bis-oxo intermediates then undergo endothermic O-O radical coupling between two Ru(III)-O(•) units in an anti-coplanar conformation leading to bridged μ-peroxo or μ-superoxo intermediates. The μ-superoxo species can liberate oxygen with the necessity for the preceding binding of a water molecule, which is possible only after four-electron oxidation is completed. The magnitude of catalytic current would be limited by the inherent sluggishness of the hinge-like bending motion of the bridged μ-superoxo complex that opens up the compact, hydrophobic active site of the catalyst and thereby allows water entry under dynamic conditions. On the basis of a newly proposed mechanism, we rationalize the experimentally observed behavior of electrode kinetics with respect to potential and discuss what causes a high overpotential for water oxidation by 1.

  5. New Non-Toxic Semi-Synthetic Derivatives from Natural Diterpenes Displaying Anti-Tuberculosis Activity.

    PubMed

    Matos, Priscilla M; Mahoney, Brian; Chan, Yohan; Day, David P; Cabral, Mirela M W; Martins, Carlos H G; Santos, Raquel A; Bastos, Jairo K; Page, Philip C Bulman; Heleno, Vladimir C G

    2015-10-07

    We report herein the synthesis of six diterpene derivatives, three of which are new, generated through known organic chemistry reactions that allowed structural modification of the existing natural products kaurenoic acid (1) and copalic acid (2). The new compounds were fully characterized using high resolution mass spectrometry, infrared spectroscopy, ¹H- and (13)C-NMR experiments. We also report the evaluation of the anti-tuberculosis potential for all compounds, which showed some promising results for Micobacterium tuberculosis inhibition. Moreover, the toxicity for each of the most active compounds was also assessed.

  6. Antimicrobial Activity of Novel Synthetic Peptides Derived from Indolicidin and Ranalexin against Streptococcus pneumoniae

    PubMed Central

    Jindal, Hassan Mahmood; Le, Cheng Foh; Mohd Yusof, Mohd Yasim; Velayuthan, Rukumani Devi; Lee, Vannajan Sanghiran; Zain, Sharifuddin Md; Isa, Diyana Mohd; Sekaran, Shamala Devi

    2015-01-01

    Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics in order to defeat multidrug-resistant bacteria such as Streptococcus pneumoniae. In this study, thirteen antimicrobial peptides were designed based on two natural peptides indolicidin and ranalexin. Our results revealed that four hybrid peptides RN7-IN10, RN7-IN9, RN7-IN8, and RN7-IN6 possess potent antibacterial activity against 30 pneumococcal clinical isolates (MIC 7.81-15.62µg/ml). These four hybrid peptides also showed broad spectrum antibacterial activity (7.81µg/ml) against S. aureus, methicillin resistant S. aureus (MRSA), and E. coli. Furthermore, the time killing assay results showed that the hybrid peptides were able to eliminate S. pneumoniae within less than one hour which is faster than the standard drugs erythromycin and ceftriaxone. The cytotoxic effects of peptides were tested against human erythrocytes, WRL-68 normal liver cell line, and NL-20 normal lung cell line. The results revealed that none of the thirteen peptides have cytotoxic or hemolytic effects at their MIC values. The in silico molecular docking study was carried out to investigate the binding properties of peptides with three pneumococcal virulent targets by Autodock Vina. RN7IN6 showed a strong affinity to target proteins; autolysin, pneumolysin, and pneumococcal surface protein A (PspA) based on rigid docking studies. Our results suggest that the hybrid peptides could be suitable candidates for antibacterial drug development. PMID:26046345

  7. Unnatural amino acids increase activity and specificity of synthetic substrates for human and malarial cathepsin C.

    PubMed

    Poreba, Marcin; Mihelic, Marko; Krai, Priscilla; Rajkovic, Jelena; Krezel, Artur; Pawelczak, Malgorzata; Klemba, Michael; Turk, Dusan; Turk, Boris; Latajka, Rafal; Drag, Marcin

    2014-04-01

    Mammalian cathepsin C is primarily responsible for the removal of N-terminal dipeptides and activation of several serine proteases in inflammatory or immune cells, while its malarial parasite ortholog dipeptidyl aminopeptidase 1 plays a crucial role in catabolizing the hemoglobin of its host erythrocyte. In this report, we describe the systematic substrate specificity analysis of three cathepsin C orthologs from Homo sapiens (human), Bos taurus (bovine) and Plasmodium falciparum (malaria parasite). Here, we present a new approach with a tailored fluorogenic substrate library designed and synthesized to probe the S1 and S2 pocket preferences of these enzymes with both natural and a broad range of unnatural amino acids. Our approach identified very efficiently hydrolyzed substrates containing unnatural amino acids, which resulted in the design of significantly better substrates than those previously known. Additionally, in this study significant differences in terms of the structures of optimal substrates for human and malarial orthologs are important from the therapeutic point of view. These data can be also used for the design of specific inhibitors or activity-based probes.

  8. H11-H12 loop retinoic acid receptor mutants exhibit distinct trans-activating and trans-repressing activities in the presence of natural or synthetic retinoids.

    PubMed

    Lefebvre, B; Mouchon, A; Formstecher, P; Lefebvre, P

    1998-06-30

    Retinoids, such as the naturally occurring all-trans-retinoic acid (atRA) and synthetic ligand CD367 modulate ligand-dependent transcription through retinoic acid receptors (RARs). Retinoid binding to RAR is believed to trigger structural transitions in the ligand-binding domain (LBD), leading to helix H1 and helix H12 repositioning and coactivator recruitment and corepressor release. Here, we carried out a detailed mutagenesis analysis of the H11-H12 loop (designated the L box) to study its contribution to hRARalpha activation process. Point mutations that reduced transactivation by atRA also reduced atRA-induced transrepression of AP1 transcription, correlating ligand-induced activation and repression. However, a correlation was not observed with these mutations when tested with another ligand CD367, a synthetic agonist with binding properties identical to those of atRA. Transcription was strongly inhibited in the presence of CD367 for some mutants, thus leading to an inverse agonist activity of this ligand. None of these mutations significantly altered binding affinity for either ligand, indicating that altered transcription was not caused by altered ligand binding by these mutations. Although simple correlations with transcriptional activities were not found, these mutations were also characterized by altered ligand-induced structural transitions, which were distinct for the atRA-hRARalpha or CD367-hRARalpha complexes. These results indicate that amino acids in the L box are involved in specifying trans-repressive and trans-activating properties of the hRARalpha, and support the notion that different agonists induce distinct conformations in the LBD of the receptor.

  9. Stage specific activity of synthetic antimalarial endoperoxides, N-89 and N-251, against Plasmodium falciparum.

    PubMed

    Morita, Masayuki; Koyama, Takahiko; Sanai, Hitomi; Sato, Akira; Hiramoto, Akiko; Masuyama, Araki; Nojima, Masatomo; Wataya, Yusuke; Kim, Hye-Sook

    2015-02-01

    We have reported that two endoperoxides, N-89 and N-251, synthesized in 2001, possess potent antimalarial activities. Aiming at their eventual use for curing malaria in humans, we have been investigating various aspects of their antimalarial actions. Here we show that N-89 and N-251 inhibit the growth of Plasmodium falciparum within human erythrocytes in vitro at its lifecycle stage 'trophozoite' specifically. It is known that artemisinin compounds, which are currently used for curing malaria, have other stage-specificities. Therefore, it is likely that the antimalarial mechanism of N-89 and N-251 differs from those of artemisinin compounds. As malaria parasites resistant to artemisinin-based combination therapy are currently emerging in some tropical regions, N-89 and N-251 are candidates for overcoming these new problems. PMID:25449979

  10. Adsorption of chlorhexidine on synthetic hydroxyapatite and in vitro biological activity.

    PubMed

    de Souza, Carlos A Soriano; Colombo, Ana Paula V; Souto, Renata M; Silva-Boghossian, Carina M; Granjeiro, Jose M; Alves, Gutemberg G; Rossi, Alexandre M; Rocha-Leão, Maria Helena M

    2011-10-15

    The kinetic of chlorhexidine digluconate (CHXDG) uptake from aqueous solution by hydroxyapatite (HA) was investigated by ultraviolet (UV) analysis performed in HA powder (UV-solid) after the CHX adsorption. Adsorption isotherm of chlorhexidine (CHX) uptake was modeled by a combination of Languimir and Langmuir-Freundlich mechanisms. Strong molecule-molecule interactions and positive cooperativity predominated in the surface when CHX concentration was above 8.6 μg(CHX)/mg(HA). UV-solid spectra (shape, intensity and band position) of CHX bound to HA revealed that long-range molecular structures, such as aggregates or micelles, started to be formed at low CHX concentrations (1.52 μg(CHX)/mg(HA)) and predominated at high concentrations. Grazing-incidence X-ray diffraction (GIXRD) analysis from synchrotron radiation discarded the formation of crystalline structures on HA surface or precipitation of CHX crystalline salts, as suggested in previous works. The effect of the HA/CHX association on HA in vitro bioactivity, cytotoxicity and CHX antimicrobial activity was evaluated. It was shown that CHX did not inhibit the precipitation of a poorly crystalline apatite at HA/CHX surface after soaking in simulating body fluid (SBF). Cell viability studies after exposure to extracts of HA and HA/CHX showed that both biomaterials did not present significant in vitro toxicity. Moreover, HA/CHX inhibited Enterococcus faecalis growth for up to 6 days, revealing that binding to HA did not affect antimicrobial activity of CHX and reduced bacterial adhesion. These results suggested that HA/CHX association could result in a potential adjuvant antimicrobial system for clinical use. PMID:21676601

  11. Mechanism of a Prototypical Synthetic Membrane-Active Antimicrobial: Efficient Hole-Punching Via Interaction With Negative Intrinsic Curvature Lipids

    SciTech Connect

    Yang, L.; Gordon, V.D.; Trinkle, D.R.; Schmidt, N.W.; Davis, M.A.; DeVries, C.; Som, A.; Cronan, J.E., Jr.; Tew, G.N.; Wong, G.C.L.

    2009-05-28

    Phenylene ethynylenes comprise a prototypical class of synthetic antimicrobial compounds that mimic antimicrobial peptides produced by eukaryotes and have broad-spectrum antimicrobial activity. We show unambiguously that bacterial membrane permeation by these antimicrobials depends on the presence of negative intrinsic curvature lipids, such as phosphatidylethanolamine (PE) lipids, found in high concentrations within bacterial membranes. Plate-killing assays indicate that a PE-knockout mutant strain of Escherichia coli drastically out-survives the wild type against the membrane-active phenylene ethynylene antimicrobials, whereas the opposite is true when challenged with traditional metabolic antibiotics. That the PE deletion is a lethal mutation in normative environments suggests that resistant bacterial strains do not evolve because a lethal mutation is required to gain immunity. PE lipids allow efficient generation of negative curvature required for the circumferential barrel of an induced membrane pore; an inverted hexagonal HII phase, which consists of arrays of water channels, is induced by a small number of antimicrobial molecules. The estimated antimicrobial occupation in these water channels is nonlinear and jumps from {approx}1 to 3 per 4 nm of induced water channel length as the global antimicrobial concentration is increased. By comparing to exactly solvable 1D spin models for magnetic systems, we quantify the cooperativity of these antimicrobials.

  12. Comparative study on composition, structure, and adsorption behavior of activated carbons derived from different synthetic waste polymers.

    PubMed

    Lian, Fei; Xing, Baoshan; Zhu, Lingyan

    2011-08-15

    The composition, structure, and adsorption behavior of activated carbons (ACs) derived from three different types of waste polymers, i.e., tire rubber (TR), polyvinyl chloride (PVC), and polyethyleneterephtalate (PET), by KOH activation were compared. The AC derived from PET exhibited the largest surface area (2831 m(2)/g) and pore volume (1.68 cm(3)/g) due to the homogenous aromatic composition of PET. The AC derived from PVC exhibited relatively lower surface area (2666 m(2)/g) but more narrowed pore size distribution (2-3 nm). The complex composition and high ash content of tire particles resulted in AC product with significantly lower surface area (398.5 m(2)/g) and heterogeneous pore width. Adsorption data of methylene blue (MB) were fitted well by Langmuir equation, indicating monolayer coverage on the ACs. The high oxygen content of PET-derived AC heavily affected its adsorption to MB and iodine. Due to the remarkable surface area and highly mesoporous structures, ACs based on both PET and PVC exhibited much higher adsorption capacities than that of TR and commercial coal-based AC (F400). This study demonstrates that the properties of ACs are highly dependent on their starting polymers and the potential of converting synthetic polymer waste into effective adsorbents for environmental remediation and cleanup.

  13. Acaricidal activity of leaf extracts of Dalbergia sissoo Roxb. (Fabaceae) against synthetic pyrethroid resistant Rhipicephalus (Boophilus) microplus.

    PubMed

    Singh, Nirbhay Kumar; Jyoti; Vemu, Bhaskar; Prerna, Mranalini; Singh, Harkirat; Dumka, V K; Sharma, S K

    2016-06-01

    Resistance status of Rhipicephalus (Boophilus) microplus against synthetic pyrethroids was assessed by larval packet test which revealed level I and II resistance against cypermethrin and deltamethrin, respectively. Adult immersion test was employed to study the acaricidal activity of leaf extracts of Dalbergia sissoo (sheesham) against these ticks. Mortality and fecundity of ticks exposed to sheesham leaf aqueous (SLA) and ethanolic (SLE) extracts were evaluated at concentrations of 0.625, 1.25, 2.5, 5.0 and 10.0% and controls (distilled water and 10% ethanol). Higher acaricidal activity was recorded in SLA with a lower LC50 (95% CL) value of 1.58% (0.92-2.71%) than SLE [5.25% (4.91-5.63%)]. A significant decrease in egg mass weight and reproductive index was recorded in treated ticks along with an increase in percent inhibition of oviposition. A complete inhibition of hatching was recorded in eggs laid by ticks treated with higher concentrations of SLA, whereas, SLE exhibited no effect on hatching percentage. PMID:27234528

  14. Localization of Interictal Epileptiform Activity Using Magnetoencephalography with Synthetic Aperture Magnetometry in Patients with a Vagus Nerve Stimulator

    PubMed Central

    Stapleton-Kotloski, Jennifer R.; Kotloski, Robert J.; Boggs, Jane A.; Popli, Gautam; O’Donovan, Cormac A.; Couture, Daniel E.; Cornell, Cassandra; Godwin, Dwayne W.

    2014-01-01

    Magnetoencephalography (MEG) provides useful and non-redundant information in the evaluation of patients with epilepsy, and in particular, during the pre-surgical evaluation of pharmaco-resistant epilepsy. Vagus nerve stimulation (VNS) is a common treatment for pharmaco-resistant epilepsy. However, interpretation of MEG recordings from patients with a VNS is challenging due to the severe magnetic artifacts produced by the VNS. We used synthetic aperture magnetometry (g2) [SAM(g2)], an adaptive beamformer that maps the excessive kurtosis, to map interictal spikes to the coregistered MRI image, despite the presence of contaminating VNS artifact. We present a series of eight patients with a VNS who underwent MEG recording. Localization of interictal epileptiform activity by SAM(g2) is compared to invasive electrophysiologic monitoring and other localizing approaches. While the raw MEG recordings were uninterpretable, analysis of the recordings with SAM(g2) identified foci of peak kurtosis and source signal activity that was unaffected by the VNS artifact. SAM(g2) analysis of MEG recordings in patients with a VNS produces interpretable results and expands the use of MEG for the pre-surgical evaluation of epilepsy. PMID:25505894

  15. Neutralization of plasminogen activator inhibitor I (PAI-1) by the synthetic antagonist PAI-749 via a dual mechanism of action.

    PubMed

    Gardell, Stephen J; Krueger, Julie A; Antrilli, Thomas A; Elokdah, Hassan; Mayer, Scott; Orcutt, Steven J; Crandall, David L; Vlasuk, George P

    2007-10-01

    PAI-749 is a potent and selective synthetic antagonist of plasminogen activator inhibitor 1 (PAI-1) that preserved tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) activities in the presence of PAI-1 (IC(50) values, 157 and 87 nM, respectively). The fluorescence (Fl) of fluorophore-tagged PAI-1 (PAI-NBD119) was quenched by PAI-749; the apparent K(d) (254 nM) was similar to the IC(50) (140 nM) for PAI-NBD119 inactivation. PAI-749 analogs displayed the same potency rank order for neutralizing PAI-1 activity and perturbing PAI-NBD119 Fl; hence, binding of PAI-749 to PAI-1 and inactivation of PAI-1 activity are tightly linked. Exposure of PAI-1 to PAI-749 for 5 min (sufficient for full inactivation) followed by PAI-749 sequestration with Tween 80 micelles yielded active PAI-1; thus, PAI-749 did not irreversibly inactivate PAI-1, a known metastable protein. Treatment of PAI-1 with a PAI-749 homolog (producing less assay interference) blocked the ability of PAI-1 to displace p-aminobenzamidine from the uPA active site. Consistent with this observation, PAI-749 abolished formation of the SDS-stable tPA/PAI-1 complex. PAI-749-mediated neutralization of PAI-1 was associated with induction of PAI-1 polymerization as assessed by native gel electrophoresis. PAI-749 did not turn PAI-1 into a substrate for tPA; however, PAI-749 promoted plasmin-mediated degradation of PAI-1. In conclusion, PAI-1 inactivation by PAI-749 using purified components can result from a dual mechanism of action. First, PAI-749 binds directly to PAI-1, blocks PAI-1 from accessing the active site of tPA, and abrogates formation of the SDS-stable tPA/PAI-1 complex. Second, binding of PAI-749 to PAI-1 renders PAI-1 vulnerable to plasmin-mediated proteolytic degradation. PMID:17622579

  16. Reduction in the mutagenicity of synthetic dyes by successive treatment with activated sludge and the ligninolytic fungus, Irpex lacteus.

    PubMed

    Malachová, Katerina; Pavlícková, Zuzana; Novotný, Cenek; Svobodová, Katerina; Lednická, Denisa; Musílková, Eva

    2006-08-01

    Synthetic dyes are released in wastewater from textile manufacturing plants, and many of these dyes are genotoxic. In the present study, the mutagenicity of azo, anthraquinone, and triphenyl methane dyes was investigated before and after successive biodegradation with activated sludge and the ligninolytic fungus, Irpex lacteus. Two biodegradation systems were used to reduce the genotoxicity of dyes that were not efficiently inactivated by activated sludge alone. Mutagenicity was monitored with the Salmonella reversion assay conducted with the base-pair substitution detector strains, TA100 and YG1042, and the frame-shift detector strains, TA98 and YG1041, with and without rat liver S9. All dyes except for Congo Red (CR) were mutagenic with S9 activation. Assays conducted with the dyes indicated that only the azo dye Reactive Orange 16 (RO16) was mutagenic in both TA98 and TA100. Methyl Red and Disperse Blue 3 (DB3) were mutagenic in TA98, YG1041 and YG1042, while Reactive Black 5 was mutagenic in YG1041 and YG1042. Remazol Brilliant Blue R (RBBR), Crystal violet (CV) and Bromophenol Blue (BPB) were mutagenic only in TA98, but the toxicity of the latter two dyes complicated the evaluation of their mutagenicity. CR was not mutagenic in any of the tester strains. Biodegradation studies conducted with RO16 and DB3 indicated that the two-step biodegradation process reduced the mutagenic potential of RO16 and DB3 to a greater extent than activated sludge alone; the mutagenicity of the two dyes was reduced by 95.2% and 77.8%, respectively, by the two-step process. These data indicate that the combined biodegradation process may be useful for reducing the mutagenicity associated with wastewater from textile factories that contain recalcitrant dyes.

  17. Evolution of strategies to prepare synthetic mimics of carboxylate-bridged diiron protein active sites.

    PubMed

    Do, Loi H; Lippard, Stephen J

    2011-12-01

    We present a comprehensive review of research conducted in our laboratory in pursuit of the long-term goal of reproducing the structures and reactivity of carboxylate-bridged diiron centers used in biology to activate dioxygen for the conversion of hydrocarbons to alcohols and related products. This article describes the evolution of strategies devised to achieve these goals and illustrates the challenges in getting there. Particular emphasis is placed on controlling the geometry and coordination environment of the diiron core, preventing formation of polynuclear iron clusters, maintaining the structural integrity of model complexes during reactions with dioxygen, and tuning the ligand framework to stabilize desired oxygenated diiron species. Studies of the various model systems have improved our understanding of the electronic and physical characteristics of carboxylate-bridged diiron units and their reactivity toward molecular oxygen and organic moieties. The principles and lessons that have emerged from these investigations will guide future efforts to develop more sophisticated diiron protein model complexes. PMID:22113107

  18. Comparison of granular activated carbon and macroreticular synthetic adsorbents for groundwater remediation

    SciTech Connect

    Musterman, J.L.; Boero, V.J.; Plantz, D.A.

    1995-12-31

    An evaluation of Calgon F-400 and Ambersorb 563 and 572 and XAD-4 resins for removal of VOCs from an activated sludge treated groundwater was performed using continuous flow reactors. Breakthrough and EBCT-ST curves were developed and the capacities of the adsorbents were determined. Comparison of the performance of the adsorbents indicated that: (1) Ambersorb 563 resin provided greater VOC adsorption capacity and run-time to breakthrough than Ambersorb 572 and XAD-4 resins or the F-400 GAC. (2) Ambersorb 563 resin could also be operated at three times the surface loading rate of the GAC system resulting in smaller equipment size. (3) The Ambersorb 563 resin showed negligible TOC removal despite a high specificity for the target organic analytes. A cost analysis indicated that the installed cost for a 6.31 L/s Ambersorb 563 resin system was 2.8 times the cost of a F-400 GAC system. The annual operating cost however, was four times lower and the total present worth was $549,000 less.

  19. Enhancing the antimicrobial activity of natural extraction using the synthetic ultrasmall metal nanoparticles

    PubMed Central

    Li, Huanhuan; Chen, Quansheng; Zhao, Jiewen; Urmila, Khulal

    2015-01-01

    The use of Catechin as an antibacterial agent is becoming ever-more common, whereas unstable and easy oxidation, have limited its application. A simple and low-energy-consuming approach to synthesize highly stable and dispersive Catechin-Cu nanoparticles(NPs) has been developed, in which the stability and dispersivity of the NPs are varied greatly with the pH value and temperature of the reaction. The results demonstrate that the optimal reaction conditions are pH 11 at room temperature. As-synthesized NPs display excellent antimicrobial activity, the survival rates of bacterial cells exposed to the NPs were evaluated using live/dead Bacterial Viability Kit. The results showed that NPs at the concentration of 10 ppm and 20 ppm provided rapid and effective killing of up to 90% and 85% of S. aureus and E. coli within 3 h, respectively. After treatment with 20 ppm and 40 ppm NPs, the bacteria are killed completely. Furthermore, on the basis of assessing the antibacterial effects by SEM, TEM, and AFM, it was found the cell membrane damage of the bacteria caused by direct contact of the bacteria with the NPs was the effective mechanism in the bacterial inactivation. PMID:26046938

  20. Synthetic peptide models for the redox-active disulfide loop of glutaredoxin. Conformational studies

    SciTech Connect

    Kishore, R.; Raghothama, S.; Balaram, P.

    1988-04-05

    Two cyclic peptide disulfides have been synthesized as models for the 14-membered redox-active disulfide loop glutaredoxin. /sup 1/H NMR studies at 270 MHz in chloroform solutions establish a type I ..beta..-turn conformation for the Pro-X segment in both peptides, stabilized by a 4 ..-->.. 1 hydrogen bond between the Cys(1) CO and Cys(4) NH groups. Nuclear Overhauser effects establish that the aromatic ring in the X = Phe peptide is oriented over the central peptide unit. In dimethyl sulfoxide solutions two conformational species are observed in slow exchange on the NMR time scale, for both peptides. These are assigned to type I and type II ..beta..-turn structures with -Pro-Tyr(Phe)-as the corner resides. The structural assignments are based on correlation of NMR parameters with model 14-membered cyclic cystine peptides with Pro-X spacers. Circular dichroism studies based on the -S-S-n-sigma* transition suggest a structural change in the disulfide bridge with changing solvent polarity, establishing conformational coupling between the peptide backbone and the disulfide linkage in these systems.

  1. Synthetic peptides.

    PubMed

    Francis, M J

    1996-01-01

    Efforts to produce more stable and defined vaccines have concentrated on studying, in detail, the immune response to many infectious diseases in order to identify the antigenic sites on the pathogens that are involved in stimulating protective immumty. Armed with this knowledge, it is possible to mimic such sites by producing short chains of amino acids (peptides) and to use these as the basis for novel vaccines. The earliest documented work on peptide immunization is actually for a plant virus, tobacco mosaic virus. In 1963, Anderer (1) demonstrated that rabbit antibodies to an isolated hexapeptide fragment from the virus-coat protein coupled to bovine serum albumm would neutralize the infectious vn-us in culture. Two years later, he used a synthetically produced copy of the same peptide to confirm this observation. This was pioneering work, and it was over 10 years before the next example of a peptide that elicited antivirus antibody appeared following work by Sela and his colleagues (2) on a virus, MS2 bacteriophage, which infects bacteria. The emergence of more accessible techniques for sequencing proteins in 1977, coupled with the ability to synthesize readily peptides already developed in 1963, heralded a decade of intensive research into experimental peptide vaccines. The first demonstration that peptides could elicit protective immunity in vivo, in addition to neutralizing activity in vitro, was obtained using a peptide from the VP1 coat protein of foot-and-mouth disease virus (FMDV) in 1982, with the guinea pig as a laboratory animal model (3, 4). PMID:21359696

  2. Synthetic environments

    NASA Astrophysics Data System (ADS)

    Lukes, George E.; Cain, Joel M.

    1996-02-01

    The Advanced Distributed Simulation (ADS) Synthetic Environments Program seeks to create robust virtual worlds from operational terrain and environmental data sources of sufficient fidelity and currency to interact with the real world. While some applications can be met by direct exploitation of standard digital terrain data, more demanding applications -- particularly those support operations 'close to the ground' -- are well-served by emerging capabilities for 'value-adding' by the user working with controlled imagery. For users to rigorously refine and exploit controlled imagery within functionally different workstations they must have a shared framework to allow interoperability within and between these environments in terms of passing image and object coordinates and other information using a variety of validated sensor models. The Synthetic Environments Program is now being expanded to address rapid construction of virtual worlds with research initiatives in digital mapping, softcopy workstations, and cartographic image understanding. The Synthetic Environments Program is also participating in a joint initiative for a sensor model applications programer's interface (API) to ensure that a common controlled imagery exploitation framework is available to all researchers, developers and users. This presentation provides an introduction to ADS and the associated requirements for synthetic environments to support synthetic theaters of war. It provides a technical rationale for exploring applications of image understanding technology to automated cartography in support of ADS and related programs benefitting from automated analysis of mapping, earth resources and reconnaissance imagery. And it provides an overview and status of the joint initiative for a sensor model API.

  3. Fungicidal activity of fluconazole against Candida albicans in a synthetic vagina-simulative medium.

    PubMed

    Moosa, Mahomed-Yunus S; Sobel, Jack D; Elhalis, Hussain; Du, Wenjin; Akins, Robert A

    2004-01-01

    Fluconazole (FLZ) has emerged as a highly successful agent in the management of systemic infections of Candida. Cure rates for symptomatic candidiasis following single 150-mg FLZ dose therapy exceed 90%. In vitro, however, FLZ is fungistatic only in a narrow pH range and is not effective at vaginal pH, 4.2. This study evaluated the effect of FLZ on Candida albicans under in vitro conditions resembling the vaginal microenvironment, using vagina-simulative medium (VS). We found that FLZ was fungicidal for C. albicans in VS, but not in other media at the same pH, 4.2. In VS, FLZ was fungicidal at concentrations of >/=8 micro g/ml and reduced viability by greater than 99.9%. Analysis of the components of VS indicated that 17 mM acetic acid, a concentration achieved in the vagina, was responsible for the synergistic, fungicidal effect. This effect was not seen at neutral pH. Other substrates were not effective substitutes for acetic acid; however, short-chained carboxylic acids, glyoxylate and malonate, were effective. Most strains of C. albicans that were resistant to FLZ under standard conditions were killed by FLZ plus acetate. Other species of Candida were also killed, except C. krusei and C. glabrata. This study shows that FLZ has fungicidal activity for Candida species under in vitro conditions that mimic the vaginal microenvironment. This raises the possibility that FLZ may also have fungicidal effects during treatment of vaginal candidiasis. Elucidating the mechanism by which FLZ and acetate interact may disclose vulnerable pathways that could be exploited in drug development. PMID:14693534

  4. Discovery of amide (peptide) bond synthetic activity in Acyl-CoA synthetase.

    PubMed

    Abe, Tomoko; Hashimoto, Yoshiteru; Hosaka, Hideaki; Tomita-Yokotani, Kaori; Kobayashi, Michihiko

    2008-04-25

    Acyl-CoA synthetase, which is one of the acid-thiol ligases (EC 6.2.1), plays key roles in metabolic and regulatory processes. This enzyme forms a carbon-sulfur bond in the presence of ATP and Mg(2+), yielding acyl-CoA thioesters from the corresponding free acids and CoA. This enzyme belongs to the superfamily of adenylate-forming enzymes, whose three-dimensional structures are analogous to one another. We here discovered a new reaction while studying the short-chain acyl-CoA synthetase that we recently reported (Hashimoto, Y., Hosaka, H., Oinuma, K., Goda, M., Higashibata, H., and Kobayashi, M. (2005) J. Biol. Chem. 280, 8660-8667). When l-cysteine was used as a substrate instead of CoA, N-acyl-l-cysteine was surprisingly detected as a reaction product. This finding demonstrated that the enzyme formed a carbon-nitrogen bond (EC 6.3.1 acid-ammonia (or amide) ligase (amide synthase); EC 6.3.2 acid-amino acid ligase (peptide synthase)) comprising the amino group of the cysteine and the carboxyl group of the acid. N-Acyl-d-cysteine, N-acyl-dl-homocysteine, and N-acyl-l-cysteine methyl ester were also synthesized from the corresponding cysteine analog substrates by the enzyme. Furthermore, this unexpected enzyme activity was also observed for acetyl-CoA synthetase and firefly luciferase, indicating the generality of the new reaction in the superfamily of adenylate-forming enzymes.

  5. Synthetic arylquinuclidine derivatives exhibit antifungal activity against Candida albicans, Candida tropicalis and Candida parapsilopsis

    PubMed Central

    2011-01-01

    Background Sterol biosynthesis is an essential pathway for fungal survival, and is the biochemical target of many antifungal agents. The antifungal drugs most widely used to treated fungal infections are compounds that inhibit cytochrome P450-dependent C14α-demethylase (CYP51), but other enzymes of this pathway, such as squalene synthase (SQS) which catalyses the first committed step in sterol biosynthesis, could be viable targets. The aim of this study was to evaluate the antifungal activity of SQS inhibitors on Candida albicans, Candida tropicalis and Candida parapsilopsis strains. Methods Ten arylquinuclidines that act as SQS inhibitors were tested as antiproliferative agents against three ATCC strains and 54 clinical isolates of Candida albicans, Candida tropicalis and Candida parapsilopsis. Also, the morphological alterations induced in the yeasts by the experimental compounds were evaluated by fluorescence and transmission electron microscopy. Results The most potent arylquinuclidine derivative (3-[1'-{4'-(benzyloxy)-phenyl}]-quinuclidine-2-ene) (WSP1267) had a MIC50 of 2 μg/ml for all species tested and MIC90 varying from 4 μg/ml to 8 μg/ml. Ultrathin sections of C. albicans treated with 1 μg/ml of WSP1267 showed several ultrastructural alterations, including (a) loss of cell wall integrity, (b) detachment of the plasma membrane from the fungal cell wall, (c) accumulation of small vesicles in the periplasmic region, (d) presence of large electron-dense vacuoles and (e) significantly increased cell size and cell wall thickness. In addition, fluorescence microscopy of cells labelled with Nile Red showed an accumulation of lipid droplets in the cytoplasm of treated yeasts. Nuclear staining with DAPI revealed the appearance of uncommon yeast buds without a nucleus or with two nuclei. Conclusion Taken together, our data demonstrate that arylquinuclidine derivatives could be useful as lead compounds for the rational synthesis of new antifungal drugs. PMID

  6. Synthetic Jets

    NASA Technical Reports Server (NTRS)

    Milanovic, Ivana M.

    2003-01-01

    Current investigation of synthetic jets and synthetic jets in cross-flow examined the effects of orifice geometry and dimensions, momentum-flux ratio, cluster of orifices, pitch and yaw angles as well as streamwise development of the flow field. This comprehensive study provided much needed experimental information related to the various control strategies. The results of the current investigation on isolated and clustered synthetic jets with and without cross-flow will be further analyzed and documented in detail. Presentations at national conferences and publication of peer- reviewed journal articles are also expected. Projected publications will present both the mean and turbulent properties of the flow field, comparisons made with the data available in an open literature, as well as recommendations for the future work.

  7. Enhanced photocatalytic activity of a self-stabilized synthetic flavin anchored on a TiO2 surface.

    PubMed

    Pandiri, Manjula; Hossain, Mohammad S; Foss, Frank W; Rajeshwar, Krishnan; Paz, Yaron

    2016-07-21

    Synthetic flavin molecules were anchored on Degussa P25 titanium dioxide (TiO2). The effect of their presence on the photocatalytic (PC) activity of TiO2 was studied. Under UV light, an increase in the degradation rate of ethanol was observed. This increase was accompanied by stabilization of the anchored flavin against self-degradation. The unprecedented stabilization effect was found also in the absence of a reducing agent such as ethanol. In contrast, under the less energetic visible light, fast degradation of the anchored flavin was observed. These rather surprising observations were attributed to the propensity for charge transport from excited flavin molecules to the semiconductor and to the role that such charge transfer may play in stabilizing the overall assembly. Anchored flavins excited by UV light to their S2, S3 electronic states were able to transfer the excited electrons to the TiO2 phase whereas anchored flavin molecules that were excited by visible light to the S1 state were less likely to transfer the photo-excited electrons and therefore were destabilized. These findings may be relevant not only to anchored flavins in general but to other functionalized photocatalysts, and may open up new vistas in the implementation of sensitizers in PC systems. PMID:27346787

  8. Nuclear and cytoplasmic maturation of mouse oocytes after treatment with synthetic meiosis-activating sterol in vitro.

    PubMed

    Hegele-Hartung, C; Kuhnke, J; Lessl, M; Grøndahl, C; Ottesen, J; Beier, H M; Eisner, S; Eichenlaub-Ritter, U

    1999-11-01

    Synthetically produced meiosis-activating sterol, a sterol originally derived from follicular fluid (FF-MAS), induces meiotic maturation of mouse oocytes in vitro. We therefore compared FF-MAS-induced maturation of naked mouse oocytes arrested in prophase I by either hypoxanthine (Hx) or forskolin (Fo) with spontaneous maturation of naked oocytes. FF-MAS-treated oocytes overcame the meiotic block by Hx or Fo, although germinal vesicle breakdown was delayed by 11 h and 7 h, respectively. We also investigated the influence of FF-MAS on chromosome, microtubule, and ultrastructural dynamics in Hx-cultured oocytes by immunocytochemistry and electron microscopy. Similarly to spontaneously matured oocytes, chromosomes became aligned, a barrel-shaped spindle formed, and overall organelle distribution was normal in FF-MAS-matured oocytes. The number of small cytoplasmic asters was elevated in FF-MAS-treated oocytes. Although the number of cortical granules (CGs) was similar to that in spontaneously matured oocytes, the overall distance between CGs and oolemma was increased in the FF-MAS group. These observations suggest that the initiation of meiotic maturation in FF-MAS-treated oocytes in the presence of high cAMP levels leads to a delayed but otherwise normal nuclear maturation. FF-MAS appears to improve oocyte quality by supporting microtubule assembly and by delaying CG release, which is known to contribute to reduced fertilization. PMID:10529286

  9. Anionic Lipid Content Presents a Barrier to the Activity of ROMP-Based Synthetic Mimics of Protein Transduction Domains (PTDMs).

    PubMed

    Lis, Michael; Dorner, Franziska; Tew, Gregory N; Lienkamp, Karen

    2016-06-14

    Many biophysical studies of protein transduction domains (PTDs) and their synthetic mimics (PTDMs) focus on the interaction between the polycationic PTD(M) and anionic phospholipid surfaces. Most, but not all, of these studies suggest that these cation-anion interactions are vital for membrane activity. In this study, the effect of anionic lipid content on PTDM performance was examined for three ring-opening metathesis (ROMP)-based PTDMs with varying hydrophobicity. Using a series of dye-loaded vesicles with gradually increasing anionic lipid content, we saw that increased anionic lipid content inhibited dye release caused by these PTDMs. This result is the opposite of what was found in studies with poly- and oligo-arginine. While the effect is reduced for more hydrophobic PTDMs, it is observable even with the most hydrophobic PTDMs of our test panel. Additional experiments included dynamic light scattering and zeta potential measurements to measure size as a function of vesicle surface charge in the presence of increasing PTDM concentration and surface plasmon resonance spectroscopy to quantify binding between PTDMs and surface-bound lipid layers with varying anion content. The results from these measurements suggested that PTDM hydrophobicity, not cation-anion interactions, is the main driving force of the interaction between our PTDMs and the model membranes investigated. This suggests a model of interaction where surface association and membrane insertion are driven by PTDM hydrophobicity, while anionic lipid content serves primarily to "pin" the PTDM to the membrane surface and limit insertion. PMID:27182683

  10. Enhanced photocatalytic activity of a self-stabilized synthetic flavin anchored on a TiO2 surface.

    PubMed

    Pandiri, Manjula; Hossain, Mohammad S; Foss, Frank W; Rajeshwar, Krishnan; Paz, Yaron

    2016-07-21

    Synthetic flavin molecules were anchored on Degussa P25 titanium dioxide (TiO2). The effect of their presence on the photocatalytic (PC) activity of TiO2 was studied. Under UV light, an increase in the degradation rate of ethanol was observed. This increase was accompanied by stabilization of the anchored flavin against self-degradation. The unprecedented stabilization effect was found also in the absence of a reducing agent such as ethanol. In contrast, under the less energetic visible light, fast degradation of the anchored flavin was observed. These rather surprising observations were attributed to the propensity for charge transport from excited flavin molecules to the semiconductor and to the role that such charge transfer may play in stabilizing the overall assembly. Anchored flavins excited by UV light to their S2, S3 electronic states were able to transfer the excited electrons to the TiO2 phase whereas anchored flavin molecules that were excited by visible light to the S1 state were less likely to transfer the photo-excited electrons and therefore were destabilized. These findings may be relevant not only to anchored flavins in general but to other functionalized photocatalysts, and may open up new vistas in the implementation of sensitizers in PC systems.

  11. Anionic Lipid Content Presents a Barrier to the Activity of ROMP-Based Synthetic Mimics of Protein Transduction Domains (PTDMs).

    PubMed

    Lis, Michael; Dorner, Franziska; Tew, Gregory N; Lienkamp, Karen

    2016-06-14

    Many biophysical studies of protein transduction domains (PTDs) and their synthetic mimics (PTDMs) focus on the interaction between the polycationic PTD(M) and anionic phospholipid surfaces. Most, but not all, of these studies suggest that these cation-anion interactions are vital for membrane activity. In this study, the effect of anionic lipid content on PTDM performance was examined for three ring-opening metathesis (ROMP)-based PTDMs with varying hydrophobicity. Using a series of dye-loaded vesicles with gradually increasing anionic lipid content, we saw that increased anionic lipid content inhibited dye release caused by these PTDMs. This result is the opposite of what was found in studies with poly- and oligo-arginine. While the effect is reduced for more hydrophobic PTDMs, it is observable even with the most hydrophobic PTDMs of our test panel. Additional experiments included dynamic light scattering and zeta potential measurements to measure size as a function of vesicle surface charge in the presence of increasing PTDM concentration and surface plasmon resonance spectroscopy to quantify binding between PTDMs and surface-bound lipid layers with varying anion content. The results from these measurements suggested that PTDM hydrophobicity, not cation-anion interactions, is the main driving force of the interaction between our PTDMs and the model membranes investigated. This suggests a model of interaction where surface association and membrane insertion are driven by PTDM hydrophobicity, while anionic lipid content serves primarily to "pin" the PTDM to the membrane surface and limit insertion.

  12. In vitro acaricidal activity of Murraya koenigii (L.) Spreng (Rutaceae) extracts against synthetic pyrethroid-resistant Rhipicephalus (Boophilus) microplus.

    PubMed

    Singh, Nirbhay Kumar; Jyoti; Vemu, Bhaskar; Singh, Harkirat; Prerna, Mranalini; Daundkar, Prashant S; Sharma, S K; Dumka, V K

    2015-04-01

    Larval packet test was used for detection of resistance status against cypermethrin and deltamethrin, the most commonly used synthetic pyrethroids in Rhipicephalus (Boophilus) microplus collected from Faridkot district, Punjab (India). The slope of mortality, lethal concentration for 50 % (LC50) and resistance levels were determined from the regression graphs of probit mortality of ticks plotted against log values of increasing concentrations of cypermethrin and deltamethrin. Results indicated presence of resistance of levels I and II against cypermethrin (resistance factor (RF) = 2.82) and deltamethrin (RF = 8.44), respectively. Adult immersion test was used to assess the acaricidal activity of aqueous (MLAq), ethanol (MLE), chloroform (MLC), acetone (MLA) and hexane (MLH) extracts of leaves of Murraya koenigii against these synthetic pyrethroid (SP)-resistant engorged adult females of R. (B.) microplus by determination of per cent adult mortality, reproductive index (RI), per cent inhibition of oviposition (%IO) and hatching rate. The per cent mortality caused by various extracts at concentrations ranging from 0.625 to 10.0% varied from 0.0 to 100.0% with maximum per cent mortality of 10.0, 100.0, 70.0, 40.0 and 10.0 recorded against MLAq, MLE, MLC, MLA and MLH, respectively. Among all extracts, the highest acaricidal property against SP-resistant R. (B.) microplus was exhibited by the MLE as it showed the minimum LC50 [95% confidence limit (CL)] values of 2.97% (2.82-3.12%), followed by MLC as 10.26% (8.84-11.91 %) and MLA as 18.22% (16.18-20.52%). The average egg mass weight recorded in live ticks treated with various concentrations of different extracts was lower than the respective control group ticks and was significantly (p < 0.01) lower in ticks treated with MLH extract. However, no significant effect on hatchability of eggs of treated groups when compared to control was recorded. A significant (p < 0.05) decrease in the RI was recorded in

  13. 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

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

    2006-01-01

    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-κB 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

  14. Selective antiviral activity of synthetic soluble L-tyrosine and L-dopa melanins against human immunodeficiency virus in vitro.

    PubMed

    Montefiori, D C; Zhou, J Y

    1991-01-01

    Melanins are pigments found in hair, skin, irides of the eye, and brain. Their functions in mammals include protection from exposure to sunlight, camouflage from predators, sexual recognition within species, and possible electron transfer reactants. Most natural melanins exist in an insoluble form, which is one reason there is little information on the biological properties of soluble melanins. Here, synthetic soluble melanins were obtained by chemical oxidation of L-tyrosine or spontaneous oxidation of L-beta-3,4-dihydroxyphenylalanine (L-dopa). Replication of human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) was inhibited by soluble melanin in two human lymphoblastoid cell lines (MT-2 and H9) and in phytohemagglutinin-stimulated human T cells. Effective concentrations of 0.15-10 micrograms/ml had no cell toxicity. Melanin blocked infection by cell-free virus and interfered with HIV-induced syncytium formation and cytopathic effects when fusion-susceptible, uninfected cells, were mixed with chronically infected cells. Melanin also impeded the HIV-1 envelope surface glycoprotein, and T cell specific monoclonal antibody leu-3a (CD4), but not leu-5b (CD2), from binding to the surface of MT-2 cells. No effect on HIV-1 reverse transcriptase activity in viral lysates was observed. These results identify a unique biological property of melanin, and suggest that soluble melanins may represent a new class of pharmacologically active substances which should be further investigated for potential therapeutic utility in the treatment of Acquired Immune Deficiency Syndrome (AIDS).

  15. CCL-34, a synthetic toll-like receptor 4 activator, modulates differentiation and maturation of myeloid dendritic cells

    PubMed Central

    Fu, Shu-Ling; Lin, Chun-Cheng; Hsu, Ming-Ling; Liu, Sheng-Hung; Huang, Yu-Chuen; Chen, Yu-Jen

    2016-01-01

    CCL-34, a synthetic α-galactosylceramide analog, has been reported as an activator of toll-like receptor 4 (TLR4) in macrophages. TLR4 is highly expressed in dendritic cell (DC) and several TLR4 agonists are known to trigger DC maturation. We herein evaluated the effect of CCL-34 on DC maturation. Human CD14+ monocyte-derived immature DC were treated with CCL-34, its inactive structural analog CCL-44, or LPS to assess the DC maturation. CCL-34 induced DC maturation according to their characteristically dendrite-forming morphology, CD83 expression and IL-12p70 production. The allostimulatory activity of DC on proliferation of naive CD4+CD45+RA+ T cells and their secretion of interferon-γ was increased by CCL-34. Phagocytosis, an important function of immature DC, was reduced after CCL-34 treatment. All these effects related to DC maturation were evidently induced by positive control LPS but not by CCL-44 treatment. TLR4 neutralization impaired human DC maturation triggered by CCL-34. The induction of IL-12, a hallmark of DC maturation, by CCL-34 and LPS was only evident in TLR4-competent C3H/HeN, but not in TLR4-defective C3H/HeJ mice. CCL-34 could further elicit the antigen presentation capability in mice inoculated with doxorubicin-treated colorectal cancer cells. In summary, CCL-34 triggers DC maturation via a TLR4-dependent manner, which supports its potential application as an immunostimulator. PMID:26883191

  16. Acaricidal activity of Cymbopogon winterianus, Vitex negundo and Withania somnifera against synthetic pyrethroid resistant Rhipicephalus (Boophilus) microplus.

    PubMed

    Singh, Nirbhay Kumar; Jyoti; Vemu, Bhaskar; Nandi, Abhijit; Singh, Harkirat; Kumar, Rajender; Dumka, V K

    2014-01-01

    Detection of resistance levels against cypermethrin and deltamethrin, the most commonly used synthetic pyrethroids (SPs) against Rhipicephalus (Boophilus) microplus collected from Moga, Punjab (India) was carried out using larval packet test. Results indicated the presence of resistance of level I and III against cypermethrin (resistance factors (RF) = 4.67) and deltamethrin (RF = 34.2), respectively. Adult immersion test was used to assess the acaricidal activity of aqueous and ethanolic extracts of leaves of Cymbopogon winterianus, Vitex negundo, and Withania somnifera along with roots of V. negundo against the SP resistant engorged females of R. (B.) microplus. The efficacy of various extracts was assessed by estimation of percent adult mortality, reproductive index (RI), percent inhibition of oviposition (%IO), and hatching rate. A concentration dependent increase in tick mortality was recorded which was more marked with various ethanolic extracts, and highest mortality was recorded in ticks treated with ethanolic extract of leaves of C. winterianus. The LC50 values were determined by applying regression equation analysis to the probit transformed data of mortality for various aqueous and ethanolic extracts. Acaricidal property was recorded to be higher in ethanolic extracts, and high activity was found with the ethanolic extract of leaves of C. winterianus with LC50 (95% CL) values of 0.46% (0.35-0.59%), followed by W. somnifera as 5.21% (4.45-6.09%) and V. negundo as 7.02% (4.58-10.74%). The egg mass weight of the live ticks treated with different concentrations of the various extract was significantly (p < 0.01) lower than that of control ticks; consequently, the RI and the %IO value of the treated ticks were reduced. Further, complete inhibition of hatching was recorded in eggs laid by ticks treated with ethanolic extracts of leaves of V. negundo and aqueous extracts of leaves of W. somnifera. The results of the current study indicate that extracts of C

  17. Synthetic Cathinones ("Bath Salts")

    MedlinePlus

    ... still unknown about how synthetic cathinones affect the human brain. Researchers do know that synthetic cathinones are chemically ... of the chemicals in synthetic cathinones affect the human brain. Synthetic cathinones can cause: nosebleeds paranoia increased sociability ...

  18. Synthetic Cannabinoids.

    PubMed

    Mills, Brooke; Yepes, Andres; Nugent, Kenneth

    2015-07-01

    Synthetic cannabinoids (SCBs), also known under the brand names of "Spice," "K2," "herbal incense," "Cloud 9," "Mojo" and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors. Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis. This is likely due to SCBs being direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants. The largest group of users is men in their 20s who participate in polydrug use. The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use. Treatment mostly involves symptom management and supportive care. More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.

  19. Cancer Cell Growth Is Differentially Affected by Constitutive Activation of NRF2 by KEAP1 Deletion and Pharmacological Activation of NRF2 by the Synthetic Triterpenoid, RTA 405

    PubMed Central

    Probst, Brandon L.; McCauley, Lyndsey; Trevino, Isaac; Wigley, W. Christian; Ferguson, Deborah A.

    2015-01-01

    Synthetic triterpenoids are antioxidant inflammation modulators (AIMs) that exhibit broad anticancer activity. AIMs bind to KEAP1 and inhibit its ability to promote NRF2 degradation. As a result, NRF2 increases transcription of genes that restore redox balance and reduce inflammation. AIMs inhibit tumor growth and metastasis by increasing NRF2 activity in the tumor microenvironment and by modulating the activity of oncogenic signaling pathways, including NF-κB, in tumor cells. Accumulating evidence suggests that KEAP1 loss or mutation—which results in high levels of sustained NRF2 activity—may promote cancer growth and increase chemoresistance. Loss of KEAP1 also increases the levels of other oncogenic proteins, including IKKβ and BCL2. The apparent survival advantage provided to some tumor cells by loss of functional KEAP1 raises the question of whether pharmacological inhibition of KEAP1 could promote tumor growth. To address this issue, we characterized the basal levels of KEAP1 and NRF2 in a panel of human tumor cell lines and profiled the activity of an AIM, RTA 405. We found that in tumor cell lines with low or mutant KEAP1, and in Keap1-/- murine embryonic fibroblasts, multiple KEAP1 targets including NRF2, IKKβ, and BCL2 were elevated. Keap1-/- murine embryonic fibroblasts also had higher rates of proliferation and colony formation than their wild-type counterparts. In cells with functional KEAP1, RTA 405 increased NRF2 levels, but not IKKβ or BCL2 levels, and did not increase cell proliferation or survival. Moreover, RTA 405 inhibited growth at similar concentrations in cells with different basal NRF2 activity levels and in cells with wild-type or mutant KRAS. Finally, pre-treatment with RTA 405 did not protect tumor cells from doxorubicin- or cisplatin-mediated growth inhibition. Collectively, these data demonstrate that pharmacological activation of NRF2 by AIMs is distinct from genetic activation and does not provide a growth or survival

  20. C- and N-Selective Grignard Addition Reactions of α-Aldimino Esters in the Presence or Absence of Zinc(II) Chloride: Synthetic Applications to Optically Active Azacycles.

    PubMed

    Hatano, Manabu; Yamashita, Kenji; Ishihara, Kazuaki

    2015-05-15

    Highly practical synthetic methods were developed for the C- and N-selective Grignard addition reactions of N-4-MeOC6H4-protected α-aldimino esters in the presence or absence of zinc(II) chloride. Diastereoselective C-alkyl addition, tandem C-alkyl addition-N-alkylation, and some transformations to synthetically useful optically active azacycles were demonstrated.

  1. Synthetic Brainbows

    PubMed Central

    Wan, Y.; Otsuna, H.; Hansen, C.

    2014-01-01

    Brainbow is a genetic engineering technique that randomly colorizes cells. Biological samples processed with this technique and imaged with confocal microscopy have distinctive colors for individual cells. Complex cellular structures can then be easily visualized. However, the complexity of the Brainbow technique limits its applications. In practice, most confocal microscopy scans use different florescence staining with typically at most three distinct cellular structures. These structures are often packed and obscure each other in rendered images making analysis difficult. In this paper, we leverage a process known as GPU framebuffer feedback loops to synthesize Brainbow-like images. In addition, we incorporate ID shuffing and Monte-Carlo sampling into our technique, so that it can be applied to single-channel confocal microscopy data. The synthesized Brainbow images are presented to domain experts with positive feedback. A user survey demonstrates that our synthetic Brainbow technique improves visualizations of volume data with complex structures for biologists. PMID:25018576

  2. DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma

    PubMed Central

    Amodio, Nicola; Leotta, Marzia; Bellizzi, Dina; Di Martino, Maria Teresa; D'Aquila, Patrizia; Lionetti, Marta; Fabiani, Fernanda; Leone, Emanuela; Gullà, Anna Maria; Passarino, Giuseppe; Caraglia, Michele; Negrini, Massimo; Neri, Antonino; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2012-01-01

    Aberrant DNA methylation plays a relevant role in multiple myeloma (MM) pathogenesis. MicroRNAs (miRNAs) are a class of small non-coding RNAs that recently emerged as master regulator of gene expression by targeting protein-coding mRNAs. However, miRNAs involvement in the regulation of the epigenetic machinery and their potential use as therapeutics in MM remain to be investigated. Here, we provide evidence that the expression of de novo DNA methyltransferases (DNMTs) is deregulated in MM cells. Moreover, we show that miR-29b targets DNMT3A and DNMT3B mRNAs and reduces global DNA methylation in MM cells. In vitro transfection of MM cells with synthetic miR-29b mimics significantly impairs cell cycle progression and also potentiates the growth-inhibitory effects induced by the demethylating agent 5-azacitidine. Most importantly, in vivo intratumor or systemic delivery of synthetic miR-29b mimics, in two clinically relevant murine models of human MM, including the SCID-synth-hu system, induces significant anti-tumor effects. All together, our findings demonstrate that aberrant DNMTs expression is efficiently modulated by tumor suppressive synthetic miR-29b mimics, indicating that methyloma modulation is a novel matter of investigation in miRNA-based therapy of MM. PMID:23100393

  3. MAM-2201, a synthetic cannabinoid drug of abuse, suppresses the synaptic input to cerebellar Purkinje cells via activation of presynaptic CB1 receptors.

    PubMed

    Irie, Tomohiko; Kikura-Hanajiri, Ruri; Usami, Makoto; Uchiyama, Nahoko; Goda, Yukihiro; Sekino, Yuko

    2015-08-01

    Herbal products containing synthetic cannabinoids-initially sold as legal alternatives to marijuana-have become major drugs of abuse. Among the synthetic cannabinoids, [1-(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl)-methanone (MAM-2201) has been recently detected in herbal products and has psychoactive and intoxicating effects in humans, suggesting that MAM-2201 alters brain function. Nevertheless, the pharmacological actions of MAM-2201 on cannabinoid receptor type 1 (CB1R) and neuronal functions have not been elucidated. We found that MAM-2201 acted as an agonist of human CB1Rs expressed in AtT-20 cells. In whole-cell patch-clamp recordings made from Purkinje cells (PCs) in slice preparations of the mouse cerebellum, we also found that MAM-2201 inhibited glutamate release at parallel fiber-PC synapses via activation of presynaptic CB1Rs. MAM-2201 inhibited neurotransmitter release with an inhibitory concentration 50% of 0.36 μM. MAM-2201 caused greater inhibition of neurotransmitter release than Δ(9)-tetrahydrocannabinol within the range of 0.1-30 μM and JWH-018, one of the most popular and potent synthetic cannabinoids detected in the herbal products, within the range of 0.03-3 μM. MAM-2201 caused a concentration-dependent suppression of GABA release onto PCs. Furthermore, MAM-2201 induced suppression of glutamate release at climbing fiber-PC synapses, leading to reduced dendritic Ca(2+) transients in PCs. These results suggest that MAM-2201 is likely to suppress neurotransmitter release at CB1R-expressing synapses in humans. The reduction of neurotransmitter release from CB1R-containing synapses could contribute to some of the symptoms of synthetic cannabinoid intoxication including impairments in cerebellum-dependent motor coordination and motor learning. PMID:25747605

  4. MAM-2201, a synthetic cannabinoid drug of abuse, suppresses the synaptic input to cerebellar Purkinje cells via activation of presynaptic CB1 receptors.

    PubMed

    Irie, Tomohiko; Kikura-Hanajiri, Ruri; Usami, Makoto; Uchiyama, Nahoko; Goda, Yukihiro; Sekino, Yuko

    2015-08-01

    Herbal products containing synthetic cannabinoids-initially sold as legal alternatives to marijuana-have become major drugs of abuse. Among the synthetic cannabinoids, [1-(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl)-methanone (MAM-2201) has been recently detected in herbal products and has psychoactive and intoxicating effects in humans, suggesting that MAM-2201 alters brain function. Nevertheless, the pharmacological actions of MAM-2201 on cannabinoid receptor type 1 (CB1R) and neuronal functions have not been elucidated. We found that MAM-2201 acted as an agonist of human CB1Rs expressed in AtT-20 cells. In whole-cell patch-clamp recordings made from Purkinje cells (PCs) in slice preparations of the mouse cerebellum, we also found that MAM-2201 inhibited glutamate release at parallel fiber-PC synapses via activation of presynaptic CB1Rs. MAM-2201 inhibited neurotransmitter release with an inhibitory concentration 50% of 0.36 μM. MAM-2201 caused greater inhibition of neurotransmitter release than Δ(9)-tetrahydrocannabinol within the range of 0.1-30 μM and JWH-018, one of the most popular and potent synthetic cannabinoids detected in the herbal products, within the range of 0.03-3 μM. MAM-2201 caused a concentration-dependent suppression of GABA release onto PCs. Furthermore, MAM-2201 induced suppression of glutamate release at climbing fiber-PC synapses, leading to reduced dendritic Ca(2+) transients in PCs. These results suggest that MAM-2201 is likely to suppress neurotransmitter release at CB1R-expressing synapses in humans. The reduction of neurotransmitter release from CB1R-containing synapses could contribute to some of the symptoms of synthetic cannabinoid intoxication including impairments in cerebellum-dependent motor coordination and motor learning.

  5. Hyper-active non-homologous end joining selects for synthetic lethality resistant and pathological Fanconi anemia hematopoietic stem and progenitor cells

    PubMed Central

    Du, Wei; Amarachintha, Surya; Wilson, Andrew F.; Pang, Qishen

    2016-01-01

    The prominent role of Fanconi anemia (FA) proteins involves homologous recombination (HR) repair. Poly[ADP-ribose] polymerase1 (PARP1) functions in multiple cellular processes including DNA repair and PARP inhibition is an emerging targeted therapy for cancer patients deficient in HR. Here we show that PARP1 activation in hematopoietic stem and progenitor cells (HSPCs) in response to genotoxic or oxidative stress attenuates HSPC exhaustion. Mechanistically, PARP1 controls the balance between HR and non-homologous end joining (NHEJ) in double strand break (DSB) repair by preventing excessive NHEJ. Disruption of the FA core complex skews PARP1 function in DSB repair and led to hyper-active NHEJ in Fanca−/− or Fancc−/− HSPCs. Re-expression of PARP1 rescues the hyper-active NHEJ phenotype in Brca1−/−Parp1−/− but less effective in Fanca−/−Parp1−/− cells. Inhibition of NHEJ prevents myeloid/erythroid pathologies associated with synthetic lethality. Our results suggest that hyper-active NHEJ may select for “synthetic lethality” resistant and pathological HSPCs. PMID:26916217

  6. High specific selectivity and Membrane-Active Mechanism of the synthetic centrosymmetric α-helical peptides with Gly-Gly pairs.

    PubMed

    Wang, Jiajun; Chou, Shuli; Xu, Lin; Zhu, Xin; Dong, Na; Shan, Anshan; Chen, Zhihui

    2015-01-01

    We used a template-assisted approach to develop synthetic antimicrobial peptides, which differ from naturally occurring antimicrobial peptides that can compromise host natural defenses. Previous researches have demonstrated that symmetrical distribution patterns of amino acids contribute to the antimicrobial activity of natural peptides. However, there is little research describing such design ideas for synthetic α-helical peptides. Therefore, here, we established a centrosymmetric α-helical sequence template (y + hhh + y)n (h, hydrophobic amino acid; +, cationic amino acid; y, Gly or hydrophobic amino acid), which contributed to amphipathicity, and a series of centrosymmetric peptides was designed with pairs of small amino acids (Ala and Gly), which were utilized to modulate the biological activity. The centrosymmetric peptides with 3 repeat units exhibited strong antimicrobial activity; in particular, the Gly-rich centrosymmetric peptide GG3 showed stronger selectivity for gram-negative bacteria without hemolysis. Furthermore, beyond our expectation, fluorescence spectroscopy and electron microscopy analyses indicated that the GG3, which possessed poor α-helix conformation, dramatically exhibited marked membrane destruction via inducing bacterial membrane permeabilization, pore formation and disruption, even bound DNA to further exert antimicrobial activity. Collectively, the Gly-rich centrosymmetric peptide GG3 was an ideal candidate for commercialization as a clinical therapeutic to treat gram-negative bacterial infections. PMID:26530005

  7. High specific selectivity and Membrane-Active Mechanism of the synthetic centrosymmetric α-helical peptides with Gly-Gly pairs

    PubMed Central

    Wang, Jiajun; Chou, Shuli; Xu, Lin; Zhu, Xin; Dong, Na; Shan, Anshan; Chen, Zhihui

    2015-01-01

    We used a template-assisted approach to develop synthetic antimicrobial peptides, which differ from naturally occurring antimicrobial peptides that can compromise host natural defenses. Previous researches have demonstrated that symmetrical distribution patterns of amino acids contribute to the antimicrobial activity of natural peptides. However, there is little research describing such design ideas for synthetic α-helical peptides. Therefore, here, we established a centrosymmetric α-helical sequence template (y + hhh + y)n (h, hydrophobic amino acid; +, cationic amino acid; y, Gly or hydrophobic amino acid), which contributed to amphipathicity, and a series of centrosymmetric peptides was designed with pairs of small amino acids (Ala and Gly), which were utilized to modulate the biological activity. The centrosymmetric peptides with 3 repeat units exhibited strong antimicrobial activity; in particular, the Gly-rich centrosymmetric peptide GG3 showed stronger selectivity for gram-negative bacteria without hemolysis. Furthermore, beyond our expectation, fluorescence spectroscopy and electron microscopy analyses indicated that the GG3, which possessed poor α-helix conformation, dramatically exhibited marked membrane destruction via inducing bacterial membrane permeabilization, pore formation and disruption, even bound DNA to further exert antimicrobial activity. Collectively, the Gly-rich centrosymmetric peptide GG3 was an ideal candidate for commercialization as a clinical therapeutic to treat gram-negative bacterial infections. PMID:26530005

  8. In Vitro Activity of Neisseria meningitidis PglL O-Oligosaccharyltransferase with Diverse Synthetic Lipid Donors and a UDP-activated Sugar*

    PubMed Central

    Musumeci, Matias A.; Hug, Isabelle; Scott, Nichollas E.; Ielmini, M. Veronica; Foster, Leonard J.; Wang, Peng G.; Feldman, Mario F.

    2013-01-01

    Oligosaccharyltransferases (OTases) are enzymes that catalyze the transfer of an oligosaccharide from a lipid carrier to an acceptor molecule, commonly a protein. OTases are classified as N-OTases and O-OTases, depending on the nature of the glycosylation reaction. The N-OTases catalyze the glycan transfer to amide groups in asparagines in a reaction named N-linked glycosylation. The O-OTases are responsible for protein O-linked glycosylation, which involves the attachment of glycans to hydroxyl groups of serine or threonine residues. These enzymes exhibit a relaxed specificity and are able to transfer a variety of glycan structures to different protein acceptors. This property confers OTases with great biotechnological potential as these enzymes can produce glycoconjugates relevant to the pharmaceutical industry. Furthermore, OTases are thought to be involved in pathogenesis mechanisms. Several aspects of the functionality of OTases are not fully understood. In this work, we developed a novel approach to perform kinetic studies on PglL, the O-OTase from Neisseria meningitidis. We investigated the importance of the acyl moiety of the lipid glycan donor substrate on the functionality of PglL by testing the efficiency of glycosylation reactions using synthetic substrates carrying the same glycan structure but different acyl moieties. We found that PglL can function with many lipids as glycan donors, although the length and the conformation of the lipid moiety significantly influenced the catalytic efficiency. Interestingly, PglL was also able to transfer a monosaccharide employing its nucleotide-activated form, acting as a Leloir glycosyltransferase. These results provide new insights on the function and the evolution of oligosaccharyltransferases. PMID:23460642

  9. In-situ monitoring of biologically active solar UV-B radiation: a new biosensor of vitamin D synthetic capacity

    NASA Astrophysics Data System (ADS)

    Terenetskaya, Irina P.; Gvozdovskyy, I. A.

    2001-06-01

    The new biosensor of vitamin D synthetic capacity of solar/artificial UV-B radiation is based on liquid crystal with provitamin D dopant. Nematic liquid crystals (LC-805, ZLI-1695) are converted into induced cholesteric phase using photosensitive steroid biomolecules of provitamin D3 (7- dehydrocholesterol). During UV exposure remarkable decrease in the number of the Cano-Grandjean stripes has been observed in the wedge-like cell as a result of UV initiated photoisomerization of provitamin D3 that changed helical twisting power of the dopant molecules.

  10. Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: Insight into functional group effects and biological activity

    PubMed Central

    Sharpe, Robert J.; Malinowski, Justin T.; Sorana, Federico; Luft, J. Christopher; Bowerman, Charles J.; DeSimone, Joseph M.; Johnson, Jeffrey S.

    2015-01-01

    The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin’s biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation. PMID:25792144

  11. Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: insight into functional group effects and biological activity.

    PubMed

    Sharpe, Robert J; Malinowski, Justin T; Sorana, Federico; Luft, J Christopher; Bowerman, Charles J; DeSimone, Joseph M; Johnson, Jeffrey S

    2015-04-15

    The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin's biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation. PMID:25792144

  12. Definition of a physiologic aging autoantigen by using synthetic peptides of membrane protein band 3: localization of the active antigenic sites.

    PubMed

    Kay, M M; Marchalonis, J J; Hughes, J; Watanabe, K; Schluter, S F

    1990-08-01

    Senescent cell antigen (SCA), an aging antigen, is a protein that appears on old cells and marks them for removal by the immune system in mammals. It is derived from band 3, a ubiquitous membrane transport protein found in diverse cell types and tissues. We have used synthetic peptides to identify aging antigenic sites on band 3, using a competitive inhibition assay and immunoblotting with IgG directed against the aging antigen on old cells. Results indicate that: (i) the active antigenic sites of the aging antigen reside on membrane protein band 3 residues that are extracellular regions implicated in anion transport (residues 538-554 and 788-827); (ii) a putative ankyrin-binding-region peptide is not involved in SCA activity; and (iii) carbohydrate moieties are not required for the antigenicity or recognition of SCA because synthetic peptides alone abolish binding of senescent cell IgG to erythrocytes. One of the putative transport sites that contributes to the aging antigen is located toward the carboxyl terminus. A model of band 3 is presented. Localization of the active antigenic site on the band 3 molecule facilitates definition of the molecular changes occurring during aging that initiate molecular as well as cellular degeneration. PMID:1696010

  13. Semi-synthetic preparation of 1-O-(1'-/sup 14/C)hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (platelet activating factor) using plant cell cultures

    SciTech Connect

    Weber, N.; Mangold, H.K.

    1985-04-01

    Incubation of photomixotrophic cell suspension cultures of rape (Brassica napus) and heterotrophic cell suspension cultures of soya (Glycine max) with 1-O-(1'-/sup 14/C)hexadecyl-sn-glycerol or rac-1-O-(1'-/sup 14/C)hexadecylglycerol leads in high yield (up to 78%) to labeled 1-O-hexadecyl-2-acyl-sn-glycero-3-phosphocholines. Alkaline hydrolysis of the choline glycerophospholipids yields pure 1-O-(1'-/sup 14/C)hexadecyl-sn-glycero-3-phosphocholine. 1-O-(1'-14C)Hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (platelet activating factor) is obtained by acetylating the lyso compound. The semi-synthetic preparation described leads to labeled platelet activating factor in an overall yield of 50-60% without loss of specific activity.

  14. Post-Stroke Depression Modulation and in Vivo Antioxidant Activity of Gallic Acid and Its Synthetic Derivatives in a Murine Model System

    PubMed Central

    Nabavi, Seyed Fazel; Habtemariam, Solomon; Di Lorenzo, Arianna; Sureda, Antoni; Khanjani, Sedigheh; Nabavi, Seyed Mohammad; Daglia, Maria

    2016-01-01

    Gallic acid (3,4,5-trihydroxybenzoic acid, GA) is a plant secondary metabolite, which shows antioxidant activity and is commonly found in many plant-based foods and beverages. Recent evidence suggests that oxidative stress contributes to the development of many human chronic diseases, including cardiovascular and neurodegenerative pathologies, metabolic syndrome, type 2 diabetes and cancer. GA and its derivative, methyl-3-O-methyl gallate (M3OMG), possess physiological and pharmacological activities closely related to their antioxidant properties. This paper describes the antidepressive-like effects of intraperitoneal administration of GA and two synthetic analogues, M3OMG and P3OMG (propyl-3-O-methylgallate), in balb/c mice with post-stroke depression, a secondary form of depression that could be due to oxidative stress occurring during cerebral ischemia and the following reperfusion. Moreover, this study determined the in vivo antioxidant activity of these compounds through the evaluation of superoxide dismutase (SOD) and catalase (Cat) activity, thiobarbituric acid-reactive substances (TBARS) and reduced glutathione (GSH) levels in mouse brain. GA and its synthetic analogues were found to be active (at doses of 25 and 50 mg/kg) in the modulation of depressive symptoms and the reduction of oxidative stress, restoring normal behavior and, at least in part, antioxidant endogenous defenses, with M3OMG being the most active of these compounds. SOD, TBARS, and GSH all showed strong correlation with behavioral parameters, suggesting that oxidative stress is tightly linked to the pathological processes involved in stroke and PSD. As a whole, the obtained results show that the administration of GA, M3OMG and P3OMG induce a reduction in depressive symptoms and oxidative stress. PMID:27136579

  15. Post-Stroke Depression Modulation and in Vivo Antioxidant Activity of Gallic Acid and Its Synthetic Derivatives in a Murine Model System.

    PubMed

    Nabavi, Seyed Fazel; Habtemariam, Solomon; Di Lorenzo, Arianna; Sureda, Antoni; Khanjani, Sedigheh; Nabavi, Seyed Mohammad; Daglia, Maria

    2016-04-28

    Gallic acid (3,4,5-trihydroxybenzoic acid, GA) is a plant secondary metabolite, which shows antioxidant activity and is commonly found in many plant-based foods and beverages. Recent evidence suggests that oxidative stress contributes to the development of many human chronic diseases, including cardiovascular and neurodegenerative pathologies, metabolic syndrome, type 2 diabetes and cancer. GA and its derivative, methyl-3-O-methyl gallate (M3OMG), possess physiological and pharmacological activities closely related to their antioxidant properties. This paper describes the antidepressive-like effects of intraperitoneal administration of GA and two synthetic analogues, M3OMG and P3OMG (propyl-3-O-methylgallate), in balb/c mice with post-stroke depression, a secondary form of depression that could be due to oxidative stress occurring during cerebral ischemia and the following reperfusion. Moreover, this study determined the in vivo antioxidant activity of these compounds through the evaluation of superoxide dismutase (SOD) and catalase (Cat) activity, thiobarbituric acid-reactive substances (TBARS) and reduced glutathione (GSH) levels in mouse brain. GA and its synthetic analogues were found to be active (at doses of 25 and 50 mg/kg) in the modulation of depressive symptoms and the reduction of oxidative stress, restoring normal behavior and, at least in part, antioxidant endogenous defenses, with M3OMG being the most active of these compounds. SOD, TBARS, and GSH all showed strong correlation with behavioral parameters, suggesting that oxidative stress is tightly linked to the pathological processes involved in stroke and PSD. As a whole, the obtained results show that the administration of GA, M3OMG and P3OMG induce a reduction in depressive symptoms and oxidative stress.

  16. Post-Stroke Depression Modulation and in Vivo Antioxidant Activity of Gallic Acid and Its Synthetic Derivatives in a Murine Model System.

    PubMed

    Nabavi, Seyed Fazel; Habtemariam, Solomon; Di Lorenzo, Arianna; Sureda, Antoni; Khanjani, Sedigheh; Nabavi, Seyed Mohammad; Daglia, Maria

    2016-01-01

    Gallic acid (3,4,5-trihydroxybenzoic acid, GA) is a plant secondary metabolite, which shows antioxidant activity and is commonly found in many plant-based foods and beverages. Recent evidence suggests that oxidative stress contributes to the development of many human chronic diseases, including cardiovascular and neurodegenerative pathologies, metabolic syndrome, type 2 diabetes and cancer. GA and its derivative, methyl-3-O-methyl gallate (M3OMG), possess physiological and pharmacological activities closely related to their antioxidant properties. This paper describes the antidepressive-like effects of intraperitoneal administration of GA and two synthetic analogues, M3OMG and P3OMG (propyl-3-O-methylgallate), in balb/c mice with post-stroke depression, a secondary form of depression that could be due to oxidative stress occurring during cerebral ischemia and the following reperfusion. Moreover, this study determined the in vivo antioxidant activity of these compounds through the evaluation of superoxide dismutase (SOD) and catalase (Cat) activity, thiobarbituric acid-reactive substances (TBARS) and reduced glutathione (GSH) levels in mouse brain. GA and its synthetic analogues were found to be active (at doses of 25 and 50 mg/kg) in the modulation of depressive symptoms and the reduction of oxidative stress, restoring normal behavior and, at least in part, antioxidant endogenous defenses, with M3OMG being the most active of these compounds. SOD, TBARS, and GSH all showed strong correlation with behavioral parameters, suggesting that oxidative stress is tightly linked to the pathological processes involved in stroke and PSD. As a whole, the obtained results show that the administration of GA, M3OMG and P3OMG induce a reduction in depressive symptoms and oxidative stress. PMID:27136579

  17. Nanoparticles as synthetic vaccines.

    PubMed

    Smith, Josiah D; Morton, Logan D; Ulery, Bret D

    2015-08-01

    As vaccines have transitioned from the use of whole pathogens to only the required antigenic epitopes, unwanted side effects have been decreased, but corresponding immune responses have been greatly diminished. To enhance immunogenicity, a variety of controlled release vehicles have been proposed as synthetic vaccines, but nanoparticles have emerged as particularly impressive systems due to many exciting publications. In specific, nanoparticles have been shown capable of not only desirable vaccine release, but can also be targeted to immune cells of interest, loaded with immunostimulatory substances termed adjuvants, or even induce desirable immune activating effects on their own. In the present review, recent advances in the utilization of inorganic, polymeric, and biomolecular nanoparticles as synthetic vaccines are discussed.

  18. Wholly Synthetic Molecular Machines.

    PubMed

    Cheng, Chuyang; Stoddart, J Fraser

    2016-06-17

    The past quarter of a century has witnessed an increasing engagement on the part of physicists and chemists in the design and synthesis of molecular machines de novo. This minireview traces the development of artificial molecular machines from their prototypes in the form of shuttles and switches to their emergence as motors and pumps where supplies of energy in the form of chemical fuel, electrochemical potential and light activation become a minimum requirement for them to function away from equilibrium. The challenge facing this rapidly growing community of scientists and engineers today is one of putting wholly synthetic molecules to work, both individually and as collections. Here, we highlight some of the recent conceptual and practical advances relating to the operation of wholly synthetic rotary and linear motors.

  19. Synthetic Triterpenoid Cyano Enone of Methyl Boswellate (CEMB) activates intrinsic, extrinsic, & endoplasmic reticulum stress cell death pathways in tumor cell lines

    PubMed Central

    Ravanan, Palaniyandi; Sano, Renata; Priti, Talwar; Osawagia, Satoshi; Matsuzawa, Shuichi; Cuddy, Michael; Singh, Sanjay K.; Rao, G.S.R.Subba; Kondaiah, Paturu; Reed, John C.

    2014-01-01

    We explored the effect of a novel synthetic triterpenoid compound Cyano Enone of Methyl Boswellates (CEMB) on various prostate cancer and glioma cancer cell lines. CEMB displayed concentration-dependent cytotoxic activity with submicromolar lethal dose 50% (LD50) values in ten of ten tumor cell lines tested. CEMB-induced cytotoxicity is accompanied by activation of downstream effector caspases (caspases 3 and 7) and by upstream initiator caspases involved in both the extrinsic (caspase 8) and intrinsic (caspase 9) apoptotic pathways. By using small interfering RNAs (siRNAs), we show evidence that knock down of caspase 8, death receptor 4 (DR4), Apaf-1, and Bid impairs CEMB-induced cell death. Similar to other proapoptotic synthetic triterpenoid compounds, CEMB-induced apoptosis involved endoplasmic reticulum (ER) stress, as demonstrated by partial rescue of tumor cells by siRNA-mediated knock-down of expression of genes involve in the unfolded protein response such as Ire1, Perk, and ATF6. Altogether our results suggest that CEMB stimulates several apoptotic pathways in cancer cells, suggesting that this compound should be evaluated further as a potential agent for cancer therapy. PMID:21746806

  20. C- and N-Selective Grignard Addition Reactions of α-Aldimino Esters in the Presence or Absence of Zinc(II) Chloride: Synthetic Applications to Optically Active Azacycles.

    PubMed

    Hatano, Manabu; Yamashita, Kenji; Ishihara, Kazuaki

    2015-05-15

    Highly practical synthetic methods were developed for the C- and N-selective Grignard addition reactions of N-4-MeOC6H4-protected α-aldimino esters in the presence or absence of zinc(II) chloride. Diastereoselective C-alkyl addition, tandem C-alkyl addition-N-alkylation, and some transformations to synthetically useful optically active azacycles were demonstrated. PMID:25918830

  1. In vitro acaricidal activity of ethanolic and aqueous floral extracts of Calendula officinalis against synthetic pyrethroid resistant Rhipicephalus (Boophilus) microplus.

    PubMed

    Godara, R; Katoch, R; Yadav, A; Ahanger, R R; Bhutyal, A D S; Verma, P K; Katoch, M; Dutta, S; Nisa, F; Singh, N K

    2015-09-01

    Detection of resistance levels against deltamethrin and cypermethrin in Rhipicephalus (Boophilus) microplus collected from Jammu (India) was carried out using larval packet test (LPT). The results showed the presence of resistance level II and I against deltamethrin and cypermethrin, respectively. Adult immersion test (AIT) and LPT were used to evaluate the in vitro efficacy of ethanolic and aqueous floral extracts of Calendula officinalis against synthetic pyrethroid resistant adults and larvae of R. (B.) microplus. Four concentrations (1.25, 2.5, 5 and 10 %) of each extract with four replications for each concentration were used in both the bioassays. A concentration dependent mortality was observed and it was more marked with ethanolic extract. In AIT, the LC50 values for ethanolic and aqueous extracts were calculated as 9.9 and 12.9 %, respectively. The egg weight of the live ticks treated with different concentrations of the ethanolic and aqueous extracts was significantly lower than that of control ticks; consequently, the reproductive index and the percent inhibition of oviposition values of the treated ticks were reduced. The complete inhibition of hatching was recorded at 10 % of ethanolic extract. The 10 % extracts caused 100 % mortality of larvae after 24 h. In LPT, the LC50 values for ethanolic and aqueous extracts were determined to be 2.6 and 3.2 %, respectively. It can be concluded that the ethanolic extract of C. officinalis had better acaricidal properties against adults and larvae of R. (B.) microplus than the aqueous extract. PMID:26071101

  2. In vitro acaricidal activity of ethanolic and aqueous floral extracts of Calendula officinalis against synthetic pyrethroid resistant Rhipicephalus (Boophilus) microplus.

    PubMed

    Godara, R; Katoch, R; Yadav, A; Ahanger, R R; Bhutyal, A D S; Verma, P K; Katoch, M; Dutta, S; Nisa, F; Singh, N K

    2015-09-01

    Detection of resistance levels against deltamethrin and cypermethrin in Rhipicephalus (Boophilus) microplus collected from Jammu (India) was carried out using larval packet test (LPT). The results showed the presence of resistance level II and I against deltamethrin and cypermethrin, respectively. Adult immersion test (AIT) and LPT were used to evaluate the in vitro efficacy of ethanolic and aqueous floral extracts of Calendula officinalis against synthetic pyrethroid resistant adults and larvae of R. (B.) microplus. Four concentrations (1.25, 2.5, 5 and 10 %) of each extract with four replications for each concentration were used in both the bioassays. A concentration dependent mortality was observed and it was more marked with ethanolic extract. In AIT, the LC50 values for ethanolic and aqueous extracts were calculated as 9.9 and 12.9 %, respectively. The egg weight of the live ticks treated with different concentrations of the ethanolic and aqueous extracts was significantly lower than that of control ticks; consequently, the reproductive index and the percent inhibition of oviposition values of the treated ticks were reduced. The complete inhibition of hatching was recorded at 10 % of ethanolic extract. The 10 % extracts caused 100 % mortality of larvae after 24 h. In LPT, the LC50 values for ethanolic and aqueous extracts were determined to be 2.6 and 3.2 %, respectively. It can be concluded that the ethanolic extract of C. officinalis had better acaricidal properties against adults and larvae of R. (B.) microplus than the aqueous extract.

  3. The glow discharge inception and post-discharge relaxation of charged and neutral active particles in synthetic air at low pressure

    NASA Astrophysics Data System (ADS)

    Jovanović, A. P.; Marković, V. Lj; Stamenković, S. N.; Stankov, M. N.

    2015-11-01

    The study of dc glow discharge inception and post-discharge relaxation of charged and neutral active particles in synthetic air at low pressure is presented. The breakdown time delay dependence as a function of relaxation time \\overline{{{t}\\text{d}}}(τ ) (the memory curve) is measured and modelled from milliseconds to the saturation region determined by the cosmic rays and natural radioactivity level. Due to fast conversion \\text{N}2++{{\\text{O}}2}\\to {{\\text{N}}2}+\\text{O}2+ , relaxation of dc discharge in synthetic air in the time interval from one to about ninety milliseconds is dominated by the diffusion decay of molecular oxygen {{O}}_2^ + ions. The change of regimes, from ambipolar to the free diffusion limit, is investigated and the variation of effective diffusion coefficients is determined. The late relaxation is explained by the kinetics of nitrogen atoms, recombining on the surfaces of gas discharge tube and stainless steel electrodes and relevant surface recombination coefficients are determined.

  4. [Comparative study of molecular mechanisms of natural and synthetic polycationic peptides action on the activity of the adenylyl cyclase signaling system].

    PubMed

    Shpakov, A O; Gur'ianov, I A; Kuznetsova, L A; Plesneva, S A; Zakharova, E T; Vlasov, G P; Pertseva, M N

    2006-01-01

    The molecular mechanisms of action of natural and synthetic polycationic peptides, forming amphiphilic helices, on the heterotrimeric G-proteins and enzyme adenylyl cyclase (AC), components of hormone-sensitive AC system, were studied. It is shown that synthetic peptides C-epsilonAhx-WKK(C10)-KKK(C10)-KKKK(C10)-YKK(C10)-KK (peptide I) and (GRGDSGRKKRRQRRRPPQ)2-K-epsilonAhx-C(Acm)(peptide II) in dose-dependent manner stimulate the basal AC activity, inhibit forskolin-stimulated AC activity and decrease both stimulating and inhibiting AC effects of the hormones in the tissues (brain striatum, heart muscle) of rat and in smooth muscles of the mollusc Anodonta cygnea. AC effects of these peptides are decreased after membrane treatment by cholera and pertussis toxins and are inhibited in the presence of the peptides, corresponding to C-terminal regions 385-394 alphas- and 346-355 alphai2-subunits of G-proteins. These data give evidence that the peptides I and II act on the signaling pathways which are realized through Gs- and Gi-proteins. At the same time, natural polycationic peptide mastoparan acts on AC system through Gi-proteins and blocks hormonal signals mediated via Gi-proteins only. Consequently, the action of mastoparan on G-proteins is selective and differs from the action of the synthetic peptides. It is also shown that peptide II, with branched structure, directly interacts not only with G-proteins (less effective in comparison with peptide I with hydrophobic radicals and mastoparan), but also with enzyme AC, the catalytic component of AC system. On the basis of data obtained the following conclusions were made: 1) the formation of amphiphilic helices is not enough for selective activation of G-protein by polycationic peptides, and 2) the primary structure of the peptides, the distribution of positive charged amino acids and hydrophobic radicals in them are very important for selective interaction between polycationic peptides and G-proteins.

  5. The mechanism of opiorphin-induced experimental priapism in rats involves activation of the polyamine synthetic pathway

    PubMed Central

    Kanika, Nirmala Devi; Tar, Moses; Tong, Yuehong; Kuppam, Dwaraka Srinivasa Rao; Melman, Arnold

    2009-01-01

    Intracorporal injection of plasmids encoding opiorphins into retired breeder rats can result in animals developing a priapic-like condition. Microarray analysis demonstrated that following intracorporal gene transfer of plasmids expressing opiorphins the most significantly upregulated gene in corporal tissue was the ornithine decarboxylase gene (ODC). Quantitative RT-PCR confirmed the upregulation of ODC, as well as other genes involved in polyamine synthesis, such as arginase-I and -II, polyamine oxidase, spermidine synthase, spermidine acetyltransferase (SAT), and S-adenosylmethionine decarboxylase. Western blot analysis demonstrated upregulation of arginase-I and -II, ODC, and SAT at the protein level. Levels of the polyamine putrescine were upregulated in animals treated with opiorphin-expressing plasmids compared with controls. A direct role for the upregulation of polyamine synthesis in the development of the priapic-like condition was supported by the observation that the ODC inhibitor 1,3-diaminopropane, when added to the drinking water of animals treated with plasmids expressing opiorphins, prevented experimental priapism. We also demonstrate that in sickle cell mice, another model of priapism, there is increased expression of the mouse opiorphin homologue in corporal tissue compared with the background strain at a life stage prior to evidence of priapism. At a life stage when there is onset of priapism, there is increased expression of the enzymes involved in polyamine synthesis (ODC and arginase-I and -II). Our results suggest that the upregulation of enzymes involved in the polyamine synthetic pathway may play a role in the development of experimental priapism and represent a target for the prevention of priapism. PMID:19657052

  6. Β-defensin in Nile tilapia (Oreochromis niloticus): Sequence, tissue expression, and anti-bacterial activity of synthetic peptides.

    PubMed

    Dong, Jun-Jian; Wu, Fang; Ye, Xing; Sun, Cheng-Fei; Tian, Yuan-Yuan; Lu, Mai-Xin; Zhang, Rui; Chen, Zhi-Hang

    2015-07-15

    Beta-defensins (β-defensins) are small cationic amphiphilic peptides that are widely distributed in plants, insects, and vertebrates, and are important for their antimicrobial properties. In this study, the β-defensin (Onβ-defensin) gene of the Nile tilapia (Oreochromis niloticus) was cloned from spleen tissue. Onβ-defensin has a genomic DNA sequence of 674 bp and produces a cDNA of 454 bp. Sequence alignments showed that Onβ-defensin contains three exons and two introns. Sequence analysis of the cDNA identified an open reading frame of 201 bp, encoding 66 amino acids. Bioinformatic analysis showed that Onβ-defensin encodes a cytoplasmic protein molecule containing a signal peptide. The deduced amino acid sequence of this peptide contains six conserved cysteine residues and two conserved glycine residues, and shows 81.82% and 78.33% sequence similarities with β-defensin-1 of fugu (Takifugu rubripes) and rainbow trout (Oncorhynchus mykiss), respectively. Real-time quantitative PCR showed that the level of Onβ-defensin expression was highest in the skin (307.1-fold), followed by the spleen (77.3-fold), kidney (17.8-fold), and muscle (16.5-fold) compared to controls. By contrast, low levels of expression were found in the liver, heart, intestine, stomach, and gill (<3.0-fold). Artificial infection of tilapia with Streptococcus agalactiae (group B streptococcus [GBS] strain) resulted in a significantly upregulated expression of Onβ-defensin in the skin, muscle, kidney, and gill. In vitro antimicrobial experiments showed that a synthetic Onβ-defensin polypeptide had a certain degree of inhibitory effect on the growth of Escherichia coli DH5α and S. agalactiae. The results indicate that Onβ-defensin plays a role in immune responses that suppress or kill pathogens.

  7. Effect of Blood Component Coatings of Enosseal Implants on Proliferation and Synthetic Activity of Human Osteoblasts and Cytokine Production of Peripheral Blood Mononuclear Cells

    PubMed Central

    Hulejova, Hana; Bartova, Jirina; Riedel, Tomas; Pesakova, Vlasta

    2016-01-01

    The study monitored in vitro early response of connective tissue cells and immunocompetent cells to enosseal implant materials coated by different blood components (serum, activated plasma, and plasma/platelets) to evaluate human osteoblast proliferation and synthetic activity and inflammatory response presented as a cytokine profile of peripheral blood mononuclear cells (PBMCs) under conditions imitating the situation upon implantation. The cells were cultivated on coated Ti-plasma-sprayed (Ti-PS), Ti-etched (Ti-Etch), Ti-hydroxyapatite (Ti-HA), and ZrO2 surfaces. The plasma/platelets coating supported osteoblast proliferation only on osteoconductive Ti-HA and Ti-Etch whereas activated plasma enhanced proliferation on all surfaces. Differentiation (BAP) and IL-8 production remained unchanged or decreased irrespective of the coating and surface; only the serum and plasma/platelets-coated ZrO2 exhibited higher BAP and IL-8 expression. RANKL production increased on serum and activated plasma coatings. PBMCs produced especially cytokines playing role in inflammatory phase of wound healing, that is, IL-6, GRO-α, GRO, ENA-78, IL-8, GM-CSF, EGF, and MCP-1. Cytokine profiles were comparable for all tested surfaces; only ENA-78, IL-8, GM-CSF, and MCP-1 expression depended on materials and coatings. The activated plasma coating led to uniformed surfaces and represented a favorable treatment especially for bioinert Ti-PS and ZrO2 whereas all coatings had no distinctive effect on bioactive Ti-HA and Ti-Etch.

  8. Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

    PubMed Central

    Brents, Lisa K.; Reichard, Emily E.; Zimmerman, Sarah M.; Moran, Jeffery H.; Fantegrossi, William E.; Prather, Paul L.

    2011-01-01

    Background K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ9-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R). Methods/Principal Findings JWH-018, five potential monohydroxylated metabolites (M1–M5), and one carboxy metabolite (M6) were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [3H]CP-55,940, and then for CB1R intrinsic efficacy using an [35S]GTPγS binding assay. JWH-018 and M1–M5 bound CB1Rs with high affinity, exhibiting Ki values that were lower than or equivalent to Δ9-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ9-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ9-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251. Conclusions/Significance Unlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher

  9. Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety.

    PubMed

    Obata, R; Sunazuka, T; Tian, Z; Tomoda, H; Harigaya, Y; Omura, S

    1997-03-01

    Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by gamma-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC50 values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition. PMID:9127194

  10. Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety

    PubMed

    Obata; Sunazuka; Tian; Tomoda; Harigaya; Omura

    1997-03-01

    Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA : cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by gamma-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC50 values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition. PMID:9439694

  11. Treatment of melanoma cells with the synthetic retinoid CD437 induces apoptosis via activation of AP-1 in vitro, and causes growth inhibition in xenografts in vivo

    PubMed Central

    1996-01-01

    Human malignant melanoma is notoriously resistant to pharmacological modulation. We describe here for the first time that the synthetic retinoid CD437 has a strong dose-dependent antiproliferative effect on human melanoma cells (IC50: 5 x 10(-6) M) via the induction of programmed cell death, as judged by analysis of cell morphology, electron microscopical features, and DNA fragmentation. Programmed cell death was preceded by a strong activation of the AP-1 complex in CD437- treated cells as demonstrated by gel retardation and chloramphenicol transferase (CAT) assays. Northern blot analysis showed a time- dependent increase in the expression of c-fos and c-jun encoding components of AP-1, whereas bcl-2 and p53 mRNA levels remained constant. CD437 also exhibited a strong growth inhibitory effect on MeWo melanoma cells in a xenograft model. In tissue sections of CD437- treated MeWo tumors from these animals, apoptotic melanoma cells and c- fos overexpressing cells were colocalized by TdT-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) staining and in situ hybridization. Taken together, this report identifies CD437 as a retinoid that activates and upregulates the transcription factor AP-1, leading eventually to programmed cell death of exposed human melanoma cells in vitro and in vivo. Further studies are needed to evaluate whether synthetic retinoids such as CD437 represent a new class of retinoids, which may open up new ways to a more effective therapy of malignant melanoma. PMID:8991099

  12. Gibberellic Acid, Synthetic Auxins, and Ethylene Differentially Modulate α-l-Arabinofuranosidase Activities in Antisense 1-Aminocyclopropane-1-Carboxylic Acid Synthase Tomato Pericarp Discs1

    PubMed Central

    Sozzi, Gabriel O.; Greve, L. Carl; Prody, Gerry A.; Labavitch, John M.

    2002-01-01

    α-l-Arabinofuranosidases (α-Afs) are plant enzymes capable of releasing terminal arabinofuranosyl residues from cell wall matrix polymers, as well as from different glycoconjugates. Three different α-Af isoforms were distinguished by size exclusion chromatography of protein extracts from control tomatoes (Lycopersicon esculentum) and an ethylene synthesis-suppressed (ESS) line expressing an antisense 1-aminocyclopropane-1-carboxylic synthase transgene. α-Af I and II are active throughout fruit ontogeny. α-Af I is the first Zn-dependent cell wall enzyme isolated from tomato pericarp tissues, thus suggesting the involvement of zinc in fruit cell wall metabolism. This isoform is inhibited by 1,10-phenanthroline, but remains stable in the presence of NaCl and sucrose. α-Af II activity accounts for over 80% of the total α-Af activity in 10-d-old fruit, but activity drops during ripening. In contrast, α-Af III is ethylene dependent and specifically active during ripening. α-Af I released monosaccharide arabinose from KOH-soluble polysaccharides from tomato cell walls, whereas α-Af II and III acted on Na2CO3-soluble pectins. Different α-Af isoform responses to gibberellic acid, synthetic auxins, and ethylene were followed by using a novel ESS mature-green tomato pericarp disc system. α-Af I and II activity increased when gibberellic acid or 2,4-dichlorophenoxyacetic acid was applied, whereas ethylene treatment enhanced only α-Af III activity. Results suggest that tomato α-Afs are encoded by a gene family under differential hormonal controls, and probably have different in vivo functions. The ESS pericarp explant system allows comprehensive studies involving effects of physiological levels of different growth regulators on gene expression and enzyme activity with negligible wound-induced ethylene production. PMID:12114586

  13. Gibberellic acid, synthetic auxins, and ethylene differentially modulate alpha-L-Arabinofuranosidase activities in antisense 1-aminocyclopropane-1-carboxylic acid synthase tomato pericarp discs.

    PubMed

    Sozzi, Gabriel O; Greve, L Carl; Prody, Gerry A; Labavitch, John M

    2002-07-01

    Alpha-L-Arabinofuranosidases (alpha-Afs) are plant enzymes capable of releasing terminal arabinofuranosyl residues from cell wall matrix polymers, as well as from different glycoconjugates. Three different alpha-Af isoforms were distinguished by size exclusion chromatography of protein extracts from control tomatoes (Lycopersicon esculentum) and an ethylene synthesis-suppressed (ESS) line expressing an antisense 1-aminocyclopropane-1-carboxylic synthase transgene. alpha-Af I and II are active throughout fruit ontogeny. alpha-Af I is the first Zn-dependent cell wall enzyme isolated from tomato pericarp tissues, thus suggesting the involvement of zinc in fruit cell wall metabolism. This isoform is inhibited by 1,10-phenanthroline, but remains stable in the presence of NaCl and sucrose. alpha-Af II activity accounts for over 80% of the total alpha-Af activity in 10-d-old fruit, but activity drops during ripening. In contrast, alpha-Af III is ethylene dependent and specifically active during ripening. alpha-Af I released monosaccharide arabinose from KOH-soluble polysaccharides from tomato cell walls, whereas alpha-Af II and III acted on Na(2)CO(3)-soluble pectins. Different alpha-Af isoform responses to gibberellic acid, synthetic auxins, and ethylene were followed by using a novel ESS mature-green tomato pericarp disc system. alpha-Af I and II activity increased when gibberellic acid or 2,4-dichlorophenoxyacetic acid was applied, whereas ethylene treatment enhanced only alpha-Af III activity. Results suggest that tomato alpha-Afs are encoded by a gene family under differential hormonal controls, and probably have different in vivo functions. The ESS pericarp explant system allows comprehensive studies involving effects of physiological levels of different growth regulators on gene expression and enzyme activity with negligible wound-induced ethylene production.

  14. Disconnecting the Yin and Yang Relation of Epidermal Growth Factor Receptor (EGFR)-Mediated Delivery: A Fully Synthetic, EGFR-Targeted Gene Transfer System Avoiding Receptor Activation

    PubMed Central

    Schäfer, A.; Pahnke, A.; Schaffert, D.; van Weerden, W.M.; de Ridder, C.M.A.; Rödl, W.; Vetter, A.; Spitzweg, C.; Kraaij, R.; Wagner, E.

    2011-01-01

    Abstract The epidermal growth factor receptor (EGFR) is upregulated within a high percentage of solid tumors and hence is an attractive target for tumor-targeted therapies including gene therapy. The natural EGFR ligand epidermal growth factor (EGF) has been used for this purpose, despite the risk of mitogenic effects due to EGFR activation. We have developed a fully synthetic, EGFR-targeted gene delivery system based on PEGylated linear polyethylenimine (LPEI), allowing evaluation of different EGFR-binding peptides in terms of transfection efficiency and EGFR activation. Peptide sequences directly derived from the human EGF molecule enhanced transfection efficiency with concomitant EGFR activation. Only the EGFR-binding peptide GE11, which has been identified by phage display technique, showed specific enhancement of transfection on EGFR-overexpressing tumor cells including glioblastoma and hepatoma, but without EGFR activation. EGFR targeting led to high levels of cell association of fluorescently labeled polyplexes after only 30 min of incubation. EGF pretreatment of cells induced enhanced cellular internalization of all polyplex types tested, pointing at generally enhanced macropinocytosis. EGF polyplexes diminished cell surface expression of EGFR for up to 4 hr, whereas GE11 polyplexes did not. In a clinically relevant orthotopic prostate cancer model, intratumorally injected GE11 polyplexes were superior in inducing transgene expression when compared with untargeted polyplexes. PMID:21644815

  15. SYNTHETIC SLING FAILURE - EVALUATIONS & RECOMMENDATIONS

    SciTech Connect

    MACKEY TC; HENDERSON CS

    2009-10-26

    The information and evaluations provided in this report were compiled to address the recurring problem of synthetic sling failure. As safety is the number one priority in all work aspects, a solution must be devised to prevent accidents from occurring. A total of thirteen cases regarding synthetic sling failure were evaluated in order to determine their causes, effects, and preventative measures. From the collected data, it was found that all cases in which the synthetic sling contacted the edge of its load resulted in sling failure. It is required that adequate synthetic sling protection devices be used to protect slings in any lift where the sling comes in direct contact with the edge or corner of its load. However, there are no consensus codes or standards stating the type, material, or purpose of the type of protective device used to protect the sling from being cut. Numerous industry standards and codes provide vague descriptions on how to protect synthetic slings. Without a clear, concise statement of how to protect synthetic slings, it is common for inadequate materials and sling protection devices to be used in an attempt to meet the intent of these requirements. The use of an inadequate sling protection device is the main cause of synthetic sling failure in all researched cases. Commercial sling protection devices come in many shapes and sizes, and have a variety of names, as well as advertised uses. 'Abrasion pads' and 'wear protectors' are two different names for products with the same intended purpose. There is no distinguishable way to determine the extent of sling protection which these devices will provide, or what specific scenarios they are made for. This creates room for error in a field where error is unacceptable. This report provides a recommended action for hoisting and rigging activities which require synthetic slings to contact a load, as well as recommended changes to industry standards which will benefit overall industry safety.

  16. AU4S: A novel synthetic peptide to measure the activity of ATG4 in living cells

    PubMed Central

    Ni, Zhenhong; Gong, Yi; Dai, Xufang; Ding, Wen; Wang, Bin; Gong, Haiyan; Qin, Liyan; Cheng, Panke; Li, Song; Lian, Jiqin; He, Fengtian

    2015-01-01

    ATG4 plays a key role in autophagy induction, but the methods for monitoring ATG4 activity in living cells are limited. Here we designed a novel fluorescent peptide named AU4S for noninvasive detection of ATG4 activity in living cells, which consists of the cell-penetrating peptide (CPP), ATG4-recognized sequence “GTFG,” and the fluorophore FITC. Additionally, an ATG4-resistant peptide AG4R was used as a control. CPP can help AU4S or AG4R to penetrate cell membrane efficiently. AU4S but not AG4R can be recognized and cleaved by ATG4, leading to the change of fluorescence intensity. Therefore, the difference between AU4S- and AG4R-measured fluorescence values in the same sample, defined as “F-D value,” can reflect ATG4 activity. By detecting the F-D values, we found that ATG4 activity paralleled LC3B-II levels in rapamycin-treated cells, but neither paralleled LC3B-II levels in starved cells nor presented a correlation with LC3B-II accumulation in WBCs from healthy donors or leukemia patients. However, when DTT was added to the system, ATG4 activity not only paralleled LC3B-II levels in starved cells in the presence or absence of autophagy inhibitors, but also presented a positive correlation with LC3B-II accumulation in WBCs from leukemia patients (R2 = 0.5288). In conclusion, this study provides a convenient, rapid, and quantitative method to monitor ATG4 activity in living cells, which may be beneficial to basic and clinical research on autophagy. PMID:25831015

  17. Growth habit and photo-synthetic activity of shoot cultures of Medicago sativa L. transformed with the oryzacystatin II gene

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In vitro maintained shoot cultures of alfalfa (Medicago sativa L. cv. Zajeÿarska 83) that were transformed with the oryzacystatin II (OCII) gene and propagated on growth regulator-free medium were subjected to analysis of morphological characteristics and photosynthetic activity. The most striking f...

  18. Cationic Pd(II)-catalyzed C–H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies

    PubMed Central

    Nishikata, Takashi; Abela, Alexander R; Huang, Shenlin

    2016-01-01

    Summary Cationic palladium(II) complexes have been found to be highly reactive towards aromatic C–H activation of arylureas at room temperature. A commercially available catalyst [Pd(MeCN)4](BF4)2 or a nitrile-free cationic palladium(II) complex generated in situ from the reaction of Pd(OAc)2 and HBF4, effectively catalyzes C–H activation/cross-coupling reactions between aryl iodides, arylboronic acids and acrylates under milder conditions than those previously reported. The nature of the directing group was found to be critical for achieving room temperature conditions, with the urea moiety the most effective in promoting facile coupling reactions at an ortho C–H position. This methodology has been utilized in a streamlined and efficient synthesis of boscalid, an agent produced on the kiloton scale annually and used to control a range of plant pathogens in broadacre and horticultural crops. Mechanistic investigations led to a proposed catalytic cycle involving three steps: (1) C–H activation to generate a cationic palladacycle; (2) reaction of the cationic palladacycle with an aryl iodide, arylboronic acid or acrylate, and (3) regeneration of the active cationic palladium catalyst. The reaction between a cationic palladium(II) complex and arylurea allowed the formation and isolation of the corresponding palladacycle intermediate, characterized by X-ray analysis. Roles of various additives in the stepwise process have also been studied. PMID:27340491

  19. Comparison of the bony remodelling of two synthetic biomaterials: aragonite 55% and aragonite 55% with active substance.

    PubMed

    Oudadesse, H; Derrien, A C; Martin, S; Lucas-Girot, A; Cathelineau, G

    2007-03-01

    In this work, the in vivo behaviour of pure aragonite and vectabone, which is an association of aragonite and an active substance such as gentamicin, was studied to highlight the kinetic resorption of these two biomaterials with 55% of porosity destined for the filling or replacement of bony defects. The synthesis conditions and parameters we used permit us to obtain a biomaterial without a sintering stage. These conditions allow introducing of active substances at the first stage of the elaboration. In this work, the gentamycin antibiotic was associated with calcium carbonate (aragonite 55% with gentamycin) to deliver this active substance on the surgical site for local treatment. The tricalcium phosphate biomaterial was used as the control because of its high biocompatibility. The bony remodelling of these three biomaterials was studied by in vivo experiments. This study was ensured with neutron activation analysis (NAA). The resorption kinetic was elaborated and comparisons of the remodelling biomaterials CaCO(3) 55% and CaCO(3) 55% with gentamicin (vectabone) and tricalcium phosphate were carried out. The obtained results show that, 6 months after implantation, the mineral composition of vectabone and tricalcium phosphate becomes close to that of young bone. Twelve months after implantation, it becomes similar to that of mature bone.

  20. QUANTITATIVE STRUCTURE—PROPERTY RELATIONSHIPS FOR ENHANCING PREDICTIONS OF SYNTHETIC ORGANIC CHEMICAL REMOVAL FROM DRINKING WATER BY GRANULAR ACTIVATED CARBON

    EPA Science Inventory


    A number of mathematical models have been developed to predict activated carbon column performance using single-solute isotherm data as inputs. Many assumptions are built into these models to account for kinetics of adsorption and competition for adsorption sites. This work...

  1. Antifungal activity of a synthetic cationic peptide against the plant pathogens Colletotrichum graminicola and three Fusarium species

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A small cationic peptide (JH8944) was tested for activity against a number of pathogens of agricultural crops. JH8944 inhibited conidium growth in most of the tested plant pathogens with a dose of 50 µg ml 1, although one isolate of Fusarium oxysporum was inhibited at 5 µg ml 1. Most conidia of Fusa...

  2. Characterization of Antibacterial and Hemolytic Activity of Synthetic Pandinin 2 Variants and Their Inhibition against Mycobacterium tuberculosis

    PubMed Central

    Rodríguez, Alexis; Villegas, Elba; Montoya-Rosales, Alejandra; Rivas-Santiago, Bruno; Corzo, Gerardo

    2014-01-01

    The contention and treatment of Mycobacterium tuberculosis and other bacteria that cause infectious diseases require the use of new type of antibiotics. Pandinin 2 (Pin2) is a scorpion venom antimicrobial peptide highly hemolytic that has a central proline residue. This residue forms a structural “kink” linked to its pore-forming activity towards human erythrocytes. In this work, the residue Pro14 of Pin2 was both substituted and flanked using glycine residues (P14G and P14GPG) based on the low hemolytic activities of antimicrobial peptides with structural motifs Gly and GlyProGly such as magainin 2 and ponericin G1, respectively. The two Pin2 variants showed antimicrobial activity against E. coli, S. aureus, and M. tuberculosis. However, Pin2 [GPG] was less hemolytic (30%) than that of Pin2 [G] variant. In addition, based on the primary structure of Pin2 [G] and Pin2 [GPG], two short peptide variants were designed and chemically synthesized keeping attention to their physicochemical properties such as hydrophobicity and propensity to adopt alpha-helical conformations. The aim to design these two short antimicrobial peptides was to avoid the drawback cost associated to the synthesis of peptides with large sequences. The short Pin2 variants named Pin2 [14] and Pin2 [17] showed antibiotic activity against E. coli and M. tuberculosis. Besides, Pin2 [14] presented only 25% of hemolysis toward human erythrocytes at concentrations as high as 100 µM, while the peptide Pin2 [17] did not show any hemolytic effect at the same concentration. Furthermore, these short antimicrobial peptides had better activity at molar concentrations against multidrug resistance M. tuberculosis than that of the conventional antibiotics ethambutol, isoniazid and rifampicin. Therefore, Pin2 [14] and Pin2 [17] have the potential to be used as an alternative antibiotics and anti-tuberculosis agents with reduced hemolytic effects. PMID:25019413

  3. Characterization of antibacterial and hemolytic activity of synthetic pandinin 2 variants and their inhibition against Mycobacterium tuberculosis.

    PubMed

    Rodríguez, Alexis; Villegas, Elba; Montoya-Rosales, Alejandra; Rivas-Santiago, Bruno; Corzo, Gerardo

    2014-01-01

    The contention and treatment of Mycobacterium tuberculosis and other bacteria that cause infectious diseases require the use of new type of antibiotics. Pandinin 2 (Pin2) is a scorpion venom antimicrobial peptide highly hemolytic that has a central proline residue. This residue forms a structural "kink" linked to its pore-forming activity towards human erythrocytes. In this work, the residue Pro14 of Pin2 was both substituted and flanked using glycine residues (P14G and P14GPG) based on the low hemolytic activities of antimicrobial peptides with structural motifs Gly and GlyProGly such as magainin 2 and ponericin G1, respectively. The two Pin2 variants showed antimicrobial activity against E. coli, S. aureus, and M. tuberculosis. However, Pin2 [GPG] was less hemolytic (30%) than that of Pin2 [G] variant. In addition, based on the primary structure of Pin2 [G] and Pin2 [GPG], two short peptide variants were designed and chemically synthesized keeping attention to their physicochemical properties such as hydrophobicity and propensity to adopt alpha-helical conformations. The aim to design these two short antimicrobial peptides was to avoid the drawback cost associated to the synthesis of peptides with large sequences. The short Pin2 variants named Pin2 [14] and Pin2 [17] showed antibiotic activity against E. coli and M. tuberculosis. Besides, Pin2 [14] presented only 25% of hemolysis toward human erythrocytes at concentrations as high as 100 µM, while the peptide Pin2 [17] did not show any hemolytic effect at the same concentration. Furthermore, these short antimicrobial peptides had better activity at molar concentrations against multidrug resistance M. tuberculosis than that of the conventional antibiotics ethambutol, isoniazid and rifampicin. Therefore, Pin2 [14] and Pin2 [17] have the potential to be used as an alternative antibiotics and anti-tuberculosis agents with reduced hemolytic effects.

  4. Highly efficient synthetic iron-dependent nucleases activate both intrinsic and extrinsic apoptotic death pathways in leukemia cancer cells.

    PubMed

    Horn, Adolfo; Fernandes, Christiane; Parrilha, Gabrieli L; Kanashiro, Milton M; Borges, Franz V; de Melo, Edésio J T; Schenk, Gerhard; Terenzi, Hernán; Pich, Claus T

    2013-11-01

    The nuclease activity and the cytotoxicity toward human leukemia cancer cells of iron complexes, [Fe(HPClNOL)Cl2]NO3 (1), [Cl(HPClNOL)Fe(μ-O)Fe(HPClNOL)Cl]Cl2·2H2O (2), and [(SO4)(HPClNOL)Fe(μ-O)Fe(HPClNOL)(SO4)]·6H2O (3) (HPClNOL=1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol), were investigated. Each complex was able to promote plasmid DNA cleavage and change the supercoiled form of the plasmid to circular and linear ones. Kinetic data revealed that (1), (2) and (3) increase the rate of DNA hydrolysis about 278, 192 and 339 million-fold, respectively. The activity of the complexes was inhibited by distamycin, indicating that they interact with the minor groove of the DNA. The cytotoxic activity of the complexes toward U937, HL-60, Jukart and THP-1 leukemia cancer cells was studied employing 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), fluorescence and electronic transmission microscopies, flow cytometry and a cytochrome C release assay. Compound (2) has the highest activity toward cancer cells and is the least toxic for normal ones (i.e. peripheral blood mononuclear cells (PBMCs)). In contrast, compound (1) is the least active toward cancer cells but displays the highest toxicity toward normal cells. Transmission electronic microscopy indicates that cell death shows features typical of apoptotic cells, which was confirmed using the annexin V-FITC/PI (fluorescein isothiocyanate/propidium iodide) assay. Furthermore, our data demonstrate that at an early stage during the treatment with complex (2) mitochondria lose their transmembrane potential, resulting in cytochrome C release. A quantification of caspases 3, 9 (intrinsic apoptosis pathway) and caspase 8 (extrinsic apoptosis pathway) indicated that both the intrinsic (via mitochondria) and extrinsic (via death receptors) pathways are involved in the apoptotic stimuli. PMID:23933562

  5. Microtubule-stabilizing properties of the avocado-derived toxins (+)-(R)-persin and (+)-(R)-tetrahydropersin in cancer cells and activity of related synthetic analogs.

    PubMed

    Field, Jessica J; Kanakkanthara, Arun; Brooke, Darby G; Sinha, Saptarshi; Pillai, Sushila D; Denny, William A; Butt, Alison J; Miller, John H

    2016-06-01

    The avocado toxin (+)-R-persin (persin) is active at low micromolar concentrations against breast cancer cells and synergizes with the estrogen receptor modulator 4-hydroxytamoxifen. Previous studies in the estrogen receptor-positive breast cancer cell line MCF-7 indicate that persin acts as a microtubule-stabilizing agent. In the present study, we further characterize the properties of persin and several new synthetic analogues in human ovarian cancer cells. Persin and tetrahydropersin cause G2M cell cycle arrest and increase intracellular microtubule polymerization. One analog (4-nitrophenyl)-deshydroxypersin prevents cell proliferation and blocks cells in G1 of the cell cycle rather than G2M, suggesting an additional mode of action of these compounds independent of microtubules. Persin can synergize with other microtubule-stabilizing agents, and is active against cancer cells that overexpress the P-glycoprotein drug efflux pump. Evidence from Flutax-1 competition experiments suggests that while the persin binding site on β-tubulin overlaps the classical taxoid site where paclitaxel and epothilone bind, persin retains activity in cell lines with single amino acid mutations that affect these other taxoid site ligands. This implies the existence of a unique binding location for persin at the taxoid site. PMID:26968704

  6. Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment.

    PubMed

    Slootweg, Jack C; Peters, Nienke; Quarles van Ufford, H Linda C; Breukink, Eefjan; Liskamp, Rob M J; Rijkers, Dirk T S

    2014-10-01

    The antimicrobial peptide nisin is a promising template for designing novel peptide-based antibiotics to improve its drug-like properties. First steps in that direction represent the synthesis of hybrid nisin derivatives that contain a native nisin ABC-part and synthesized cross-stapled DE-ring fragments and are described here. The biological activity of the newly synthesized nisin derivatives was evaluated in order to compare the bioactivity of the synthetic DE-ring containing mimic and native lanthionine-bridged DE-ring containing nisin. The native nisin ABC-ring system was obtained via chymotrypsin digestion of full-length nisin, and was subsequently functionalized at the C-terminal carboxylate with two different amino alkyne moieties. Next, nisin hybrids were successfully prepared using Cu(I)-catalyzed azide alkyne cycloaddition 'click' chemistry by chemo-selective ligation of the ABC-alkyne with the N-terminal azido functionalized dicarba-DE ring mimic. The newly synthesized compounds were active as potent lipid II binders and retained antimicrobial activity in a growth inhibition assay. However, pore formation was not observed, possibly either due to the different character of the 'staples' as compared to the parent sulfides, or due to the triazole moiety as a sub-optimal amide bond isostere.

  7. Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment.

    PubMed

    Slootweg, Jack C; Peters, Nienke; Quarles van Ufford, H Linda C; Breukink, Eefjan; Liskamp, Rob M J; Rijkers, Dirk T S

    2014-10-01

    The antimicrobial peptide nisin is a promising template for designing novel peptide-based antibiotics to improve its drug-like properties. First steps in that direction represent the synthesis of hybrid nisin derivatives that contain a native nisin ABC-part and synthesized cross-stapled DE-ring fragments and are described here. The biological activity of the newly synthesized nisin derivatives was evaluated in order to compare the bioactivity of the synthetic DE-ring containing mimic and native lanthionine-bridged DE-ring containing nisin. The native nisin ABC-ring system was obtained via chymotrypsin digestion of full-length nisin, and was subsequently functionalized at the C-terminal carboxylate with two different amino alkyne moieties. Next, nisin hybrids were successfully prepared using Cu(I)-catalyzed azide alkyne cycloaddition 'click' chemistry by chemo-selective ligation of the ABC-alkyne with the N-terminal azido functionalized dicarba-DE ring mimic. The newly synthesized compounds were active as potent lipid II binders and retained antimicrobial activity in a growth inhibition assay. However, pore formation was not observed, possibly either due to the different character of the 'staples' as compared to the parent sulfides, or due to the triazole moiety as a sub-optimal amide bond isostere. PMID:25199583

  8. Osseointegration of dental implants in 3D-printed synthetic onlay grafts customized according to bone metabolic activity in recipient site.

    PubMed

    Tamimi, Faleh; Torres, Jesus; Al-Abedalla, Khadijeh; Lopez-Cabarcos, Enrique; Alkhraisat, Mohammad H; Bassett, David C; Gbureck, Uwe; Barralet, Jake E

    2014-07-01

    Onlay grafts made of monolithic microporous monetite bioresorbable bioceramics have the capacity to conduct bone augmentation. However, there is heterogeneity in the graft behaviour in vivo that seems to correlate with the host anatomy. In this study, we sought to investigate the metabolic activity of the regenerated bone in monolithic monetite onlays by using positron emission tomography-computed tomography (PET-CT) in rats. This information was used to optimize the design of monetite onlays with different macroporous architecture that were then fabricated using a 3D-printing technique. In vivo, bone augmentation was attempted with these customized onlays in rabbits. PET-CT findings demonstrated that bone metabolism in the calvarial bone showed higher activity in the inferior and lateral areas of the onlays. Histological observations revealed higher bone volume (up to 47%), less heterogeneity and more implant osseointegration (up to 38%) in the augmented bone with the customized monetite onlays. Our results demonstrated for the first time that it is possible to achieve osseointegration of dental implants in bone augmented with 3D-printed synthetic onlays. It was also observed that designing the macropore geometry according to the bone metabolic activity was a key parameter in increasing the volume of bone augmented within monetite onlays.

  9. Synthetic neurosteroids on brain protection

    PubMed Central

    Rey, Mariana; Coirini, Héctor

    2015-01-01

    Neurosteroids, like allopregnanolone and pregnanolone, are endogenous regulators of neuronal excitability. Inside the brain, they are highly selective and potent modulators of GABAA receptor activity. Their anticonvulsant, anesthetics and anxiolytic properties are useful for the treatments of several neurological and psychiatric disorders via reducing the risks of side effects obtained with the commercial drugs. The principal disadvantages of endogenous neurosteroids administration are their rapid metabolism and their low oral bioavailability. Synthetic steroids analogues with major stability or endogenous neurosteroids stimulation synthesis might constitute promising novel strategies for the treatment of several disorders. Numerous studies indicate that the 3α-hydroxyl configuration is the key for binding and activity, but modifications in the steroid nucleus may emphasize different pharmacophores. So far, several synthetic steroids have been developed with successful neurosteroid-like effects. In this work, we summarize the properties of various synthetic steroids probed in trials throughout the analysis of several neurosteroids-like actions. PMID:25788907

  10. Use of a Synthetic Biosensor for Neutralizing Activity-Biased Selection of Monoclonal Antibodies against Atroxlysin-I, an Hemorrhagic Metalloproteinase from Bothrops atrox Snake Venom

    PubMed Central

    Schneider, Francisco Santos; Nguyen, Dung Le; Castro, Karen Larissa; Cobo, Sandra; Machado de Avila, Ricardo Andrez; Ferreira, Nivia de Assis; Sanchez, Eladio Flores; Nguyen, Christophe; Granier, Claude; Galéa, Pascale; Chávez-Olortegui, Carlos; Molina, Franck

    2014-01-01

    Background The snake Bothrops atrox is responsible for the majority of envenomings in the northern region of South America. Severe local effects, including hemorrhage, which are mainly caused by snake venom metalloproteinases (SVMPs), are not fully neutralized by conventional serum therapy. Little is known about the immunochemistry of the P-I SVMPs since few monoclonal antibodies (mAbs) against these molecules have been obtained. In addition, producing toxin-neutralizing mAbs remains very challenging. Methodology/Principal Findings Here, we report on the set-up of a functional screening based on a synthetic peptide used as a biosensor to select neutralizing mAbs against SVMPs and the successful production of neutralizing mAbs against Atroxlysin-I (Atr-I), a P-I SVMP from B. atrox. Hybridomas producing supernatants with inhibitory effect against the proteolytic activity of Atr-I towards the FRET peptide Abz-LVEALYQ-EDDnp were selected. Six IgG1 Mabs were obtained (named mAbatr1 to mAbatr6) and also two IgM. mAbatrs1, 2, 3 and 6 were purified. All showed a high specific reactivity, recognizing only Atr-I and B. atrox venom in ELISA and a high affinity, showing equilibrium constants in the nM range for Atr-I. These mAbatrs were not able to bind to Atr-I overlapping peptides, suggesting that they recognize conformational epitopes. Conclusions/Significance For the first time a functional screening based on a synthetic biosensor was successfully used for the selection of neutralizing mAbs against SVMPs. PMID:24762927

  11. Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release.

    PubMed

    Ilyinskii, Petr O; Roy, Christopher J; O'Neil, Conlin P; Browning, Erica A; Pittet, Lynnelle A; Altreuter, David H; Alexis, Frank; Tonti, Elena; Shi, Jinjun; Basto, Pamela A; Iannacone, Matteo; Radovic-Moreno, Aleksandar F; Langer, Robert S; Farokhzad, Omid C; von Andrian, Ulrich H; Johnston, Lloyd P M; Kishimoto, Takashi Kei

    2014-05-19

    Augmentation of immunogenicity can be achieved by particulate delivery of an antigen and by its co-administration with an adjuvant. However, many adjuvants initiate strong systemic inflammatory reactions in vivo, leading to potential adverse events and safety concerns. We have developed a synthetic vaccine particle (SVP) technology that enables co-encapsulation of antigen with potent adjuvants. We demonstrate that co-delivery of an antigen with a TLR7/8 or TLR9 agonist in synthetic polymer nanoparticles results in a strong augmentation of humoral and cellular immune responses with minimal systemic production of inflammatory cytokines. In contrast, antigen encapsulated into nanoparticles and admixed with free TLR7/8 agonist leads to lower immunogenicity and rapid induction of high levels of inflammatory cytokines in the serum (e.g., TNF-a and IL-6 levels are 50- to 200-fold higher upon injection of free resiquimod (R848) than of nanoparticle-encapsulated R848). Conversely, local immune stimulation as evidenced by cellular infiltration of draining lymph nodes and by intranodal cytokine production was more pronounced and persisted longer when SVP-encapsulated TLR agonists were used. The strong local immune activation achieved using a modular self-assembling nanoparticle platform markedly enhanced immunogenicity and was equally effective whether antigen and adjuvant were co-encapsulated in a single nanoparticle formulation or co-delivered in two separate nanoparticles. Moreover, particle encapsulation enabled the utilization of CpG oligonucleotides with the natural phosphodiester backbone, which are otherwise rapidly hydrolyzed by nucleases in vivo. The use of SVP may enable clinical use of potent TLR agonists as vaccine adjuvants for indications where cellular immunity or robust humoral responses are required.

  12. Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release.

    PubMed

    Ilyinskii, Petr O; Roy, Christopher J; O'Neil, Conlin P; Browning, Erica A; Pittet, Lynnelle A; Altreuter, David H; Alexis, Frank; Tonti, Elena; Shi, Jinjun; Basto, Pamela A; Iannacone, Matteo; Radovic-Moreno, Aleksandar F; Langer, Robert S; Farokhzad, Omid C; von Andrian, Ulrich H; Johnston, Lloyd P M; Kishimoto, Takashi Kei

    2014-05-19

    Augmentation of immunogenicity can be achieved by particulate delivery of an antigen and by its co-administration with an adjuvant. However, many adjuvants initiate strong systemic inflammatory reactions in vivo, leading to potential adverse events and safety concerns. We have developed a synthetic vaccine particle (SVP) technology that enables co-encapsulation of antigen with potent adjuvants. We demonstrate that co-delivery of an antigen with a TLR7/8 or TLR9 agonist in synthetic polymer nanoparticles results in a strong augmentation of humoral and cellular immune responses with minimal systemic production of inflammatory cytokines. In contrast, antigen encapsulated into nanoparticles and admixed with free TLR7/8 agonist leads to lower immunogenicity and rapid induction of high levels of inflammatory cytokines in the serum (e.g., TNF-a and IL-6 levels are 50- to 200-fold higher upon injection of free resiquimod (R848) than of nanoparticle-encapsulated R848). Conversely, local immune stimulation as evidenced by cellular infiltration of draining lymph nodes and by intranodal cytokine production was more pronounced and persisted longer when SVP-encapsulated TLR agonists were used. The strong local immune activation achieved using a modular self-assembling nanoparticle platform markedly enhanced immunogenicity and was equally effective whether antigen and adjuvant were co-encapsulated in a single nanoparticle formulation or co-delivered in two separate nanoparticles. Moreover, particle encapsulation enabled the utilization of CpG oligonucleotides with the natural phosphodiester backbone, which are otherwise rapidly hydrolyzed by nucleases in vivo. The use of SVP may enable clinical use of potent TLR agonists as vaccine adjuvants for indications where cellular immunity or robust humoral responses are required. PMID:24593999

  13. A Synthetic Pseudo-Rh: NOx Reduction Activity and Electronic Structure of Pd-Ru Solid-solution Alloy Nanoparticles.

    PubMed

    Sato, Katsutoshi; Tomonaga, Hiroyuki; Yamamoto, Tomokazu; Matsumura, Syo; Zulkifli, Nor Diana Binti; Ishimoto, Takayoshi; Koyama, Michihisa; Kusada, Kohei; Kobayashi, Hirokazu; Kitagawa, Hiroshi; Nagaoka, Katsutoshi

    2016-06-24

    Rh is one of the most important noble metals for industrial applications. A major fraction of Rh is used as a catalyst for emission control in automotive catalytic converters because of its unparalleled activity toward NOx reduction. However, Rh is a rare and extremely expensive element; thus, the development of Rh alternative composed of abundant elements is desirable. Pd and Ru are located at the right and left of Rh in the periodic table, respectively, nevertheless this combination of elements is immiscible in the bulk state. Here, we report a Pd-Ru solid-solution-alloy nanoparticle (PdxRu1-x NP) catalyst exhibiting better NOx reduction activity than Rh. Theoretical calculations show that the electronic structure of Pd0.5Ru0.5 is similar to that of Rh, indicating that Pd0.5Ru0.5 can be regarded as a pseudo-Rh. Pd0.5Ru0.5 exhibits better activity than natural Rh, which implies promising applications not only for exhaust-gas cleaning but also for various chemical reactions.

  14. A Synthetic Pseudo-Rh: NOx Reduction Activity and Electronic Structure of Pd–Ru Solid-solution Alloy Nanoparticles

    PubMed Central

    Sato, Katsutoshi; Tomonaga, Hiroyuki; Yamamoto, Tomokazu; Matsumura, Syo; Zulkifli, Nor Diana Binti; Ishimoto, Takayoshi; Koyama, Michihisa; Kusada, Kohei; Kobayashi, Hirokazu; Kitagawa, Hiroshi; Nagaoka, Katsutoshi

    2016-01-01

    Rh is one of the most important noble metals for industrial applications. A major fraction of Rh is used as a catalyst for emission control in automotive catalytic converters because of its unparalleled activity toward NOx reduction. However, Rh is a rare and extremely expensive element; thus, the development of Rh alternative composed of abundant elements is desirable. Pd and Ru are located at the right and left of Rh in the periodic table, respectively, nevertheless this combination of elements is immiscible in the bulk state. Here, we report a Pd–Ru solid-solution-alloy nanoparticle (PdxRu1-x NP) catalyst exhibiting better NOx reduction activity than Rh. Theoretical calculations show that the electronic structure of Pd0.5Ru0.5 is similar to that of Rh, indicating that Pd0.5Ru0.5 can be regarded as a pseudo-Rh. Pd0.5Ru0.5 exhibits better activity than natural Rh, which implies promising applications not only for exhaust-gas cleaning but also for various chemical reactions. PMID:27340099

  15. Reconstitution of anti-allergic activities of PG102 derived from Actinidia arguta by combining synthetic chemical compounds.

    PubMed

    Kim, Donghyun; Choi, Jinyong; Kim, Mi-Jeong; Kim, Seon Hee; Cho, Sang Heon; Kim, Sunyoung

    2013-06-01

    PG102, a water-soluble extract from an edible fruit, Actinidia arguta, has previously been shown to control various factors involved in allergy pathogenesis. It was investigated whether the original activities of PG102 could be reconstituted by mixing chemical compounds present in PG102. Six compounds present in PG102 were, individually or in the form of mixtures, tested for their effects on the expression of various Th2 cytokines and inflammatory mediators in the cell-based assay. Each chemical inhibited IL-4 expression to varying degrees. The chemical compounds were combined at a ratio present in PG102, resulting in two formulations, CQMIIH and CQM, consisting of all or the first three of the following chemicals, citric, quinic, and malic acids, myo-inositol, isoquercitrin, and 5-hydroxymethyl-2-furaldehyde. The mixtures reconstituted original activities of PG102 to a significant level. In the murine asthma model, CQM ameliorated asthmatic symptoms and significantly decreased the level of IgE and IL-5. The decreased phosphorylation of ERK1/2 was observed in cells and mice treated with PG102 and the mixtures. Our data indicated that the substantial portion of PG102's anti-allergic activities could be reconstituted, in vitro and in vivo, by mixing six chemical compounds, suggesting the possibility of developing a new type of anti-allergic agent. This approach may be useful for developing chemically defined functional products from complex botanical extracts. PMID:23918875

  16. A Synthetic Pseudo-Rh: NOx Reduction Activity and Electronic Structure of Pd–Ru Solid-solution Alloy Nanoparticles

    NASA Astrophysics Data System (ADS)

    Sato, Katsutoshi; Tomonaga, Hiroyuki; Yamamoto, Tomokazu; Matsumura, Syo; Zulkifli, Nor Diana Binti; Ishimoto, Takayoshi; Koyama, Michihisa; Kusada, Kohei; Kobayashi, Hirokazu; Kitagawa, Hiroshi; Nagaoka, Katsutoshi

    2016-06-01

    Rh is one of the most important noble metals for industrial applications. A major fraction of Rh is used as a catalyst for emission control in automotive catalytic converters because of its unparalleled activity toward NOx reduction. However, Rh is a rare and extremely expensive element; thus, the development of Rh alternative composed of abundant elements is desirable. Pd and Ru are located at the right and left of Rh in the periodic table, respectively, nevertheless this combination of elements is immiscible in the bulk state. Here, we report a Pd–Ru solid-solution-alloy nanoparticle (PdxRu1-x NP) catalyst exhibiting better NOx reduction activity than Rh. Theoretical calculations show that the electronic structure of Pd0.5Ru0.5 is similar to that of Rh, indicating that Pd0.5Ru0.5 can be regarded as a pseudo-Rh. Pd0.5Ru0.5 exhibits better activity than natural Rh, which implies promising applications not only for exhaust-gas cleaning but also for various chemical reactions.

  17. A Synthetic Pseudo-Rh: NOx Reduction Activity and Electronic Structure of Pd-Ru Solid-solution Alloy Nanoparticles.

    PubMed

    Sato, Katsutoshi; Tomonaga, Hiroyuki; Yamamoto, Tomokazu; Matsumura, Syo; Zulkifli, Nor Diana Binti; Ishimoto, Takayoshi; Koyama, Michihisa; Kusada, Kohei; Kobayashi, Hirokazu; Kitagawa, Hiroshi; Nagaoka, Katsutoshi

    2016-01-01

    Rh is one of the most important noble metals for industrial applications. A major fraction of Rh is used as a catalyst for emission control in automotive catalytic converters because of its unparalleled activity toward NOx reduction. However, Rh is a rare and extremely expensive element; thus, the development of Rh alternative composed of abundant elements is desirable. Pd and Ru are located at the right and left of Rh in the periodic table, respectively, nevertheless this combination of elements is immiscible in the bulk state. Here, we report a Pd-Ru solid-solution-alloy nanoparticle (PdxRu1-x NP) catalyst exhibiting better NOx reduction activity than Rh. Theoretical calculations show that the electronic structure of Pd0.5Ru0.5 is similar to that of Rh, indicating that Pd0.5Ru0.5 can be regarded as a pseudo-Rh. Pd0.5Ru0.5 exhibits better activity than natural Rh, which implies promising applications not only for exhaust-gas cleaning but also for various chemical reactions. PMID:27340099

  18. Reconstitution of anti-allergic activities of PG102 derived from Actinidia arguta by combining synthetic chemical compounds.

    PubMed

    Kim, Donghyun; Choi, Jinyong; Kim, Mi-Jeong; Kim, Seon Hee; Cho, Sang Heon; Kim, Sunyoung

    2013-06-01

    PG102, a water-soluble extract from an edible fruit, Actinidia arguta, has previously been shown to control various factors involved in allergy pathogenesis. It was investigated whether the original activities of PG102 could be reconstituted by mixing chemical compounds present in PG102. Six compounds present in PG102 were, individually or in the form of mixtures, tested for their effects on the expression of various Th2 cytokines and inflammatory mediators in the cell-based assay. Each chemical inhibited IL-4 expression to varying degrees. The chemical compounds were combined at a ratio present in PG102, resulting in two formulations, CQMIIH and CQM, consisting of all or the first three of the following chemicals, citric, quinic, and malic acids, myo-inositol, isoquercitrin, and 5-hydroxymethyl-2-furaldehyde. The mixtures reconstituted original activities of PG102 to a significant level. In the murine asthma model, CQM ameliorated asthmatic symptoms and significantly decreased the level of IgE and IL-5. The decreased phosphorylation of ERK1/2 was observed in cells and mice treated with PG102 and the mixtures. Our data indicated that the substantial portion of PG102's anti-allergic activities could be reconstituted, in vitro and in vivo, by mixing six chemical compounds, suggesting the possibility of developing a new type of anti-allergic agent. This approach may be useful for developing chemically defined functional products from complex botanical extracts.

  19. Plant synthetic biology.

    PubMed

    Liu, Wusheng; Stewart, C Neal

    2015-05-01

    Plant synthetic biology is an emerging field that combines engineering principles with plant biology toward the design and production of new devices. This emerging field should play an important role in future agriculture for traditional crop improvement, but also in enabling novel bioproduction in plants. In this review we discuss the design cycles of synthetic biology as well as key engineering principles, genetic parts, and computational tools that can be utilized in plant synthetic biology. Some pioneering examples are offered as a demonstration of how synthetic biology can be used to modify plants for specific purposes. These include synthetic sensors, synthetic metabolic pathways, and synthetic genomes. We also speculate about the future of synthetic biology of plants.

  20. Survival, mobility, and membrane-bound enzyme activities of freshwater planarian, Dugesia japonica, exposed to synthetic and natural surfactants.

    PubMed

    Li, Mei-Hui

    2012-04-01

    Surfactants are a major class of emerging pollutants widely used in large quantities in everyday life and commonly found in surface waters worldwide. Freshwater planarian was selected to examine the effects of different surfactants by measuring mortality, mobility, and membrane-bound enzyme activities. Among the 10 surfactants tested, the acute toxicities of betaine and polyethylene glycol (PEG-200) to planarians were relatively low, with a median lethal concentration (LC50) greater than 10,000 mg/L. The toxicity to planarians of the other eight surfactants based on 48-h LC50 could be arranged in the descending order of cetylpyridinum chloride (CPC) > 4-tert-octylphenol (4-tert-OP) > ammonium lauryl sulfate > benzalkonium chloride > saponin > sodium lauroylsarcosinate > dioctyl sulfosuccinate > dodecyl trimethyl ammonium bromide (DTAB). Both CPC and 4-tert-OP were very toxic to planarians, with 48-h LC50 values <1 mg/L. The median effective concentrations (EC50s) of planarian mobility were in the 0.1 to 50 mg/L range and were in the same range as the 24-h LC50 of planarians exposed to different surfactants, except for DTAB. In addition, significant inhibition of cholinesterase activity activities was found in planarians exposed to 4-tert-OP at 2.5 and 5 mg/L and to saponin at 10 mg/L after 2-h treatments. This result suggests that planarian mobility responses can be used as an alternative indicator for acute toxicity of surfactants after a very short exposure period.

  1. Synergistic effect of phosphorothioate, 5'-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA.

    PubMed

    Prakash, Thazha P; Kinberger, Garth A; Murray, Heather M; Chappell, Alfred; Riney, Stan; Graham, Mark J; Lima, Walt F; Swayze, Eric E; Seth, Punit P

    2016-06-15

    Chemical modifications are essential to improve metabolic stability and pharmacokinetic properties of siRNA to enable their systemic delivery. We investigated the effect of combing the phosphorothioate (PS) modification with metabolically stable phosphate analog (E)-5'-vinylphosphonate and GalNAc cluster conjugation on the activity of fully 2'-modified siRNA in cell culture and mice. Our data suggest that integrating multiple chemical approaches in one siRNA molecule improved potency 5-10 fold and provide a roadmap for developing more efficient siRNA drugs.

  2. Effect of Blood Component Coatings of Enosseal Implants on Proliferation and Synthetic Activity of Human Osteoblasts and Cytokine Production of Peripheral Blood Mononuclear Cells.

    PubMed

    Himmlova, Lucie; Kubies, Dana; Hulejova, Hana; Bartova, Jirina; Riedel, Tomas; Stikarova, Jana; Suttnar, Jiri; Pesakova, Vlasta

    2016-01-01

    The study monitored in vitro early response of connective tissue cells and immunocompetent cells to enosseal implant materials coated by different blood components (serum, activated plasma, and plasma/platelets) to evaluate human osteoblast proliferation and synthetic activity and inflammatory response presented as a cytokine profile of peripheral blood mononuclear cells (PBMCs) under conditions imitating the situation upon implantation. The cells were cultivated on coated Ti-plasma-sprayed (Ti-PS), Ti-etched (Ti-Etch), Ti-hydroxyapatite (Ti-HA), and ZrO2 surfaces. The plasma/platelets coating supported osteoblast proliferation only on osteoconductive Ti-HA and Ti-Etch whereas activated plasma enhanced proliferation on all surfaces. Differentiation (BAP) and IL-8 production remained unchanged or decreased irrespective of the coating and surface; only the serum and plasma/platelets-coated ZrO2 exhibited higher BAP and IL-8 expression. RANKL production increased on serum and activated plasma coatings. PBMCs produced especially cytokines playing role in inflammatory phase of wound healing, that is, IL-6, GRO-α, GRO, ENA-78, IL-8, GM-CSF, EGF, and MCP-1. Cytokine profiles were comparable for all tested surfaces; only ENA-78, IL-8, GM-CSF, and MCP-1 expression depended on materials and coatings. The activated plasma coating led to uniformed surfaces and represented a favorable treatment especially for bioinert Ti-PS and ZrO2 whereas all coatings had no distinctive effect on bioactive Ti-HA and Ti-Etch. PMID:27651560

  3. Effect of Blood Component Coatings of Enosseal Implants on Proliferation and Synthetic Activity of Human Osteoblasts and Cytokine Production of Peripheral Blood Mononuclear Cells

    PubMed Central

    Hulejova, Hana; Bartova, Jirina; Riedel, Tomas; Pesakova, Vlasta

    2016-01-01

    The study monitored in vitro early response of connective tissue cells and immunocompetent cells to enosseal implant materials coated by different blood components (serum, activated plasma, and plasma/platelets) to evaluate human osteoblast proliferation and synthetic activity and inflammatory response presented as a cytokine profile of peripheral blood mononuclear cells (PBMCs) under conditions imitating the situation upon implantation. The cells were cultivated on coated Ti-plasma-sprayed (Ti-PS), Ti-etched (Ti-Etch), Ti-hydroxyapatite (Ti-HA), and ZrO2 surfaces. The plasma/platelets coating supported osteoblast proliferation only on osteoconductive Ti-HA and Ti-Etch whereas activated plasma enhanced proliferation on all surfaces. Differentiation (BAP) and IL-8 production remained unchanged or decreased irrespective of the coating and surface; only the serum and plasma/platelets-coated ZrO2 exhibited higher BAP and IL-8 expression. RANKL production increased on serum and activated plasma coatings. PBMCs produced especially cytokines playing role in inflammatory phase of wound healing, that is, IL-6, GRO-α, GRO, ENA-78, IL-8, GM-CSF, EGF, and MCP-1. Cytokine profiles were comparable for all tested surfaces; only ENA-78, IL-8, GM-CSF, and MCP-1 expression depended on materials and coatings. The activated plasma coating led to uniformed surfaces and represented a favorable treatment especially for bioinert Ti-PS and ZrO2 whereas all coatings had no distinctive effect on bioactive Ti-HA and Ti-Etch. PMID:27651560

  4. [SYNTHETIC PEPTIDE VACCINES].

    PubMed

    Sergeyev, O V; Barinsky, I F

    2016-01-01

    An update on the development and trials of synthetic peptide vaccines is reviewed. The review considers the successful examples of specific protection as a result of immunization with synthetic peptides using various protocols. The importance of conformation for the immunogenicity of the peptide is pointed out. An alternative strategy of the protection of the organism against the infection using synthetic peptides is suggested.

  5. A mild synthetic route to Fe3O4@TiO2-Au composites: preparation, characterization and photocatalytic activity

    NASA Astrophysics Data System (ADS)

    Ma, Jianqi; Guo, Shaobo; Guo, Xiaohua; Ge, Hongguang

    2015-10-01

    To prevent and avoid magnetic loss caused by magnetite core phase transitions involved in high-temperature crystallization of sol-gel TiO2, a direct and feasible low-temperature crystallization technique was developed to deposit anatase TiO2 nanoparticle shell on Fe3O4 sphere cores. To promote the photocatalytic efficiency of the obtained core-shell Fe3O4@TiO2 magnetic photocatalyst, uniformly distributed Au nanoparticles (NPs) were successfully immobilized on the core-shell Fe3O4@TiO2 spheres via a seed-mediated growth procedure. The 3 nm Au colloid absorbed on Fe3O4@TiO2 served as a nucleation site for the growth of Au NPs overlayer. The morphology, structure, composition and magnetism of the resulting composites were characterized, and their photocatalytic activities were also evaluated. In comparison to Fe3O4@TiO2, Fe3O4@TiO2-Au exhibited higher photocatalytic activity for organic degradation under UV irradiation. This enhanced mechanism may have resulted from efficient charge separation of photogenerated electrons and holes due to the Au NPs attached on the TiO2. In addition, the composites possessed superparamagnetic properties with a high saturation magnetization of 44.6 emu g-1 and could be easily separated and recycled by a magnet.

  6. Silver nanoparticles influence on the blood activation process and their release to blood plasma from synthetic polymer scaffold

    NASA Astrophysics Data System (ADS)

    Major, R.; Lackner, J. M.; Sanak, M.; Major, B.

    2016-03-01

    In the present work, blood and blood plasma interaction to silver stabilised polyelectrolytes was investigated in vitro. The designed materials are dedicated for regeneration of the cardiovascular system. Silver nanoparticles were introduced into the polyelectrolyte structure in order to reduce the risk of bacterial biofilm formation. The introduction of Ag nanoparticles occurred by deposition at high vacuum by magnetron sputtering. The analysis of blood-materials interactions were performed by using commercially available tester, Impact-R (Diamed). The assessment of silver ion nanoparticles release into the plasma consisted in determining the Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT). Unmodified surface of polyelectrolytes is a strong activator for blood elements. The introduction of silver nanoparticles resulted in a significant reduction in the probability of clotting. The extrinsic pathway of coagulation determined on the basis of the PT and the intrinsic and common pathways of coagulation measured by the APTT did not indicate the danger out of range. Microstructure was studied using TEM on thin foils prepared from the cross-section of samples subjected to biomedical treatments. The observations revealed hetero- interface between two different crystalline solids.

  7. [From synthetic biology to synthetic humankind].

    PubMed

    Nouvel, Pascal

    2015-01-01

    In this paper, we propose an historical survey of the expression "synthetic biology" in order to identify its main philosophical components. The result of the analysis is then used to investigate the meaning of the notion of "synthetic man". It is shown that both notions share a common philosophical background that can be summed up by the short but meaningful assertion: "biology is technology". The analysis allows us to distinguish two notions that are often confused in transhumanist literature: the notion of synthetic man and the notion of renewed man. The consequences of this crucial distinction are discussed.

  8. Building Better Scientists through Cross-Disciplinary Collaboration in Synthetic Biology: A Report from the Genome Consortium for Active Teaching Workshop 2010

    ERIC Educational Resources Information Center

    Wolyniak, Michael J.; Alvarez, Consuelo J.; Chandrasekaran, Vidya; Grana, Theresa M.; Holgado, Andrea; Jones, Christopher J.; Morris, Robert W.; Pereira, Anil L.; Stamm, Joyce; Washington, Talitha M.; Yang, Yixin

    2010-01-01

    Synthetic biology is the application of engineering and mathematical principles to develop novel biological devices and circuits. What separates synthetic biology from traditional molecular biology is the development of standardized interchangeable DNA "parts," just as advances in engineering in the nineteenth century brought about standardized…

  9. Comparison of the Exposure Time Dependence of the Activities of Synthetic Ozonide Antimalarials and Dihydroartemisinin against K13 Wild-Type and Mutant Plasmodium falciparum Strains.

    PubMed

    Yang, Tuo; Xie, Stanley C; Cao, Pengxing; Giannangelo, Carlo; McCaw, James; Creek, Darren J; Charman, Susan A; Klonis, Nectarios; Tilley, Leann

    2016-08-01

    Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of the in vitro responses of Plasmodium falciparum to the new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed-exposure assay format to interrogate the time dependence of the response. Because the ozonides have physicochemical properties different from those of the artemisinins, assay optimization was required to ensure that the drugs were completely removed following the pulsed exposure. Like that of artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective than short pulses of dihydroartemisinin; however, when early-ring-stage parasites were exposed to drugs for periods relevant to their in vivo exposure, the ozonide antimalarials were markedly more effective. PMID:27161632

  10. Comparison of the Exposure Time Dependence of the Activities of Synthetic Ozonide Antimalarials and Dihydroartemisinin against K13 Wild-Type and Mutant Plasmodium falciparum Strains

    PubMed Central

    Yang, Tuo; Xie, Stanley C.; Cao, Pengxing; Giannangelo, Carlo; McCaw, James; Creek, Darren J.; Charman, Susan A.; Klonis, Nectarios

    2016-01-01

    Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of the in vitro responses of Plasmodium falciparum to the new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed-exposure assay format to interrogate the time dependence of the response. Because the ozonides have physicochemical properties different from those of the artemisinins, assay optimization was required to ensure that the drugs were completely removed following the pulsed exposure. Like that of artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective than short pulses of dihydroartemisinin; however, when early-ring-stage parasites were exposed to drugs for periods relevant to their in vivo exposure, the ozonide antimalarials were markedly more effective. PMID:27161632

  11. The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.

    PubMed

    Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

    2014-05-01

    Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.

  12. A novel synthetic compound MCAP suppresses LPS-induced murine microglial activation in vitro via inhibiting NF-kB and p38 MAPK pathways

    PubMed Central

    Kim, Byung-Wook; More, Sandeep Vasant; Yun, Yo-Sep; Ko, Hyun-Myung; Kwak, Jae-Hwan; Lee, Heesoon; Suk, Kyoungho; Kim, In-Su; Choi, Dong-Kug

    2016-01-01

    Aim: To investigate the anti-neuroinflammatory activity of a novel synthetic compound, 7-methylchroman-2-carboxylic acid N-(2-trifluoromethyl) phenylamide (MCAP) against LPS-induced microglial activation in vitro. Methods: Primary mouse microglia and BV2 microglia cells were exposed to LPS (50 or 100 ng/mL). The expression of iNOS and COX-2, proinflammatory cytokines, NF-κB and p38 MAPK signaling molecules were analyzed by RT-PCR, Western blot and ELISA. The morphological changes of microglia and nuclear translocation of NF-ĸB were visualized using phase contrast and fluorescence microscopy, respectively. Results: Pretreatment with MCAP (0.1, 1, 10 μmol/L) dose-dependently inhibited LPS-induced expression of iNOS and COX-2 in BV2 microglia cells. Similar results were obtained in primary microglia pretreated with MCAP (0.1, 0.5 μmol/L). MCAP dose-dependently abated LPS-induced release of TNF-α, IL-6 and IL-1β, and mitigated LPS-induced activation of NF-κB by reducing the phosphorylation of IκBα in BV2 microglia cells. Moreover, MCAP attenuated LPS-induced phosphorylation of p38 MAPK, whereas SB203580, a p38 MAPK inhibitor, significantly potentiated MCAP-caused inhibition on the expression of MEF-2 (a transcription factor downstream of p38 MAPK). Conclusion: MCAP exerts anti-inflammatory effects in murine microglia in vitro by inhibiting the p38 MAPK and NF-κB signaling pathways and proinflammatory responses. MCAP may be developed as a novel agent for treating diseases involving activated microglial cells. PMID:26838070

  13. Monitoring synaptic and neuronal activity in 3D with synthetic and genetic indicators using a compact acousto-optic lens two-photon microscope☆

    PubMed Central

    Fernández-Alfonso, Tomás; Nadella, K.M. Naga Srinivas; Iacaruso, M. Florencia; Pichler, Bruno; Roš, Hana; Kirkby, Paul A.; Silver, R. Angus

    2014-01-01

    Background Two-photon microscopy is widely used to study brain function, but conventional microscopes are too slow to capture the timing of neuronal signalling and imaging is restricted to one plane. Recent development of acousto-optic-deflector-based random access functional imaging has improved the temporal resolution, but the utility of these technologies for mapping 3D synaptic activity patterns and their performance at the excitation wavelengths required to image genetically encoded indicators have not been investigated. New method Here, we have used a compact acousto-optic lens (AOL) two-photon microscope to make high speed [Ca2+] measurements from spines and dendrites distributed in 3D with different excitation wavelengths (800–920 nm). Results We show simultaneous monitoring of activity from many synaptic inputs distributed over the 3D arborisation of a neuronal dendrite using both synthetic as well as genetically encoded indicators. We confirm the utility of AOL-based imaging for fast in vivo recordings by measuring, simultaneously, visually evoked responses in 100 neurons distributed over a 150 μm focal depth range. Moreover, we explore ways to improve the measurement of timing of neuronal activation by choosing specific regions within the cell soma. Comparison with existing methods These results establish that AOL-based 3D random access two-photon microscopy has a wider range of neuroscience applications than previously shown. Conclusions Our findings show that the compact AOL microscope design has the speed, spatial resolution, sensitivity and wavelength flexibility to measure 3D patterns of synaptic and neuronal activity on individual trials. PMID:24200507

  14. Antifungal Activity of a Synthetic Cationic Peptide against the Plant Pathogens Colletotrichum graminicola and Three Fusarium Species

    PubMed Central

    Johnson, Eric T.; Evans, Kervin O.; Dowd, Patrick F.

    2015-01-01

    A small cationic peptide (JH8944) was tested for activity against a number of pathogens of agricultural crops. JH8944 inhibited conidium growth in most of the tested plant pathogens with a dose of 50 μg/ml, although one isolate of Fusarium oxysporum was inhibited at 5 μg/ml of JH8944. Most conidia of Fusarium graminearum were killed within 6 hours of treatment with 50 μg/ml of JH8944. Germinating F. graminearum conidia required 238 μg/ml of JH8944 for 90% growth inhibition. The peptide did not cause any damage to tissues surrounding maize leaf punctures when tested at a higher concentration of 250 μg/ml even after 3 days. Liposomes consisting of phosphatidylglycerol were susceptible to leakage after treatment with 25 and 50 μg/ml of JH8944. These experiments suggest this peptide destroys fungal membrane integrity and could be utilized for control of crop fungal pathogens. PMID:26361481

  15. Active control of passive acoustic fields: passive synthetic aperture/Doppler beamforming with data from an autonomous vehicle.

    PubMed

    D'Spain, Gerald L; Terrill, Eric; Chadwell, C David; Smith, Jerome A; Lynch, Stephen D

    2006-12-01

    The maneuverability of autonomous underwater vehicles (AUVs) equipped with hull-mounted arrays provides the opportunity to actively modify received acoustic fields to optimize extraction of information. This paper uses ocean acoustic data collected by an AUV-mounted two-dimensional hydrophone array, with overall dimension one-tenth wavelength at 200-500 Hz, to demonstrate aspects of this control through vehicle motion. Source localization is performed using Doppler shifts measured at a set of receiver velocities by both single elements and a physical array. Results show that a source in the presence of a 10-dB higher-level interferer having exactly the same frequency content (as measured by a stationary receiver) is properly localized and that white-noise-constrained adaptive beamforming applied to the physical aperture data in combination with Doppler beamforming provides greater spatial resolution than physical-aperture-alone beamforming and significantly lower sidelobes than single element Doppler beamforming. A new broadband beamformer that adjusts for variations in vehicle velocity on a sample by sample basis is demonstrated with data collected during a high-acceleration maneuver. The importance of including the cost of energy expenditure in determining optimal vehicle motion is demonstrated through simulation, further illustrating how the vehicle characteristics are an integral part of the signal/array processing structure.

  16. Anticancer activity of synthetic bis(indolyl)methane-ortho-biaryls against human cervical cancer (HeLa) cells.

    PubMed

    Jamsheena, Vellekkatt; Shilpa, Ganesan; Saranya, Jayaram; Harry, Nissy Ann; Lankalapalli, Ravi Shankar; Priya, Sulochana

    2016-03-01

    Bis(indolyl)methane appended biaryls were designed, synthesized and evaluated in human cervical cancer cell lines (HeLa) for their anticancer activities and compared against normal rat cardiac myoblasts (H9C2) cells. Compounds 1-12 were synthesized, with variations in one of the phenyl unit, in a single step by condensation of biaryl-2-carbaldehydes with indole in the presence of para-toluenesulfonic acid. Compound 1 exhibited a GI50 value of 11.00 ± 0.707 μM and the derivatives, compounds 4 and 11 showed a GI50 value of 8.33 ± 0.416 μM and 9.13 ± 0.177 μM respectively in HeLa cells and was found to be non-toxic to H9C2 cells up to 20 μM. Furthermore, compounds 1, 4 and 11 induced caspase dependent cellular apoptosis in a concentration-dependent manner, reduced mitochondrial membrane potential, inhibited the cell migration and downregulated the production of MMP-2 and MMP-9 in HeLa cells.

  17. A bridge between the aminoacylation and editing domains of leucyl-tRNA synthetase is crucial for its synthetic activity

    PubMed Central

    Huang, Qian; Zhou, Xiao-Long; Hu, Qin-Hua; Lei, Hui-Yan; Fang, Zhi-Peng; Yao, Peng; Wang, En-Duo

    2014-01-01

    Leucyl-tRNA synthetases (LeuRSs) catalyze the linkage of leucine with tRNALeu. LeuRS contains a catalysis domain (aminoacylation) and a CP1 domain (editing). CP1 is inserted 35 Å from the aminoacylation domain. Aminoacylation and editing require CP1 to swing to the coordinated conformation. The neck between the CP1 domain and the aminoacylation domain is defined as the CP1 hairpin. The location of the CP1 hairpin suggests a crucial role in the CP1 swing and domain–domain interaction. Here, the CP1 hairpin of Homo sapiens cytoplasmic LeuRS (hcLeuRS) was deleted or substituted by those from other representative species. Lack of a CP1 hairpin led to complete loss of aminoacylation, amino acid activation, and tRNA binding; however, the mutants retained post-transfer editing. Only the CP1 hairpin from Saccharomyces cerevisiae LeuRS (ScLeuRS) could partly rescue the hcLeuRS functions. Further site-directed mutagenesis indicated that the flexibility of small residues and the charge of polar residues in the CP1 hairpin are crucial for the function of LeuRS. PMID:25051973

  18. Enhancement of intracellular concentration and biological activity of PNA after conjugation with a cell-penetrating synthetic model peptide.

    PubMed

    Oehlke, Johannes; Wallukat, Gerd; Wolf, Yvonne; Ehrlich, Angelika; Wiesner, Burkhard; Berger, Hartmut; Bienert, Michael

    2004-07-01

    In order to evaluate the ability of the cell-penetrating alpha-helical amphipathic model peptide KLALKLALKALKAALKLA-NH(2) (MAP) to deliver peptide nucleic acids (PNAs) into mammalian cells, MAP was covalently linked to the 12-mer PNA 5'-GGAGCAGGAAAG-3' directed against the mRNA of the nociceptin/orphanin FQ receptor. The cellular uptake of both the naked PNA and its MAP-conjugate was studied by means of capillary electrophoresis combined with laser-induced fluorescence detection, confocal laser scanning microscopy and fluorescence-activated cell sorting. Incubation with the fluorescein-labelled PNA-peptide conjugate led to three- and eightfold higher intracellular concentrations in neonatal rat cardiomyocytes and CHO cells, respectively, than found after exposure of the cells to the naked PNA. Correspondingly, pretreatment of spontaneously-beating neonatal rat cardiomyocytes with the PNA-peptide conjugate and the naked PNA slowed down the positive chronotropic effect elicited by the neuropeptide nociceptin by 10- and twofold, respectively. The main reasons for the higher bioavailability of the PNA-peptide conjugate were found to be a more rapid cellular uptake in combination with a lowered re-export and resistance against influences of serum.

  19. A ligand field chemistry of oxygen generation by the oxygen-evolving complex and synthetic active sites

    PubMed Central

    Betley, Theodore A; Surendranath, Yogesh; Childress, Montana V; Alliger, Glen E; Fu, Ross; Cummins, Christopher C; Nocera, Daniel G

    2007-01-01

    Oxygen–oxygen bond formation and O2 generation occur from the S4 state of the oxygen-evolving complex (OEC). Several mechanistic possibilities have been proposed for water oxidation, depending on the formal oxidation state of the Mn atoms. All fall under two general classifications: the AB mechanism in which nucleophilic oxygen (base, B) attacks electrophilic oxygen (acid, A) of the Mn4Ca cluster or the RC mechanism in which radical-like oxygen species couple within OEC. The critical intermediate in either mechanism involves a metal oxo, though the nature of this oxo for AB and RC mechanisms is disparate. In the case of the AB mechanism, assembly of an even-electron count, high-valent metal-oxo proximate to a hydroxide is needed whereas, in an RC mechanism, two odd-electron count, high-valent metal oxos are required. Thus the two mechanisms give rise to very different design criteria for functional models of the OEC active site. This discussion presents the electron counts and ligand geometries that support metal oxos for AB and RC O–O bond-forming reactions. The construction of architectures that bring two oxygen functionalities together under the purview of the AB and RC scenarios are described. PMID:17971328

  20. Active control of passive acoustic fields: passive synthetic aperture/Doppler beamforming with data from an autonomous vehicle.

    PubMed

    D'Spain, Gerald L; Terrill, Eric; Chadwell, C David; Smith, Jerome A; Lynch, Stephen D

    2006-12-01

    The maneuverability of autonomous underwater vehicles (AUVs) equipped with hull-mounted arrays provides the opportunity to actively modify received acoustic fields to optimize extraction of information. This paper uses ocean acoustic data collected by an AUV-mounted two-dimensional hydrophone array, with overall dimension one-tenth wavelength at 200-500 Hz, to demonstrate aspects of this control through vehicle motion. Source localization is performed using Doppler shifts measured at a set of receiver velocities by both single elements and a physical array. Results show that a source in the presence of a 10-dB higher-level interferer having exactly the same frequency content (as measured by a stationary receiver) is properly localized and that white-noise-constrained adaptive beamforming applied to the physical aperture data in combination with Doppler beamforming provides greater spatial resolution than physical-aperture-alone beamforming and significantly lower sidelobes than single element Doppler beamforming. A new broadband beamformer that adjusts for variations in vehicle velocity on a sample by sample basis is demonstrated with data collected during a high-acceleration maneuver. The importance of including the cost of energy expenditure in determining optimal vehicle motion is demonstrated through simulation, further illustrating how the vehicle characteristics are an integral part of the signal/array processing structure. PMID:17225392

  1. Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9-Epipolygodial against Drug-Resistant Cancer Cells.

    PubMed

    Dasari, Ramesh; De Carvalho, Annelise; Medellin, Derek C; Middleton, Kelsey N; Hague, Frédéric; Volmar, Marie N M; Frolova, Liliya V; Rossato, Mateus F; De La Chapa, Jorge J; Dybdal-Hargreaves, Nicholas F; Pillai, Akshita; Mathieu, Véronique; Rogelj, Snezna; Gonzales, Cara B; Calixto, João B; Evidente, Antonio; Gautier, Mathieu; Munirathinam, Gnanasekar; Glass, Rainer; Burth, Patricia; Pelly, Stephen C; van Otterlo, Willem A L; Kiss, Robert; Kornienko, Alexander

    2015-12-01

    Polygodial, a terpenoid dialdehyde isolated from Polygonum hydropiper L., is a known agonist of the transient receptor potential vanilloid 1 (TRPV1). In this investigation a series of polygodial analogues were prepared and investigated for TRPV1-agonist and anticancer activities. These experiments led to the identification of 9-epipolygodial, which has antiproliferative potency significantly exceeding that of polygodial. 9-Epipolygodial was found to maintain potency against apoptosis-resistant cancer cells as well as those displaying the multidrug-resistant (MDR) phenotype. In addition, the chemical feasibility for the previously proposed mechanism of action of polygodial, involving the formation of a Paal-Knorr pyrrole with a lysine residue on the target protein, was demonstrated by the synthesis of a stable polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives. These compounds should inspire further work in this area aimed at the development of new pharmacological agents, or the exploration of novel mechanisms of covalent modification of biological molecules with natural products. PMID:26434977

  2. A mutant leucine aminopeptidase from Streptomyces cinnamoneus with enhanced L-aspartyl L-amino acid methyl ester synthetic activity.

    PubMed

    Arima, Jiro; Kono, Mirai; Kita, Manami; Mori, Nobuhiro

    2012-06-01

    L-aspartyl L-amino acid methyl ester was synthesized using a mutant of a thermostable leucine aminopeptidase from Streptomyces cinnamoneus, D198 K SSAP, obtained in previously. A peptide of high-intensity sweetener, L-aspartyl-L-phenylalanine methyl ester, was selected as a model for demonstrating the synthesis of L-aspartyl L-amino acid methyl ester. The hydrolytic activities of D198 K SSAP toward L-aspartyl-L-phenylalanine and its methyl ester were, respectively, 74-fold and fourfold higher than those of wild type. Similarly, the initial rate of the enzyme for L-aspartyl-L-phenylalanine methyl ester synthesis was over fivefold higher than that of wild-type SSAP in 90% methanol (v/v) in a one-pot reaction. Furthermore, other L-aspartyl L-amino acid methyl esters were synthesized efficiently using D198 K SSAP. Results show that the substitution of Asp198 of SSAP with Lys is effective for synthesizing L-aspartyl L-amino acid methyl ester.

  3. Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9-Epipolygodial against Drug-Resistant Cancer Cells.

    PubMed

    Dasari, Ramesh; De Carvalho, Annelise; Medellin, Derek C; Middleton, Kelsey N; Hague, Frédéric; Volmar, Marie N M; Frolova, Liliya V; Rossato, Mateus F; De La Chapa, Jorge J; Dybdal-Hargreaves, Nicholas F; Pillai, Akshita; Mathieu, Véronique; Rogelj, Snezna; Gonzales, Cara B; Calixto, João B; Evidente, Antonio; Gautier, Mathieu; Munirathinam, Gnanasekar; Glass, Rainer; Burth, Patricia; Pelly, Stephen C; van Otterlo, Willem A L; Kiss, Robert; Kornienko, Alexander

    2015-12-01

    Polygodial, a terpenoid dialdehyde isolated from Polygonum hydropiper L., is a known agonist of the transient receptor potential vanilloid 1 (TRPV1). In this investigation a series of polygodial analogues were prepared and investigated for TRPV1-agonist and anticancer activities. These experiments led to the identification of 9-epipolygodial, which has antiproliferative potency significantly exceeding that of polygodial. 9-Epipolygodial was found to maintain potency against apoptosis-resistant cancer cells as well as those displaying the multidrug-resistant (MDR) phenotype. In addition, the chemical feasibility for the previously proposed mechanism of action of polygodial, involving the formation of a Paal-Knorr pyrrole with a lysine residue on the target protein, was demonstrated by the synthesis of a stable polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives. These compounds should inspire further work in this area aimed at the development of new pharmacological agents, or the exploration of novel mechanisms of covalent modification of biological molecules with natural products.

  4. Antifungal Activity of a Synthetic Cationic Peptide against the Plant Pathogens Colletotrichum graminicola and Three Fusarium Species.

    PubMed

    Johnson, Eric T; Evans, Kervin O; Dowd, Patrick F

    2015-09-01

    A small cationic peptide (JH8944) was tested for activity against a number of pathogens of agricultural crops. JH8944 inhibited conidium growth in most of the tested plant pathogens with a dose of 50 μg/ml, although one isolate of Fusarium oxysporum was inhibited at 5 μg/ml of JH8944. Most conidia of Fusarium graminearum were killed within 6 hours of treatment with 50 μg/ml of JH8944. Germinating F. graminearum conidia required 238 μg/ml of JH8944 for 90% growth inhibition. The peptide did not cause any damage to tissues surrounding maize leaf punctures when tested at a higher concentration of 250 μg/ml even after 3 days. Liposomes consisting of phosphatidylglycerol were susceptible to leakage after treatment with 25 and 50 μg/ml of JH8944. These experiments suggest this peptide destroys fungal membrane integrity and could be utilized for control of crop fungal pathogens. PMID:26361481

  5. Synthetic biology in cellular immunotherapy

    PubMed Central

    Chakravarti, Deboki; Wong, Wilson W.

    2015-01-01

    The adoptive transfer of genetically engineered T cells with cancer-targeting receptors has shown tremendous promise for eradicating tumors in clinical trials. This form of cellular immunotherapy presents a unique opportunity to incorporate advanced systems and synthetic biology approaches to create cancer therapeutics with novel functions. Here, we first review the development of synthetic receptors, switches, and circuits to control the location, duration, and strength of T cell activity against tumors. In addition, we discuss the cellular engineering and genome editing of host cells (or the chassis) to improve the efficacy of cell-based cancer therapeutics, and to reduce the time and cost of manufacturing. PMID:26088008

  6. Improved antimicrobial activities of synthetic-hybrid bacteriocins designed from enterocin E50-52 and pediocin PA-1.

    PubMed

    Tiwari, Santosh Kumar; Sutyak Noll, Katia; Cavera, Veronica L; Chikindas, Michael L

    2015-03-01

    Two hybrid bacteriocins, enterocin E50-52/pediocin PA-1 (EP) and pediocin PA-1/enterocin E50-52 (PE), were designed by combining the N terminus of enterocin E50-52 and the C terminus of pediocin PA-1 and by combining the C terminus of pediocin PA-1 and the N terminus of enterocin E50-52, respectively. Both hybrid bacteriocins showed reduced MICs compared to those of their natural counterparts. The MICs of hybrid PE and EP were 64- and 32-fold lower, respectively, than the MIC of pediocin PA-1 and 8- and 4-fold lower, respectively, than the MIC of enterocin E50-52. In this study, the effect of hybrid as well as wild-type (WT) bacteriocins on the transmembrane electrical potential (ΔΨ) and their ability to induce the efflux of intracellular ATP were investigated. Enterocin E50-52, pediocin PA-1, and hybrid bacteriocin PE were able to dissipate ΔΨ, but EP was unable to deplete this component. Both hybrid bacteriocins caused a loss of the intracellular concentration of ATP. EP, however, caused a faster efflux than PE and enterocin E50-52. Enterocin E50-52 and hybrids PE and EP were active against the Gram-positive and Gram-negative bacteria tested, such as Micrococcus luteus, Salmonella enterica serovar Enteritidis 20E1090, and Escherichia coli O157:H7. The hybrid bacteriocins designed and described herein are antimicrobial peptides with MICs lower those of their natural counterparts. Both hybrid peptides induce the loss of intracellular ATP and are capable of inhibiting Gram-negative bacteria, and PE dissipates the electrical potential. In this study, the MIC of hybrid bacteriocin PE decreased 64-fold compared to the MIC of its natural peptide counterpart, pediocin PA-1. Inhibition of Gram-negative pathogens confers an additional advantage for the application of these peptides in therapeutics.

  7. Synthetic cannabinoids as drugs of abuse.

    PubMed

    Ashton, John C

    2012-06-01

    In the last decade a number of products have appeared in various countries that contain synthetic cannabinoids. This article reviews the history of the sale of these drugs, and the evidence that they contain synthetic cannabinoids. The biochemistry of the synthetic cannabinoids identified thus far is discussed, including a discussion of chemical structures and biochemical targets. The cannabinoid receptor targets for these drugs are discussed, as well as other possible targets such as serotonin receptors. Evidence for the abuse potential of these drugs is reviewed. The toxicity of synthetic cannabinoids and cannabinoid products is reviewed and compared to that of the phytocannabinoid Δ9- tetrahydrocannabinol (THC). As cannabinoids are a structurally diverse class of drugs, it is concluded that synthetic cannabinoids should be classified by biological activity rather than by structure, and that if this isn't done, novel synthetic cannabinoids will continue to emerge that fall outside of current regulatory classification models.

  8. Synthetic catecholamine triggers β1-adrenergic receptor activation and stimulates cardiotoxicity via oxidative stress mediated apoptotic cell death in rats: Abrogating action of thymol.

    PubMed

    Meeran, M F Nagoor; Jagadeesh, G S; Selvaraj, P

    2016-05-01

    Nowadays, there are considerable interests in the studies which are more connected with the impact of natural antioxidants against the free radical mediated damage in biological systems. Cardiotoxicity is one of the lethal manifestations of cardiovascular diseases (CVDs) which have been associated with the incidence of apoptotic cell death due to oxidative stress. We evaluated the impact of thymol, a dietary monoterpene phenol on isoproterenol (ISO), a synthetic catecholamine and a β1-adrenergic receptor agonist in rats. Thymol (7.5 mg/kg body weight) was pre and co-treated into male albino Wistar rats daily for a period of 7 days. Induction of cardiotoxicity was done by the subcutaneous administration of ISO (100 mg/kg body weight) into rats on 6th and 7th day. Cardiotoxicity in rats was confirmed by the increased levels/activity of serum troponin-T and creatine kinase in the serum alongwith decreased activity of creatine kinase in the heart. ISO induced cardiotoxic rats also showed a significant increase in the concentrations of lipid peroxidation products and a significant decrease in the activities/levels of antioxidants in the myocardium whereas Reverse Transcription Polymerase Chain Reaction study revealed an increased expression of caspase-8, caspase-9 and Fas genes along with a decreased expression of Bcl-xL gene in the myocardium. Thymol pre and co-treated ISO induced cardiotoxic rats showed considerable protective effects on all the biochemical parameters studied. Histopathological and in vitro findings are found in line with our biochemical findings. Thus, the present study revealed that thymol counters ISO induced cardiotoxicity by inhibiting oxidative stress and apoptotic cell death in rats by virtue of its potent antioxidant property. PMID:26996544

  9. Biological activity and molecular docking studies of curcumin-related α,β-unsaturated carbonyl-based synthetic compounds as anticancer agents and mushroom tyrosinase inhibitors.

    PubMed

    Bukhari, Syed Nasir Abbas; Jantan, Ibrahim; Unsal Tan, Oya; Sher, Muhammad; Naeem-Ul-Hassan, M; Qin, Hua-Li

    2014-06-18

    Hyperpigmentation in human skin and enzymatic browning in fruits, which are caused by tyrosinase enzyme, are not desirable. Investigations in the discovery of tyrosinase enzyme inhibitors and search for improved cytotoxic agents continue to be an important line in drug discovery and development. In present work, a new series of 30 compounds bearing α,β-unsaturated carbonyl moiety was designed and synthesized following curcumin as model. All compounds were evaluated for their effects on human cancer cell lines and mushroom tyrosinase enzyme. Moreover, the structure-activity relationships of these compounds are also explained. Molecular modeling studies of these new compounds were carried out to explore interactions with tyrosinase enzyme. Synthetic curcumin-like compounds (2a-b) were identified as potent anticancer agents with 81-82% cytotoxicity. Five of these newly synthesized compounds (1a, 8a-b, 10a-b) emerged to be the potent inhibitors of mushroom tyrosinase, providing further insight into designing compounds useful in fields of food, health, and agriculture.

  10. Cr(VI) removal from synthetic wastewater using coconut shell charcoal and commercial activated carbon modified with oxidizing agents and/or chitosan.

    PubMed

    Babel, Sandhya; Kurniawan, Tonni Agustiono

    2004-02-01

    In this study, the technical feasibility of coconut shell charcoal (CSC) and commercial activated carbon (CAC) for Cr(VI) removal is investigated in batch studies using synthetic electroplating wastewater. Both granular adsorbents are made up of coconut shell (Cocos nucifera L.), an agricultural waste from local coconut industries. Surface modifications of CSC and CAC with chitosan and/or oxidizing agents, such as sulfuric acid and nitric acid, respectively, are also conducted to improve removal performance. The results of their Cr removal performances are statistically compared. It is evident that adsorbents chemically modified with an oxidizing agent demonstrate better Cr(VI) removal capabilities than as-received adsorbents in terms of adsorption rate. Both CSC and CAC, which have been oxidized with nitric acid, have higher Cr adsorption capacities (CSC: 10.88, CAC: 15.47 mg g(-1)) than those oxidized with sulfuric acid (CSC: 4.05, CAC: 8.94 mg g(-1)) and non-treated CSC coated with chitosan (CSCCC: 3.65 mg g(-1)), respectively, suggesting that surface modification of a carbon adsorbent with a strong oxidizing agent generates more adsorption sites on their solid surface for metal adsorption.

  11. Biological activity and molecular docking studies of curcumin-related α,β-unsaturated carbonyl-based synthetic compounds as anticancer agents and mushroom tyrosinase inhibitors.

    PubMed

    Bukhari, Syed Nasir Abbas; Jantan, Ibrahim; Unsal Tan, Oya; Sher, Muhammad; Naeem-Ul-Hassan, M; Qin, Hua-Li

    2014-06-18

    Hyperpigmentation in human skin and enzymatic browning in fruits, which are caused by tyrosinase enzyme, are not desirable. Investigations in the discovery of tyrosinase enzyme inhibitors and search for improved cytotoxic agents continue to be an important line in drug discovery and development. In present work, a new series of 30 compounds bearing α,β-unsaturated carbonyl moiety was designed and synthesized following curcumin as model. All compounds were evaluated for their effects on human cancer cell lines and mushroom tyrosinase enzyme. Moreover, the structure-activity relationships of these compounds are also explained. Molecular modeling studies of these new compounds were carried out to explore interactions with tyrosinase enzyme. Synthetic curcumin-like compounds (2a-b) were identified as potent anticancer agents with 81-82% cytotoxicity. Five of these newly synthesized compounds (1a, 8a-b, 10a-b) emerged to be the potent inhibitors of mushroom tyrosinase, providing further insight into designing compounds useful in fields of food, health, and agriculture. PMID:24901506

  12. Effect of heat-processing on the antioxidant and prooxidant activities of β-carotene from natural and synthetic origins on red blood cells.

    PubMed

    Phan-Thi, Hanh; Durand, Philippe; Prost, Michel; Prost, Emmanuelle; Waché, Yves

    2016-01-01

    Extraction of bioactives is a cause of structural changes in these molecules. In this work, the bioactivity of commercial natural β-carotenes, one softly extracted without heat-assistance from Momordica cochinchinensis (BCG), one conventionally extracted from another natural source (BCC), and a synthetic one (BCS), was assessed during an additional heat-treatment mimicking formulation. Their antioxidant activities were evaluated after heat-treatment at different concentrations through hemolysis of horse red blood cells. The thermal 15-cis-isomerization of β-carotene, characterized by DAD-HPLC, resulted in a 2.5- to 4.8-fold increase in the anti-hemolytic effect but this was undetected in chemical assay, at 4 μM. At 100 μM, BCC lost its antioxidant properties and became pro-oxidant. This effect might be caused by long-chain-oxidized-products of BCC. Results demonstrated that a short heat-treatment improves the bioactivity of β-carotene but longer treatments made BCC prooxidant, showing that samples that underwent drastic extraction processes could not tolerate additional steps for functional food production. PMID:26213087

  13. Effect of heat-processing on the antioxidant and prooxidant activities of β-carotene from natural and synthetic origins on red blood cells.

    PubMed

    Phan-Thi, Hanh; Durand, Philippe; Prost, Michel; Prost, Emmanuelle; Waché, Yves

    2016-01-01

    Extraction of bioactives is a cause of structural changes in these molecules. In this work, the bioactivity of commercial natural β-carotenes, one softly extracted without heat-assistance from Momordica cochinchinensis (BCG), one conventionally extracted from another natural source (BCC), and a synthetic one (BCS), was assessed during an additional heat-treatment mimicking formulation. Their antioxidant activities were evaluated after heat-treatment at different concentrations through hemolysis of horse red blood cells. The thermal 15-cis-isomerization of β-carotene, characterized by DAD-HPLC, resulted in a 2.5- to 4.8-fold increase in the anti-hemolytic effect but this was undetected in chemical assay, at 4 μM. At 100 μM, BCC lost its antioxidant properties and became pro-oxidant. This effect might be caused by long-chain-oxidized-products of BCC. Results demonstrated that a short heat-treatment improves the bioactivity of β-carotene but longer treatments made BCC prooxidant, showing that samples that underwent drastic extraction processes could not tolerate additional steps for functional food production.

  14. New synthetic routes for the preparation of ruthenium-1,10-phenanthroline complexes. Tests of cytotoxic and antibacterial activity of selected ruthenium complexes.

    PubMed

    Turel, Iztok; Golobič, Amalija; Kljun, Jakob; Samastur, Petra; Batista, Urška; Sepčić, Kristina

    2015-01-01

    Three novel complexes have been prepared through reactions of precursor [(dmso)2H][trans-RuCl4(dmso-S)2] (P) and 1,10-phenanthroline (phen) at different conditions. Whereas the analogs of mer-[RuCl3(dmso-S)(phen)] (1) and [Ru(phen)3]Cl2·6CH3OH (3·6CH3OH) have already been prepared by other synthetic routes before, product (H3O)[RuCl4(phen)]·4H2O (2·4H2O) is unprecedented. In the latter, isolated from highly acidic medium, one strongly bound dmso molecule in precursor P was substituted by chloride. Biological activity of 1 and previously isolated ruthenium-purine complexes ([mer-RuCl3(dmso-S)(acv)(CH3OH)] (4) (acv = acyclovir); [trans-RuCl4(dmso-S)(guaH)] (5) (guaH = protonated guanine)) was tested and compared. These data show that compounds 1, 4 and 5 are slightly cytotoxic against B-16 malignant melanoma cells but not against non-transformed V-79-379A cells. It seems that coordinated phen ligand increases the cytotoxicity of 1 in comparison to ruthenium precursor. The inability of tested compounds to induce lysis of bovine erythrocytes suggests that their cytotoxic effect is not due to the membrane damage. PMID:26085415

  15. Substrate-Triggered Activation of a Synthetic [Fe2(μ-O)2] Diamond Core for C–H Bond Cleavage

    PubMed Central

    Xue, Genqiang; Pokutsa, Alexander; Que, Lawrence

    2011-01-01

    An [FeIV2(μ-O)2] diamond core structure has been postulated for intermediate Q of soluble methane monooxygenase (sMMO-Q), the oxidant responsible for cleaving the strong C–H bond of methane and its hydroxylation. By extension, analogous species may be involved in the mechanisms of related diiron hydroxylases and desaturases. Due to the paucity of well-defined synthetic examples, there are few, if any, mechanistic studies on the oxidation of hydrocarbon substrates by complexes with high-valent [Fe2(μ-O)2] cores. We report here that water or alcohol substrates can activate synthetic [FeIIIFeIV(μ-O)2] complexes supported by tetradentate tris(pyridyl-2-methyl)amine ligands (1 and 2) by several orders of magnitude for C–H bond oxidation. On the basis of detailed kinetic studies, it is postulated that the activation results from Lewis base attack on the [FeIIIFeIV(μ-O)2] core, resulting in the formation of a more reactive species with a [X–FeIII–O–FeIV=O] ring-opened structure (1-X, 2-X, X = OH− or OR−). Treatment of 2 with methoxide at −80 °C forms the 2-methoxide adduct in high yield, which is characterized by an S = 1/2 EPR signal indicative of an antiferromagnetically coupled [S = 5/2 FeIII/S = 2 FeIV] pair. Even at this low temperature, the complex undergoes facile intramolecular C–H bond cleavage to generate formaldehyde, showing that the terminal high-spin FeIV=O unit is capable of oxidizing a C–H bond as strong as 96 kcal mol−1. This intramolecular oxidation of the methoxide ligand can in fact be competitive with intermolecular oxidation of triphenylmethane, which has a much weaker C–H bond (DC-H 81 kcal mol−1). The activation of the [FeIIIFeIV(μ-O)2] core is dramatically illustrated by the oxidation of 9,10-dihydroanthracene by 2-methoxide, which has a second order rate constant that is 3.6 x 107-fold larger than that for the parent diamond core complex 2. These observations provide strong support for the DFT-based notion that an

  16. Antilipopolysaccharide factor (ALF) of mud crab Scylla paramamosain: molecular cloning, genomic organization and the antimicrobial activity of its synthetic LPS binding domain.

    PubMed

    Imjongjirak, Chanprapa; Amparyup, Piti; Tassanakajon, Anchalee; Sittipraneed, Siriporn

    2007-05-01

    Antilipopolysaccharide factors (ALFs) are small basic proteins that can bind and neutralize lipopolysaccharide (LPS) and have broad spectrum antimicrobial activities. In this study, we describe the isolation of the full-length cDNA encoding for ALF peptide (ALFSp) of mud crab, Scylla paramamosain by sequencing a hemocyte cDNA library and using the rapid amplification cDNA end (RACE) method. A full-length ALFSp cDNA of 614 bp contains an open reading frame (ORF) of 372 bp, encoding 123 amino acid protein with 26 residues signal sequence. The calculated molecular mass of the mature protein is 11.18 kDa. The highly two conserve cysteine residues and putative LPS binding domain were observed in ALFSp peptide. Comparison of amino acid sequences revealed that ALFSp shared high identity with other known ALFs and had an overall similarity of 65, 64, 63, 61 and 59% to those of Fenneropenaeus chinensis, Litopenaeus vannamei, Marsupenaeus japonicus, Limulus polyphemus, and Tachypleus tridentatus, respectively. A neighbour-joining tree showed a clear differentiation of each species and also indicated that ALF from S. paramamosain, Carcinus maenas and Callinectes sapidus are closely related phylogenetically. The genomic DNA sequence of ALFSp gene consists of 1075 bp containing three exons and two introns. Tissue distribution analysis revealed that ALFSp was abundantly expressed in hemocytes, intestine, and muscle but not in eyestalk. The synthetic ALFSp peptide containing putative LPS binding domain revealed a strong antimicrobial activity against several bacteria especially on the growth of Gram-positive bacteria, Micrococcus luteus and Gram-negative bacteria, Vibrio harveyi suggested that ALFSp could play an essential role in defense mechanism in S. paramamosain. PMID:17368541

  17. Phemindole, a Synthetic Di-indole Derivative Maneuvers the Store Operated Calcium Entry (SOCE) to Induce Potent Anti-Carcinogenic Activity in Human Triple Negative Breast Cancer Cells

    PubMed Central

    Chakraborty, Supriya; Ghosh, Swatilekha; Banerjee, Bhaswati; Santra, Abhishek; Adhikary, Arghya; Misra, Anup K.; Sen, Parimal C.

    2016-01-01

    Triple-negative breast cancer (TNBC), is a specific subtype of epithelial breast tumors that are immuno-histochemically negative for the protein expression of the estrogen receptor (ER), the progesterone receptor (PR) and lack over expression/gene amplification of HER2. This subtype of breast cancers is highly metastatic, shows poor prognosis and hence represents an important clinical challenge to researchers worldwide. Thus alternative approaches of drug development for TNBC have gained utmost importance in the present times. Dietary indole and its derivatives have gained prominence as anti-cancer agents and new therapeutic approaches are being developed to target them against TNBC. But a major drawback with 3, 3′di Indolyl methane (DIM) is their poor bioavailability and high effective concentration against TNBC. However, the Aryl methyl ring substituted analogs of DIM display interesting anti-cancer activity in breast cancer cells. In the current study we report the synthesis of a novel synthetic aryl methyl ring substituted analog of DIM, named as Phemindole as an effective anti-tumor agent against TNBC cells. Furthermore, we enumerated that Phemindole caused reactive oxygen species mediated mitochondrial-dependent apoptosis in MDAMB-231 cells. Furthermore, Phemindole mediated Store Operated Calcium Entry (SOCE) retardation favored inactivation of STIM1 and henceforth activated ER stress to induce apoptosis in TNBC cells. Simultaneously, Phemindole was also found to restrict the in vitro cell migration through its anti mitotic property and pFAK regulation. Studies extended to ex ovo and in vivo mice models further validated the efficacy of Phemindole. Thus our results cumulatively propose Phemindole as a new chemotherapeutic regime which might be effective to target the deadly aspects of the TNBC. PMID:27199756

  18. A novel synthetic derivative of the natural product berbamine inhibits cell viability and induces apoptosis of human osteosarcoma cells, associated with activation of JNK/AP-1 signaling.

    PubMed

    Yang, Fan; Nam, Sangkil; Zhao, Robin; Tian, Yan; Liu, Lucy; Horne, David A; Jove, Richard

    2013-11-01

    Osteosarcoma is the most common primary bone tumor in children and adolescents. There is a critical need to find more potent drugs for patients with metastatic or recurrent disease. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plants. BBM and its derivatives have been shown to have antitumor effects in several cancers. Here, we report that a novel synthetic berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of G292, KHOS, and MG-63 human osteosarcoma cells. Induction of apoptosis in these tumor cells depends on activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). Since pan-caspase inhibitor (Z-VAD-FMK) and caspase-9 inhibitor (Z-LEHD-FMK) could block the cleavage of PARP, the apoptosis induced by BBMD3 is through intrinsic signaling pathway. BBMD3 increased phosphorylation of c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), resulting in increase of phosphorylated c-Jun and total c-Fos, the major components of transcriptional factor AP-1. JNK inhibitor could partially suppress antitumor effect of BBMD3 on osteosarcoma cells. BBMD3 increased the production of reactive oxygen species (ROS) and ROS scavenger, N-acetylcysteine (NAC), could block the phosphorylation of JNK and c-Jun induced by BBMD3. BBMD3 increased the expression of the pro-apototic gene Bad, associated with apoptosis induction. Finally, BBMD3 also decreased the expression of cyclin D1 and D2, the positive cell cycle regulators, which is correlated with growth inhibition in osteosarcoma cells. Collectively, these findings indicate that BBMD3 is a potentially promising drug for the treatment of human osteosarcoma.

  19. A new pro-migratory activity on human myogenic precursor cells for a synthetic peptide within the E domain of the mechano growth factor

    SciTech Connect

    Mills, Philippe; Lafreniere, Jean-Francois; Benabdallah, Basma Fattouma; El Fahime, El Mostafa; Tremblay, Jacques-P. . E-mail: Jacques-P.Tremblay@crchul.ulaval.ca

    2007-02-01

    Duchenne muscular dystrophy (DMD) is an inherited disease that leads to progressive muscle wasting. Myogenic precursor cell transplantation is an approach that can introduce the normal dystrophin gene in the muscle fibers of the patients. Unfortunately, these myogenic precursor cells do not migrate well in the muscle and thus many injections have to be done to enable a good graft success. Recent reports have shown that there is extensive splicing of the IGF-1 gene in muscles. The MGF isoform contains a C-terminal 24 amino acids peptide in the E domain (MGF-Ct24E) that has intrinsic properties. It can promote the proliferation while delaying the differentiation of C{sub 2}C{sub 12} cells. Here, we demonstrated that this synthetic peptide is a motogenic factor for human precursor myogenic cells in vitro and in vivo. Indeed, MGF-Ct24E peptide can modulate members of the fibrinolytic and metalloproteinase systems, which are implicated in the migration of myogenic cells. MGF-Ct24E peptide enhances the expression of u-PA, u-PAR and MMP-7 while reducing PAI-1 activity. Moreover, it has no effect on the gelatinases MMP-2 and -9. Those combined effects can favour cell migration. Finally, we present some results suggesting that the MGF-Ct24E peptide induces these cell responses through a mechanism that does not involve the IGF-1 receptor. Thus, this MGF-Ct24E peptide has a new pro-migratory activity on human myogenic precursor cells that may be helpful in the treatment of DMD. Those results reinforce the possibility that the IGF-1Ec isoform may produce an E domain peptide that can act as a cytokine.

  20. Phemindole, a Synthetic Di-indole Derivative Maneuvers the Store Operated Calcium Entry (SOCE) to Induce Potent Anti-Carcinogenic Activity in Human Triple Negative Breast Cancer Cells.

    PubMed

    Chakraborty, Supriya; Ghosh, Swatilekha; Banerjee, Bhaswati; Santra, Abhishek; Adhikary, Arghya; Misra, Anup K; Sen, Parimal C

    2016-01-01

    Triple-negative breast cancer (TNBC), is a specific subtype of epithelial breast tumors that are immuno-histochemically negative for the protein expression of the estrogen receptor (ER), the progesterone receptor (PR) and lack over expression/gene amplification of HER2. This subtype of breast cancers is highly metastatic, shows poor prognosis and hence represents an important clinical challenge to researchers worldwide. Thus alternative approaches of drug development for TNBC have gained utmost importance in the present times. Dietary indole and its derivatives have gained prominence as anti-cancer agents and new therapeutic approaches are being developed to target them against TNBC. But a major drawback with 3, 3'di Indolyl methane (DIM) is their poor bioavailability and high effective concentration against TNBC. However, the Aryl methyl ring substituted analogs of DIM display interesting anti-cancer activity in breast cancer cells. In the current study we report the synthesis of a novel synthetic aryl methyl ring substituted analog of DIM, named as Phemindole as an effective anti-tumor agent against TNBC cells. Furthermore, we enumerated that Phemindole caused reactive oxygen species mediated mitochondrial-dependent apoptosis in MDAMB-231 cells. Furthermore, Phemindole mediated Store Operated Calcium Entry (SOCE) retardation favored inactivation of STIM1 and henceforth activated ER stress to induce apoptosis in TNBC cells. Simultaneously, Phemindole was also found to restrict the in vitro cell migration through its anti mitotic property and pFAK regulation. Studies extended to ex ovo and in vivo mice models further validated the efficacy of Phemindole. Thus our results cumulatively propose Phemindole as a new chemotherapeutic regime which might be effective to target the deadly aspects of the TNBC. PMID:27199756

  1. Evolvable synthetic neural system

    NASA Technical Reports Server (NTRS)

    Curtis, Steven A. (Inventor)

    2009-01-01

    An evolvable synthetic neural system includes an evolvable neural interface operably coupled to at least one neural basis function. Each neural basis function includes an evolvable neural interface operably coupled to a heuristic neural system to perform high-level functions and an autonomic neural system to perform low-level functions. In some embodiments, the evolvable synthetic neural system is operably coupled to one or more evolvable synthetic neural systems in a hierarchy.

  2. Synthetic cathinone abuse

    PubMed Central

    Capriola, Michael

    2013-01-01

    The abuse of synthetic cathinones, widely known as bath salts, has been increasing since the mid-2000s. These substances are derivatives of the naturally occurring compound cathinone, which is the primary psychoactive component of khat. The toxicity of synthetic cathinones includes significant sympathomimetic effects, as well as psychosis, agitation, aggression, and sometimes violent and bizarre behavior. Mephedrone and methylenedioxypyrovalerone are currently the predominantly abused synthetic cathinones. PMID:23869180

  3. [SYNTHETIC PEPTIDE VACCINES].

    PubMed

    Sergeyev, O V; Barinsky, I F

    2016-01-01

    An update on the development and trials of synthetic peptide vaccines is reviewed. The review considers the successful examples of specific protection as a result of immunization with synthetic peptides using various protocols. The importance of conformation for the immunogenicity of the peptide is pointed out. An alternative strategy of the protection of the organism against the infection using synthetic peptides is suggested. PMID:27145593

  4. Antinociceptive activity of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone, on nociception-induced models in mice.

    PubMed

    Ming-Tatt, Lee; Khalivulla, Shaik Ibrahim; Akhtar, Muhammad Nadeem; Mohamad, Azam Shah; Perimal, Enoch Kumar; Khalid, Mohamed Hanief; Akira, Ahmad; Lajis, Nordin; Israf, Daud Ahmad; Sulaiman, Mohd Roslan

    2012-03-01

    This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC), using chemical- and thermal-induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose-related inhibition in the acetic acid-induced abdominal constriction test in mice with an ID(50) of 0.15 (0.13-0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin-induced paw licking test with an ID(50) of 0.35 (0.27-0.46) mg/kg and 0.07 (0.06-0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot-plate test. Moreover, the antinociceptive effect of the BHMC in the formalin-induced paw licking test and the hot-plate test was antagonized by pre-treatment with the non-selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID(50) of 0.66 (0.41-1.07) mg/kg and 0.42 (0.38-0.51) mg/kg, respectively. Finally, it was also shown that BHMC-induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of

  5. A synthetic gene increases TGFβ3 accumulation by 75-fold in tobacco chloroplasts enabling rapid purification and folding into a biologically active molecule.

    PubMed

    Gisby, Martin F; Mellors, Philip; Madesis, Panagiotis; Ellin, Marianne; Laverty, Hugh; O'Kane, Sharon; Ferguson, Mark W J; Day, Anil

    2011-06-01

    Human transforming growth factor-β3 (TGFβ3) is a new therapeutic protein used to reduce scarring during wound healing. The active molecule is a nonglycosylated, homodimer comprised of 13-kDa polypeptide chains linked by disulphide bonds. Expression of recombinant human TGFβ3 in chloroplasts and its subsequent purification would provide a sustainable source of TGFβ3 free of animal pathogens. A synthetic sequence (33% GC) containing frequent chloroplast codons raised accumulation of the 13-kDa TGFβ3 polypeptide by 75-fold compared to the native coding region (56% GC) when expressed in tobacco chloroplasts. The 13-kDa TGFβ3 monomer band was more intense than the RuBisCO 15-kDa small subunit on Coomassie blue-stained SDS-PAGE gels. TGFβ3 accumulated in insoluble aggregates and was stable in leaves of different ages but was not detected in seeds. TGFβ3 represented 12% of leaf protein and appeared as monomer, dimer and trimer bands on Western blots of SDS-PAGE gels. High yield and insolubility facilitated initial purification and refolding of the 13-kDa polypeptide into the TGFβ3 homodimer recognized by a conformation-dependent monoclonal antibody. The TGFβ3 homodimer and trace amounts of monomer were the only bands visible on silver-stained gels following purification by hydrophobic interaction chromatography and cation exchange chromatography. N-terminal sequencing and electronspray ionization mass spectrometry showed the removal of the initiator methionine and physical equivalence of the chloroplast-produced homodimer to standard TGFβ3. Functional equivalence was demonstrated by near-identical dose-response curves showing the inhibition of mink lung epithelial cell proliferation. We conclude that chloroplasts are an attractive production platform for synthesizing recombinant human TGFβ3. PMID:21535357

  6. TOMO3D: 3-D joint refraction and reflection traveltime tomography parallel code for active-source seismic data—synthetic test

    NASA Astrophysics Data System (ADS)

    Meléndez, A.; Korenaga, J.; Sallarès, V.; Miniussi, A.; Ranero, C. R.

    2015-10-01

    We present a new 3-D traveltime tomography code (TOMO3D) for the modelling of active-source seismic data that uses the arrival times of both refracted and reflected seismic phases to derive the velocity distribution and the geometry of reflecting boundaries in the subsurface. This code is based on its popular 2-D version TOMO2D from which it inherited the methods to solve the forward and inverse problems. The traveltime calculations are done using a hybrid ray-tracing technique combining the graph and bending methods. The LSQR algorithm is used to perform the iterative regularized inversion to improve the initial velocity and depth models. In order to cope with an increased computational demand due to the incorporation of the third dimension, the forward problem solver, which takes most of the run time (˜90 per cent in the test presented here), has been parallelized with a combination of multi-processing and message passing interface standards. This parallelization distributes the ray-tracing and traveltime calculations among available computational resources. The code's performance is illustrated with a realistic synthetic example, including a checkerboard anomaly and two reflectors, which simulates the geometry of a subduction zone. The code is designed to invert for a single reflector at a time. A data-driven layer-stripping strategy is proposed for cases involving multiple reflectors, and it is tested for the successive inversion of the two reflectors. Layers are bound by consecutive reflectors, and an initial velocity model for each inversion step incorporates the results from previous steps. This strategy poses simpler inversion problems at each step, allowing the recovery of strong velocity discontinuities that would otherwise be smoothened.

  7. Variable Synthetic Capacitance

    NASA Technical Reports Server (NTRS)

    Kleinberg, L. L.

    1986-01-01

    Feedback amplifier circuit synthesizes electronically variable capacitance. Variable Synthetic Capacitor is amplifier circuit with follower/feedback configuration. Effective input capacitance depends on input set current. If synthetic capacitor is connected across resonant element of oscillator, oscillator frequency controlled via input set current. Circuit especially suitable for fine frequency adjustments of piezoelectric-crystal or inductor/capacitor resonant oscillators.

  8. Chemical aspects of synthetic biology.

    PubMed

    Luisi, Pier Luigi

    2007-04-01

    Synthetic biology as a broad and novel field has also a chemical branch: whereas synthetic biology generally has to do with bioengineering of new forms of life (generally bacteria) which do not exist in nature, 'chemical synthetic biology' is concerned with the synthesis of chemical structures such as proteins, nucleic acids, vesicular forms, and other which do not exist in nature. Three examples of this 'chemical synthetic biology' approach are given in this article. The first example deals with the synthesis of proteins that do not exist in nature, and dubbed as 'the never born proteins' (NBPs). This research is related to the question why and how the protein structures existing in our world have been selected out, with the underlying question whether they have something very particular from the structural or thermodynamic point of view (for example, the folding). The NBPs are produced in the laboratory by the modern molecular biology technique, the phage display, so as to produce a very large library of proteins having no homology with known proteins. The second example of chemical synthetic biology has also to do with the laboratory synthesis of proteins, but, this time, adopting a prebiotic synthetic procedure, the fragment condensation of short peptides, where short means that they have a length that can be obtained by prebiotic methods; for example, from the condensation of N-carboxy anhydrides. The scheme is illustrated and discussed, being based on the fragment condensation catalyzed by peptides endowed with proteolitic activity. Selection during chain growth is determined by solubility under the contingent environmental conditions, i.e., the peptides which result insoluble are eliminated from further growth. The scheme is tested preliminarily with a synthetic chemical fragment-condensation method and brings to the synthesis of a 44-residues-long protein, which has no homology with known proteins, and which has a stable tertiary folding. Finally, the third

  9. Where Synthetic Biology Meets ET

    NASA Technical Reports Server (NTRS)

    Rothschild, Lynn J.

    2016-01-01

    Synthetic biology - the design and construction of new biological parts and systems and the redesign of existing ones for useful purposes - has the potential to transform fields from pharmaceuticals to fuels. Our lab has focused on the potential of synthetic biology to revolutionize all three major parts of astrobiology: Where do we come from? Where are we going? and Are we alone? For the first and third, synthetic biology is allowing us to answer whether the evolutionary narrative that has played out on planet earth is likely to have been unique or universal. For example, in our lab we are re-evolving the biosynthetic pathways of amino acids in order to understand potential capabilities of an early organism with a limited repertoire of amino acids and developing techniques for the recovery of metals from spent electronics on other planetary bodies. And what about the limits for life? Can we create organisms that expand the envelope for life? In the future synthetic biology will play an increasing role in human activities both on earth, in fields as diverse as human health and the industrial production of novel bio-composites. Beyond earth, we will rely increasingly on biologically-provided life support, as we have throughout our evolutionary history. In order to do this, the field will build on two of the great contributions of astrobiology: studies of the origin of life and life in extreme environments.

  10. Synthetic therapeutic gene circuits in mammalian cells.

    PubMed

    Ye, Haifeng; Fussenegger, Martin

    2014-08-01

    In the emerging field of synthetic biology, scientists are focusing on designing and creating functional devices, systems, and organisms with novel functions by engineering and assembling standardised biological building blocks. The progress of synthetic biology has significantly advanced the design of functional gene networks that can reprogram metabolic activities in mammalian cells and provide new therapeutic opportunities for future gene- and cell-based therapies. In this review, we describe the most recent advances in synthetic mammalian gene networks designed for biomedical applications, including how these synthetic therapeutic gene circuits can be assembled to control signalling networks and applied to treat metabolic disorders, cancer, and immune diseases. We conclude by discussing the various challenges and future prospects of using synthetic mammalian gene networks for disease therapy.

  11. Mammalian synthetic biology: emerging medical applications

    PubMed Central

    Kis, Zoltán; Pereira, Hugo Sant'Ana; Homma, Takayuki; Pedrigi, Ryan M.; Krams, Rob

    2015-01-01

    In this review, we discuss new emerging medical applications of the rapidly evolving field of mammalian synthetic biology. We start with simple mammalian synthetic biological components and move towards more complex and therapy-oriented gene circuits. A comprehensive list of ON–OFF switches, categorized into transcriptional, post-transcriptional, translational and post-translational, is presented in the first sections. Subsequently, Boolean logic gates, synthetic mammalian oscillators and toggle switches will be described. Several synthetic gene networks are further reviewed in the medical applications section, including cancer therapy gene circuits, immuno-regulatory networks, among others. The final sections focus on the applicability of synthetic gene networks to drug discovery, drug delivery, receptor-activating gene circuits and mammalian biomanufacturing processes. PMID:25808341

  12. Mammalian synthetic biology: emerging medical applications.

    PubMed

    Kis, Zoltán; Pereira, Hugo Sant'Ana; Homma, Takayuki; Pedrigi, Ryan M; Krams, Rob

    2015-05-01

    In this review, we discuss new emerging medical applications of the rapidly evolving field of mammalian synthetic biology. We start with simple mammalian synthetic biological components and move towards more complex and therapy-oriented gene circuits. A comprehensive list of ON-OFF switches, categorized into transcriptional, post-transcriptional, translational and post-translational, is presented in the first sections. Subsequently, Boolean logic gates, synthetic mammalian oscillators and toggle switches will be described. Several synthetic gene networks are further reviewed in the medical applications section, including cancer therapy gene circuits, immuno-regulatory networks, among others. The final sections focus on the applicability of synthetic gene networks to drug discovery, drug delivery, receptor-activating gene circuits and mammalian biomanufacturing processes.

  13. Synthetic mammalian gene circuits for biomedical applications.

    PubMed

    Ye, Haifeng; Aubel, Dominique; Fussenegger, Martin

    2013-12-01

    Synthetic biology is the science of reassembling cataloged and standardized biological items in a systematic and rational manner to create and engineer functional biological designer devices, systems and organisms with novel and useful, preferably therapeutic functions. Synthetic biology has significantly advanced the design of complex genetic networks that can reprogram metabolic activities in mammalian cells and provide novel therapeutic strategies for future gene-based and cell-based therapies. Synthetic biology-inspired therapeutic strategies provide new opportunities for improving human health in the 21st century. This review covers the most recent synthetic mammalian circuits designed for therapy of diseases such as metabolic disorders, cancer, and immune disorders. We conclude by discussing current challenges and future perspectives for biomedical applications of synthetic mammalian gene networks.

  14. Characterization of active phosphorus surface sites at synthetic carbonate-free fluorapatite using single-pulse 1H, 31P, and 31P CP MAS NMR.

    PubMed

    Jarlbring, Mathias; Sandström, Dan E; Antzutkin, Oleg N; Forsling, Willis

    2006-05-01

    The chemically active phosphorus surface sites defined as PO(x), PO(x)H, and PO(x)H2, where x = 1, 2, or 3, and the bulk phosphorus groups of PO4(3-) at synthetic carbonate-free fluorapatite (Ca5(PO4)3F) have been studied by means of single-pulse 1H,31P, and 31P CP MAS NMR. The changes in composition and relative amounts of each surface species are evaluated as a function of pH. By combining spectra from single-pulse 1H and 31P MAS NMR and data from 31P CP MAS NMR experiments at varying contact times in the range 0.2-3.0 ms, it has been possible to distinguish between resonance lines in the NMR spectra originating from active surface sites and bulk phosphorus groups and also to assign the peaks in the NMR spectra to the specific phosphorus species. In the 31P CP MAS NMR experiments, the spinning frequency was set to 4.2 kHz; in the single-pulse 1H MAS NMR experiments, the spinning frequency was 10 kHz. The 31P CP MAS NMR spectrum of fluorapatite at pH 5.9 showed one dominating resonance line at 2.9 ppm assigned to originate from PO4(3-) groups and two weaker shoulder peaks at 5.4 and 0.8 ppm which were assigned to the unprotonated PO(x) (PO, PO2-, and PO3(2-)) and protonated PO(x)H (PO2H and PO3H-) surface sites. At pH 12.7, the intensity of the peak representing unprotonated PO(x) surface sites has increased 1.7% relative to the bulk peak, while the intensity of the peaks of the protonated species PO(x)H have decreased 1.4% relative to the bulk peak. At pH 3.5, a resonance peak at -4.5 ppm has appeared in the 31P CP MAS NMR spectrum assigned to the surface species PO(x)H2 (PO3H2). The results from the 1H MAS and 31P CP MAS NMR measurements indicated that H+, OH-, and physisorbed H2O at the surface were released during the drying process at 200 degrees C.

  15. Synthetic biology and its regulation in the European Union.

    PubMed

    Buhk, Hans-Jörg

    2014-12-25

    The term synthetic biology is used increasingly, but without a clear definition. Most of the recent research carried out in this field is genetic engineering, as defined by current GMO-legislation in the EU. Synthetic biology has developed its own language. In vitro synthesis of DNA also carries the label synthetic biology. It is important to analyze whether present and future activities of synthetic biology are within the scope of existing EU-legislation.

  16. Synthetic inhibitors of elastase.

    PubMed

    Edwards, P D; Bernstein, P R

    1994-03-01

    For more than two decades investigators around the world, in both academic and industrial institutions, have been developing inhibitors of human neutrophil elastase. A number of very elegant and insightful strategies have been reported. In the case of reversible peptidic inhibitors, this has resulted in the identification of some extremely potent compounds with dissociation constants in the 10(-11) M range. This is quite an accomplishment considering that these low molecular-weight inhibitors are only tri- and tetrapeptides. In the case of the heterocyclic-based inhibitors, the challenge of balancing the heterocycle's inherent reactivity and aqueous stability with the stability of the enzyme-inhibitor adduct has been meet by either using a latent, reactive functionality which is only activated within the enzyme, or by incorporating features which selectively obstruct deacylation but have little effect on the enzyme acylation step. The underlying goal of this research has been the identification of agents to treat diseases associated with HNE. Several animal models have been developed for evaluating the in vivo activity of elastase inhibitors, and compounds have been shown to be effective in all of these models by the intravenous, intratrachael or oral routes of administration. However, only a very small percentage of compounds have possessed all the necessary properties, including lack of toxicity, for progression into the clinic. The peptidyl TFMK ICI 200,880 (25-12) has many of the desired characteristics of a drug to treat the diseases associated with HNE: chemical stability, in vitro and in vivo activity, a long duration of action, and adequate metabolic stability. Currently ICI 200,880 is the only low molecular-weight HNE inhibitor known to be undergoing clinical trials, and may be the compound which finally demonstrates the clinical utility of a synthetic HNE inhibitor. PMID:8189835

  17. Saga of synthetic rubber

    SciTech Connect

    Solo, R.A.

    1980-04-01

    The proposal to establish an Energy Mobilization Board and a synthetic fuels industry is reminiscent of World War II efforts to produce synthetic rubber. To avoid the mistakes made in the earlier effort, Mr. Solo suggests that the synthetic-fuel program should (1) use a more-successful technological development project as a model; (2) commit public funding and not rely on profit-oriented private enterprise; and (3) avoid entrusting social planning to single-purpose entities that have not been sensitive to social values. (DCK)

  18. Synthetic Base Fluids

    NASA Astrophysics Data System (ADS)

    Brown, M.; Fotheringham, J. D.; Hoyes, T. J.; Mortier, R. M.; Orszulik, S. T.; Randles, S. J.; Stroud, P. M.

    The chemical nature and technology of the main synthetic lubricant base fluids is described, covering polyalphaolefins, alkylated aromatics, gas-to-liquid (GTL) base fluids, polybutenes, aliphatic diesters, polyolesters, polyalkylene glycols or PAGs and phosphate esters.Other synthetic lubricant base oils such as the silicones, borate esters, perfluoroethers and polyphenylene ethers are considered to have restricted applications due to either high cost or performance limitations and are not considered here.Each of the main synthetic base fluids is described for their chemical and physical properties, manufacture and production, their chemistry, key properties, applications and their implications when used in the environment.

  19. Building synthetic memory

    PubMed Central

    Inniss, Mara C.; Silver, Pamela A.

    2013-01-01

    Synopsis Cellular memory – conversion of a transient signal into a sustained response – is a common feature of biological systems. Synthetic biologists aim to understand and reengineer such systems in a reliable and predictable manner. Synthetic memory circuits have been designed and built in vitro and in vivo based on diverse mechanisms such as oligonucleotide hybridization, recombination, transcription, phosphorylation, and RNA editing. Thus far, building these circuits has helped us explore the basic principles required for stable memory and ask novel biological questions. Here we discuss strategies for building synthetic memory circuits, their use as research tools, and future applications of these devices in medicine and industry. PMID:24028965

  20. Requiem for synthetic fuels

    SciTech Connect

    Myers, R.

    1982-01-27

    US plans to launch a synthetic fuels industry revive whenever a price or supply crisis occurs, but industrial hopes descend as soon as the short-term market begins improving in terms of real prices. The capital requirements of a synthetic fuels project combined with fears of a noncompetitive product have caused several major oil companies to scale down or cancel their plans. In the author's view, the Reagan administration's hands-off policy and false sense of security from the current oil supply glut have further discouraged industry. The Synthetic Fuels Corporation has been slow to organize, and appears to be favoring small-size plants. (DCK)

  1. Synthetic Foveal Imaging Technology

    NASA Technical Reports Server (NTRS)

    Hoenk, Michael; Monacos, Steve; Nikzad, Shouleh

    2009-01-01

    Synthetic Foveal imaging Technology (SyFT) is an emerging discipline of image capture and image-data processing that offers the prospect of greatly increased capabilities for real-time processing of large, high-resolution images (including mosaic images) for such purposes as automated recognition and tracking of moving objects of interest. SyFT offers a solution to the image-data processing problem arising from the proposed development of gigapixel mosaic focal-plane image-detector assemblies for very wide field-of-view imaging with high resolution for detecting and tracking sparse objects or events within narrow subfields of view. In order to identify and track the objects or events without the means of dynamic adaptation to be afforded by SyFT, it would be necessary to post-process data from an image-data space consisting of terabytes of data. Such post-processing would be time-consuming and, as a consequence, could result in missing significant events that could not be observed at all due to the time evolution of such events or could not be observed at required levels of fidelity without such real-time adaptations as adjusting focal-plane operating conditions or aiming of the focal plane in different directions to track such events. The basic concept of foveal imaging is straightforward: In imitation of a natural eye, a foveal-vision image sensor is designed to offer higher resolution in a small region of interest (ROI) within its field of view. Foveal vision reduces the amount of unwanted information that must be transferred from the image sensor to external image-data-processing circuitry. The aforementioned basic concept is not new in itself: indeed, image sensors based on these concepts have been described in several previous NASA Tech Briefs articles. Active-pixel integrated-circuit image sensors that can be programmed in real time to effect foveal artificial vision on demand are one such example. What is new in SyFT is a synergistic combination of recent

  2. What Are Synthetic Cannabinoids?

    MedlinePlus

    ... those produced by marijuana: elevated mood relaxation altered perception —awareness of surrounding objects and conditions symptoms of ... those produced by marijuana: elevated mood relaxation altered perception symptoms of psychosis Synthetic cannabinoids can also cause ...

  3. Analysis of Synthetic Polymers.

    ERIC Educational Resources Information Center

    Smith, Charles G.; And Others

    1989-01-01

    Reviews techniques for the characterization and analysis of synthetic polymers, copolymers, and blends. Includes techniques for structure determination, separation, and quantitation of additives and residual monomers; determination of molecular weight; and the study of thermal properties including degradation mechanisms. (MVL)

  4. Synthetic cannabinoids: analysis and metabolites.

    PubMed

    Elsohly, Mahmoud A; Gul, Waseem; Wanas, Amira S; Radwan, Mohamed M

    2014-02-27

    Cannabimimetics (commonly referred to as synthetic cannabinoids), a group of compounds encompassing a wide range of chemical structures, have been developed by scientists with the hope of achieving selectivity toward one or the other of the cannabinoid receptors CB1 and CB2. The goal was to have compounds that could possess high therapeutic activity without many side effects. However, underground laboratories have used the information generated by the scientific community to develop these compounds for illicit use as marijuana substitutes. This chapter reviews the different classes of these "synthetic cannabinoids" with particular emphasis on the methods used for their identification in the herbal products with which they are mixed and identification of their metabolites in biological specimens.

  5. Synthetic battery cycling techniques

    NASA Technical Reports Server (NTRS)

    Leibecki, H.; Thaller, L. H.

    1982-01-01

    The group of techniques that as a class are referred to as synthetic battery cycling are described with reference to spacecraft battery systems. Synthetic battery cycling makes use of the capability of computer graphics to illustrate some of the basic characteristics of operation of individual electrodes within an operating electrochemical cell. It can also simulate the operation of an entire string of cells that are used as the energy storage subsystem of a power system.

  6. Synthetic approaches to monofluoroalkenes.

    PubMed

    Landelle, Grégory; Bergeron, Maxime; Turcotte-Savard, Marc-Olivier; Paquin, Jean-François

    2011-05-01

    Monofluoroalkenes are an important fluorinated class of compounds with applications in medicinal chemistry, material sciences and organic chemistry. An overview of methods allowing synthetic access to these fluorinated building blocks is provided. In particular, this critical review, which covers publications up to October 2010, will be divided according to the substitution pattern of the monofluoroalkenes, i.e. di-, tri- or tetra-substituted. Within each group, the various synthetic approaches will be divided according to the reaction type (282 references).

  7. Synthetic biology and biosecurity.

    PubMed

    Robienski, Jürgen; Simon, Jürgen

    2014-01-01

    This article discusses the conflict fields and legal questions of synthetic biology, esp. concerning biosecurity. A respective jurisprudential discussion has not taken place yet in Germany apart from few statements and recommendations. But in Germany, Europe and the USA, it is generally accepted that a broad discussion is necessary. This is esp. true for the question of biosecurity and the possible dangers arising from Synthetic Biology. PMID:25845204

  8. Synthetic Vision Systems

    NASA Technical Reports Server (NTRS)

    Prinzel, L.J.; Kramer, L.J.

    2009-01-01

    A synthetic vision system is an aircraft cockpit display technology that presents the visual environment external to the aircraft using computer-generated imagery in a manner analogous to how it would appear to the pilot if forward visibility were not restricted. The purpose of this chapter is to review the state of synthetic vision systems, and discuss selected human factors issues that should be considered when designing such displays.

  9. Differential Synthetic Aperture Ladar

    SciTech Connect

    Stappaerts, E A; Scharlemann, E

    2005-02-07

    We report a differential synthetic aperture ladar (DSAL) concept that relaxes platform and laser requirements compared to conventional SAL. Line-of-sight translation/vibration constraints are reduced by several orders of magnitude, while laser frequency stability is typically relaxed by an order of magnitude. The technique is most advantageous for shorter laser wavelengths, ultraviolet to mid-infrared. Analytical and modeling results, including the effect of speckle and atmospheric turbulence, are presented. Synthetic aperture ladars are of growing interest, and several theoretical and experimental papers have been published on the subject. Compared to RF synthetic aperture radar (SAR), platform/ladar motion and transmitter bandwidth constraints are especially demanding at optical wavelengths. For mid-IR and shorter wavelengths, deviations from a linear trajectory along the synthetic aperture length have to be submicron, or their magnitude must be measured to that precision for compensation. The laser coherence time has to be the synthetic aperture transit time, or transmitter phase has to be recorded and a correction applied on detection.

  10. The emerging world of synthetic genetics.

    PubMed

    Chaput, John C; Yu, Hanyang; Zhang, Su

    2012-11-21

    For over 20 years, laboratories around the world have been applying the principles of Darwinian evolution to isolate DNA and RNA molecules with specific ligand-binding or catalytic activities. This area of synthetic biology, commonly referred to as in vitro genetics, is made possible by the availability of natural polymerases that can replicate genetic information in the laboratory. Moving beyond natural nucleic acids requires organic chemistry to synthesize unnatural analogues and polymerase engineering to create enzymes that recognize artificial substrates. Progress in both of these areas has led to the emerging field of synthetic genetics, which explores the structural and functional properties of synthetic genetic polymers by in vitro evolution. This review examines recent advances in the Darwinian evolution of artificial genetic polymers and their potential downstream applications in exobiology, molecular medicine, and synthetic biology.

  11. Synthetic battery cycling techniques

    NASA Technical Reports Server (NTRS)

    Leibecki, H. F.; Thaller, L. H.

    1982-01-01

    Synthetic battery cycling makes use of the fast growing capability of computer graphics to illustrate some of the basic characteristics of operation of individual electrodes within an operating electrochemical cell. It can also simulate the operation of an entire string of cells that are used as the energy storage subsystem of a power system. The group of techniques that as a class have been referred to as Synthetic Battery Cycling is developed in part to try to bridge the gap of understanding that exists between single cell characteristics and battery system behavior.

  12. Synthetic guide star generation

    DOEpatents

    Payne, Stephen A.; Page, Ralph H.; Ebbers, Christopher A.; Beach, Raymond J.

    2004-03-09

    A system for assisting in observing a celestial object and providing synthetic guide star generation. A lasing system provides radiation at a frequency at or near 938 nm and radiation at a frequency at or near 1583 nm. The lasing system includes a fiber laser operating between 880 nm and 960 nm and a fiber laser operating between 1524 nm and 1650 nm. A frequency-conversion system mixes the radiation and generates light at a frequency at or near 589 nm. A system directs the light at a frequency at or near 589 nm toward the celestial object and provides synthetic guide star generation.

  13. Synthetic guide star generation

    DOEpatents

    Payne, Stephen A [Castro Valley, CA; Page, Ralph H [Castro Valley, CA; Ebbers, Christopher A [Livermore, CA; Beach, Raymond J [Livermore, CA

    2008-06-10

    A system for assisting in observing a celestial object and providing synthetic guide star generation. A lasing system provides radiation at a frequency at or near 938 nm and radiation at a frequency at or near 1583 nm. The lasing system includes a fiber laser operating between 880 nm and 960 nm and a fiber laser operating between 1524 nm and 1650 nm. A frequency-conversion system mixes the radiation and generates light at a frequency at or near 589 nm. A system directs the light at a frequency at or near 589 nm toward the celestial object and provides synthetic guide star generation.

  14. Influence of synthetic and natural food dyes on activities of CYP2A6, UGT1A6, and UGT2B7.

    PubMed

    Kuno, Nayumi; Mizutani, Takaharu

    2005-08-27

    Synthetic or natural food dyes are typical xenobiotics, as are drugs and pollutants. After ingestion, part of these dyes may be absorbed and metabolized by phase I and II drug-metabolizing enzymes and excreted by transporters of phase III enzymes. However, there is little information regarding the metabolism of these dyes. It was investigated whether these dyes are substrates for CYP2A6 and UDP-glucuronosyltransferase (UGT). The in vitro inhibition of drug-metabolizing enzymes by these dyes was also examined. The synthetic food dyes studied were amaranth (food red no. 2), erythrosine B (food red no. 3), allura red (food red no. 40), new coccine (food red no. 102), acid red (food red no. 106), tartrazine (food Yellow no. 4), sunset yellow FCF (food yellow no. 5), brilliant blue FCF (food blue no. 1), and indigo carmine (food blue no. 2). The natural additive dyes studied were extracts from purple sweet potato, purple corn, cochineal, monascus, grape skin, elderberry, red beet, gardenia, and curthamus. Data confirmed that these dyes were not substrates for CYP2A6, UGT1A6, and UGT2B7. Only indigo carmine inhibited CYP2A6 in a noncompetitive manner, while erythrosine B inhibited UGT1A6 (glucuronidation of p-nitrophenol) and UGT2B7 (glucuronidation of androsterone). In the natural additive dyes just listed, only monascus inhibited UGT1A6 and UGT2B7.

  15. Synthetic Visibility System

    NASA Technical Reports Server (NTRS)

    1989-01-01

    Test pilot Lee Person evaluates a Synthetic Visibility System - in essence, two helmet-mounted eyepieces connected to video cameras that swivel in response to head movements. Photograph published in Winds of Change, 75th Anniversary NASA publication (page 113), by James Schultz.

  16. Adaptive synthetic vision

    NASA Astrophysics Data System (ADS)

    Julier, Simon J.; Brown, Dennis; Livingston, Mark A.; Thomas, Justin

    2006-05-01

    Through their ability to safely collect video and imagery from remote and potentially dangerous locations, UAVs have already transformed the battlespace. The effectiveness of this information can be greatly enhanced through synthetic vision. Given knowledge of the extrinsic and intrinsic parameters of the camera, synthetic vision superimposes spatially-registered computer graphics over the video feed from the UAV. This technique can be used to show many types of data such as landmarks, air corridors, and the locations of friendly and enemy forces. However, the effectiveness of a synthetic vision system strongly depends on the accuracy of the registration - if the graphics are poorly aligned with the real world they can be confusing, annoying, and even misleading. In this paper, we describe an adaptive approach to synthetic vision that modifies the way in which information is displayed depending upon the registration error. We describe an integrated software architecture that has two main components. The first component automatically calculates registration error based on information about the uncertainty in the camera parameters. The second component uses this information to modify, aggregate, and label annotations to make their interpretation as clear as possible. We demonstrate the use of this approach on some sample datasets.

  17. Synthetic Aperture Radar Interferometry

    NASA Technical Reports Server (NTRS)

    Rosen, P. A.; Hensley, S.; Joughin, I. R.; Li, F.; Madsen, S. N.; Rodriguez, E.; Goldstein, R. M.

    1998-01-01

    Synthetic aperture radar interferometry is an imaging technique for measuring the topography of a surface, its changes over time, and other changes in the detailed characteristics of the surface. This paper reviews the techniques of interferometry, systems and limitations, and applications in a rapidly growing area of science and engineering.

  18. Towards a Synthetic Chloroplast

    PubMed Central

    Agapakis, Christina M.; Niederholtmeyer, Henrike; Noche, Ramil R.; Lieberman, Tami D.; Megason, Sean G.; Way, Jeffrey C.; Silver, Pamela A.

    2011-01-01

    Background The evolution of eukaryotic cells is widely agreed to have proceeded through a series of endosymbiotic events between larger cells and proteobacteria or cyanobacteria, leading to the formation of mitochondria or chloroplasts, respectively. Engineered endosymbiotic relationships between different species of cells are a valuable tool for synthetic biology, where engineered pathways based on two species could take advantage of the unique abilities of each mutualistic partner. Results We explored the possibility of using the photosynthetic bacterium Synechococcus elongatus PCC 7942 as a platform for studying evolutionary dynamics and for designing two-species synthetic biological systems. We observed that the cyanobacteria were relatively harmless to eukaryotic host cells compared to Escherichia coli when injected into the embryos of zebrafish, Danio rerio, or taken up by mammalian macrophages. In addition, when engineered with invasin from Yersinia pestis and listeriolysin O from Listeria monocytogenes, S. elongatus was able to invade cultured mammalian cells and divide inside macrophages. Conclusion Our results show that it is possible to engineer photosynthetic bacteria to invade the cytoplasm of mammalian cells for further engineering and applications in synthetic biology. Engineered invasive but non-pathogenic or immunogenic photosynthetic bacteria have great potential as synthetic biological devices. PMID:21533097

  19. Biodegradable synthetic bone composites

    DOEpatents

    Liu, Gao; Zhao, Dacheng; Saiz, Eduardo; Tomsia, Antoni P.

    2013-01-01

    The invention provides for a biodegradable synthetic bone composition comprising a biodegradable hydrogel polymer scaffold comprising a plurality of hydrolytically unstable linkages, and an inorganic component; such as a biodegradable poly(hydroxyethylmethacrylate)/hydroxyapatite (pHEMA/HA) hydrogel composite possessing mineral content approximately that of human bone.

  20. Synthetic Bursae for Robots

    NASA Technical Reports Server (NTRS)

    Lovchik, Christopher S.

    2005-01-01

    Synthetic bursae are under development for incorporation into robot joints that are actuated by motor-driven cables in a manner similar to that of arthropod joints actuated by muscle-driven tendons. Like natural bursae, the synthetic bursae would serve as cushions and friction reducers. A natural bursa is a thin bladder filled with synovial fluid, which serves to reduce friction and provide a cushion between a bone and a muscle or a tendon. A synthetic bursa would be similar in form and function: It would be, essentially, a compact, soft roller consisting of a bladder filled with a non-Newtonian fluid. The bladder would be constrained to approximately constant volume. The synthetic bursa would cushion an actuator cable against one of the members of a robot joint and would reduce the friction between the cable and the member. Under load, the pressure in the bladder would hold the opposite walls of the bladder apart, making it possible for them to move freely past each other without rubbing.

  1. Synthetic Confrontation Therapy.

    ERIC Educational Resources Information Center

    Gilliam, Larry

    After initially dispelling predictable fears that his paper might suggest that computers can be equated with man, the author states the problem: what part, if any, might computers play in counseling. Specifically, the possibilities for therapeutic synthetic (artificial) counseling encounters are discussed. Two propositions are significant: (1) the…

  2. Synthetic Vision Workshop 2

    NASA Technical Reports Server (NTRS)

    Kramer, Lynda J. (Compiler)

    1999-01-01

    The second NASA sponsored Workshop on Synthetic/Enhanced Vision (S/EV) Display Systems was conducted January 27-29, 1998 at the NASA Langley Research Center. The purpose of this workshop was to provide a forum for interested parties to discuss topics in the Synthetic Vision (SV) element of the NASA Aviation Safety Program and to encourage those interested parties to participate in the development, prototyping, and implementation of S/EV systems that enhance aviation safety. The SV element addresses the potential safety benefits of synthetic/enhanced vision display systems for low-end general aviation aircraft, high-end general aviation aircraft (business jets), and commercial transports. Attendance at this workshop consisted of about 112 persons including representatives from industry, the FAA, and other government organizations (NOAA, NIMA, etc.). The workshop provided opportunities for interested individuals to give presentations on the state of the art in potentially applicable systems, as well as to discuss areas of research that might be considered for inclusion within the Synthetic Vision Element program to contribute to the reduction of the fatal aircraft accident rate. Panel discussions on topical areas such as databases, displays, certification issues, and sensors were conducted, with time allowed for audience participation.

  3. Synthetic plant defense elicitors

    PubMed Central

    Bektas, Yasemin; Eulgem, Thomas

    2015-01-01

    To defend themselves against invading pathogens plants utilize a complex regulatory network that coordinates extensive transcriptional and metabolic reprogramming. Although many of the key players of this immunity-associated network are known, the details of its topology and dynamics are still poorly understood. As an alternative to forward and reverse genetic studies, chemical genetics-related approaches based on bioactive small molecules have gained substantial popularity in the analysis of biological pathways and networks. Use of such molecular probes can allow researchers to access biological space that was previously inaccessible to genetic analyses due to gene redundancy or lethality of mutations. Synthetic elicitors are small drug-like molecules that induce plant defense responses, but are distinct from known natural elicitors of plant immunity. While the discovery of some synthetic elicitors had already been reported in the 1970s, recent breakthroughs in combinatorial chemical synthesis now allow for inexpensive high-throughput screens for bioactive plant defense-inducing compounds. Along with powerful reverse genetics tools and resources available for model plants and crop systems, comprehensive collections of new synthetic elicitors will likely allow plant scientists to study the intricacies of plant defense signaling pathways and networks in an unparalleled fashion. As synthetic elicitors can protect crops from diseases, without the need to be directly toxic for pathogenic organisms, they may also serve as promising alternatives to conventional biocidal pesticides, which often are harmful for the environment, farmers and consumers. Here we are discussing various types of synthetic elicitors that have been used for studies on the plant immune system, their modes-of-action as well as their application in crop protection. PMID:25674095

  4. Synthetic River Valleys

    NASA Astrophysics Data System (ADS)

    Brown, R.; Pasternack, G. B.

    2011-12-01

    The description of fluvial form has evolved from anecdotal descriptions to artistic renderings to 2D plots of cross section or longitudinal profiles and more recently 3D digital models. Synthetic river valleys, artificial 3D topographic models of river topography, have a plethora of potential applications in fluvial geomorphology, and the earth sciences in general, as well as in computer science and ecology. Synthetic river channels have existed implicitly since approximately the 1970s and can be simulated from a variety of approaches spanning the artistic and numerical. An objective method of synthesizing 3D stream topography based on reach scale attributes would be valuable for sizing 3D flumes in the physical and numerical realms, as initial input topography for morphodynamic models, stream restoration design, historical reconstruction, and mechanistic testing of interactions of channel geometric elements. Quite simply - simulation of synthetic channel geometry of prescribed conditions can allow systematic evaluation of the dominant relationships between river flow and geometry. A new model, the control curve method, is presented that uses hierarchically scaled parametric curves in over-lapping 2D planes to create synthetic river valleys. The approach is able to simulate 3D stream geometry from paired 2D descriptions and can allow experimental insight into form-process relationships in addition to visualizing past measurements of channel form that are limited to two dimension descriptions. Results are presented that illustrate the models ability to simulate fluvial topography representative of real world rivers as well as how channel geometric elements can be adjusted. The testing of synthetic river valleys would open up a wealth of knowledge as to why some 3D attributes of river channels are more prevalent than others as well as bridging the gap between the 2D descriptions that have dominated fluvial geomorphology the past century and modern, more complete, 3D

  5. New Synthetic Methods for Hypericum Natural Products

    SciTech Connect

    Jeon, Insik

    2006-01-01

    Organic chemistry has served as a solid foundation for interdisciplinary research areas, such as molecular biology and medicinal chemistry. An understanding of the biological activities and structural elucidations of natural products can lead to the development of clinically valuable therapeutic options. The advancements of modern synthetic methodologies allow for more elaborate and concise natural product syntheses. The theme of this study centers on the synthesis of natural products with particularly challenging structures and interesting biological activities. The synthetic expertise developed here will be applicable to analog syntheses and to other research problems.

  6. Catalysts from synthetic genetic polymers.

    PubMed

    Taylor, Alexander I; Pinheiro, Vitor B; Smola, Matthew J; Morgunov, Alexey S; Peak-Chew, Sew; Cozens, Christopher; Weeks, Kevin M; Herdewijn, Piet; Holliger, Philipp

    2015-02-19

    The emergence of catalysis in early genetic polymers such as RNA is considered a key transition in the origin of life, pre-dating the appearance of protein enzymes. DNA also demonstrates the capacity to fold into three-dimensional structures and form catalysts in vitro. However, to what degree these natural biopolymers comprise functionally privileged chemical scaffolds for folding or the evolution of catalysis is not known. The ability of synthetic genetic polymers (XNAs) with alternative backbone chemistries not found in nature to fold into defined structures and bind ligands raises the possibility that these too might be capable of forming catalysts (XNAzymes). Here we report the discovery of such XNAzymes, elaborated in four different chemistries (arabino nucleic acids, ANA; 2'-fluoroarabino nucleic acids, FANA; hexitol nucleic acids, HNA; and cyclohexene nucleic acids, CeNA) directly from random XNA oligomer pools, exhibiting in trans RNA endonuclease and ligase activities. We also describe an XNA-XNA ligase metalloenzyme in the FANA framework, establishing catalysis in an entirely synthetic system and enabling the synthesis of FANA oligomers and an active RNA endonuclease FANAzyme from its constituent parts. These results extend catalysis beyond biopolymers and establish technologies for the discovery of catalysts in a wide range of polymer scaffolds not found in nature. Evolution of catalysis independent of any natural polymer has implications for the definition of chemical boundary conditions for the emergence of life on Earth and elsewhere in the Universe.

  7. Catalysts from synthetic genetic polymers

    PubMed Central

    Taylor, Alexander I.; Pinheiro, Vitor B.; Smola, Matthew J.; Morgunov, Alexey S.; Peak-Chew, Sew; Cozens, Christopher; Weeks, Kevin M.; Herdewijn, Piet; Holliger, Philipp

    2014-01-01

    The emergence of catalysis in early genetic polymers like RNA is considered a key transition in the origin of life1, predating the appearance of protein enzymes. DNA also demonstrates the capacity to fold into three-dimensional structures and form catalysts in vitro2. However, to what degree these natural biopolymers comprise functionally privileged chemical scaffolds3 for folding or the evolution of catalysis is not known. The ability of synthetic genetic polymers (XNAs) with alternative backbone chemistries not found in nature to fold into defined structures and bind ligands4 raises the possibility that these too might be capable of forming catalysts (XNAzymes). Here we report the discovery of such XNAzymes, elaborated in four different chemistries (ANA (arabino nucleic acids)5, FANA (2′-fluoroarabino nucleic acids)6, HNA (hexitol nucleic acids) and CeNA (cyclohexene nucleic acids)7 directly from random XNA oligomer pools, exhibiting in trans RNA endonuclease and ligase activities. We also describe an XNA-XNA ligase metalloenzyme in the FANA framework, establishing catalysis in an entirely synthetic system and enabling the synthesis of FANA oligomers and an active RNA endonuclease FANAzyme from its constituent parts. These results extend catalysis beyond biopolymers and establish technologies for the discovery of catalysts in a wide range of polymer scaffolds not found in nature8. Evolution of catalysis independent of any natural polymer has implications for the definition of chemical boundary conditions for the emergence of life on earth and elsewhere in the universe9. PMID:25470036

  8. Synthetic Foveal Imaging Technology

    NASA Technical Reports Server (NTRS)

    Monacos, Steve P. (Inventor); Hoenk, Michael E. (Inventor); Nikzad, Shouleh (Inventor)

    2013-01-01

    Apparatuses and methods are disclosed that create a synthetic fovea in order to identify and highlight interesting portions of an image for further processing and rapid response. Synthetic foveal imaging implements a parallel processing architecture that uses reprogrammable logic to implement embedded, distributed, real-time foveal image processing from different sensor types while simultaneously allowing for lossless storage and retrieval of raw image data. Real-time, distributed, adaptive processing of multi-tap image sensors with coordinated processing hardware used for each output tap is enabled. In mosaic focal planes, a parallel-processing network can be implemented that treats the mosaic focal plane as a single ensemble rather than a set of isolated sensors. Various applications are enabled for imaging and robotic vision where processing and responding to enormous amounts of data quickly and efficiently is important.

  9. Engineered Asymmetric Synthetic Vesicles

    NASA Astrophysics Data System (ADS)

    Lu, Li; Chiarot, Paul

    2013-11-01

    Synthetic vesicles are small, fluid-filled spheres that are enclosed by a bilayer of lipid molecules. They can be used as models for investigating membrane biology and as delivery vehicles for pharmaceuticals. In practice, it is difficult to simultaneously control membrane asymmetry, unilamellarity, vesicle size, vesicle-to-vesicle uniformity, and luminal content. Membrane asymmetry, where each leaflet of the bilayer is composed of different lipids, is of particular importance as it is a feature of most natural membranes. In this study, we leverage microfluidic technology to build asymmetric vesicles at high-throughput. We use the precise flow control offered by microfluidic devices to make highly uniform emulsions, with controlled internal content, that serve as templates to build the synthetic vesicles. Flow focusing, dielectrophoretic steering, and interfacial lipid self-assembly are critical procedures performed on-chip to produce the vesicles. Fluorescent and confocal microscopy are used to evaluate the vesicle characteristics.

  10. EXPEDITIOUS SYNTHETIC TRANSFORMATIONS USING MICROWAVES

    EPA Science Inventory

    Microwave-expedited solvent-free synthetic processes will be described for the synthesis of a variety of industrially significant compounds and intermediates namely, enamines, nitroalkenes, enones, oxidized sulfur compounds and ionic liquids. This solvent-free synthetic methodolo...

  11. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity.

    PubMed

    Brents, Lisa K; Gallus-Zawada, Anna; Radominska-Pandya, Anna; Vasiljevik, Tamara; Prisinzano, Thomas E; Fantegrossi, William E; Moran, Jeffery H; Prather, Paul L

    2012-04-01

    K2 and several similar purported "incense products" spiked with synthetic cannabinoids are abused as cannabis substitutes. We hypothesized that metabolism of JWH-073, a prevalent cannabinoid found in K2, contributes to toxicity associated with K2 use. Competition receptor binding studies and G-protein activation assays, both performed by employing mouse brain homogenates, were used to determine the affinity and intrinsic activity, respectively, of potential monohydroxylated (M1, M3-M5) and monocarboxylated (M6) metabolites at cannabinoid 1 receptors (CB1Rs). Surprisingly, M1, M4 and M5 retain nanomolar affinity for CB1Rs, while M3 displays micromolar affinity and M6 does not bind to CB1Rs. JWH-073 displays equivalent efficacy to that of the CB1R full agonist CP-55,940, while M1, M3, and M5 act as CB1R partial agonists, and M4 shows little or no intrinsic activity. Further in vitro investigation by Schild analysis revealed that M4 acts as a competitive neutral CB1R antagonist (K(b)∼40nM). In agreement with in vitro studies, M4 also demonstrates CB1R antagonism in vivo by blunting cannabinoid-induced hypothermia in mice. Interestingly, M4 does not block agonist-mediated responses of other measures in the cannabinoid tetrad (e.g., locomotor suppression, catalepsy or analgesia). Finally, also as predicted by in vitro results, M1 exhibits agonist activity in vivo by inducing significant hypothermia and suppression of locomotor activity in mice. In conclusion, the present study indicates that further work examining the physiological effects of synthetic cannabinoid metabolism is warranted. Such a complex mix of metabolically produced CB1R ligands may contribute to the adverse effect profile of JWH-073-containing products.

  12. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity

    PubMed Central

    Brents, Lisa K.; Gallus-Zawada, Anna; Radominska-Pandya, Anna; Vasiljevik, Tamara; Prisinzano, Thomas E.; Fantegrossi, William E.; Moran, Jeffery H.; Prather, Paul L.

    2012-01-01

    K2 and several similar purported “incense products” spiked with synthetic cannabinoids are abused as cannabis substitutes. We hypothesized that metabolism of JWH-073, a prevalent cannabinoid found in K2, contributes to toxicity associated with K2 use. Competition receptor binding studies and G-protein activation assays, both performed by employing mouse brain homogenates, were used to determine the affinity and intrinsic activity, respectively, of potential monohydroxylated (M1, M3–M5) and monocarboxylated (M6) metabolites at cannabinoid 1 receptors (CB1Rs). Surprisingly, M1, M4 and M5 retain nanomolar affinity for CB1Rs, while M3 displays micromolar affinity and M6 does not bind to CB1Rs. JWH-073 displays equivalent efficacy to that of the CB1R full agonist CP-55,940, while M1, M3, and M5 act as CB1R partial agonists, and M4 shows little or no intrinsic activity. Further in vitro investigation by Schild analysis revealed that M4 acts as a competitive neutral CB1R antagonist (Kb~40nM). In agreement with in vitro studies, M4 also demonstrates CB1R antagonism in vivo by blunting cannabinoid-induced hypothermia in mice. Interestingly, M4 does not block agonist-mediated responses of other measures in the cannabinoid tetrad (e.g., locomotor suppression, catalepsy or analgesia). Finally, also as predicted by in vitro results, M1 exhibits agonist activity in vivo by inducing significant hypothermia and suppression of locomotor activity in mice. In conclusion, the present study indicates that further work examining the physiological effects of synthetic cannabinoid metabolism is warranted. Such a complex mix of metabolically produced CB1R ligands may contribute to the adverse effect profile of JWH-073-containing products. PMID:22266354

  13. Chemical synthetic biology.

    PubMed

    Chiarabelli, Cristiano; Luisi, Pier Luigi

    2014-01-01

    Although both the most popular form of synthetic biology (SB) and chemical synthetic biology (CSB) share the biotechnologically useful aim of making new forms of life, SB does so by using genetic manipulation of extant microorganism, while CSB utilises classic chemical procedures in order to obtain biological structures which are non-existent in nature. The main query concerning CSB is the philosophical question: why did nature do this, and not that? The idea then is to synthesise alternative structures in order to understand why nature operated in such a particular way. We briefly present here some various examples of CSB, including those cases of nucleic acids synthesised with pyranose instead of ribose, and proteins with a reduced alphabet of amino acids; also we report the developing research on the "never born proteins" (NBP) and "never born RNA" (NBRNA), up to the minimal cell project, where the issue is the preparation of semi-synthetic cells that can perform the basic functions of biological cells.

  14. Optical synthetic aperture radar

    NASA Astrophysics Data System (ADS)

    Ilovitsh, Asaf; Zach, Shlomo; Zalevsky, Zeev

    2013-06-01

    A method is proposed for increasing the resolution of an object and overcoming the diffraction limit of an optical system installed on top of a moving imaging system, such as an airborne platform or satellite. The resolution improvement is obtained via a two-step process. First, three low resolution differently defocused images are captured and the optical phase is retrieved using an improved iterative Gershberg-Saxton based algorithm. The phase retrieval allows numerical back propagation of the field to the aperture plane. Second, the imaging system is shifted and the first step is repeated. The obtained optical fields at the aperture plane are combined and a synthetically increased lens aperture is generated along the direction of movement, yielding higher imaging resolution. The method resembles a well-known approach from the microwave regime called the synthetic aperture radar in which the antenna size is synthetically increased along the platform propagation direction. The proposed method is demonstrated via Matlab simulation as well as through laboratory experiment.

  15. Synthetic surgical gloves.

    PubMed

    2002-06-01

    Surgical gloves are used by healthcare workers to protect them against bloodborne pathogens and other potential infectants and to prevent wound contamination in patients. In response to the increasing prevalence of allergies to natural rubber latex (NRL) among patients and medical staff, the trend toward purchasing gloves made of synthetic materials is on the rise. However, latex continues to dominate the market, and some people still perceive synthetic gloves as providing less protection and being less comfortable than NRL gloves. For this Update Evaluation, we present our findings for three newly evaluated glove models from three manufacturers and summarize our findings for the seven previously evaluated models that are still on the market. (Our earlier Evaluation was published in the February-March 2000 Health Devices.) As in the previous Evaluation, our ratings are based on the gloves' barrier effectiveness--that is, their resistance to viral penetration and their durability--and comfort. We also compared these characteristics of the synthetic gloves to those of NRL gloves. We found that all the evaluated gloves offer adequate barrier protection but that their level of comfort varies considerably. We rate three models Preferred, five models Acceptable, and two models Not Recommended. PMID:12116503

  16. Synthetic biology in plastids.

    PubMed

    Scharff, Lars B; Bock, Ralph

    2014-06-01

    Plastids (chloroplasts) harbor a small gene-dense genome that is amenable to genetic manipulation by transformation. During 1 billion years of evolution from the cyanobacterial endosymbiont to present-day chloroplasts, the plastid genome has undergone a dramatic size reduction, mainly as a result of gene losses and the large-scale transfer of genes to the nuclear genome. Thus the plastid genome can be regarded as a naturally evolved miniature genome, the gradual size reduction and compaction of which has provided a blueprint for the design of minimum genomes. Furthermore, because of the largely prokaryotic genome structure and gene expression machinery, the high transgene expression levels attainable in transgenic chloroplasts and the very low production costs in plant systems, the chloroplast lends itself to synthetic biology applications that are directed towards the efficient synthesis of green chemicals, biopharmaceuticals and other metabolites of commercial interest. This review describes recent progress with the engineering of plastid genomes with large constructs of foreign or synthetic DNA, and highlights the potential of the chloroplast as a model system in bottom-up and top-down synthetic biology approaches.

  17. Synthetic biology in Streptomyces bacteria.

    PubMed

    Medema, Marnix H; Breitling, Rainer; Takano, Eriko

    2011-01-01

    Actinomycete bacteria of the genus Streptomyces are major producers of bioactive compounds for the biotechnology industry. They are the source of most clinically used antibiotics, as well as of several widely used drugs against common diseases, including cancer . Genome sequencing has revealed that the potential of Streptomyces species for the production of valuable secondary metabolites is even larger than previously realized. Accessing this rich genomic resource to discover new compounds by activating "cryptic" pathways is an interesting challenge for synthetic biology. This approach is facilitated by the inherent natural modularity of secondary metabolite biosynthetic pathways, at the level of individual enzymes (such as modular polyketide synthases), but also of gene cassettes/operons and entire biosynthetic gene clusters. It also benefits from a long tradition of molecular biology in Streptomyces, which provides a number of specific tools, ranging from cloning vectors to inducible promoters and translational control elements. In this chapter, we first provide an overview of the synthetic biology challenges in Streptomyces and then present the existing toolbox of molecular methods that can be employed in this organism. PMID:21601100

  18. Opportunities in plant synthetic biology.

    PubMed

    Cook, Charis; Martin, Lisa; Bastow, Ruth

    2014-05-01

    Synthetic biology is an emerging field uniting scientists from all disciplines with the aim of designing or re-designing biological processes. Initially, synthetic biology breakthroughs came from microbiology, chemistry, physics, computer science, materials science, mathematics, and engineering disciplines. A transition to multicellular systems is the next logical step for synthetic biologists and plants will provide an ideal platform for this new phase of research. This meeting report highlights some of the exciting plant synthetic biology projects, and tools and resources, presented and discussed at the 2013 GARNet workshop on plant synthetic biology.

  19. Opportunities in plant synthetic biology.

    PubMed

    Cook, Charis; Martin, Lisa; Bastow, Ruth

    2014-05-01

    Synthetic biology is an emerging field uniting scientists from all disciplines with the aim of designing or re-designing biological processes. Initially, synthetic biology breakthroughs came from microbiology, chemistry, physics, computer science, materials science, mathematics, and engineering disciplines. A transition to multicellular systems is the next logical step for synthetic biologists and plants will provide an ideal platform for this new phase of research. This meeting report highlights some of the exciting plant synthetic biology projects, and tools and resources, presented and discussed at the 2013 GARNet workshop on plant synthetic biology. PMID:24502956

  20. Aerosol delivery of synthetic lung surfactant

    PubMed Central

    Hernández-Juviel, José M.; Waring, Alan J.

    2014-01-01

    Background. Nasal continuous positive airway pressure (nCPAP) is a widely accepted technique of non-invasive respiratory support in premature infants with respiratory distress syndrome due to lack of lung surfactant. If this approach fails, the next step is often intubation, mechanical ventilation (MV) and intratracheal instillation of clinical lung surfactant. Objective. To investigate whether aerosol delivery of advanced synthetic lung surfactant, consisting of peptide mimics of surfactant proteins B and C (SP-B and SP-C) and synthetic lipids, during nCPAP improves lung function in surfactant-deficient rabbits. Methods. Experimental synthetic lung surfactants were produced by formulating 3% Super Mini-B peptide (SMB surfactant), a highly surface active SP-B mimic, and a combination of 1.5% SMB and 1.5% of the SP-C mimic SP-Css ion-lock 1 (BC surfactant), with a synthetic lipid mixture. After testing aerosol generation using a vibrating membrane nebulizer and aerosol conditioning (particle size, surfactant composition and surface activity), we investigated the effects of aerosol delivery of synthetic SMB and BC surfactant preparations on oxygenation and lung compliance in saline-lavaged, surfactant-deficient rabbits, supported with either nCPAP or MV. Results. Particle size distribution of the surfactant aerosols was within the 1–3 µm distribution range and surfactant activity was not affected by aerosolization. At a dose equivalent to clinical surfactant therapy in premature infants (100 mg/kg), aerosol delivery of both synthetic surfactant preparations led to a quick and clinically relevant improvement in oxygenation and lung compliance in the rabbits. Lung function recovered to a greater extent in rabbits supported with MV than with nCPAP. BC surfactant outperformed SMB surfactant in improving lung function and was associated with higher phospholipid values in bronchoalveolar lavage fluid; these findings were irrespective of the type of ventilatory support

  1. Synthetic gene networks in plant systems.

    PubMed

    Junker, Astrid; Junker, Björn H

    2012-01-01

    Synthetic biology methods are routinely applied in the plant field as in other eukaryotic model systems. Several synthetic components have been developed in plants and an increasing number of studies report on the assembly into functional synthetic genetic circuits. This chapter gives an overview of the existing plant genetic networks and describes in detail the application of two systems for inducible gene expression. The ethanol-inducible system relies on the ethanol-responsive interaction of the AlcA transcriptional activator and the AlcR receptor resulting in the transcription of the gene of interest (GOI). In comparison, the translational fusion of GOI and the glucocorticoid receptor (GR) domain leads to the dexamethasone-dependent nuclear translocation of the GOI::GR protein. This chapter contains detailed protocols for the application of both systems in the model plants potato and Arabidopsis, respectively.

  2. WISB: Warwick Integrative Synthetic Biology Centre

    PubMed Central

    McCarthy, John

    2016-01-01

    Synthetic biology promises to create high-impact solutions to challenges in the areas of biotechnology, human/animal health, the environment, energy, materials and food security. Equally, synthetic biologists create tools and strategies that have the potential to help us answer important fundamental questions in biology. Warwick Integrative Synthetic Biology (WISB) pursues both of these mutually complementary ‘build to apply’ and ‘build to understand’ approaches. This is reflected in our research structure, in which a core theme on predictive biosystems engineering develops underpinning understanding as well as next-generation experimental/theoretical tools, and these are then incorporated into three applied themes in which we engineer biosynthetic pathways, microbial communities and microbial effector systems in plants. WISB takes a comprehensive approach to training, education and outreach. For example, WISB is a partner in the EPSRC/BBSRC-funded U.K. Doctoral Training Centre in synthetic biology, we have developed a new undergraduate module in the subject, and we have established five WISB Research Career Development Fellowships to support young group leaders. Research in Ethical, Legal and Societal Aspects (ELSA) of synthetic biology is embedded in our centre activities. WISB has been highly proactive in building an international research and training network that includes partners in Barcelona, Boston, Copenhagen, Madrid, Marburg, São Paulo, Tartu and Valencia. PMID:27284024

  3. WISB: Warwick Integrative Synthetic Biology Centre.

    PubMed

    McCarthy, John

    2016-06-15

    Synthetic biology promises to create high-impact solutions to challenges in the areas of biotechnology, human/animal health, the environment, energy, materials and food security. Equally, synthetic biologists create tools and strategies that have the potential to help us answer important fundamental questions in biology. Warwick Integrative Synthetic Biology (WISB) pursues both of these mutually complementary 'build to apply' and 'build to understand' approaches. This is reflected in our research structure, in which a core theme on predictive biosystems engineering develops underpinning understanding as well as next-generation experimental/theoretical tools, and these are then incorporated into three applied themes in which we engineer biosynthetic pathways, microbial communities and microbial effector systems in plants. WISB takes a comprehensive approach to training, education and outreach. For example, WISB is a partner in the EPSRC/BBSRC-funded U.K. Doctoral Training Centre in synthetic biology, we have developed a new undergraduate module in the subject, and we have established five WISB Research Career Development Fellowships to support young group leaders. Research in Ethical, Legal and Societal Aspects (ELSA) of synthetic biology is embedded in our centre activities. WISB has been highly proactive in building an international research and training network that includes partners in Barcelona, Boston, Copenhagen, Madrid, Marburg, São Paulo, Tartu and Valencia.

  4. WISB: Warwick Integrative Synthetic Biology Centre.

    PubMed

    McCarthy, John

    2016-06-15

    Synthetic biology promises to create high-impact solutions to challenges in the areas of biotechnology, human/animal health, the environment, energy, materials and food security. Equally, synthetic biologists create tools and strategies that have the potential to help us answer important fundamental questions in biology. Warwick Integrative Synthetic Biology (WISB) pursues both of these mutually complementary 'build to apply' and 'build to understand' approaches. This is reflected in our research structure, in which a core theme on predictive biosystems engineering develops underpinning understanding as well as next-generation experimental/theoretical tools, and these are then incorporated into three applied themes in which we engineer biosynthetic pathways, microbial communities and microbial effector systems in plants. WISB takes a comprehensive approach to training, education and outreach. For example, WISB is a partner in the EPSRC/BBSRC-funded U.K. Doctoral Training Centre in synthetic biology, we have developed a new undergraduate module in the subject, and we have established five WISB Research Career Development Fellowships to support young group leaders. Research in Ethical, Legal and Societal Aspects (ELSA) of synthetic biology is embedded in our centre activities. WISB has been highly proactive in building an international research and training network that includes partners in Barcelona, Boston, Copenhagen, Madrid, Marburg, São Paulo, Tartu and Valencia. PMID:27284024

  5. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial

    PubMed Central

    Phyo, Aung Pyae; Jittamala, Podjanee; Nosten, François H; Pukrittayakamee, Sasithon; Imwong, Mallika; White, Nicholas J; Duparc, Stephan; Macintyre, Fiona; Baker, Mark; Möhrle, Jörg J

    2016-01-01

    Summary Background Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria. Methods This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966. Findings Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3–6·7) to 5·6 h (2·0–8·5) for P falciparum and 2·3 h (1·2–3·9) to 3·2 h (0·9–15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46–62 h. No serious drug-related adverse effects

  6. Anti-Inflammatory Activity of Choisya ternata Kunth Essential Oil, Ternanthranin, and Its Two Synthetic Analogs (Methyl and Propyl N-Methylanthranilates)

    PubMed Central

    Pinheiro, Mariana Martins Gomes; Miltojević, Ana B.; Radulović, Niko S.; Abdul-Wahab, Ikarastika Rahayu; Boylan, Fabio; Fernandes, Patrícia Dias

    2015-01-01

    Choisya ternata Kunth (Rutaceae) is native to North America where it is popularly known as “Mexican orange”. In this study, the anti-inflammatory effects of the essential oil (EO) obtained from the leaves of C. ternata, one of its minor components (ternanthranin—ISOAN) and its two synthetic analogues (methyl and propyl N-methylanthranilate – MAN and PAN) were evaluated. Mice pretreated with the EO (EO) obtained from C. ternata leaves (3–100 mg/kg, p.o.), ISOAN, MAN or PAN (1–30 mg/kg, p.o.) and the reference drugs, morphine (1 mg/kg, p.o.) and acetylsalicylic acid (ASA, 100 mg/kg, p.o.), were evaluated in inflammation models such as formalin and subcutaneous air pouch models, with measurement of cell migration, exudate volume, protein extravasation, nitric oxide and pro-inflammatory cytokines. The EO from C. ternata significantly inhibited the time that the animals spent licking the formalin-injected paw in the second phase of the model at their higher doses (30 and 100 mg/kg, respectively). An inhibition of the inflammatory reaction induced after subcutaneous carrageenan injection into air pouch was also observed. In this model, the EO significantly reduced cell migration, exudate volume, protein extravased, and the increase in levels of inflammatory mediators (nitric oxide, TNF-α and IL-1β). ISOAN, MAN and PAN behaved in the same fashion at much smaller doses. Also, these molecules were able to show significant effects in the reduction of paw edema (at all tested doses) when the phlogistic agent was carrageenan, bradykinin, 5-HT, PGE2, C48/80 or 12-O-tetradecanoylphorbol-acetate (TPA). None of the tested doses had any effect in reducing histamine-induced edema. Our results indicate that the EO from C. ternata and anthranilate derivatives demonstrates an anti-inflammatory effect. PMID:25807367

  7. Anti-inflammatory activity of Choisya ternata Kunth essential oil, ternanthranin, and its two synthetic analogs (methyl and propyl N-methylanthranilates).

    PubMed

    Pinheiro, Mariana Martins Gomes; Miltojević, Ana B; Radulović, Niko S; Abdul-Wahab, Ikarastika Rahayu; Boylan, Fabio; Fernandes, Patrícia Dias

    2015-01-01

    Choisya ternata Kunth (Rutaceae) is native to North America where it is popularly known as "Mexican orange". In this study, the anti-inflammatory effects of the essential oil (EO) obtained from the leaves of C. ternata, one of its minor components (ternanthranin-ISOAN) and its two synthetic analogues (methyl and propyl N-methylanthranilate--MAN and PAN) were evaluated. Mice pretreated with the EO (EO) obtained from C. ternata leaves (3-100 mg/kg, p.o.), ISOAN, MAN or PAN (1-30 mg/kg, p.o.) and the reference drugs, morphine (1 mg/kg, p.o.) and acetylsalicylic acid (ASA, 100 mg/kg, p.o.), were evaluated in inflammation models such as formalin and subcutaneous air pouch models, with measurement of cell migration, exudate volume, protein extravasation, nitric oxide and pro-inflammatory cytokines. The EO from C. ternata significantly inhibited the time that the animals spent licking the formalin-injected paw in the second phase of the model at their higher doses (30 and 100 mg/kg, respectively). An inhibition of the inflammatory reaction induced after subcutaneous carrageenan injection into air pouch was also observed. In this model, the EO significantly reduced cell migration, exudate volume, protein extravased, and the increase in levels of inflammatory mediators (nitric oxide, TNF-α and IL-1β). ISOAN, MAN and PAN behaved in the same fashion at much smaller doses. Also, these molecules were able to show significant effects in the reduction of paw edema (at all tested doses) when the phlogistic agent was carrageenan, bradykinin, 5-HT, PGE2, C48/80 or 12-O-tetradecanoylphorbol-acetate (TPA). None of the tested doses had any effect in reducing histamine-induced edema. Our results indicate that the EO from C. ternata and anthranilate derivatives demonstrates an anti-inflammatory effect. PMID:25807367

  8. Analog synthetic biology.

    PubMed

    Sarpeshkar, R

    2014-03-28

    We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog-digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA-protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations. PMID:24567476

  9. Analog synthetic biology

    PubMed Central

    Sarpeshkar, R.

    2014-01-01

    We analyse the pros and cons of analog versus digital computation in living cells. Our analysis is based on fundamental laws of noise in gene and protein expression, which set limits on the energy, time, space, molecular count and part-count resources needed to compute at a given level of precision. We conclude that analog computation is significantly more efficient in its use of resources than deterministic digital computation even at relatively high levels of precision in the cell. Based on this analysis, we conclude that synthetic biology must use analog, collective analog, probabilistic and hybrid analog–digital computational approaches; otherwise, even relatively simple synthetic computations in cells such as addition will exceed energy and molecular-count budgets. We present schematics for efficiently representing analog DNA–protein computation in cells. Analog electronic flow in subthreshold transistors and analog molecular flux in chemical reactions obey Boltzmann exponential laws of thermodynamics and are described by astoundingly similar logarithmic electrochemical potentials. Therefore, cytomorphic circuits can help to map circuit designs between electronic and biochemical domains. We review recent work that uses positive-feedback linearization circuits to architect wide-dynamic-range logarithmic analog computation in Escherichia coli using three transcription factors, nearly two orders of magnitude more efficient in parts than prior digital implementations. PMID:24567476

  10. Performance of air stripping and GAC (granular activated carbon) for SOC (synthetic organic chemical) and VOC (volatile organic chemical) removal from ground water. Final report, October 1983-November 1987

    SciTech Connect

    Hand, D.W.; Crittenden, J.C.; Miller, J.M.; Gehin, J.L.

    1988-09-01

    This study compares the ability and cost-effectiveness of granular activated carbon and packed-tower aeration (air stripping) in removing synthetic organic and volatile organic chemicals (SOCs and VOCs) from a contaminated groundwater source in Wausau, WI. Among the SOCs and VOCs identified and targeted for removal were cis-1,2-dichloroethene, trichloroethene, tetrachlorethene, and toluene. A liquid-phase GAC pilot-plant, full-scale GAS adsorber, and a full-scale air-stripping tower were designed, built, and operated to provide data so that the process performance could be evaluated. Extensive laboratory studies were performed. Mathematical models and correlations for obtaining kinetic parameters and single-solute isotherm parameters were developed and tested by comparing their results to those obtained from the pilot plant. Possible surrogate parameters were investigated. Cost estimates are compared.

  11. Production Pathways and Separation Procedures for High-Diagnostic-Value Activation Species, Fission Products, and Actinides Required for Preparation of Realistic Synthetic Post-Detonation Nuclear Debris: Status Report and FY16 Project Plan

    SciTech Connect

    Faye, S. A.; Shaughnessy, D. A.

    2015-08-19

    The objective of this project is to provide a comprehensive study on the production routes and chemical separation requirements for activation products, fission products, and actinides required for the creation of realistic post-detonation surrogate debris. Isotopes that have been prioritized by debris diagnosticians will be examined for their ability to be produced at existing irradiation sources, production rates, and availability of target materials, and chemical separation procedures required to rapidly remove the products from the bulk target matrix for subsequent addition into synthetic debris samples. The characteristics and implications of the irradiation facilities on the isotopes of interest will be addressed in addition to a summary of the isotopes that are already regularly produced. This is a planning document only.

  12. Synthetic RNAs Mimicking Structural Domains in the Foot-and-Mouth Disease Virus Genome Elicit a Broad Innate Immune Response in Porcine Cells Triggered by RIG-I and TLR Activation.

    PubMed

    Borrego, Belén; Rodríguez-Pulido, Miguel; Revilla, Concepción; Álvarez, Belén; Sobrino, Francisco; Domínguez, Javier; Sáiz, Margarita

    2015-07-17

    The innate immune system is the first line of defense against viral infections. Exploiting innate responses for antiviral, therapeutic and vaccine adjuvation strategies is being extensively explored. We have previously described, the ability of small in vitro RNA transcripts, mimicking the sequence and structure of different domains in the non-coding regions of the foot-and-mouth disease virus (FMDV) genome (ncRNAs), to trigger a potent and rapid innate immune response. These synthetic non-infectious molecules have proved to have a broad-range antiviral activity and to enhance the immunogenicity of an FMD inactivated vaccine in mice. Here, we have studied the involvement of pattern-recognition receptors (PRRs) in the ncRNA-induced innate response and analyzed the antiviral and cytokine profiles elicited in swine cultured cells, as well as peripheral blood mononuclear cells (PBMCs).

  13. Synthetic RNAs Mimicking Structural Domains in the Foot-and-Mouth Disease Virus Genome Elicit a Broad Innate Immune Response in Porcine Cells Triggered by RIG-I and TLR Activation

    PubMed Central

    Borrego, Belén; Rodríguez-Pulido, Miguel; Revilla, Concepción; Álvarez, Belén; Sobrino, Francisco; Domínguez, Javier; Sáiz, Margarita

    2015-01-01

    The innate immune system is the first line of defense against viral infections. Exploiting innate responses for antiviral, therapeutic and vaccine adjuvation strategies is being extensively explored. We have previously described, the ability of small in vitro RNA transcripts, mimicking the sequence and structure of different domains in the non-coding regions of the foot-and-mouth disease virus (FMDV) genome (ncRNAs), to trigger a potent and rapid innate immune response. These synthetic non-infectious molecules have proved to have a broad-range antiviral activity and to enhance the immunogenicity of an FMD inactivated vaccine in mice. Here, we have studied the involvement of pattern-recognition receptors (PRRs) in the ncRNA-induced innate response and analyzed the antiviral and cytokine profiles elicited in swine cultured cells, as well as peripheral blood mononuclear cells (PBMCs). PMID:26193305

  14. Antimicrobial and demelanizing activity of Ganoderma lucidum extract, p-hydroxybenzoic and cinnamic acids and their synthetic acetylated glucuronide methyl esters.

    PubMed

    Heleno, Sandrina A; Ferreira, Isabel C F R; Esteves, Ana P; Ćirić, Ana; Glamočlija, Jasmina; Martins, Anabela; Soković, Marina; Queiroz, Maria João R P

    2013-08-01

    Mushroom extracts or isolated compounds may be useful in the search of new potent antimicrobial agents. Herein, it is described the synthesis of protected (acetylated) glucuronide derivatives of p-hydroxybenzoic and cinnamic acids, two compounds identified in the medicinal mushroom Ganoderma lucidum. Their antimicrobial and demelanizing activities were evaluated and compared to the parent acids and G. lucidum extract. p-Hydroxybenzoic and cinnamic acids, as also their protected glucuronide derivatives revealed high antimicrobial (antibacterial and antifungal) activity, even better than the one showed by commercial standards. Despite the variation in the order of parent acids and the protected glucuronide derivatives, their antimicrobial activity was always higher than the one revealed by the extract. Nevertheless, the extract was the only one with demelanizing activity against Aspergillus niger. The acetylated glucuronide derivatives could be deprotected to obtain glucuronide metabolites, which circulate in the human organism as products of the metabolism of the parent compounds.

  15. New synthetic surfactant - how and when?

    PubMed

    Curstedt, Tore; Johansson, Jan

    2006-01-01

    Animal-derived surfactant preparations are very effective in the treatment of premature infants with respiratory distress syndrome but they are expensive to produce and supplies are limited. In order to widen the indications for surfactant treatment there is a need for synthetic preparations, which can be produced in large quantities and at a reasonable cost. However, development of clinically active synthetic surfactants has turned out to be more complicated than initially anticipated. The hydrophobic surfactant proteins, SP-B and SP-C, which are involved in the adsorption of surface-active lipids to the air-liquid interface of the alveoli and increase alveolar stability, are either too big to synthesize, structurally complex or unstable in pure form. A new generation of synthetic surfactants containing simplified phospholipid mixtures and small amounts of peptides replacing the hydrophobic proteins is currently under development and will in the near future be introduced into the market. However, more trials need to be performed before any conclusions can be drawn about the effectiveness of these synthetic surfactants in relation to natural animal-derived preparations.

  16. On the use of the activation energy concept to investigate analyte and network deformations in entangled polymer solution capillary electrophoresis of synthetic polyelectrolytes.

    PubMed

    Cottet, H; Gareil, P

    2001-01-01

    The activation energy associated with the electrophoretic migration of an analyte under given electrolyte conditions can be accessed through the determination of the analyte electrophoretic mobility at various temperatures. In the case of the electrophoretic separation of polyelectrolytes in the presence of an entangled polymer network, activation energy can be regarded as the energy needed by the analyte to overcome the obstacles created by the separating network. Any deformation undergone by the analyte or the network is expected to induce a decrease in the activation energy. In this work, the electrophoretic mobilities of poly(styrenesulfonates) (PSSs) of various molecular weights (Mr 16 x 10(3) to 990 x 10(3)) were determined in entangled polyethylene oxide (PEO) solutions as a function of temperature (in the 17-60 degrees C range) and the PSS activation energies were calculated. The influences of the PSS molecular weight, blob sizes zetab of the separating network (related to the PEO concentration), ionic strength of the electrolyte and electric field strength (75-600 V/cm) were investigated. The results were interpreted in terms of analyte and network deformations and were confronted with those previously obtained for DNA migration in polymer solutions and chemical gels. For a radius of gyration Rgactivation energy increases with the PSS molecular mass, while the reverse is true for Rg>zetab, suggesting PSS and network deformations in the latter case. Increasing ionic strength resulted in an increase in the PSS activation energy, because of the decrease of their radii of gyration, which makes them less deformable. Finally, the activation energies of all the PSSs are a decreasing function of field strength and at high field strength tend to reach a constant value close to that for a small molecule.

  17. Progress toward synthetic cells.

    PubMed

    Blain, J Craig; Szostak, Jack W

    2014-01-01

    The complexity of even the simplest known life forms makes efforts to synthesize living cells from inanimate components seem like a daunting task. However, recent progress toward the creation of synthetic cells, ranging from simple protocells to artificial cells approaching the complexity of bacteria, suggests that the synthesis of life is now a realistic goal. Protocell research, fueled by advances in the biophysics of primitive membranes and the chemistry of nucleic acid replication, is providing new insights into the origin of cellular life. Parallel efforts to construct more complex artificial cells, incorporating translational machinery and protein enzymes, are providing information about the requirements for protein-based life. We discuss recent advances and remaining challenges in the synthesis of artificial cells, the possibility of creating new forms of life distinct from existing biology, and the promise of this research for gaining a deeper understanding of the nature of living systems. PMID:24606140

  18. Synthetic antibiofilm peptides.

    PubMed

    de la Fuente-Núñez, César; Cardoso, Marlon Henrique; de Souza Cândido, Elizabete; Franco, Octavio Luiz; Hancock, Robert E W

    2016-05-01

    Bacteria predominantly exist as multicellular aggregates known as biofilms that are associated with at least two thirds of all infections and exhibit increased adaptive resistance to conventional antibiotic therapies. Therefore, biofilms are major contributors to the global health problem of antibiotic resistance, and novel approaches to counter them are urgently needed. Small molecules of the innate immune system called host defense peptides (HDPs) have emerged as promising templates for the design of potent, broad-spectrum antibiofilm agents. Here, we review recent developments in the new field of synthetic antibiofilm peptides, including mechanistic insights, synergistic interactions with available antibiotics, and their potential as novel antimicrobials against persistent infections caused by biofilms. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID:26724202

  19. Entraining synthetic genetic oscillators

    NASA Astrophysics Data System (ADS)

    Wagemakers, Alexandre; Buldú, Javier M.; Sanjuán, Miguel A. F.; de Luis, Oscar; Izquierdo, Adriana; Coloma, Antonio

    2009-09-01

    We propose a new approach for synchronizing a population of synthetic genetic oscillators, which consists in the entrainment of a colony of repressilators by external modulation. We present a model where the repressilator dynamics is affected by periodic changes in temperature. We introduce an additional plasmid in the bacteria in order to correlate the temperature variations with the enhancement of the transcription rate of a certain gene. This can be done by introducing a promoter that is related to the heat shock response. This way, the expression of that gene results in a protein that enhances the overall oscillations. Numerical results show coherent oscillations of the population for a certain range of the external frequency, which is in turn related to the natural oscillation frequency of the modified repressilator. Finally we study the transient times related with the loss of synchronization and we discuss possible applications in biotechnology of large-scale production coupled to synchronization events induced by heat shock.

  20. Evaluation of anti-herpetic and antioxidant activities, and cytotoxic and genotoxic effects of synthetic alkyl-esters of gallic acid.

    PubMed

    Savi, Luciane A; Leal, Paulo C; Vieira, Tiago O; Rosso, Rober; Nunes, Ricardo J; Yunes, Rosendo A; Creczynski-Pasa, Tânia B; Barardi, Célia R M; Simões, Cláudia M O

    2005-01-01

    The n-alkyl esters of gallic acid (CAS 13857-8) have a diverse range of uses as antioxidants in food, cosmetics and pharmaceutical industries. Pharmaceutical studies performed with these compounds have found that they have many therapeutic potentialities including anti-cancer, antiviral and antimicrobial properties. However, more interest has been devoted to their antioxidant activity due to the ability to scavenge and reduce reactive oxygen species (ROS) formation. In this study, gallic acid and 14 different alkyl gallates were tested. The cytotoxicity and anti-herpetic (HSV-1, KOS and 29-R strains) activity were studied by using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) colorimetric assay and the cell viability by using the Trypan blue dye exclusion method. The genotoxicity was studied by the Comet assay and the antioxidant activity by using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging and microsomal lipid peroxidation-inhibiting activities. The results showed that all the tested compounds have anti-herpetic activity at non cytotoxic concentrations with selectivity indices (SI = CC50/EC50) varying from 0.89 to 18.34, depending on the used HSV-1 strain. It was observed that all tested alkyl gallates showed some degree of genotoxicity, at the tested concentrations, except cetyl gallate, at 256.60 micromol/L (p <0.05, t-Student test), probably induced by ROS released by infected cells and/or by the alkyl gallates that were not antioxidants, at the tested concentrations, in which they demonstrated anti-herpetic activity. The hydroxyl groups can induce DNA damage due interactions with some metal ions, which are naturally present in the culture medium supplemented with fetal bovine serum, probably explaining the genotoxicity detected. However, the obtained results showed considerable antioxidant activity at smaller concentrations, when compared to quercetin which is considered as a reference drug due to its already described

  1. Structure-Activity Relationship and Mode of Action of a Frog Secreted Antibacterial Peptide B1CTcu5 Using Synthetically and Modularly Modified or Deleted (SMMD) Peptides

    PubMed Central

    Abraham, Parvin; Sundaram, Anand; R, Asha; V, Reshmy; George, Sanil; Kumar, K. Santhosh

    2015-01-01

    All life forms are equipped with rapidly acting, evolutionally conserved components of an innate immune defense system that consists of a group of unique and diverse molecules known as host defense peptides (HDPs). A Systematic and Modular Modification and Deletion (SMMD) approach was followed to analyse the structural requirement of B1CTcu5, a brevinin antibacterial peptide amide identified from the skin secretion of frog Clinotarsus curtipes, India, to show antibacterial activity and to explore the active core region. Seventeen SMMD-B1CTcu5 analogs were designed and synthesised by C and N-terminal amino acid substitution or deletion. Enhancement in cationicity by N-terminal Lys/Arg substitution or hydrophobicity by Trp substitution produced no drastic change in bactericidal nature against selected bacterial strains except S. aureus. But the sequential removal of N-terminal amino acids had a negative effect on bactericidal potency. Analog B1CTcu5-LIAG obtained by the removal of four N-terminal amino acids displayed bactericidal effect comparable to, or in excess of, the parent peptide with reduced hemolytic character. Its higher activity was well correlated with the improved inner membrane permeabilisation capacity. This region may act as the active core of B1CTcu5. Presence of C-terminal disulphide bond was not a necessary condition to display antibacterial activity but helped to promote hemolytic nature. Removal of the C-terminal rana box region drastically reduced antibacterial and hemolytic activity of the peptide, showing that this region is important for membrane targeting. The bactericidal potency of the D-peptide (DB1CTcu5) helped to rule out the stereospecific interaction with the bacterial membrane. Our data suggests that both the C and N-terminal regions are necessary for bactericidal activity, even though the active core region is located near the N-terminal of B1CTcu5. A judicious modification at the N-terminal region may produce a short SMMD analog

  2. Suppression of TNF-α induced NFκB activity by gallic acid and its semi-synthetic esters: possible role in cancer chemoprevention.

    PubMed

    Morais, Mauro C C; Luqman, Suaib; Kondratyuk, Tamara P; Petronio, Maicon S; Regasini, Luis O; Silva, Dulce H S; Bolzani, Vanderlan S; Soares, Christiane P; Pezzuto, John M

    2010-11-01

    Gallic acid (3,4,5-trihydroxybenzoic acid), found in many plants either in free-form or part of tannins, is known to possess anti-microbial, antioxidant and cytotoxic properties. NFκB regulates the expression of several genes involved in carcinogenesis. These include anti-apoptotic, cytokines and cell cycle-regulatory genes. It is well established that the transcriptional factor NFκB is deregulated in many forms of cancer. Thus, agents that can suppress NFκB activation have the potential of suppressing carcinogenesis. In the present investigation, gallic acid was isolated from Alchornea glandulosa (Euphorbiaceae) and eight esters were synthesised. These compounds were evaluated against TNF-α-induced NFκB activation with stably transfected 293/NFκB-Luc human embryonic kidney cells. Gallates with IC(50) values in a range of 10-56 µM mediated inhibitory activity higher than gallic acid (IC(50) 76.0 ± 4.9 µM). In addition to inhibiting NFκB activation, gallic acid mediated a modest cytotoxic effect, and some of the gallates affected cell viability at the tested concentrations. Based on these results, suppression of NFκB activation by gallate esters could play a chemopreventive role in carcinogenesis.

  3. Latifolicinin A from a Fermented Soymilk Product and the Structure-Activity Relationship of Synthetic Analogues as Inhibitors of Breast Cancer Cell Growth.

    PubMed

    Ke, Yi-Yu; Tsai, Chen-Hsuan; Yu, Hui-Ming; Jao, Yu-Chen; Fang, Jim-Min; Wong, Chi-Huey

    2015-11-11

    The functional components in soymilk may vary depending upon the fermentation process. A fermented soymilk product (FSP) obtained by incubation with the microorganisms of intestinal microflora was found to reduce the risk of breast cancer. Guided by the inhibitory activities against breast cancer cells, two cytotoxic compounds, daidzein and (S)-latifolicinin A, were isolated from the FSP by repetitive extraction and chromatography. Latifolicinin A is the n-butyl ester of β-(4-hydroxyphenyl)lactic acid (HPLA). A series of the ester and amide derivatives of (S)-HPLA and L-tyrosine were synthesized for evaluation of their cytotoxic activities. In comparison, (S)-HPLA derivatives exhibited equal or superior inhibitory activities to their L-tyrosine counterparts, and (S)-HPLA amides showed better cytotoxic activities than their corresponding esters. In particular, (S)-HPLA farnesyl amide was active to triple-negative MDA-MB-231 breast cancer cells (IC50 = 27 μM) and 10-fold less toxic to Detroit-551 normal cells. PMID:26499209

  4. Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes.

    PubMed

    Genet, Cédric; Strehle, Axelle; Schmidt, Céline; Boudjelal, Geoffrey; Lobstein, Annelise; Schoonjans, Kristina; Souchet, Michel; Auwerx, Johan; Saladin, Régis; Wagner, Alain

    2010-01-14

    We describe here the biological screening of a collection of natural occurring triterpenoids against the G protein-coupled receptor TGR5, known to be activated by bile acids and which mediates some important cell functions. This work revealed that betulinic (1), oleanolic (2), and ursolic acid (3) exhibited TGR5 agonist activity in a selective manner compared to bile acids, which also activated FXR, the nuclear bile acid receptor. The most potent natural triterpenoid betulinic acid was chosen as a reference compound for an SAR study. Hemisyntheses were performed on the betulinic acid scaffold, and we focused on structural modifications of the C-3 alcohol, the C-17 carboxylic acid, and the C-20 alkene. In particular, structural variations around the C-3 position gave rise to major improvements of potency exemplified with derivatives 18 dia 2 (RG-239) and 19 dia 2. The best derivative was tested in vitro and in vivo, and its biological profile is discussed.

  5. [Synthetic transformations of higher terpenoids. XXX. Synthesis and cytotoxic activity of betulonic acid amides with a piperidine or pyrrolidine nitroxide moiety].

    PubMed

    Antimonova, A N; Petrenko, N I; Shults, E E; Polienko, Iu F; Shakirov, M M; Irtegova, I G; Pokrovskiĭ, M A; Sherman, K M; Grigor'ev, I A; Pokrovskiĭ, A G; Tolstikov, G A

    2013-01-01

    The reaction of betulonic acid chloride with 4-amino-2,2,6,6-tetramethylpeperidine-1-oxyl, 3-amino-2,2,5,5-tetramethylpyrrolidine-1-oxyl and 3-aminomethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl gave corresponding triterpenoid amides. It was found that new derivatives exhibit cytotoxic activity against tumor cells CEM-13, U-937, MT-4. CCID50 value for most activity compound--N-[3-oxolup-20(29)-en-30-yl]-(2,2,6,6-tetramethylpiperidine-4-yl)-1-oxyl--was 5.7-33.1 microM.

  6. Synthetic Genomics and Synthetic Biology Applications Between Hopes and Concerns

    PubMed Central

    König, Harald; Frank, Daniel; Heil, Reinhard; Coenen, Christopher

    2013-01-01

    New organisms and biological systems designed to satisfy human needs are among the aims of synthetic genomics and synthetic biology. Synthetic biology seeks to model and construct biological components, functions and organisms that do not exist in nature or to redesign existing biological systems to perform new functions. Synthetic genomics, on the other hand, encompasses technologies for the generation of chemically-synthesized whole genomes or larger parts of genomes, allowing to simultaneously engineer a myriad of changes to the genetic material of organisms. Engineering complex functions or new organisms in synthetic biology are thus progressively becoming dependent on and converging with synthetic genomics. While applications from both areas have been predicted to offer great benefits by making possible new drugs, renewable chemicals or clean energy, they have also given rise to concerns about new safety, environmental and socio-economic risks – stirring an increasingly polarizing debate. Here we intend to provide an overview on recent progress in biomedical and biotechnological applications of synthetic genomics and synthetic biology as well as on arguments and evidence related to their possible benefits, risks and governance implications. PMID:23997647

  7. Synthetic Oligodeoxynucleotides Containing Multiple Telemeric TTAGGG Motifs Suppress Inflammasome Activity in Macrophages Subjected to Oxygen and Glucose Deprivation and Reduce Ischemic Brain Injury in Stroke-Prone Spontaneously Hypertensive Rats.

    PubMed

    Zhao, Jing; Mou, Yongshan; Bernstock, Joshua D; Klimanis, Dace; Wang, Sixian; Spatz, Maria; Maric, Dragan; Johnson, Kory; Klinman, Dennis M; Li, Xiaohong; Li, Xinhui; Hallenbeck, John M

    2015-01-01

    The immune system plays a fundamental role in both the development and pathobiology of stroke. Inflammasomes are multiprotein complexes that have come to be recognized as critical players in the inflammation that ultimately contributes to stroke severity. Inflammasomes recognize microbial and host-derived danger signals and activate caspase-1, which in turn controls the production of the pro-inflammatory cytokine IL-1β. We have shown that A151, a synthetic oligodeoxynucleotide containing multiple telemeric TTAGGG motifs, reduces IL-1β production by activated bone marrow derived macrophages that have been subjected to oxygen-glucose deprivation and LPS stimulation. Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells. In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion. These findings clearly suggest that the modulation of inflammasome activity via A151 may contribute to a reduction in pro-inflammatory cytokine production by macrophages subjected to conditions that model brain ischemia and modulate ischemic brain damage in an animal model of stroke. Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies. PMID:26473731

  8. USING ISOTHERMS TO PREDICT GAC'S CAPACITY FOR SYNTHETIC ORGANICS

    EPA Science Inventory

    This investigation involved operating a pilot granular activated carbon (GAC) plant to obtain capacity data under typical field conditions, determining isotherms for selected synthetic organic chemicals, and comparing the capacity predicted by the isotherm data with the pilot-pla...

  9. Highly efficient visible-light-driven photocatalytic activities in synthetic ordered monoclinic BiVO4 quantum tubes-graphene nanocomposites

    NASA Astrophysics Data System (ADS)

    Sun, Yongfu; Qu, Bingyan; Liu, Qin; Gao, Shan; Yan, Zixian; Yan, Wensheng; Pan, Bicai; Wei, Shiqiang; Xie, Yi

    2012-05-01

    Photocatalytic purification of polluted water is a very promising way to alleviate the increasingly serious water resources crisis. Despite tremendous efforts, developing visible-light-driven photocatalysts with high activity at low cost still remains a great challenge. Herein, we report for the first time the design and synthesis of ordered m-BiVO4 quantum tubes-graphene nanocomposites that exhibit unprecedented visible-light-driven photocatalytic activities, over 20 times faster than that of commercial P25 or bulk BiVO4 and roughly 1.5 times more active than that of bare m-BiVO4 quantum tubes. Notably, the unusual photoreactivities arise from the synergistic effects between the microscopic crystal structure of m-BiVO4 and macroscopic morphological features of ordered m-BiVO4 quantum tubes and two-dimensional graphene sheets. These structural features help to provide increased photocatalytic reaction sites, extended photoresponding range, enhanced charge transportation and separation efficiency simultaneously. Briefly, this work not only provides a simple and straightforward strategy for fabricating highly efficient and stable graphene-based nanocomposites, but also proves that these unique structures are excellent platforms for significantly improving their visible-light-driven photoactivities, holding great promise for their applications in the field of purifying polluted water resources.Photocatalytic purification of polluted water is a very promising way to alleviate the increasingly serious water resources crisis. Despite tremendous efforts, developing visible-light-driven photocatalysts with high activity at low cost still remains a great challenge. Herein, we report for the first time the design and synthesis of ordered m-BiVO4 quantum tubes-graphene nanocomposites that exhibit unprecedented visible-light-driven photocatalytic activities, over 20 times faster than that of commercial P25 or bulk BiVO4 and roughly 1.5 times more active than that of bare m

  10. A nanostructured synthetic collagen mimic for hemostasis.

    PubMed

    Kumar, Vivek A; Taylor, Nichole L; Jalan, Abhishek A; Hwang, Lyahn K; Wang, Benjamin K; Hartgerink, Jeffery D

    2014-04-14

    Collagen is a major component of the extracellular matrix and plays a wide variety of important roles in blood clotting, healing, and tissue remodeling. Natural, animal derived, collagen is used in many clinical applications but concerns exist with respect to its role in inflammation, batch-to-batch variability, and possible disease transfection. Therefore, development of synthetic nanomaterials that can mimic the nanostructure and properties of natural collagen has been a heavily pursued goal in biomaterials. Previously, we reported on the design and multihierarchial self-assembly of a 36 amino acid collagen mimetic peptide (KOD) that forms nanofibrous triple helices that entangle to form a hydrogel. In this report, we utilize this nanofiber forming collagen mimetic peptide as a synthetic biomimetic matrix useful in thrombosis. We demonstrate that nanofibrous KOD synthetic collagen matrices adhere platelets, activate them (indicated by soluble P-selectin secretion), and clot plasma and blood similar to animal derived collagen and control surfaces. In addition to the thrombotic potential, THP-1 monocytes incubated with our KOD collagen mimetic showed minimal proinflammatory cytokine (TNF-α or IL-1β) production. Together, the data presented demonstrates the potential of a novel synthetic collagen mimetic as a hemostat.

  11. A nanostructured synthetic collagen mimic for hemostasis.

    PubMed

    Kumar, Vivek A; Taylor, Nichole L; Jalan, Abhishek A; Hwang, Lyahn K; Wang, Benjamin K; Hartgerink, Jeffery D

    2014-04-14

    Collagen is a major component of the extracellular matrix and plays a wide variety of important roles in blood clotting, healing, and tissue remodeling. Natural, animal derived, collagen is used in many clinical applications but concerns exist with respect to its role in inflammation, batch-to-batch variability, and possible disease transfection. Therefore, development of synthetic nanomaterials that can mimic the nanostructure and properties of natural collagen has been a heavily pursued goal in biomaterials. Previously, we reported on the design and multihierarchial self-assembly of a 36 amino acid collagen mimetic peptide (KOD) that forms nanofibrous triple helices that entangle to form a hydrogel. In this report, we utilize this nanofiber forming collagen mimetic peptide as a synthetic biomimetic matrix useful in thrombosis. We demonstrate that nanofibrous KOD synthetic collagen matrices adhere platelets, activate them (indicated by soluble P-selectin secretion), and clot plasma and blood similar to animal derived collagen and control surfaces. In addition to the thrombotic potential, THP-1 monocytes incubated with our KOD collagen mimetic showed minimal proinflammatory cytokine (TNF-α or IL-1β) production. Together, the data presented demonstrates the potential of a novel synthetic collagen mimetic as a hemostat. PMID:24694012

  12. A Comparative Analysis of Synthetic Quorum Sensing Modulators in Pseudomonas aeruginosa: New Insights into Mechanism, Active Efflux Susceptibility, Phenotypic Response, and Next-Generation Ligand Design

    PubMed Central

    2015-01-01

    Quorum sensing (QS) is a chemical signaling mechanism that allows bacterial populations to coordinate gene expression in response to social and environmental cues. Many bacterial pathogens use QS to initiate infection at high cell densities. Over the past two decades, chemical antagonists of QS in pathogenic bacteria have attracted substantial interest for use both as tools to further elucidate QS mechanisms and, with further development, potential anti-infective agents. Considerable recent research has been devoted to the design of small molecules capable of modulating the LasR QS receptor in the opportunistic pathogen Pseudomonas aeruginosa. These molecules hold significant promise in a range of contexts; however, as most compounds have been developed independently, comparative activity data for these compounds are scarce. Moreover, the mechanisms by which the bulk of these compounds act are largely unknown. This paucity of data has stalled the choice of an optimal chemical scaffold for further advancement. Herein, we submit the best-characterized LasR modulators to standardized cell-based reporter and QS phenotypic assays in P. aeruginosa, and we report the first comprehensive set of comparative LasR activity data for these compounds. Our experiments uncovered multiple interesting mechanistic phenomena (including a potential alternative QS-modulatory ligand binding site/partner) that provide new, and unexpected, insights into the modes by which many of these LasR ligands act. The lead compounds, data trends, and mechanistic insights reported here will significantly aid the design of new small molecule QS inhibitors and activators in P. aeruginosa, and in other bacteria, with enhanced potencies and defined modes of action. PMID:26491787

  13. Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlor.

    PubMed

    You, Li; Casanova, Mercedes; Bartolucci, Erika J; Fryczynski, Mary W; Dorman, David C; Everitt, Jeffrey I; Gaido, Kevin W; Ross, Susan M; Heck Hd, Henry d'A

    2002-03-01

    Humans and wildlife are frequently exposed to mixtures of endocrine active-compounds (EAC). The objective of the present study was to investigate the potential of the phytoestrogen genistein to influence the reproductive developmental toxicity of the endocrine-active pesticide methoxychlor. Three levels of genistein (0, 300, or 800 ppm) and two levels of methoxychlor (0 or 800 ppm) were used in this study. Sprague-Dawley rats were exposed to the two compounds, either alone or in combinations, through dietary administration to dams during pregnancy and lactation and to the offspring directly after weaning. Both compounds, methoxychlor in particular, were associated with reduced body growth at 800 ppm, but pregnancy outcome was not affected by either treatment. An acceleration of vaginal opening (VO) in the exposed female offspring was the only observed effect of genistein at 300 ppm. Exposure to 800 ppm genistein or 800 ppm methoxychlor caused accelerated VO and also altered estrous cyclicity toward persistent estrus in the female offspring. The estrogenic responses to genistein and methoxychlor administered together were apparently accumulative of the effects associated with each compound alone. Methoxychlor, but not genistein, delayed preputial separation (PPS) in the male rats. When administered with methoxychlor, genistein at 800 ppm enhanced the effect of methoxychlor on delaying PPS. Genistein and methoxychlor treatment did not change gender-specific motor activity patterns in either sex. To explore possible mechanisms for interaction between the two compounds on development, we performed estrogen receptor (ER)- and androgen receptor (AR)-based in vitro transcriptional activation assays using genistein and the primary methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). While the in vitro assays supported the estrogenic effects of genistein and methoxychlor and the antiandrogenic effects of methoxychlor, the reactivity of these

  14. A novel synthetic derivative of melatonin, 5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation

    SciTech Connect

    Shim, Do-Wan; Shin, Hee Jae; Han, Ji-Won; Ji, Young-Eun; Jang, Cheol-Hun; Koppula, Sushruta; Kang, Tae-Bong; Lee, Kwang-Ho

    2015-04-15

    Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2′-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-α in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-β (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1β, IL-6 and interferon-β production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases. - Highlights: • Νovel compound, 5-hydroxy-2′-isobutyl-streptochlorin (HIS) was

  15. Recent advances in synthetic biosafety.

    PubMed

    Simon, Anna J; Ellington, Andrew D

    2016-01-01

    Synthetically engineered organisms hold promise for a broad range of medical, environmental, and industrial applications. Organisms can potentially be designed, for example, for the inexpensive and environmentally benign synthesis of pharmaceuticals and industrial chemicals, for the cleanup of environmental pollutants, and potentially even for biomedical applications such as the targeting of specific diseases or tissues. However, the use of synthetically engineered organisms comes with several reasonable safety concerns, one of which is that the organisms or their genes could escape their intended habitats and cause environmental disruption. Here we review key recent developments in this emerging field of synthetic biocontainment and discuss further developments that might be necessary for the widespread use of synthetic organisms. Specifically, we discuss the history and modern development of three strategies for the containment of synthetic microbes: addiction to an exogenously supplied ligand; self-killing outside of a designated environment; and self-destroying encoded DNA circuitry outside of a designated environment. PMID:27635235

  16. Synthetic cannabis and respiratory depression.

    PubMed

    Jinwala, Felecia N; Gupta, Mayank

    2012-12-01

    In recent years, synthetic cannabis use has been increasing in appeal among adolescents, and its use is now at a 30 year peak among high school seniors. The constituents of synthetic cannabis are difficult to monitor, given the drug's easy accessibility. Currently, 40 U.S. states have banned the distribution and use of some known synthetic cannabinoids, and have included these drugs in the Schedule I category. The depressive respiratory effect in humans caused by synthetic cannabis inhalation has not been thoroughly investigated in the medical literature. We are the first to report, to our knowledge, two cases of self-reported synthetic cannabis use leading to respiratory depression and necessary intubation. PMID:23234589

  17. Recent advances in synthetic biosafety

    PubMed Central

    Simon, Anna J.; Ellington, Andrew D.

    2016-01-01

    Synthetically engineered organisms hold promise for a broad range of medical, environmental, and industrial applications. Organisms can potentially be designed, for example, for the inexpensive and environmentally benign synthesis of pharmaceuticals and industrial chemicals, for the cleanup of environmental pollutants, and potentially even for biomedical applications such as the targeting of specific diseases or tissues. However, the use of synthetically engineered organisms comes with several reasonable safety concerns, one of which is that the organisms or their genes could escape their intended habitats and cause environmental disruption. Here we review key recent developments in this emerging field of synthetic biocontainment and discuss further developments that might be necessary for the widespread use of synthetic organisms. Specifically, we discuss the history and modern development of three strategies for the containment of synthetic microbes: addiction to an exogenously supplied ligand; self-killing outside of a designated environment; and self-destroying encoded DNA circuitry outside of a designated environment.

  18. Recent advances in synthetic biosafety

    PubMed Central

    Simon, Anna J.; Ellington, Andrew D.

    2016-01-01

    Synthetically engineered organisms hold promise for a broad range of medical, environmental, and industrial applications. Organisms can potentially be designed, for example, for the inexpensive and environmentally benign synthesis of pharmaceuticals and industrial chemicals, for the cleanup of environmental pollutants, and potentially even for biomedical applications such as the targeting of specific diseases or tissues. However, the use of synthetically engineered organisms comes with several reasonable safety concerns, one of which is that the organisms or their genes could escape their intended habitats and cause environmental disruption. Here we review key recent developments in this emerging field of synthetic biocontainment and discuss further developments that might be necessary for the widespread use of synthetic organisms. Specifically, we discuss the history and modern development of three strategies for the containment of synthetic microbes: addiction to an exogenously supplied ligand; self-killing outside of a designated environment; and self-destroying encoded DNA circuitry outside of a designated environment. PMID:27635235

  19. A novel synthetic compound exerts effective anti-tumour activity in vivo via the inhibition of tubulin polymerisation in A549 cells.

    PubMed

    Yan, Jun; Pang, Yanqing; Sheng, Jianfeng; Wang, Yali; Chen, Jie; Hu, Jinhui; Huang, Ling; Li, Xingshu

    2015-09-01

    Microtubules are critical elements that are involved in a wide range of cellular processes, and thus, they have become an attractive target for many anticancer drugs. A novel synthesised compound, 12P, was identified as new microtubule inhibitor. This compound inhibits tubulin polymerisation through binding to the colchicine-binding site of tubulin. 12P exhibits excellent anti-proliferative activities against a panel of human cancer cell lines, with IC₅₀ values range from 9 to 55nM. Interestingly, compound 12P also displayed equally potent cytotoxicity against several drug-resistant cell lines, and it showed high selectivity for active human umbilical vein endothelial cells (HUVECs). Further flow cytometric analysis showed that 12P induces G₂/M phase arrest and apoptosis in A549 cells. Cellular studies have revealed that the induction of apoptosis by 12P was associated with a collapse of mitochondrial membrane potential (MMP), accumulation of reactive oxygen species (ROS), alterations in the expression of some cell cycle-related proteins (e.g. Cyclin B1, Cdc25c, Cdc2) and some apoptosis-related proteins (e.g. Bax, Bad, Bcl-2, Bcl-xl). Importantly, 12P significantly reduced the growth of xenograft tumours of A549 cells in vivo (tumour inhibitory rate of 12P: 84.2%), without any loss of body weight. Taken together, these in vitro and in vivo results suggested that 12P may become a promising lead compound for the development of new anticancer drugs.

  20. INTRACELLULAR ANTIOXIDANT ACTIVITY OF A STREPTOMYCES SP. 8812 SECONDARY METABOLITE, 6,7-DIHYDROXY-3,4-DIHYDROISOQINO- LINE-3-CARBOXYLIC ACID, AND ITS SYNTHETIC DERIVATIVES.

    PubMed

    Guśpiel, Adam; Ziemska, Joanna; Cześcik, Agnieszka; Kawecki, Robert; Solecka, Jolanta

    2016-01-01

    The aim of this study was to determine the antioxidant properties of 6,7-dihydroxy-3,4-dihydroiso- quinoline-3-carboxylic acid (1) and its derivatives in living cells against reactive forms of oxygen and nitrogen, i.e., hydrogen peroxide and nitric oxide. Four of tested compounds scavenged the reactive form of nitrogen more efficiently or similarly to Trolox (EC50 = 55.80 µM). Two compounds exhibited antioxidant activity against reactive oxygen species better than Trolox (EC50 = 51.88 µM). The most active derivative of 1 was the compound containing an iodine atom at position 8 (6,7-dihydroxy-8-iodo-3,4-dihydroisoquinoline-3-carboxylic acid). Our studies showed that some of the derivatives had the ability to cross the cell membrane and scavenge free radicals inside living cells. Thus, they are able to protect DNA and other cellular structures from the dam- aging effects of reactive oxygen and nitrogen species. In addition, some molecular descriptors of the tested compounds were determined with the use of ICM Pro (Molsoft L.L.C.). PMID:27476282

  1. Ecotoxicology of synthetic pyrethroids.

    PubMed

    Maund, S J; Campbell, P J; Giddings, J M; Hamer, M J; Henry, K; Pilling, E D; Warinton, J S; Wheeler, J R

    2012-01-01

    In this chapter we review the ecotoxicology of the synthetic pyrethroids (SPs). SPs are potent, broad-spectrum insecticides. Their effects on a wide range of nontarget species have been broadly studied, and there is an extensive database available to evaluate their effects. SPs are highly toxic to fish and aquatic invertebrates in the laboratory, but effects in the field are mitigated by rapid dissipation and degradation. Due to their highly lipophilic nature, SPs partition extensively into sediments. Recent studies have shown that toxicity in sediment can be predicted on the basis of equilibrium partitioning, and whilst other factors can influence this, organic carbon content is a key determining variable. At present for SPs, there is no clear evidence for adverse population-relevant effects with an underlying endocrine mode of action. SPs have been studied intensively in aquatic field studies, and their effects under field conditions are mitigated from those measured in the laboratory by their rapid dissipation and degradation. Studies with a range of test systems have shown consistent aquatic field endpoints across a variety of geographies and trophic states. SPs are also highly toxic to bees and other nontarget arthropods in the laboratory. These effects are mitigated in the field through repellency and dissipation of residues, and recovery from any adverse effects tends to be rapid.

  2. Synthetic retinoids in dermatology

    PubMed Central

    Heller, Elizabeth H.; Shiffman, Norman J.

    1985-01-01

    The potential of vitamin A, or retinol, in the treatment of a variety of skin diseases has long been recognized, but because of serious toxic effects this substance generally could not be used. The recent development and marketing of two relatively nontoxic synthetic analogues, which are known as retinoids, has made it possible to treat some of the diseases that are resistant to standard forms of therapy. Isotretinoin is very effective in cystic and conglobate acne, while etretinate is especially useful in the more severe forms of psoriasis. Good results have also been obtained in other disorders of keratinization. Vitamin A and its derivatives apparently have an antineoplastic effect as well and may come to be used in both the prevention and the treatment of epithelial cancer. In many of these diseases the retinoids act by enhancing the normal differentiation and proliferation of epidermal tissues, but the exact mechanisms are not well understood. Their influence on the intracellular polyamines that control the synthesis of nucleic acids and proteins may be an important factor. Although the retinoids have few serious systemic effects, they are teratogenic, and because they persist in the body their use in women of childbearing potential is limited. ImagesFig. 3 PMID:3158386

  3. Synthetic molecular walkers.

    PubMed

    Leigh, David A; Lewandowska, Urszula; Lewandowski, Bartosz; Wilson, Miriam R

    2014-01-01

    In biological systems, molecular motors have been developed to harness Brownian motion and perform specific tasks. Among the cytoskeletal motor proteins, kinesins ensure directional transport of cargoes to the periphery of the cell by taking discrete steps along microtubular tracks. In the past decade there has been an increasing interest in the development of molecules that mimic aspects of the dynamics of biological systems and can became a starting point for the creation of artificial transport systems.To date, both DNA-based and small-molecule walkers have been developed, each taking advantage of the different chemistries available to them. DNA strollers exploit orthogonal base pairing and utilize strand-displacement reactions to control the relative association of the component parts. Small-molecule walkers take advantage of the reversibility of weak noncovalent interactions as well as the robustness of dynamic covalent bonds in order to transport molecular fragments along surfaces and molecular tracks using both diffusional processes and ratchet mechanisms. Here we review both types of synthetic systems, including their designs, dynamics, and how they are being used to perform functions by controlled mechanical motion at the molecular level.

  4. Computing with synthetic protocells.

    PubMed

    Courbet, Alexis; Molina, Franck; Amar, Patrick

    2015-09-01

    In this article we present a new kind of computing device that uses biochemical reactions networks as building blocks to implement logic gates. The architecture of a computing machine relies on these generic and composable building blocks, computation units, that can be used in multiple instances to perform complex boolean functions. Standard logical operations are implemented by biochemical networks, encapsulated and insulated within synthetic vesicles called protocells. These protocells are capable of exchanging energy and information with each other through transmembrane electron transfer. In the paradigm of computation we propose, protoputing, a machine can solve only one problem and therefore has to be built specifically. Thus, the programming phase in the standard computing paradigm is represented in our approach by the set of assembly instructions (specific attachments) that directs the wiring of the protocells that constitute the machine itself. To demonstrate the computing power of protocellular machines, we apply it to solve a NP-complete problem, known to be very demanding in computing power, the 3-SAT problem. We show how to program the assembly of a machine that can verify the satisfiability of a given boolean formula. Then we show how to use the massive parallelism of these machines to verify in less than 20 min all the valuations of the input variables and output a fluorescent signal when the formula is satisfiable or no signal at all otherwise.

  5. Synthetic biology: lessons from the history of synthetic organic chemistry.

    PubMed

    Yeh, Brian J; Lim, Wendell A

    2007-09-01

    The mid-nineteenth century saw the development of a radical new direction in chemistry: instead of simply analyzing existing molecules, chemists began to synthesize them--including molecules that did not exist in nature. The combination of this new synthetic approach with more traditional analytical approaches revolutionized chemistry, leading to a deep understanding of the fundamental principles of chemical structure and reactivity and to the emergence of the modern pharmaceutical and chemical industries. The history of synthetic chemistry offers a possible roadmap for the development and impact of synthetic biology, a nascent field in which the goal is to build novel biological systems. PMID:17710092

  6. Synthetic biology: Understanding biological design from synthetic circuits

    PubMed Central

    Mukherji, Shankar; van Oudenaarden, Alexander

    2011-01-01

    An important aim of synthetic biology is to uncover the design principles of natural biological systems through the rational design of gene and protein circuits. Here we highlight how the process of engineering biological systems — from synthetic promoters to the control of cell–cell interactions — has contributed to our understanding of how endogenous systems are put together and function. Synthetic biological devices allow us to intuitively grasp the ranges of behavior generated by simple biological circuits, such as linear cascades and interlocking feedback loops, as well as to exert control over natural processes such as gene expression and population dynamics. PMID:19898500

  7. Structure-Activity Relationship of Synthetic 2-Phenylnaphthalenes with Hydroxyl Groups that Inhibit Proliferation and Induce Apoptosis of MCF-7 Cancer Cells

    PubMed Central

    Chang, Chi-Fen; Ke, Ci-Yi; Wu, Yang-Chang; Chuang, Ta-Hsien

    2015-01-01

    In this study, six 2-phenylnaphthalenes with hydroxyl groups were synthesized in high yields by the demethylation of the corresponding methoxy-2-phenylnaphthalenes, and one 2-phenylnaphthalene with an amino group was obtained by hydrogenation. All of the 2-phenylnaphthalene derivatives were evaluated for cytotoxicity, and the structure-activity relationship (SAR) against human breast cancer (MCF-7) cells was also determined. The SAR results revealed that cytotoxicity was markedly promoted by the hydroxyl group at the C-7 position of the naphthalene ring. The introduction of hydroxyl groups at the C-6 position of the naphthalene ring and the C-4' position of the phenyl ring fairly enhanced cytotoxicity, but the introduction of a hydroxyl group at the C-3' position of the phenyl ring slightly decreased cytotoxicity. Overall, 6,7-dihydroxy-2-(4'-hydroxyphenyl)naphthalene (PNAP-6h) exhibited the best cytotoxicity, with an IC50 value of 4.8 μM against the MCF-7 cell line, and showed low toxicity toward normal human mammary epithelial cells (MCF-10A). PNAP-6h led to cell arrest at the S phase, most likely due to increasing levels of p21 and p27 and decreasing levels of cyclin D1, CDK4, cyclin E, and CDK2. In addition, PNAP-6h decreased CDK1 and cyclin B1 expression, most likely leading to G2/M arrest, and induced morphological changes, such as nuclear shrinkage, nuclear fragmentation, and nuclear hypercondensation, as observed by Hoechst 33342 staining. PNAP-6h induced apoptosis, most likely by the promotion of Fas expression, increased PARP activity, caspase-7, caspase-8, and caspase-9 expression, the Bax/Bcl-2 ratio, and the phosphorylation of p38, and decreased the phosphorylation of ERK. This study provides the first demonstration of the cytotoxicity of PNAPs against MCF-7 cells and elucidates the mechanism underlying PNAP-induced cytotoxicity. PMID:26492346

  8. Structure and Active Stie Residues of Pg1D, an N-Acetyltransferase from the Bacillosamine Synthetic Pathway Required for N-Glycan Synthesis in Campylobacter jejuni

    SciTech Connect

    Rangarajan,E.; Ruane, K.; Sulea, T.; Watson, D.; Proteau, A.; Leclerc, S.; Cygler, M.; Matte, A.; Young, N.

    2008-01-01

    Campylobacter jejuni is highly unusual among bacteria in forming N-linked glycoproteins. The heptasaccharide produced by its pgl system is attached to protein Asn through its terminal 2, 4-diacetamido-2, 4,6-trideoxy-d-Glc (QuiNAc4NAc or N, N'-diacetylbacillosamine) moiety. The crucial, last part of this sugar's synthesis is the acetylation of UDP-2-acetamido-4-amino-2, 4,6-trideoxy-d-Glc by the enzyme PglD, with acetyl-CoA as a cosubstrate. We have determined the crystal structures of PglD in CoA-bound and unbound forms, refined to 1.8 and 1.75 Angstroms resolution, respectively. PglD is a trimer of subunits each comprised of two domains, an N-terminal {alpha}/{beta}-domain and a C-terminal left-handed {beta}-helix. Few structural differences accompany CoA binding, except in the C-terminal region following the {beta}-helix (residues 189-195), which adopts an extended structure in the unbound form and folds to extend the {beta}-helix upon binding CoA. Computational molecular docking suggests a different mode of nucleotide-sugar binding with respect to the acetyl-CoA donor, with the molecules arranged in an 'L-shape', compared with the 'in-line' orientation in related enzymes. Modeling indicates that the oxyanion intermediate would be stabilized by the NH group of Gly143', with His125' the most likely residue to function as a general base, removing H+ from the amino group prior to nucleophilic attack at the carbonyl carbon of acetyl-CoA. Site-specific mutations of active site residues confirmed the importance of His125', Glu124', and Asn118. We conclude that Asn118 exerts its function by stabilizing the intricate hydrogen bonding network within the active site and that Glu124' may function to increase the pKa of the putative general base, His125'.

  9. Magma storage depths beneath an active rift volcano in Afar (Dabbahu), constrained by melt inclusion analyses, seismicity and Interferometric Synthetic Aperture Radar (INSAR)

    NASA Astrophysics Data System (ADS)

    Field, L.; Blundy, J.; Wright, T. J.; Yirgu, G.; Afar Consortium

    2010-12-01

    Dabbahu volcano is located at the northern end of the active Manda Hararo rift segment in western Afar, Ethiopia. In 2005 a major rifting episode began in the segment, which has been modelled as basalt dyke injections (1). Seismic activity, inflation and deflation have been recorded at the volcano. The aim of this research is to provide an insight into the history and evolution of a silicic magmatic centre in the rift, and to contribute to the wider aims of the NERC Afar Consortium to track the creation, migration, evolution and emplacement of magma from the asthenosphere to the crust. The volatile contents of rare melt inclusions trapped within phenocrysts of alkali feldspar, clinopyroxene and olivine from Dabbahu have been studied using secondary ion mass spectrometry. The host lavas are mildly peralkaline obsidians, which, based on field evidence and preliminary results from 40Ar-39Ar dating, represent the youngest samples on the volcano (<4 ka). Whilst the obsidian and pumice groundmass glasses are largely degassed, the H2O contents of the analysed inclusions are up to 5.8 wt%. CO2 contents are generally low; <462 ppm in the alkali feldspar-hosted inclusions, but higher values (up to 1457 ppm) have been found in the clinopyroxene-hosted inclusions. The pressure (and depth) of pre-eruptive magma storage beneath Dabbahu has been constrained using H2O and CO2 data, which suggest shallow magma storage at depths of ~1 - 5 km below the surface. These depths are consistent with observations from recorded seismicity and InSAR at Dabbahu. Seismicity has been recorded from deformation caused by deflation of the magma chamber following the 2005 dyke emplacement event (Oct 2005 - Apr 2006)(2) and InSAR has monitored deflation and subsequent steady inflation after this event. We show that melt inclusions accurately record a stable, shallow magma chamber as corroborated by remote sensing and geophysical observations at Dabbahu volcano. 1 Ayele et al. 2009 ‘September 2005

  10. Bistatic synthetic aperture radar

    NASA Astrophysics Data System (ADS)

    Yates, Gillian

    Synthetic aperture radar (SAR) allows all-weather, day and night, surface surveillance and has the ability to detect, classify and geolocate objects at long stand-off ranges. Bistatic SAR, where the transmitter and the receiver are on separate platforms, is seen as a potential means of countering the vulnerability of conventional monostatic SAR to electronic countermeasures, particularly directional jamming, and avoiding physical attack of the imaging platform. As the receiving platform can be totally passive, it does not advertise its position by RF emissions. The transmitter is not susceptible to jamming and can, for example, operate at long stand-off ranges to reduce its vulnerability to physical attack. This thesis examines some of the complications involved in producing high-resolution bistatic SAR imagery. The effect of bistatic operation on resolution is examined from a theoretical viewpoint and analytical expressions for resolution are developed. These expressions are verified by simulation work using a simple 'point by point' processor. This work is extended to look at using modern practical processing engines for bistatic geometries. Adaptations of the polar format algorithm and range migration algorithm are considered. The principal achievement of this work is a fully airborne demonstration of bistatic SAR. The route taken in reaching this is given, along with some results. The bistatic SAR imagery is analysed and compared to the monostatic imagery collected at the same time. Demonstrating high-resolution bistatic SAR imagery using two airborne platforms represents what I believe to be a European first and is likely to be the first time that this has been achieved outside the US (the UK has very little insight into US work on this topic). Bistatic target characteristics are examined through the use of simulations. This also compares bistatic imagery with monostatic and gives further insight into the utility of bistatic SAR.

  11. Spicing thing up: Synthetic cannabinoids

    PubMed Central

    Spaderna, Max; Addy, Peter H; D’Souza, Deepak Cyril

    2013-01-01

    Rationale Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. Objectives The availability, acute subjective effects—including self-reports posted on Erowid—laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Results Spice is sold under the guise of potpourri or incense. Unlike THC, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid-receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. Conclusions There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug-detection tests for synthetic cannabinoids need to become clinically available. PMID:23836028

  12. Activation of superoxide formation and lysozyme release in human neutrophils by the synthetic lipopeptide Pam3Cys-Ser-(Lys)4. Involvement of guanine-nucleotide-binding proteins and synergism with chemotactic peptides.

    PubMed Central

    Seifert, R; Schultz, G; Richter-Freund, M; Metzger, J; Wiesmüller, K H; Jung, G; Bessler, W G; Hauschildt, S

    1990-01-01

    Upon exposure to the bacterial chemotactic peptide fMet-Leu-Phe, human neutrophils release lysozyme and generate superoxide anions (O2.-). The synthetic lipoamino acid N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteine (Pam3Cys), which is derived from the N-terminus of bacterial lipoprotein, when attached to Ser-(Lys)4 [giving Pam3Cys-Ser-(Lys)4], activated O2.- formation and lysozyme release in human neutrophils with an effectiveness amounting to about 15% of that of fMet-Leu-Phe. Palmitic acid, muramyl dipeptide, lipopolysaccharide and the lipopeptides Pam3Cys-Ala-Gly, Pam3Cys-Ser-Gly, Pam3Cys-Ser, Pam3Cys-OMe and Pam3Cys-OH did not activate O2.- formation. Pertussis toxin, which ADP-ribosylates guanine-nucleotide-binding proteins (G-proteins) and functionally uncouples formyl peptide receptors from G-proteins, prevented activation of O2.- formation by fMet-Leu-Phe and inhibited Pam3Cys-Ser-(Lys)4-induced O2.- formation by 85%. Lipopeptide-induced exocytosis was pertussis-toxin-insensitive. O2.- formation induced by Pam3Cys-Ser-(Lys)4 and fMet-Leu-Phe was enhanced by cytochalasin B, by a phorbol ester and by a diacylglycerol kinase inhibitor. Addition of activators of adenylate cyclase and removal of extracellular Ca2+ inhibited O2.- formation by fMet-Leu-Phe and Pam3Cys-Ser-(Lys)4 to different extents. Pam3Cys-Ser-(Lys)4 synergistically enhanced fMet-Leu-Phe-induced O2.- formation and primed neutrophils to respond to the chemotactic peptide at non-stimulatory concentrations. Our data suggest the following. (1) Pam3Cys-Ser-(Lys)4 activates neutrophils through G-proteins, involving pertussis-toxin-sensitive and -insensitive processes. (2) The signal transduction pathways activated by fMet-Leu-Phe and Pam3Cys-Ser-(Lys)4 are similar but not identical. (3) In inflammatory processes, bacterial lipoproteins and chemotactic peptides may interact synergistically to activate O2.- formation, leading to enhanced bactericidal activity. PMID:2160237

  13. THE IN VIVO PROTEIN SYNTHETIC ACTIVITIES OF FREE VERSUS MEMBRANE-BOUND RIBONUCLEOPROTEIN IN A PLASMA-CELL TUMOR OF THE MOUSE

    PubMed Central

    Kuff, E. L.; Hymer, W. C.; Shelton, E.; Roberts, N. E.

    1966-01-01

    Cytoplasmic extracts of the transplantable RPC-20 plasma-cell tumor were fractionated by sucrose density gradient centrifugation. Four major fractions were distinguished: (a) microsomes and mitochondria; (b) membrane-free polyribosomes; (c) free monomeric ribosomes; and (d) soluble fraction. The fractions were analyzed for RNA and lipid phosphorus, and their particulate components were characterized by electron microscopy. Particular attention was paid to the problem of membrane contamination of the free polyribosome fraction. It was shown that this contamination was small in relation with the total content of ribosomes in the fraction, and that it consisted primarily of smooth-surfaced membranes which were not physically associated with the polyribosomes themselves. In vivo incorporation studies were carried out by injecting tumor-bearing animals intravenously with leucine-C14, removing the tumors at various times thereafter, and determining the distribution of protein radioactivity among the gradient-separated cytoplasmic fractions. The free polyribosome and the microsome-mitochondria fractions constituted active centers for protein synthesis. It was shown that nascent protein of the free polyribosome fractions was not associated significantly with the contaminating membranes. The kinetics of labeling during incorporation times up to 11 min suggested that protein synthesized on the free polyribosomes was rapidly transferred in vivo to the soluble fraction of the cell, while protein synthesized by the microsomes and mitochondria remained localized within these elements. It was estimated that the free polyribosome fraction and the microsome-mitochondria fraction accounted for approximately equal proportions of the total cytoplasmic protein synthesis in vivo. PMID:5920197

  14. Active site specificity profiling of the matrix metalloproteinase family: Proteomic identification of 4300 cleavage sites by nine MMPs explored with structural and synthetic peptide cleavage analyses.

    PubMed

    Eckhard, Ulrich; Huesgen, Pitter F; Schilling, Oliver; Bellac, Caroline L; Butler, Georgina S; Cox, Jennifer H; Dufour, Antoine; Goebeler, Verena; Kappelhoff, Reinhild; Keller, Ulrich Auf dem; Klein, Theo; Lange, Philipp F; Marino, Giada; Morrison, Charlotte J; Prudova, Anna; Rodriguez, David; Starr, Amanda E; Wang, Yili; Overall, Christopher M

    2016-01-01

    Secreted and membrane tethered matrix metalloproteinases (MMPs) are key homeostatic proteases regulating the extracellular signaling and structural matrix environment of cells and tissues. For drug targeting of proteases, selectivity for individual molecules is highly desired and can be met by high yield active site specificity profiling. Using the high throughput Proteomic Identification of protease Cleavage Sites (PICS) method to simultaneously profile both the prime and non-prime sides of the cleavage sites of nine human MMPs, we identified more than 4300 cleavages from P6 to P6' in biologically diverse human peptide libraries. MMP specificity and kinetic efficiency were mainly guided by aliphatic and aromatic residues in P1' (with a ~32-93% preference for leucine depending on the MMP), and basic and small residues in P2' and P3', respectively. A wide differential preference for the hallmark P3 proline was found between MMPs ranging from 15 to 46%, yet when combined in the same peptide with the universally preferred P1' leucine, an unexpected negative cooperativity emerged. This was not observed in previous studies, probably due to the paucity of approaches that profile both the prime and non-prime sides together, and the masking of subsite cooperativity effects by global heat maps and iceLogos. These caveats make it critical to check for these biologically highly important effects by fixing all 20 amino acids one-by-one in the respective subsites and thorough assessing of the inferred specificity logo changes. Indeed an analysis of bona fide MEROPS physiological substrate cleavage data revealed that of the 37 natural substrates with either a P3-Pro or a P1'-Leu only 5 shared both features, confirming the PICS data. Upon probing with several new quenched-fluorescent peptides, rationally designed on our specificity data, the negative cooperativity was explained by reduced non-prime side flexibility constraining accommodation of the rigidifying P3 proline with

  15. Approaches to chemical synthetic biology.

    PubMed

    Chiarabelli, Cristiano; Stano, Pasquale; Anella, Fabrizio; Carrara, Paolo; Luisi, Pier Luigi

    2012-07-16

    Synthetic biology is first represented in terms of two complementary aspects, the bio-engineering one, based on the genetic manipulation of extant microbial forms in order to obtain forms of life which do not exist in nature; and the chemical synthetic biology, an approach mostly based on chemical manipulation for the laboratory synthesis of biological structures that do not exist in nature. The paper is mostly devoted to shortly review chemical synthetic biology projects currently carried out in our laboratory. In particular, we describe: the minimal cell project, then the "Never Born Proteins" and lastly the Never Born RNAs. We describe and critically analyze the main results, emphasizing the possible relevance of chemical synthetic biology for the progress in basic science and biotechnology.

  16. Is synthetic biology mechanical biology?

    PubMed

    Holm, Sune

    2015-12-01

    A widespread and influential characterization of synthetic biology emphasizes that synthetic biology is the application of engineering principles to living systems. Furthermore, there is a strong tendency to express the engineering approach to organisms in terms of what seems to be an ontological claim: organisms are machines. In the paper I investigate the ontological and heuristic significance of the machine analogy in synthetic biology. I argue that the use of the machine analogy and the aim of producing rationally designed organisms does not necessarily imply a commitment to mechanical biology. The ideal of applying engineering principles to biology is best understood as expressing recognition of the machine-unlikeness of natural organisms and the limits of human cognition. The paper suggests an interpretation of the identification of organisms with machines in synthetic biology according to which it expresses a strategy for representing, understanding, and constructing living systems that are more machine-like than natural organisms.

  17. Synthetic Biology for Specialty Chemicals.

    PubMed

    Markham, Kelly A; Alper, Hal S

    2015-01-01

    In this review, we address recent advances in the field of synthetic biology and describe how those tools have been applied to produce a wide variety of chemicals in microorganisms. Here we classify the expansion of the synthetic biology toolbox into three different categories based on their primary function in strain engineering-for design, for construction, and for optimization. Next, focusing on recent years, we look at how chemicals have been produced using these new synthetic biology tools. Advances in producing fuels are briefly described, followed by a more thorough treatment of commodity chemicals, specialty chemicals, pharmaceuticals, and nutraceuticals. Throughout this review, an emphasis is placed on how synthetic biology tools are applied to strain engineering. Finally, we discuss organism and host strain diversity and provide a future outlook in the field.

  18. Synthetic Turf Multiplies Stadium Use.

    ERIC Educational Resources Information Center

    Leach, Richard

    1979-01-01

    The high school stadium in Flint, Michigan, once was used only for varsity football games. After the installation of synthetic turf, an average of 332 events have been staged there each year. (Author/MLF)

  19. Programming languages for synthetic biology.

    PubMed

    Umesh, P; Naveen, F; Rao, Chanchala Uma Maheswara; Nair, Achuthsankar S

    2010-12-01

    In the backdrop of accelerated efforts for creating synthetic organisms, the nature and scope of an ideal programming language for scripting synthetic organism in-silico has been receiving increasing attention. A few programming languages for synthetic biology capable of defining, constructing, networking, editing and delivering genome scale models of cellular processes have been recently attempted. All these represent important points in a spectrum of possibilities. This paper introduces Kera, a state of the art programming language for synthetic biology which is arguably ahead of similar languages or tools such as GEC, Antimony and GenoCAD. Kera is a full-fledged object oriented programming language which is tempered by biopart rule library named Samhita which captures the knowledge regarding the interaction of genome components and catalytic molecules. Prominent feature of the language are demonstrated through a toy example and the road map for the future development of Kera is also presented. PMID:22132053

  20. Programming languages for synthetic biology.

    PubMed

    Umesh, P; Naveen, F; Rao, Chanchala Uma Maheswara; Nair, Achuthsankar S

    2010-12-01

    In the backdrop of accelerated efforts for creating synthetic organisms, the nature and scope of an ideal programming language for scripting synthetic organism in-silico has been receiving increasing attention. A few programming languages for synthetic biology capable of defining, constructing, networking, editing and delivering genome scale models of cellular processes have been recently attempted. All these represent important points in a spectrum of possibilities. This paper introduces Kera, a state of the art programming language for synthetic biology which is arguably ahead of similar languages or tools such as GEC, Antimony and GenoCAD. Kera is a full-fledged object oriented programming language which is tempered by biopart rule library named Samhita which captures the knowledge regarding the interaction of genome components and catalytic molecules. Prominent feature of the language are demonstrated through a toy example and the road map for the future development of Kera is also presented.

  1. Synthetic Cannabinoid 'Bonzai' Intoxication: Six Case Series.

    PubMed

    Ergül, Dursun Fırat; Ekemen, Serdar; Yelken, Birgül Büyükkıdan

    2015-10-01

    In the language of the streets, 'bonzai', known as '1-naphthalenyl of methanol', also known as JWH-18 group, is a drug belonging to the group of synthetic cannabinoids. At the beginning of 2004, it started to be sold on the internet and it is seen that private markets. It has structurally similar chemical characteristics as delta 9-tetrahydrocannabinol (THC), the active substance in marijuana. In 2013, in a study conducted by the European Monitoring Centre of Drugs and Drug Addiction (EMCDDA), 102 varieties of synthetic cannabinoids were identified; however, more than 200 substances have been reported since 1997. In this study, we report the difficulties in the clinical course, treatment and management of six patients that had a use history of bonzai although it was not detected in blood in a short period of time in the intensive care unit. PMID:27366526

  2. Bio-based polycarbonate as synthetic toolbox.

    PubMed

    Hauenstein, O; Agarwal, S; Greiner, A

    2016-01-01

    Completely bio-based poly(limonene carbonate) is a thermoplastic polymer, which can be synthesized by copolymerization of limonene oxide (derived from limonene, which is found in orange peel) and CO2. Poly(limonene carbonate) has one double bond per repeating unit that can be exploited for further chemical modifications. These chemical modifications allow the tuning of the properties of the aliphatic polycarbonate in nearly any direction. Here we show synthetic routes to demonstrate that poly(limonene carbonate) is the perfect green platform polymer, from which many functional materials can be derived. The relevant examples presented in this study are the transformation from an engineering thermoplastic into a rubber, addition of permanent antibacterial activity, hydrophilization and even pH-dependent water solubility of the polycarbonate. Finally, we show a synthetic route to yield the completely saturated counterpart that exhibits improved heat processability due to lower reactivity. PMID:27302694

  3. Bio-based polycarbonate as synthetic toolbox

    NASA Astrophysics Data System (ADS)

    Hauenstein, O.; Agarwal, S.; Greiner, A.

    2016-06-01

    Completely bio-based poly(limonene carbonate) is a thermoplastic polymer, which can be synthesized by copolymerization of limonene oxide (derived from limonene, which is found in orange peel) and CO2. Poly(limonene carbonate) has one double bond per repeating unit that can be exploited for further chemical modifications. These chemical modifications allow the tuning of the properties of the aliphatic polycarbonate in nearly any direction. Here we show synthetic routes to demonstrate that poly(limonene carbonate) is the perfect green platform polymer, from which many functional materials can be derived. The relevant examples presented in this study are the transformation from an engineering thermoplastic into a rubber, addition of permanent antibacterial activity, hydrophilization and even pH-dependent water solubility of the polycarbonate. Finally, we show a synthetic route to yield the completely saturated counterpart that exhibits improved heat processability due to lower reactivity.

  4. Bio-based polycarbonate as synthetic toolbox.

    PubMed

    Hauenstein, O; Agarwal, S; Greiner, A

    2016-06-15

    Completely bio-based poly(limonene carbonate) is a thermoplastic polymer, which can be synthesized by copolymerization of limonene oxide (derived from limonene, which is found in orange peel) and CO2. Poly(limonene carbonate) has one double bond per repeating unit that can be exploited for further chemical modifications. These chemical modifications allow the tuning of the properties of the aliphatic polycarbonate in nearly any direction. Here we show synthetic routes to demonstrate that poly(limonene carbonate) is the perfect green platform polymer, from which many functional materials can be derived. The relevant examples presented in this study are the transformation from an engineering thermoplastic into a rubber, addition of permanent antibacterial activity, hydrophilization and even pH-dependent water solubility of the polycarbonate. Finally, we show a synthetic route to yield the completely saturated counterpart that exhibits improved heat processability due to lower reactivity.

  5. Bio-based polycarbonate as synthetic toolbox

    PubMed Central

    Hauenstein, O.; Agarwal, S.; Greiner, A.

    2016-01-01

    Completely bio-based poly(limonene carbonate) is a thermoplastic polymer, which can be synthesized by copolymerization of limonene oxide (derived from limonene, which is found in orange peel) and CO2. Poly(limonene carbonate) has one double bond per repeating unit that can be exploited for further chemical modifications. These chemical modifications allow the tuning of the properties of the aliphatic polycarbonate in nearly any direction. Here we show synthetic routes to demonstrate that poly(limonene carbonate) is the perfect green platform polymer, from which many functional materials can be derived. The relevant examples presented in this study are the transformation from an engineering thermoplastic into a rubber, addition of permanent antibacterial activity, hydrophilization and even pH-dependent water solubility of the polycarbonate. Finally, we show a synthetic route to yield the completely saturated counterpart that exhibits improved heat processability due to lower reactivity. PMID:27302694

  6. Design of synthetic yeast promoters via tuning of nucleosome architecture.

    PubMed

    Curran, Kathleen A; Crook, Nathan C; Karim, Ashty S; Gupta, Akash; Wagman, Allison M; Alper, Hal S

    2014-01-01

    Model-based design of biological parts is a critical goal of synthetic biology, especially for eukaryotes. Here we demonstrate that nucleosome architecture can have a role in defining yeast promoter activity and utilize a computationally-guided approach that can enable both the redesign of endogenous promoter sequences and the de novo design of synthetic promoters. Initially, we use our approach to reprogram native promoters for increased expression and evaluate their performance in various genetic contexts. Increases in expression ranging from 1.5- to nearly 6-fold in a plasmid-based system and up to 16-fold in a genomic context were obtained. Next, we demonstrate that, in a single design cycle, it is possible to create functional, purely synthetic yeast promoters that achieve substantial expression levels (within the top sixth percentile among native yeast promoters). In doing so, this work establishes a unique DNA-level specification of promoter activity and demonstrates predictive design of synthetic parts. PMID:24862902

  7. Compounding in synthetic aperture imaging.

    PubMed

    Hansen, Jens Munk; Jensen, Jørgen Arendt

    2012-09-01

    A method for obtaining compound images using synthetic aperture data is investigated using a convex array transducer. The new approach allows spatial compounding to be performed for any number of angles without reducing the frame rate or temporal resolution. This important feature is an intrinsic property of how the compound images are constructed using synthetic aperture data and an improvement compared with how spatial compounding is obtained using conventional methods. The synthetic aperture compound images are created by exploiting the linearity of delay-and-sum beamformation for data collected from multiple spherical emissions to synthesize multiple transmit and receive apertures, corresponding to imaging the tissue from multiple directions. The many images are added incoherently, to produce a single compound image. Using a 192-element, 3.5-MHz, λ-pitch transducer, it is demonstrated from tissue-phantom measurements that the speckle is reduced and the contrast resolution improved when applying synthetic aperture compound imaging. At a depth of 4 cm, the size of the synthesized apertures is optimized for lesion detection based on the speckle information density. This is a performance measure for tissue contrast resolution which quantifies the tradeoff between resolution loss and speckle reduction. The speckle information density is improved by 25% when comparing synthetic aperture compounding to a similar setup for compounding using dynamic receive focusing. The cystic resolution and clutter levels are measured using a wire phantom setup and compared with conventional application of the array, as well as to synthetic aperture imaging without compounding. If the full aperture is used for synthetic aperture compounding, the cystic resolution is improved by 41% compared with conventional imaging, and is at least as good as what can be obtained using synthetic aperture imaging without compounding. PMID:23007781

  8. Superresolution and Synthetic Aperture Radar

    SciTech Connect

    DICKEY,FRED M.; ROMERO,LOUIS; DOERRY,ARMIN W.

    2001-05-01

    Superresolution concepts offer the potential of resolution beyond the classical limit. This great promise has not generally been realized. In this study we investigate the potential application of superresolution concepts to synthetic aperture radar. The analytical basis for superresolution theory is discussed. The application of the concept to synthetic aperture radar is investigated as an operator inversion problem. Generally, the operator inversion problem is ill posed. A criterion for judging superresolution processing of an image is presented.

  9. Synthetic biology as red herring.

    PubMed

    Preston, Beth

    2013-12-01

    It has become commonplace to say that with the advent of technologies like synthetic biology the line between artifacts and living organisms, policed by metaphysicians since antiquity, is beginning to blur. But that line began to blur 10,000 years ago when plants and animals were first domesticated; and has been thoroughly blurred at least since agriculture became the dominant human subsistence pattern many millennia ago. Synthetic biology is ultimately only a late and unexceptional offshoot of this prehistoric development. From this perspective, then, synthetic biology is a red herring, distracting us from more thorough philosophical consideration of the most truly revolutionary human practice-agriculture. In the first section of this paper I will make this case with regard to ontology, arguing that synthetic biology crosses no ontological lines that were not crossed already in the Neolithic. In the second section I will construct a parallel case with regard to cognition, arguing that synthetic biology as biological engineering represents no cognitive advance over what was required for domestication and the new agricultural subsistence pattern it grounds. In the final section I will make the case with regard to human existence, arguing that synthetic biology, even if wildly successful, is not in a position to cause significant existential change in what it is to be human over and above the massive existential change caused by the transition to agriculture. I conclude that a longer historical perspective casts new light on some important issues in philosophy of technology and environmental philosophy.

  10. Tangential synthetic jets for separation control

    NASA Astrophysics Data System (ADS)

    Esmaeili Monir, H.; Tadjfar, M.; Bakhtian, A.

    2014-02-01

    A numerical study of separation control has been made to investigate aerodynamic characteristics of a NACA23012 airfoil with a tangential synthetic jet. Simulations are carried out at the chord Reynolds number of Re=2.19×106. The present approach relies on solving the Unsteady Reynolds-Averaged Navier-Stokes (URANS) equations. The turbulence model used in the present computation is the Spalart-Allmaras one-equation model. All computations are performed with a finite volume based code. Stall characteristics are significantly improved by controlling the formation of separation vortices in the flow. We placed the synthetic jet at the 12% chord, xj=0.12c, where we expected the separation to occur. Two distinct jet oscillating frequencies: Fj+=0.159 and Fj+=1 were considered. We studied the effect of blowing ratio, Vj/U∞, where it was varied from 0 to 5. The inclined angle of the synthetic jet was varied from αj=0° up to αj=83°. For the non-zero inclined angles, the local maximum in the aerodynamic performance, Cl/Cd, of 6.89 was found for the inclined angle of about 43°. In the present method, by means of creating a dent on the airfoil, linear momentum is transferred to the flow system in tangential direction to the airfoil surface. Thus the absolute maximum of 11.19 was found for the tangential synthetic jet at the inclined angle of the jet of 0°. The mechanisms involved for a tangential jet appear to behave linearly, as by multiplying the activation frequency of the jet by a factor produces the same multiplication factor in the resulting frequency in the flow. However, the mechanisms involved in the non-zero inclined angle cases behave nonlinearly when the activation frequency is multiplied.

  11. Synthetic Eelgrass Oil Barrier

    NASA Astrophysics Data System (ADS)

    Curtis, T. G.

    2013-05-01

    Although surviving in situ micro-organisms eventually consume spilled oil, extensive inundation of shore biota by oil requires cleanup to enable ecological recovery within normal time scales. Although effective in calm seas and quiet waters, oil is advected over and under conventional curtain oil booms by wave actions and currents when seas are running. Most sorbent booms are not reusable, and are usually disposed of in landfills, creating excessive waste. A new concept is proposed for a floating oil barrier, to be positioned off vulnerable coasts, to interdict, contain, and sequester spilled oil, which can then be recovered and the barrier reused. While conventional oil boom designs rely principally on the immiscibility of oil in water and its relative buoyancy, the new concept barrier avoids the pitfalls of the former by taking advantage of the synergistic benefits of numerous fluid and material properties, including: density, buoyancy, elasticity, polarity, and surface area to volume ratio. Modeled after Zostera marina, commonly called eelgrass, the new barrier, referred to as synthetic eelgrass (SE), behaves analogously. Eelgrass has very long narrow, ribbon-like, leaves which support periphyton, a complex matrix of algae and heterotrophic microbes, which position themselves there to extract nutrients from the seawater flowing past them. In an analogous fashion, oil on, or in, seawater, which comes in contact with SE, is adsorbed on the surface and sequestered there. Secured to the bottom, in shoal waters, SE rises to the surface, and, if the tide is low enough, floats on the sea surface down wind, or down current to snare floating oil. The leaves of SE, called filaments, consist of intrinsically buoyant strips of ethylene methyl acrylate, aka EMA. EMA, made of long chain, saturated, hydrocarbon molecules with nearly homogeneous electron charge distributions, is a non-polar material which is oleophilic and hydrophobic. Oil must be in close proximity to the

  12. Environmental data energy technology characterizations: synthetic fuels

    SciTech Connect

    Not Available

    1980-04-01

    Environmental Data Energy Technology Characterizations are publications which are intended to provide policy analysts and technical analysts with basic environmental data associated with key energy technologies. This publication provides documentation on synthetic fuels (coal-derived and oil shale). The transformation of the energy in coal and oil shale into a more useful form is described in this publication in terms of major activity areas in the synthetic fuel cycles, that is, in terms of activities which produce either an energy product or a fuel leading to the production of an energy product in a different form. The activities discussed in this document are coal liquefaction, coal gasification, in-situ gasification, and oil shales. These activities represent both well-documented and advanced activity areas. The former activities are characterized in terms of actual operating data with allowance for future modification where appropriate. Emissions are assumed to conform to environmental standards. The advanced activity areas examined are those like coal liquefaction and in-situ retorting of oil shale. For these areas, data from pilot or demonstration plants were used where available; otherwise, engineering studies provided the data. The organization of the chapters in this volume is designed to support the tabular presentation in the summary volume. Each chapter begins with a brief description of the activity under consideration. The standard characteristics, size, availability, mode of functioning and place in the fuel cycle are presented. Next, major legislative and/or technological factors influencing the commercial operation of the activity are offered. Discussions of resources consumed, residuals produced, and economics follow. To aid in comparing and linking the different activity areas, data for each area are normalized to 10/sup 12/ Btu of energy output from the activity.

  13. Freedom and Responsibility in Synthetic Genomics: The Synthetic Yeast Project.

    PubMed

    Sliva, Anna; Yang, Huanming; Boeke, Jef D; Mathews, Debra J H

    2015-08-01

    First introduced in 2011, the Synthetic Yeast Genome (Sc2.0) PROJECT is a large international synthetic genomics project that will culminate in the first eukaryotic cell (Saccharomyces cerevisiae) with a fully synthetic genome. With collaborators from across the globe and from a range of institutions spanning from do-it-yourself biology (DIYbio) to commercial enterprises, it is important that all scientists working on this project are cognizant of the ethical and policy issues associated with this field of research and operate under a common set of principles. In this commentary, we survey the current ethics and regulatory landscape of synthetic biology and present the Sc2.0 Statement of Ethics and Governance to which all members of the project adhere. This statement focuses on four aspects of the Sc2.0 PROJECT: societal benefit, intellectual property, safety, and self-governance. We propose that such project-level agreements are an important, valuable, and flexible model of self-regulation for similar global, large-scale synthetic biology projects in order to maximize the benefits and minimize potential harms. PMID:26272997

  14. Freedom and Responsibility in Synthetic Genomics: The Synthetic Yeast Project.

    PubMed

    Sliva, Anna; Yang, Huanming; Boeke, Jef D; Mathews, Debra J H

    2015-08-01

    First introduced in 2011, the Synthetic Yeast Genome (Sc2.0) PROJECT is a large international synthetic genomics project that will culminate in the first eukaryotic cell (Saccharomyces cerevisiae) with a fully synthetic genome. With collaborators from across the globe and from a range of institutions spanning from do-it-yourself biology (DIYbio) to commercial enterprises, it is important that all scientists working on this project are cognizant of the ethical and policy issues associated with this field of research and operate under a common set of principles. In this commentary, we survey the current ethics and regulatory landscape of synthetic biology and present the Sc2.0 Statement of Ethics and Governance to which all members of the project adhere. This statement focuses on four aspects of the Sc2.0 PROJECT: societal benefit, intellectual property, safety, and self-governance. We propose that such project-level agreements are an important, valuable, and flexible model of self-regulation for similar global, large-scale synthetic biology projects in order to maximize the benefits and minimize potential harms.

  15. Freedom and Responsibility in Synthetic Genomics: The Synthetic Yeast Project

    PubMed Central

    Sliva, Anna; Yang, Huanming; Boeke, Jef D.; Mathews, Debra J. H.

    2015-01-01

    First introduced in 2011, the Synthetic Yeast Genome (Sc2.0) Project is a large international synthetic genomics project that will culminate in the first eukaryotic cell (Saccharomyces cerevisiae) with a fully synthetic genome. With collaborators from across the globe and from a range of institutions spanning from do-it-yourself biology (DIYbio) to commercial enterprises, it is important that all scientists working on this project are cognizant of the ethical and policy issues associated with this field of research and operate under a common set of principles. In this commentary, we survey the current ethics and regulatory landscape of synthetic biology and present the Sc2.0 Statement of Ethics and Governance to which all members of the project adhere. This statement focuses on four aspects of the Sc2.0 Project: societal benefit, intellectual property, safety, and self-governance. We propose that such project-level agreements are an important, valuable, and flexible model of self-regulation for similar global, large-scale synthetic biology projects in order to maximize the benefits and minimize potential harms. PMID:26272997

  16. Shaping the science-industry-policy interface in synthetic biology.

    PubMed

    Gaisser, Sibylle; Reiss, Thomas

    2009-12-01

    Current advances in the emerging field of synthetic biology and the improvements in key technologies promise great impacts, not only on future scientific development, but also on the economy. In this paper we will adopt the triple helix concept for analyzing the early stages of a new field of science and innovation, namely synthetic biology. Synthetic biology is based on the creation and assembly of parts in order to create new and more complex structures and functions. These features of synthetic biology raise questions related to standardization and intellectual property, but also to security and public perception issues that go beyond the classical biotechnology discussions. These issues concern all involved actors in the synthetic biology field and affect the interrelationship between science, industry and policy. Based on the results of the recently finished EU FP-6 funded project TESSY ( http://www.tessy-europe.de ), the article analyzes these issues. Additionally, it illustrates the setting of clear framework conditions for synthetic biology research and development and the identification and definition of common goals for the future development of the field which will be needed for efficient science-industry-policy interaction. It was shown that it will be crucial to develop approaches that consider the needs of science and industry, on the one hand, and comply with the expectations of society, on the other hand. As synthetic biology is a global activity, the involvement of national decision-makers in international initiatives will further stimulate the development of the field. PMID:19816806

  17. Synthetic biology approaches to fluorinated polyketides

    PubMed Central

    Thuronyi, Benjamin W.; Chang, Michelle C. Y.

    2016-01-01

    Conspectus The catalytic diversity of living systems offers a broad range of opportunities for developing new methods to produce small molecule targets such as fuels, materials, and pharmaceuticals. In addition to providing cost-effective and renewable methods for large-scale commercial processes, the exploration of the unusual chemical phenotypes found in living organisms can also enable the expansion of chemical space for discovery of novel function by combining orthogonal attributes from both synthetic and biological chemistry. In this context, we have focused on the development of new fluorine chemistry using synthetic biology approaches. While fluorine has become an important feature in compounds of synthetic origin, the scope of biological fluorine chemistry in living systems is limited, with fewer than 20 organofluorine natural products identified to date. In order to expand the diversity of biosynthetically accessible organofluorines, we have begun to develop methods for the site-selective introduction of fluorine into complex natural products by engineering biosynthetic machinery to incorporate fluorinated building blocks. To gain insight into how both enzyme active sites and metabolic pathways can be evolved to manage and select for fluorinated compounds, we have studied one of the only characterized natural hosts for organofluorine biosynthesis, the soil microbe Streptomyces cattleya. This information provides a template for designing engineered organofluorine enzymes, pathways, and hosts and has allowed us to initiate construction of enzymatic and cellular pathways for the production of fluorinated polyketides. PMID:25719427

  18. Spatiotemporal dynamics of distributed synthetic genetic circuits

    NASA Astrophysics Data System (ADS)

    Kanakov, Oleg; Laptyeva, Tetyana; Tsimring, Lev; Ivanchenko, Mikhail

    2016-04-01

    We propose and study models of two distributed synthetic gene circuits, toggle-switch and oscillator, each split between two cell strains and coupled via quorum-sensing signals. The distributed toggle switch relies on mutual repression of the two strains, and oscillator is comprised of two strains, one of which acts as an activator for another that in turn acts as a repressor. Distributed toggle switch can exhibit mobile fronts, switching the system from the weaker to the stronger spatially homogeneous state. The circuit can also act as a biosensor, with the switching front dynamics determined by the properties of an external signal. Distributed oscillator system displays another biosensor functionality: oscillations emerge once a small amount of one cell strain appears amid the other, present in abundance. Distribution of synthetic gene circuits among multiple strains allows one to reduce crosstalk among different parts of the overall system and also decrease the energetic burden of the synthetic circuit per cell, which may allow for enhanced functionality and viability of engineered cells.

  19. Effects of the Synthetic Neurosteroid

    PubMed Central

    Parésys, Lucie; Hoffmann, Kerstin; Bianchi, Massimiliano; Villey, Isabelle; Baulieu, Etienne-Emile; Fuchs, Eberhard

    2016-01-01

    Background: Most currently available active antidepressant drugs are selective serotonin/noradrenaline reuptake inhibitors. However, as their clinical efficacy is not immediate, long-term administration is often accompanied by substantial side effects, and numerous patients remain non- or partial responders. We have recently found that the synthetic neurosteroid derivative 3β-methoxypregnenolone, which binds to the microtubule-associated protein-2, can provide a novel therapeutic approach in experimental model of depressive disorders in rats. To further validate the antidepressant-like efficacy of 3β-methoxypregnenolone, we investigated effects of a longer treatment (4-week oral administration; 50mg/kg/d) in a nonrodent species, the tree shrew, exposed to psychosocial stress that elicits close-to-human alterations observed in patients with depressive disorders. Methods: During the experimental period, physiological parameters were registered, including core body temperature and electroencephalogram, while animals were videotaped to analyze their avoidance behavior. Morning urine samples were collected for measurements of cortisol and noradrenaline levels. Results: We found that treatment with 3β-methoxypregnenolone abolished stress-triggered avoidance behavior and prevented hormone hypersecretion, hypothermia, and sleep disturbances, further suggesting its antidepressant-like efficacy. Comparative treatment with fluoxetine also prevented some of the physiological alterations, while the hypersecretion of cortisol and sleep disturbances were not or partially restored by fluoxetine, suggesting a better efficacy of 3β-methoxypregnenolone. Alpha-tubulin isoforms were measured in hippocampi: we found that 3β-methoxypregnenolone reversed the specific decrease in acetylation of α-tubulin induced by psychosocial stress, while it did not modify the psychosocial stress-elicited reduction of tyrosinated α-tubulin. Conclusions: Taken together, these data strongly suggest

  20. Control theory meets synthetic biology.

    PubMed

    Del Vecchio, Domitilla; Dy, Aaron J; Qian, Yili

    2016-07-01

    The past several years have witnessed an increased presence of control theoretic concepts in synthetic biology. This review presents an organized summary of how these control design concepts have been applied to tackle a variety of problems faced when building synthetic biomolecular circuits in living cells. In particular, we describe success stories that demonstrate how simple or more elaborate control design methods can be used to make the behaviour of synthetic genetic circuits within a single cell or across a cell population more reliable, predictable and robust to perturbations. The description especially highlights technical challenges that uniquely arise from the need to implement control designs within a new hardware setting, along with implemented or proposed solutions. Some engineering solutions employing complex feedback control schemes are also described, which, however, still require a deeper theoretical analysis of stability, performance and robustness properties. Overall, this paper should help synthetic biologists become familiar with feedback control concepts as they can be used in their application area. At the same time, it should provide some domain knowledge to control theorists who wish to enter the rising and exciting field of synthetic biology. PMID:27440256

  1. Control theory meets synthetic biology.

    PubMed

    Del Vecchio, Domitilla; Dy, Aaron J; Qian, Yili

    2016-07-01

    The past several years have witnessed an increased presence of control theoretic concepts in synthetic biology. This review presents an organized summary of how these control design concepts have been applied to tackle a variety of problems faced when building synthetic biomolecular circuits in living cells. In particular, we describe success stories that demonstrate how simple or more elaborate control design methods can be used to make the behaviour of synthetic genetic circuits within a single cell or across a cell population more reliable, predictable and robust to perturbations. The description especially highlights technical challenges that uniquely arise from the need to implement control designs within a new hardware setting, along with implemented or proposed solutions. Some engineering solutions employing complex feedback control schemes are also described, which, however, still require a deeper theoretical analysis of stability, performance and robustness properties. Overall, this paper should help synthetic biologists become familiar with feedback control concepts as they can be used in their application area. At the same time, it should provide some domain knowledge to control theorists who wish to enter the rising and exciting field of synthetic biology.

  2. Control theory meets synthetic biology

    PubMed Central

    2016-01-01

    The past several years have witnessed an increased presence of control theoretic concepts in synthetic biology. This review presents an organized summary of how these control design concepts have been applied to tackle a variety of problems faced when building synthetic biomolecular circuits in living cells. In particular, we describe success stories that demonstrate how simple or more elaborate control design methods can be used to make the behaviour of synthetic genetic circuits within a single cell or across a cell population more reliable, predictable and robust to perturbations. The description especially highlights technical challenges that uniquely arise from the need to implement control designs within a new hardware setting, along with implemented or proposed solutions. Some engineering solutions employing complex feedback control schemes are also described, which, however, still require a deeper theoretical analysis of stability, performance and robustness properties. Overall, this paper should help synthetic biologists become familiar with feedback control concepts as they can be used in their application area. At the same time, it should provide some domain knowledge to control theorists who wish to enter the rising and exciting field of synthetic biology. PMID:27440256

  3. Content metamorphosis in synthetic holography

    NASA Astrophysics Data System (ADS)

    Desbiens, Jacques

    2013-02-01

    A synthetic hologram is an optical system made of hundreds of images amalgamated in a structure of holographic cells. Each of these images represents a point of view on a three-dimensional space which makes us consider synthetic holography as a multiple points of view perspective system. In the composition of a computer graphics scene for a synthetic hologram, the field of view of the holographic image can be divided into several viewing zones. We can attribute these divisions to any object or image feature independently and operate different transformations on image content. In computer generated holography, we tend to consider content variations as a continuous animation much like a short movie. However, by composing sequential variations of image features in relation with spatial divisions, we can build new narrative forms distinct from linear cinematographic narration. When observers move freely and change their viewing positions, they travel from one field of view division to another. In synthetic holography, metamorphoses of image content are within the observer's path. In all imaging Medias, the transformation of image features in synchronisation with the observer's position is a rare occurrence. However, this is a predominant characteristic of synthetic holography. This paper describes some of my experimental works in the development of metamorphic holographic images.

  4. Meeting Report: Synthetic Biology Jamboree for Undergraduates

    ERIC Educational Resources Information Center

    Campbell, A. Malcolm

    2005-01-01

    The field of synthetic biology (the name is derived from an analogy to synthetic chemistry) has recognized itself as a "field" only since about 2002. Synthetic biology has gotten some high-profile attention recently, but most people are not aware the field even exists. Synthetic biologists apply engineering principles to genomic circuits to…

  5. [How to be prudent with synthetic biology. Synthetic Biology and the precautionary principle].

    PubMed

    Rodríguez López, Blanca

    2014-01-01

    Synthetic biology is a new discipline that is twofold: firstly it offers the promise to pay benefits that can alleviate some of the ills that plague mankind; On the other hand, like all technologies, holds risks. Given these, the most critical and concerned about the risks, invoke the application of the precautionary principle, common in cases where an activity or new technology creates risks to the environment and/or human health, but far from universally accepted happens to be currently one of the most controversial principles. In this paper the question of the risks and benefits of synthetic biology and the relevance of applying the precautionary principle are analyzed. To do this we proceed as follows. The first part focuses on synthetic biology. At first, this discipline is characterized, with special attention to what is novel compared to the known as "genetic engineering". In the second stage both the benefits and the risks associated with it are discussed. The first part concludes with a review of the efforts currently being made to control or minimize the risks. The second part aims to analyze the precautionary principle and its possible relevance to the case of Synthetic Biology. At first, the different versions and interpretations of the principle and the various criticisms of which has been the subject are reviewed. Finally, after discarding the Precautionary Principle as an useful tool, it is seen as more appropriate some recent proposals to treat technologies that take into account not only risks but also their benefits. PMID:25845210

  6. [How to be prudent with synthetic biology. Synthetic Biology and the precautionary principle].

    PubMed

    Rodríguez López, Blanca

    2014-01-01

    Synthetic biology is a new discipline that is twofold: firstly it offers the promise to pay benefits that can alleviate some of the ills that plague mankind; On the other hand, like all technologies, holds risks. Given these, the most critical and concerned about the risks, invoke the application of the precautionary principle, common in cases where an activity or new technology creates risks to the environment and/or human health, but far from universally accepted happens to be currently one of the most controversial principles. In this paper the question of the risks and benefits of synthetic biology and the relevance of applying the precautionary principle are analyzed. To do this we proceed as follows. The first part focuses on synthetic biology. At first, this discipline is characterized, with special attention to what is novel compared to the known as "genetic engineering". In the second stage both the benefits and the risks associated with it are discussed. The first part concludes with a review of the efforts currently being made to control or minimize the risks. The second part aims to analyze the precautionary principle and its possible relevance to the case of Synthetic Biology. At first, the different versions and interpretations of the principle and the various criticisms of which has been the subject are reviewed. Finally, after discarding the Precautionary Principle as an useful tool, it is seen as more appropriate some recent proposals to treat technologies that take into account not only risks but also their benefits.

  7. Advanced high performance vertical hybrid synthetic jet actuator

    NASA Technical Reports Server (NTRS)

    Xu, Tian-Bing (Inventor); Jiang, Xiaoning (Inventor); Su, Ji (Inventor)

    2011-01-01

    The present invention comprises a high performance, vertical, zero-net mass-flux, synthetic jet actuator for active control of viscous, separated flow on subsonic and supersonic vehicles. The present invention is a vertical piezoelectric hybrid zero-net mass-flux actuator, in which all the walls of the chamber are electrically controlled synergistically to reduce or enlarge the volume of the synthetic jet actuator chamber in three dimensions simultaneously and to reduce or enlarge the diameter of orifice of the synthetic jet actuator simultaneously with the reduction or enlargement of the volume of the chamber. The jet velocity and mass flow rate for the present invention will be several times higher than conventional piezoelectric synthetic jet actuators.

  8. Synthetic biology: An emerging research field in China

    PubMed Central

    Pei, Lei; Schmidt, Markus; Wei, Wei

    2011-01-01

    Synthetic biology is considered as an emerging research field that will bring new opportunities to biotechnology. There is an expectation that synthetic biology will not only enhance knowledge in basic science, but will also have great potential for practical applications. Synthetic biology is still in an early developmental stage in China. We provide here a review of current Chinese research activities in synthetic biology and its different subfields, such as research on genetic circuits, minimal genomes, chemical synthetic biology, protocells and DNA synthesis, using literature reviews and personal communications with Chinese researchers. To meet the increasing demand for a sustainable development, research on genetic circuits to harness biomass is the most pursed research within Chinese researchers. The environmental concerns are driven force of research on the genetic circuits for bioremediation. The research on minimal genomes is carried on identifying the smallest number of genomes needed for engineering minimal cell factories and research on chemical synthetic biology is focused on artificial proteins and expanded genetic code. The research on protocells is more in combination with the research on molecular-scale motors. The research on DNA synthesis and its commercialisation are also reviewed. As for the perspective on potential future Chinese R&D activities, it will be discussed based on the research capacity and governmental policy. PMID:21729747

  9. Designer Drugs: A Synthetic Catastrophe

    PubMed Central

    Fratantonio, James; Andrade, Lawrence; Febo, Marcelo

    2016-01-01

    Synthetic stimulants can cause hallucinations, aggressive behaviors, death and are sometimes legal. These substances are sold as plant food and bath salts that are “Not for Human Consumption”, therefore skirting the 1986 Federal Analogue Act and giving a false pretense of safety. Studies have proved that these substances are toxic, have a high abuse potential, and are becoming extremely prevalent in the United States. This creates a dilemma for law enforcement agents, hospitals, and substance use disorder treatment centers. Urine Drug Testing is utilized as a clinical diagnostic tool in substance use disorder treatment centers, and the furious pace at which new synthetic stimulants are introduced to the black market are making the detection via urine increasingly difficult. This article will discuss the prevalence, pharmacology and difficulty developing laboratory assays to detect synthetic stimulants. PMID:27617301

  10. Synthetic Peptides as Protein Mimics

    PubMed Central

    Groß, Andrea; Hashimoto, Chie; Sticht, Heinrich; Eichler, Jutta

    2016-01-01

    The design and generation of molecules capable of mimicking the binding and/or functional sites of proteins represents a promising strategy for the exploration and modulation of protein function through controlled interference with the underlying molecular interactions. Synthetic peptides have proven an excellent type of molecule for the mimicry of protein sites because such peptides can be generated as exact copies of protein fragments, as well as in diverse chemical modifications, which includes the incorporation of a large range of non-proteinogenic amino acids as well as the modification of the peptide backbone. Apart from extending the chemical and structural diversity presented by peptides, such modifications also increase the proteolytic stability of the molecules, enhancing their utility for biological applications. This article reviews recent advances by this and other laboratories in the use of synthetic protein mimics to modulate protein function, as well as to provide building blocks for synthetic biology. PMID:26835447

  11. Differential Optical Synthetic Aperture Radar

    DOEpatents

    Stappaerts, Eddy A.

    2005-04-12

    A new differential technique for forming optical images using a synthetic aperture is introduced. This differential technique utilizes a single aperture to obtain unique (N) phases that can be processed to produce a synthetic aperture image at points along a trajectory. This is accomplished by dividing the aperture into two equal "subapertures", each having a width that is less than the actual aperture, along the direction of flight. As the platform flies along a given trajectory, a source illuminates objects and the two subapertures are configured to collect return signals. The techniques of the invention is designed to cancel common-mode errors, trajectory deviations from a straight line, and laser phase noise to provide the set of resultant (N) phases that can produce an image having a spatial resolution corresponding to a synthetic aperture.

  12. A novel synthetic C-1 analogue of 7-deoxypancratistatin induces apoptosis in p53 positive and negative human colorectal cancer cells by targeting the mitochondria: enhancement of activity by tamoxifen.

    PubMed

    Ma, Dennis; Tremblay, Phillip; Mahngar, Kevinjeet; Akbari-Asl, Pardis; Collins, Jonathan; Hudlicky, Tomas; McNulty, James; Pandey, Siyaram

    2012-06-01

    The natural compound pancratistatin (PST), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines. Unlike many other chemotherapeutics, PST is not genotoxic and has minimal adverse effects on non-cancerous cells. However, its availability for preclinical and clinical work is limited due to its low availability in its natural source and difficulties in its chemical synthesis. Several synthetic analogues of 7-deoxypancratistatin with different modifications at C-1 were synthesized and screened for apoptosis inducing activity in human colorectal cancer (CRC) cells. We found that a C-1 acetoxymethyl derivative of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), was effective in inducing apoptosis in both p53 positive (HCT 116) and p53 negative (HT-29) human CRC cell lines, demonstrating similar efficacy to that of natural PST. JCTH-4 was able to decrease mitochondrial membrane potential (MMP), increase levels of reactive oxygen species in isolated mitochondria, cause release of the apoptogenic factor cytochrome c (Cyto c) from isolated mitochondria, and induce autophagy in HCT 116 and HT-29 cells. Interestingly, when JCTH-4 was administered with tamoxifen (TAM), there was an enhanced effect in apoptosis induction, reactive oxygen species (ROS) production and Cyto c release by isolated mitochondria, and autophagic induction by CRC cells. Minimal toxicity was exhibited by a normal human fetal fibroblast (NFF) and a normal colon fibroblast (CCD-18Co) cell line. Hence, JCTH-4 is a novel compound capable of selectively inducing apoptosis and autophagy in CRC cells alone and in combination with TAM and may serve as a safer and more effective alternative to current cancer therapies. PMID:21494837

  13. US Competitiveness in Synthetic Biology.

    PubMed

    Gronvall, Gigi Kwik

    2015-01-01

    Synthetic biology is an emerging technical field that aims to make biology easier to engineer; the field has applications in strategically important sectors for the US economy. While the United States currently leads in synthetic biology R&D, other nations are heavily investing in order to boost their economies, which will inevitably diminish the US leadership position. This outcome is not entirely negative--additional investments will expand markets--but it is critical that the US government take steps to remain competitive: There are applications from which the US population and economy may benefit; there are specific applications with importance for national defense; and US technical leadership will ensure that US experts have a leading role in synthetic biology governance, regulation, and oversight. Measures to increase competitiveness in S&T generally are broadly applicable for synthetic biology and should be pursued. However, the US government will also need to take action on fundamental issues that will affect the field's development, such as countering anti-GMO (genetically modified organism) sentiments and anti-GMO legislation. The United States should maintain its regulatory approach so that it is the product that is regulated, not the method used to create a product. At the same time, the United States needs to ensure that the regulatory framework is updated so that synthetic biology products do not fall into regulatory gaps. Finally, the United States needs to pay close attention to how synthetic biology applications may be governed internationally, such as through the Nagoya Protocol of the Convention on Biological Diversity, so that beneficial applications may be realized. PMID:26690379

  14. US Competitiveness in Synthetic Biology.

    PubMed

    Gronvall, Gigi Kwik

    2015-01-01

    Synthetic biology is an emerging technical field that aims to make biology easier to engineer; the field has applications in strategically important sectors for the US economy. While the United States currently leads in synthetic biology R&D, other nations are heavily investing in order to boost their economies, which will inevitably diminish the US leadership position. This outcome is not entirely negative--additional investments will expand markets--but it is critical that the US government take steps to remain competitive: There are applications from which the US population and economy may benefit; there are specific applications with importance for national defense; and US technical leadership will ensure that US experts have a leading role in synthetic biology governance, regulation, and oversight. Measures to increase competitiveness in S&T generally are broadly applicable for synthetic biology and should be pursued. However, the US government will also need to take action on fundamental issues that will affect the field's development, such as countering anti-GMO (genetically modified organism) sentiments and anti-GMO legislation. The United States should maintain its regulatory approach so that it is the product that is regulated, not the method used to create a product. At the same time, the United States needs to ensure that the regulatory framework is updated so that synthetic biology products do not fall into regulatory gaps. Finally, the United States needs to pay close attention to how synthetic biology applications may be governed internationally, such as through the Nagoya Protocol of the Convention on Biological Diversity, so that beneficial applications may be realized.

  15. The design of synthetic genes.

    PubMed Central

    Presnell, S R; Benner, S A

    1988-01-01

    Computer programs are described that aid in the design of synthetic genes coding for proteins that are targets of a research program in site directed mutagenesis. These programs "reverse-translate" protein sequences into general nucleic acid sequences (those where codons have not yet been selected), map restriction sites into general DNA sequences, identify points in the synthetic gene where unique restriction sites can be introduced, and assist in the design of genes coding for hybrids and evolutionary intermediates between homologous proteins. Application of these programs therefore facilitates the use of modular mutagenesis to create variants of proteins, and the implementation of evolutionary guidance as a strategy for selecting mutants. PMID:2451218

  16. The Case for Synthetic Injectables.

    PubMed

    Joseph, John H

    2015-11-01

    There are several different classes of synthetic dermal fillers and volume enhancers including semipermanent and permanent products available in the United States. Based on clinical and scientific evidence, this article reviews the chemical and polymeric properties, clinical data, patient selection, indications for use, injection technique, and adverse event profiles of permanent synthetic injectables currently used in clinical practice in the United States: medical-grade liquid injectable silicone and polymethyl methacrylate. Understanding the unique characteristics of these two products reinforces the advantages and disadvantages of each, including under what circumstances they should be used and why they perform the way they do. PMID:26505540

  17. The Case for Synthetic Injectables.

    PubMed

    Joseph, John H

    2015-11-01

    There are several different classes of synthetic dermal fillers and volume enhancers including semipermanent and permanent products available in the United States. Based on clinical and scientific evidence, this article reviews the chemical and polymeric properties, clinical data, patient selection, indications for use, injection technique, and adverse event profiles of permanent synthetic injectables currently used in clinical practice in the United States: medical-grade liquid injectable silicone and polymethyl methacrylate. Understanding the unique characteristics of these two products reinforces the advantages and disadvantages of each, including under what circumstances they should be used and why they perform the way they do.

  18. Synthetic Phage for Tissue Regeneration

    PubMed Central

    Merzlyak, Anna; Lee, Seung-Wuk

    2014-01-01

    Controlling structural organization and signaling motif display is of great importance to design the functional tissue regenerating materials. Synthetic phage, genetically engineered M13 bacteriophage has been recently introduced as novel tissue regeneration materials to display a high density of cell-signaling peptides on their major coat proteins for tissue regeneration purposes. Structural advantages of their long-rod shape and monodispersity can be taken together to construct nanofibrous scaffolds which support cell proliferation and differentiation as well as direct orientation of their growth in two or three dimensions. This review demonstrated how functional synthetic phage is designed and subsequently utilized for tissue regeneration that offers potential cell therapy. PMID:24991085

  19. Transfer of Instrument Training and the Synthetic Flight Training System.

    ERIC Educational Resources Information Center

    Caro, Paul W.

    One phase of an innovative flight training program, its development, and initial administration is described in this paper. The operational suitability test activities related to a determination of the transfer of instrument training value of the Army's Synthetic Flight Training System (SFTS) Device 2B24. Sixteen active Army members of an Officer…

  20. Methods for preparing synthetic freshwaters.

    PubMed

    Smith, E J; Davison, W; Hamilton-Taylor, J

    2002-03-01

    Synthetic solutions that emulate the major ion compositions of natural waters are useful in experiments aimed at understanding biogeochemical processes. Standard recipes exist for preparing synthetic analogues of seawater, with its relatively constant composition, but, due to the diversity of freshwaters, a range of compositions and recipes is required. Generic protocols are developed for preparing synthetic freshwaters of any desired composition. The major problems encountered in preparing hard and soft waters include dissolving sparingly soluble calcium carbonate, ensuring that the ionic components of each concentrated stock solution cannot form an insoluble salt and dealing with the supersaturation of calcium carbonate in many hard waters. For acidic waters the poor solubility of aluminium salts requires attention. These problems are overcome by preparing concentrated stock solutions according to carefully designed reaction paths that were tested using a combination of experiment and equilibrium modeling. These stock solutions must then be added in a prescribed order to prepare a final solution that is brought into equilibrium with the atmosphere. The example calculations for preparing hard, soft and acidic freshwater surrogates with major ion compositions the same as published analyses, are presented in a generalized fashion that should allow preparation of any synthetic freshwater according to its known analysis. PMID:11902783

  1. Digital 'faces' of synthetic biology.

    PubMed

    Friedrich, Kathrin

    2013-06-01

    In silicio design plays a fundamental role in the endeavour to synthesise biological systems. In particular, computer-aided design software enables users to manage the complexity of biological entities that is connected to their construction and reconfiguration. The software's graphical user interface bridges the gap between the machine-readable data on the algorithmic subface of the computer and its human-amenable surface represented by standardised diagrammatic elements. Notations like the Systems Biology Graphical Notation (SBGN), together with interactive operations such as drag & drop, allow the user to visually design and simulate synthetic systems as 'bio-algorithmic signs'. Finally, the digital programming process should be extended to the wet lab to manufacture the designed synthetic biological systems. By exploring the different 'faces' of synthetic biology, I argue that in particular computer-aided design (CAD) is pushing the idea to automatically produce de novo objects. Multifaceted software processes serve mutually aesthetic, epistemic and performative purposes by simultaneously black-boxing and bridging different data sources, experimental operations and community-wide standards. So far, synthetic biology is mainly a product of digital media technologies that structurally mimic the epistemological challenge to take both qualitative as well as quantitative aspects of biological systems into account in order to understand and produce new and functional entities.

  2. Synthetic Division and Matrix Factorization

    ERIC Educational Resources Information Center

    Barabe, Samuel; Dubeau, Franc

    2007-01-01

    Synthetic division is viewed as a change of basis for polynomials written under the Newton form. Then, the transition matrices obtained from a sequence of changes of basis are used to factorize the inverse of a bidiagonal matrix or a block bidiagonal matrix.

  3. Synthetic biology meets tissue engineering.

    PubMed

    Davies, Jamie A; Cachat, Elise

    2016-06-15

    Classical tissue engineering is aimed mainly at producing anatomically and physiologically realistic replacements for normal human tissues. It is done either by encouraging cellular colonization of manufactured matrices or cellular recolonization of decellularized natural extracellular matrices from donor organs, or by allowing cells to self-organize into organs as they do during fetal life. For repair of normal bodies, this will be adequate but there are reasons for making unusual, non-evolved tissues (repair of unusual bodies, interface to electromechanical prostheses, incorporating living cells into life-support machines). Synthetic biology is aimed mainly at engineering cells so that they can perform custom functions: applying synthetic biological approaches to tissue engineering may be one way of engineering custom structures. In this article, we outline the 'embryological cycle' of patterning, differentiation and morphogenesis and review progress that has been made in constructing synthetic biological systems to reproduce these processes in new ways. The state-of-the-art remains a long way from making truly synthetic tissues, but there are now at least foundations for future work. PMID:27284030

  4. SEASAT Synthetic Aperture Radar Data

    NASA Technical Reports Server (NTRS)

    Henderson, F. M.

    1981-01-01

    The potential of radar imagery from space altitudes is discussed and the advantages of radar over passive sensor systems are outlined. Specific reference is made to the SEASAT synthetic aperture radar. Possible applications include oil spill monitoring, snow and ice reconnaissance, mineral exploration, and monitoring phenomena in the urban environment.

  5. Synthetic substrates for enzyme analysis

    DOEpatents

    Bissell, E.R.; Mitchell, A.R.; Pearson, K.W.; Smith, R.E.

    1983-06-14

    Synthetic substrates are provided which may be represented as A-D. The A moiety includes an amino acid, polypeptide, or derivative. The D moiety includes 7-amino coumarin derivatives having an electron withdrawing substituent group at the 3 position carbon or fused between the 3 and 4 position carbons. No Drawings

  6. Synthetic substrates for enzyme analysis

    DOEpatents

    Bissell, Eugene R.; Mitchell, Alexander R.; Pearson, Karen W.; Smith, Robert E.

    1983-01-01

    Synthetic substrates are provided which may be represented as A-D. The A moiety thereof includes an amino acid, polypeptide, or derivative thereof. The D moiety thereof includes 7-amino coumarin derivatives having an electron withdrawing substituent group at the 3 position carbon or fused between the 3 and 4 position carbons.

  7. The synthetic biology open language.

    PubMed

    Myers, Chris; Clancy, Kevin; Misirli, Goksel; Oberortner, Ernst; Pocock, Matthew; Quinn, Jacqueline; Roehner, Nicholas; Sauro, Herbert M

    2015-01-01

    The design and construction of engineered organisms is an emerging new discipline called synthetic biology and holds considerable promise as a new technological platform. The design of biologically engineered systems is however nontrivial, requiring contributions from a wide array of disciplines. One particular issue that confronts synthetic biologists is the ability to unambiguously describe novel designs such that they can be reengineered by a third-party. For this reason, the synthetic biology open language (SBOL) was developed as a community wide standard for formally representing biological designs. A design created by one engineering team can be transmitted electronically to another who can then use this design to reproduce the experimental results. The development and the community of the SBOL standard started in 2008 and has since grown in use with now over 80 participants, including international, academic, and industrial interests. SBOL has stimulated the development of repositories and software tools to help synthetic biologists in their design efforts. This chapter summarizes the latest developments and future of the SBOL standard and its supporting infrastructure.

  8. Relative potency estimation for synthetic petroleum skin carcinogens.

    PubMed Central

    Holland, J M; Wolf, D A; Clark, B R

    1981-01-01

    A procedure for quantitative analysis of skin carcinogenesis data, for the purpose of establishing carcinogenic potency, has been applied to observations obtained from C3H mice exposed continuously to synthetic and natural petroleums. The importance of total polynuclear aromatic (PNA) content to the skin carcinogenic activity of the crude materials was also examined. Of three synthetic petroleums evaluated, all were shown capable of inducing skin neoplasms within a two-year exposure period. Under comparable exposure conditions a composite sample of five natural petroleums was noncarcinogenic. Comparison of the distributions of times to initial skin neoplasm versus dose rate, for groups exposed to synthetic fossil liquids and the reference skin carcinogen, benzo(a)pyrene, provided estimates of relative carcinotenic potency for the synthetic petroleums ranging from 1/500 to 1/1400 the potency of benzo(a)pyrene. The carcinogenic activity of a chemically isolated PNA fraction versus the crude from which it was derived suggested that this fraction was responsible for the carcinogenic activity of these synthetic petroleums in mouse skin. PMID:7238444

  9. Effects of synthetic sphingosine-1-phosphate analogs on cytosolic phospholipase A2alpha-independent release of arachidonic acid and cell toxicity in L929 fibrosarcoma cells: the structure-activity relationship.

    PubMed

    Shimizu, Masaya; Muramatsu, Yuki; Tada, Eiko; Kurosawa, Takeshi; Yamaura, Erika; Nakamura, Hiroyuki; Fujino, Hiromichi; Houjyo, Yuuya; Miyasaka, Yuri; Koide, Yuuki; Nishida, Atsushi; Murayama, Toshihiko

    2009-03-01

    Sphingolipid metabolites including ceramide, sphingosine, and their phosphorylated products [sphingosine-1-phosphate (S1P) and ceramide-1-phosphate] regulate cell functions including arachidonic acid (AA) metabolism and cell death. The development of analogs of S1P may be useful for regulating these mediator-induced cellular responses. We synthesized new analogs of S1P and examined their effects on the release of AA and cell death in L929 mouse fibrosarcoma cells. Among the analogs tested, several compounds including DMB-mC11S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMB-mC9S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-nonyl)phenylpropyl phosphate] released AA within 1 h and caused cell death 6 h after treatment. The release of AA was observed in C12 cells [a L929 variant lacking a type alpha cytosolic phospholipase A(2) (cPLA(2)alpha)] and L929-cPLAalpha-siRNA cells (L929 cells treated with small interference RNA for cPLA(2)alpha). Treatment with pharmacological inhibitors of secretory and Ca(2+)-independent PLA(2)s decreased the DMB-mC11S-induced release of AA. The effect of the S1P analogs tested on the release of AA was comparable to that on cell death in L929 cells, and a high correlation coefficient was observed. Two analogs lacking a butoxycarbonyl moiety [DMAc-mC11S (dimethyl (2S,3R)-2-acetamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMAm-mC11S [dimethyl (2S,3R)-2-amino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate)] had inhibitory effects on the release of AA and cell toxicity induced by DMB-mC11S. Synthetic phosphorylated lipid analogs may be useful for studying PLA(2) activity and its toxicity in cells. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08284FP].

  10. Synthetic Metal-Containing Polymers

    NASA Astrophysics Data System (ADS)

    Manners, Ian

    2004-04-01

    The development of the field of synthetic metal-containing polymers - where metal atoms form an integral part of the main chain or side group structure of a polymer - aims to create new materials which combine the processability of organic polymers with the physical or chemical characteristics associated with the metallic element or complex. This book covers the major developments in the synthesis, properties, and applications of synthetic metal-containing macromolecules, and includes chapters on the preparation and characterization of metal-containing polymers, metallocene-based polymers, rigid-rod organometallic polymers, coordination polymers, polymers containing main group metals, and also covers dendritic and supramolecular systems. The book describes both polymeric materials with metals in the main chain or side group structure and covers the literature up to the end of 2002.

  11. DNA recognition by synthetic constructs.

    PubMed

    Pazos, Elena; Mosquera, Jesús; Vázquez, M Eugenio; Mascareñas, José L

    2011-09-01

    The interaction of transcription factors with specific DNA sites is key for the regulation of gene expression. Despite the availability of a large body of structural data on protein-DNA complexes, we are still far from fully understanding the molecular and biophysical bases underlying such interactions. Therefore, the development of non-natural agents that can reproduce the DNA-recognition properties of natural transcription factors remains a major and challenging goal in chemical biology. In this review we summarize the basics of double-stranded DNA recognition by transcription factors, and describe recent developments in the design and preparation of synthetic DNA binders. We mainly focus on synthetic peptides that have been designed by following the DNA interaction of natural proteins, and we discuss how the tools of organic synthesis can be used to make artificial constructs equipped with functionalities that introduce additional properties to the recognition process, such as sensing and controllability.

  12. Synthetic microbial ecosystems for biotechnology.

    PubMed

    Pandhal, Jagroop; Noirel, Josselin

    2014-06-01

    Most highly controlled and specific applications of microorganisms in biotechnology involve pure cultures. Maintaining single strain cultures is important for industry as contaminants can reduce productivity and lead to longer "down-times" during sterilisation. However, microbes working together provide distinct advantages over pure cultures. They can undertake more metabolically complex tasks, improve efficiency and even expand applications to open systems. By combining rapidly advancing technologies with ecological theory, the use of microbial ecosystems in biotechnology will inevitably increase. This review provides insight into the use of synthetic microbial communities in biotechnology by applying the engineering paradigm of measure, model, manipulate and manufacture, and illustrate the emerging wider potential of the synthetic ecology field. Systems to improve biofuel production using microalgae are also discussed.

  13. Engineering key components in a synthetic eukaryotic signal transduction pathway

    PubMed Central

    Antunes, Mauricio S; Morey, Kevin J; Tewari-Singh, Neera; Bowen, Tessa A; Smith, J Jeff; Webb, Colleen T; Hellinga, Homme W; Medford, June I

    2009-01-01

    Signal transduction underlies how living organisms detect and respond to stimuli. A goal of synthetic biology is to rewire natural signal transduction systems. Bacteria, yeast, and plants sense environmental aspects through conserved histidine kinase (HK) signal transduction systems. HK protein components are typically comprised of multiple, relatively modular, and conserved domains. Phosphate transfer between these components may exhibit considerable cross talk between the otherwise apparently linear pathways, thereby establishing networks that integrate multiple signals. We show that sequence conservation and cross talk can extend across kingdoms and can be exploited to produce a synthetic plant signal transduction system. In response to HK cross talk, heterologously expressed bacterial response regulators, PhoB and OmpR, translocate to the nucleus on HK activation. Using this discovery, combined with modification of PhoB (PhoB-VP64), we produced a key component of a eukaryotic synthetic signal transduction pathway. In response to exogenous cytokinin, PhoB-VP64 translocates to the nucleus, binds a synthetic PlantPho promoter, and activates gene expression. These results show that conserved-signaling components can be used across kingdoms and adapted to produce synthetic eukaryotic signal transduction pathways. PMID:19455134

  14. Cell microencapsulation with synthetic polymers

    PubMed Central

    Olabisi, Ronke M

    2015-01-01

    The encapsulation of cells into polymeric microspheres or microcapsules has permitted the transplantation of cells into human and animal subjects without the need for immunosuppressants. Cell-based therapies use donor cells to provide sustained release of a therapeutic product, such as insulin, and have shown promise in treating a variety of diseases. Immunoisolation of these cells via microencapsulation is a hotly investigated field, and the preferred material of choice has been alginate, a natural polymer derived from seaweed due to its gelling conditions. Although many natural polymers tend to gel in conditions favorable to mammalian cell encapsulation, there remain challenges such as batch to batch variability and residual components from the original source that can lead to an immune response when implanted into a recipient. Synthetic materials have the potential to avoid these issues; however, historically they have required harsh polymerization conditions that are not favorable to mammalian cells. As research into microencapsulation grows, more investigators are exploring methods to microencapsulate cells into synthetic polymers. This review describes a variety of synthetic polymers used to microencapsulate cells. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 846–859, 2015. PMID:24771675

  15. Hydrogen speciation in synthetic quartz

    USGS Publications Warehouse

    Aines, R.D.; Kirby, S.H.; Rossman, G.R.

    1984-01-01

    The dominant hydrogen impurity in synthetic quartz is molecular H2O. H-OH groups also occur, but there is no direct evidence for the hydrolysis of Si-O-Si bonds to yield Si-OH HO-Si groups. Molecular H2O concentrations in the synthetic quartz crystals studied range from less than 10 to 3,300 ppm (H/Si), and decrease smoothly by up to an order of magnitude with distance away from the seed. OH- concentrations range from 96 to 715 ppm, and rise smoothly with distance away from the seed by up to a factor of three. The observed OH- is probably all associated with cationic impurities, as in natural quartz. Molecular H2O is the dominant initial hydrogen impurity in weak quartz. The hydrolytic weakening of quartz may be caused by the transformation H2O + Si-O-Si ??? 2SiOH, but this may be a transitory change with the SiOH groups recombining to form H2O, and the average SiOH concentration remaining very low. Synthetic quartz is strengthened when the H2O is accumulated into fluid inclusions and cannot react with the quartz framework. ?? 1984 Springer-Verlag.

  16. Nano-enabled synthetic biology

    PubMed Central

    Doktycz, Mitchel J; Simpson, Michael L

    2007-01-01

    Biological systems display a functional diversity, density and efficiency that make them a paradigm for synthetic systems. In natural systems, the cell is the elemental unit and efforts to emulate cells, their components, and organization have relied primarily on the use of bioorganic materials. Impressive advances have been made towards assembling simple genetic systems within cellular scale containers. These biological system assembly efforts are particularly instructive, as we gain command over the directed synthesis and assembly of synthetic nanoscale structures. Advances in nanoscale fabrication, assembly, and characterization are providing the tools and materials for characterizing and emulating the smallest scale features of biology. Further, they are revealing unique physical properties that emerge at the nanoscale. Realizing these properties in useful ways will require attention to the assembly of these nanoscale components. Attention to systems biology principles can lead to the practical development of nanoscale technologies with possible realization of synthetic systems with cell-like complexity. In turn, useful tools for interpreting biological complexity and for interfacing to biological processes will result. PMID:17625513

  17. Synthetic metabolons for metabolic engineering.

    PubMed

    Singleton, Chloe; Howard, Thomas P; Smirnoff, Nicholas

    2014-05-01

    It has been proposed that enzymes can associate into complexes (metabolons) that increase the efficiency of metabolic pathways by channelling substrates between enzymes. Metabolons may increase flux by increasing the local concentration of intermediates, decreasing the concentration of enzymes needed to maintain a given flux, directing the products of a pathway to a specific subcellular location or minimizing the escape of reactive intermediates. Metabolons can be formed by relatively loose non-covalent protein-protein interaction, anchorage to membranes, and (in bacteria) by encapsulation of enzymes in protein-coated microcompartments. Evidence that non-coated metabolons are effective at channelling substrates is scarce and difficult to obtain. In plants there is strong evidence that small proportions of glycolytic enzymes are associated with the outside of mitochondria and are effective in substrate channelling. More recently, synthetic metabolons, in which enzymes are scaffolded to synthetic proteins or nucleic acids, have been expressed in microorganisms and these provide evidence that scaffolded enzymes are more effective than free enzymes for metabolic engineering. This provides experimental evidence that metabolons may have a general advantage and opens the way to improving the outcome of metabolic engineering in plants by including synthetic metabolons in the toolbox.

  18. Synthetic biology with RNA motifs.

    PubMed

    Saito, Hirohide; Inoue, Tan

    2009-02-01

    Structural motifs in naturally occurring RNAs and RNPs can be employed as new molecular parts for synthetic biology to facilitate the development of novel devices and systems that modulate cellular functions. In this review, we focus on the following: (i) experimental evolution techniques of RNA molecules in vitro and (ii) their applications for regulating gene expression systems in vivo. For experimental evolution, new artificial RNA aptamers and RNA enzymes (ribozymes) have been selected in vitro. These functional RNA molecules are likely to be applicable in the reprogramming of existing gene regulatory systems. Furthermore, they may be used for designing hypothetical RNA-based living systems in the so-called RNA world. For the regulation of gene expressions in living cells, the development of new riboswitches allows us to modulate the target gene expression in a tailor-made manner. Moreover, recently RNA-based synthetic genetic circuits have been reported by employing functional RNA molecules, expanding the repertory of synthetic biology with RNA motifs. PMID:18775792

  19. Synthetic LDL as targeted drug delivery vehicle

    DOEpatents

    Forte, Trudy M.; Nikanjam, Mina

    2012-08-28

    The present invention provides a synthetic LDL nanoparticle comprising a lipid moiety and a synthetic chimeric peptide so as to be capable of binding the LDL receptor. The synthetic LDL nanoparticle of the present invention is capable of incorporating and targeting therapeutics to cells expressing the LDL receptor for diseases associated with the expression of the LDL receptor such as central nervous system diseases. The invention further provides methods of using such synthetic LDL nanoparticles.

  20. 21 CFR 175.250 - Paraffin (synthetic).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Paraffin (synthetic). 175.250 Section 175.250 Food....250 Paraffin (synthetic). Synthetic paraffin may be safely used as an impregnant in, coating on, or... catalytically converted to a mixture of paraffin hydrocarbons. Lower molecular-weight fractions are removed...