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51.
Lakshmi Ganapathi Simon Van Haren David J. Dowling Ilana Bergelson Nikunj M. Shukla Subbalakshmi S. Malladi Rajalakshmi Balakrishna Hiromi Tanji Umeharu Ohto Toshiyuki Shimizu Sunil A. David Ofer Levy 《PloS one》2015,10(8)
Background
Newborns and young infants are at higher risk for infections than adults, and manifest suboptimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848).Methods
TLRA-induced NF-κB activation was measured in TLR-transfected HEK cells. Cytokine production in human newborn cord and adult peripheral blood and in monocyte-derived dendritic cell cultures were measured by ELISA and multiplex assays. X-ray crystallography characterized the interaction of human TLR8 with Hybrid-2.Results
Hybrid-2 selectively activated both TLR7 and 8 and was more potent than R848 in inducing adult-like levels of TNF-α, and IL-1β. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxymethyl substituent, which can engage in unfavorable electrostatic and/or dipolar interactions with the carbonyl oxygen of Gly572 in human TLR8, may confer greater efficacy and potency compared to R848.Conclusions
Hybrid-2 is a selective and potent TLR7/8 agonist that is a candidate adjuvant for early life immunization. 相似文献52.
N. Kent Dalley Charles R. Petrie III Ganapathi R. Revankar Roland K. Robins 《Nucleosides, nucleotides & nucleic acids》2013,32(5):651-659
Abstract 2-β-D-Ribofuranosylthiazole-4-carboxamide-N3-oxide (3) has been prepared by oxidation of tiazofurin (2) with hydrogen peroxide in the presence of trifluoroacetic acid. The absolute structure of 3 has been determined by X-ray diffraction techniques employing Mo Kα radiation. The thiazole ring in 3 is planar and the glycon moiety is in the 3E configuration. The N3-C4 bond in 3 is significantly larger (1.412 Å) than that found in tiazofurin (1.376 Å). Similar to tiazofurin, the S…04’ intramolecular contact distance is considerably shorter than the sum of the van der Waals radii, which favors the anti conformation of 3. 相似文献
53.
Naeem B. Hanna Krishna G. Upadhya Charles R. Petrie Roland K. Robins Ganapathi R. Revankar 《Nucleosides, nucleotides & nucleic acids》2013,32(4):343-362
Abstract The synthesis of several 5′-substituted derivatives of ribavirin (1) and tiazofurin (3) are described. Direct acylation of 1 with the appropriate acyl chloride in pyridine-DMF gave the corresponding 5′-O-acyl derivatives (4a-h). Tosylation of the 2′, 3′-O-isopropylidene-ribavirin (6) and tiazofurin (11) with p-toluenesulfonyl chloride gave the respective 5′-O-p-tolylsulfonyl derivatives (7a and 12a), which were converted to 5′-azido-5′-deoxy derivatives (7b and 12b) by reacting with sodium/lithium azide. Deisopropylidenation of 7b and 12b, followed by catalytic hydrogenation afforded 1-(5-amino-5-deoxy-β-D)-ribofuranosyl)-1, 2, 4-triazole-3-carboxamide (10b) and 2 - (5 -amino- 5-deoxy- β-D-ribofuranosyl) thiazole-4-carboxamide (16), respectively. Treatment of 6 with phthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate furnished the corresponding 5′-deoxy-5′-phthaloylamino derivative (9). Reaction of 9 with n-butylamine and subsequent deisopropylidenation provided yet another route to 10b. Selective 5′-thioacetylation of 6 and 11 with thiolacetic acid, followed by saponification and deisopropylidenation afforded 5′-deoxy-5′-thio derivatives of 1-β-D-ribofuranosyl-1, 2, 4-triazole-3-carboxamide (8a) and 2-β-D-ribofuranosylthiazole-4-carboxamide (15), respectively. 相似文献
54.
Manoharan Rajesh Murugaraj Jeyaraj Ganeshan Sivanandhan Kondeti Subramanyam Thankaraj Salammal Mariashibu Subramanian Mayavan Gnanajothi Kapil Dev Vasudevan Ramesh Anbazhagan Markandan Manickavasagam Andy Ganapathi 《Plant Cell, Tissue and Organ Culture》2013,114(1):71-82
An efficient Agrobacterium-mediated genetic transformation method has been developed for the medicinal plant Podophyllum hexandrum Royle, an important source of the anticancer agent podophyllotoxin. Highly proliferating embryogenic cells were infected with Agrobacterium tumefaciens harbouring pCAMBIA 2301, which contains npt II and gusA as selection marker and reporter genes, respectively. The transformed somatic embryos and plantlets were selected on Murashige and Skoog (MS) basal medium containing kanamycin and germination medium, respectively. GUS histochemical analysis, polymerase chain reaction and Southern blot hybridisation confirmed that gusA was successfully integrated and expressed in the P. hexandrum genome. Compared with cefotaxime, 200 mg l?1 timentin completely arrested Agrobacterium growth and favoured somatic embryo development from embryogenic cells. Among the different Agrobacterium strains, acetosyringone concentrations and co-cultivation durations tested, embryogenic callus infected with A. tumefaciens EHA 105 and co-cultivated for 3 days on MS basal medium containing 100 μM acetosyringone proved to be optimal and produced a transformation efficiency of 29.64 % with respect to germinated GUS-positive plantlets. The Agrobacterium-mediated genetic transformation method developed in the present study facilitates the transference of desirable genes into P. hexandrum to improve the podophyllotoxin content and to enhance other useful traits. 相似文献
55.
Ganeshan Sivanandhan Thankaraj Salammal Mariashibu Muthukrishnan Arun Manoharan Rajesh Sampath Kasthurirengan Natesan Selvaraj Andy Ganapathi 《Acta Physiologiae Plantarum》2011,33(6):2279-2288
An efficient mass multiplication protocol was developed for Withania somnifera (L.) Dunal from nodal explants of field-grown plants on Murashige and Skoog medium (MS) supplemented with 6-benzyladenine
(BA) [1.5 mg L−l], indole-3-acetic acid (IAA) [0.3 mg L−l] and with the addition of polyamine, spermidine (20 mg L−l) (shoot multiplication medium). A total of 46.4 shoots were obtained from nodal explants and they were elongated in the same
medium in a culture duration of 6 weeks. The elongated shoots produced roots in MS medium fortified with putrescine (20 mg L−l) after 4 weeks, and all the rooted plants were successfully hardened and acclimatized with a survival rate of 100%. An average
of 276 shoots (46 × 6) was produced when at least six nodal explants obtained from each of the 46 in vitro grown shoots were
cultured by microcutting method in the same shoot multiplication medium. On an average, 12,696 plants could be produced from
all the shoots (276 × 46) by microcuttings in a period of 7 months. HPLC revealed a significant increase in the quantities
of withanolide A, withanolide B, withaferin A and withanone in the leaves, stems, and roots of in vitro regenerated plants
compared to the field-grown parent plants. Ploidy analysis using flow cytometry revealed genetic stability of in vitro regenerated
plants. This protocol will be useful for scale-up production of withanolides on commercial scale. 相似文献
56.
Balusamy Jaganath Kondeti Subramanyam Subramanian Mayavan Sivabalan Karthik Dhandapani Elayaraja Rajangam Udayakumar Markandan Manickavasagam Andy Ganapathi 《Protoplasma》2014,251(3):591-601
An efficient and reproducible Agrobacterium-mediated in planta transformation was developed in Jatropha curcas. The various factors affecting J. curcas in planta transformation were optimized, including decapitation, Agrobacterium strain, pin-pricking, vacuum infiltration duration and vacuum pressure. Simple vegetative in vivo cleft grafting method was adopted in the multiplication of transformants without the aid of tissue culture. Among the various parameters evaluated, decapitated plants on pin-pricking and vacuum infiltrated at 250 mmHg for 3 min with the Agrobacterium strain EHA 105 harbouring the binary vector pGA 492 was proved to be efficient in all terms with a transformation efficiency of 62.66 %. Transgene integration was evinced by the GUS histochemical analysis, and the GUS positive plants were subjected to grafting. Putatively transformed J. curcas served as "Scion" and the wild type J. curcas plant severed as "Stock". There was no occurrence of graft rejection and the plants were then confirmed by GUS histochemical analysis, polymerase chain reaction (PCR) and Southern hybridization. Genetic stability of the grafted plants was evaluated by using randomly amplified polymorphic DNA (RAPD), marker which showed 100 % genetic stability between mother and grafted plants. Thus, an efficient in planta transformation and grafting based multiplication of J. curcas was established. 相似文献
57.
Siddhesh B. Ghag Upendra K. Singh Shekhawat Thumballi R. Ganapathi 《Plant Cell, Tissue and Organ Culture》2014,119(2):247-255
Plant defensins are group of small, cysteine stabilized antimicrobial peptides rich in basic amino acids which inhibit growth of a multitude of phytopathogens. These defensins have been explored widely to generate transgenic crop plants resistant to varied fungal and bacterial diseases. In the present study, gene sequence coding for a seed defensin (Sm-AMP-D1) of common chickweed Stellaria media was synthesized artificially and cloned downstream of a strong constitutive promoter in pCAMBIA-1301 plant expression vector. Transgenic banana plants expressing the Sm-AMP-D1 gene were subsequently generated via Agrobacterium-mediated genetic transformation. Transgenic nature of the regenerated banana plants was confirmed by genomic DNA PCR and Southern blotting analysis. Northern blots demonstrated efficient expression of Sm-AMP-D1 mRNA in transgenic banana plants. Further, two selected transgenic lines challenged with a pathogenic isolate of Fusarium oxysporum f. sp. cubense race 1 showed improved resistance as compared to untransformed control banana plants. These transgenic lines continued to show resistance against Foc race 1 6 months post-infection. This study demonstrates that overexpression of potent plant defensins such as Sm-AMP-D1 in important food crops like banana can lead to development of durable resistance against fungal pathogens. 相似文献
58.
Jeevaraj Theboral Ganeshan Sivanandhan Kondeti Subramanyam Muthukrishnan Arun Natesan Selvaraj Markandan Manickavasagam Andy Ganapathi 《Plant Cell, Tissue and Organ Culture》2014,117(3):477-481
A combined treatment of sonication (2 min) and vacuum infiltration (2 min) stimulated isoflavones production of 75.26 mg g?1 DW which was 15.11-fold higher than control hairy root line at optimal harvest time of 40 days. Addition of MeJ at 100 μM concentration with 72 h exposure time on 30 day-old hairy root culture further enhanced total isoflavones production of 53.16 mg g?1 DW (10.67-fold) and SA at 200 μM concentration with 96 h exposure period enhanced the production of isoflavones (28.79 mg g?1 DW; 5.78-fold). MeJ-treated hairy roots reduced biomass accumulation whereas sonication, vacuum infiltration and SA did not exhibit a negative effect on biomass growth. 相似文献
59.
Overexpression of tobacco osmotin (Tbosm) in soybean conferred resistance to salinity stress and fungal infections 总被引:2,自引:0,他引:2
60.
Plasmodium falciparum, the causative agent of the fatal form of malaria, synthesizes GMP primarily from IMP and, hence, needs active GMPS (GMP synthetase) for its survival. GMPS, a G-type amidotransferase, catalyses the amination of XMP to GMP with the reaction occurring in two domains, the GAT (glutamine amidotransferase) and ATPPase (ATP pyrophosphatase). The GAT domain hydrolyses glutamine to glutamate and ammonia, while the ATPPase domain catalyses the formation of the intermediate AMP-XMP from ATP and XMP. Co-ordination of activity across the two domains, achieved through channelling of ammonia from GAT to the effector domain, is the hallmark of amidotransferases. Our studies aimed at understanding the kinetic mechanism of PfGMPS (Plasmodium falciparum GMPS) indicated steady-state ordered binding of ATP followed by XMP to the ATPPase domain with glutamine binding in a random manner to the GAT domain. We attribute the irreversible, Ping Pong step seen in initial velocity kinetics to the release of glutamate before the attack of the adenyl-XMP intermediate by ammonia. Specific aspects of the overall kinetic mechanism of PfGMPS are different from that reported for the human and Escherichia coli enzymes. Unlike human GMPS, absence of tight co-ordination of activity across the two domains was evident in the parasite enzyme. Variations seen in the inhibition by nucleosides and nucleotide analogues between human GMPS and PfGMPS highlighted differences in ligand specificity that could serve as a basis for the design of specific inhibitors. The present study represents the first report on recombinant His-tagged GMPS from parasitic protozoa. 相似文献