Probing binding mechanism of interleukin-6 and olokizumab: in silico design of potential lead antibodies for autoimmune and inflammatory diseases

Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen–antibody (Ag???Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag???Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases.     

The determination of spatial pattern inDictyostelium discoideum

Free-living amoebae of the cellular slime mouldDictyostelium discoideum aggregate when starved and give rise to a long and thin multicellular structure, the slug. The slug resembles a metazoan embryo, and as with other embryos it is possible to specify a fate map. In the case ofDictyostelium discoideum the map is especially simple: cells in the anterior fifth of the slug die and form a stalk while the majority of those in the posterior differentiate into spores. The genesis of this anterior-posterior distinction is the subject of our review. In particular, we ask: what are the relative roles of individual pre-aggregative predispositions and post-aggregative position in determining cell fate? We review the literature on the subject and conclude that both factors are important. Variations in nutritional status, or in cell cycle phase at starvation, can bias the probability that an amoeba differentiates into a stalk cell or a spore. On the other hand, isolates, or slug fragments, consisting of only prestalk cells or only prespore cells can regulate so as to result in a normal range of both cell types. We identify three levels of control, each being responsible for guiding patterning in normal development: (i) ‘coin tossing’, whereby a cell autonomously exhibits a preference for developing along either the stalk or the spore pathway with relative probabilities that can be influenced by the environment; (ii) ‘chemical kinetics’, whereby prestalk and prespore cells originate from undifferentiated amoebae on a probabilistic basis but, having originated, interact (e.g. via positive and negative feedbacks), and the interaction influences the possibility of conversion of one cell type into the other; and (iii) ‘positional information’, in which the spatial distribution of morphogens in the slug influences the pathway of differentiation. In the case of possibilities (i) and (ii), sorting out of like cell types leads to the final spatial pattern. In the case of possibility (iii), the pattern arisesin situ     

MORPHOLOGICAL AND EMBRYOLOGICAL STUDIES ON THE LEMNACEAE. I. THE FLORAL STRUCTURE AND GAMETOPHYTES OF LEMNA PAUCICOSTATA

Maheshwari, Satish C., and R. N. Kapil. (U. Delhi, Delhi, India.) Morphological and embryological studies on the Lemnaceae. I. The floral structure and gametophytes of Lemna paucicostata. Amer. Jour. Bot. 50(7): 677–686. Illus. 1963.—In Lemna paucicostata, a locally occurring member of the Lemnaceae, the plant body is represented by a frond which is devoid of lignified elements. The root shows a winged root sheath but does not have root hairs. There are no distinctive layers like the endodermis and xylem. The male archesporium is hypodermal and differentiates normally as in other angiosperms into parietal and sporogenous layers. The tapetum is single-layered and plasmodial. The partition walls of the anther are not derived by sterilization of the sporogenous cells as believed earlier. The microspore tetrads are isobilateral and decussate, the meiotic divisions being successive. The pollen grains are shed at the 3-celled stage. The ovary contains a single hemianatropous, bitegminal and crassinucellar ovule. The development of the embryo sac conforms to the Allium type.     

Plasmid elimination from clinical isolates of Echerichia coli by ciprofloxacin and other inhibitors of DNA gyrase

Summary The susceptibility of 50 drug resistant strains of Escherichia coli of human gut was determined against ciprofloxacin, acridine orange (AO) and sodium dodecyl sulphate (SDS). Curing efficacy of these agents were worked out at subminimal inhibitory concentrations. Ciprofloaxacin was found a better curing agent for E coli R-plasmids, eliminating R-factors from 48% of the strains followed by SDS and AO which eliminated 24% and 20% of the drug resistance determinants, respectively. Elimination of R-plasmids was found dependent on the concentrations of curing agents and nature of R-plasmids.     

Toddanol and toddanone,two coumarins from Toddalia asiatica

Two new constituents isolated from the roots of Toddalia asiatica and designated as toddanol and toddanone have been characterized as 5,7-dimethoxy-6-(2-hydroxy-3-methylbut-3-enyl)coumarin (1) and 5,7-dimethoxy-6-(3-methyl-2-oxobutanyl)coumarin (3), respectively, by spectral analysis and interconversion experiments.     

New alkaloids from Glycosmis mauritiana

Chemical investigation of the roots of G. mauritiana resulted in the isolation of two new alkaloids; 1-hydroxy-3-methoxy-2-(3-methylbut-2-enyl)-N-methylacridan-9-one (1) and 4,8-dimethoxy-3-(3-methylbut-2-enyl)-N-methyl-2-quinolone (6). The structures of these new bases have been established by chemical and spectroscopic methods and confirmed in the case of 6 by its synthesis. Interestingly, the formic acid-catalysed cyclisation of 1 gave the dealkylated product 3 along with the pyrano-[2, 3-a]-acridine (4).     

Dietary Mannan-oligosaccharides potentiate the beneficial effects of Bifidobacterium bifidum in broiler chicken

This study investigated the effects of dietary Bifidobacterium bifidum (BFD) and mannan-oligosaccharide (MOS), as a synbiotic, on the production performance, gut microbiology, serum biochemistry, antioxidant profile and health indices of broiler chicken. Six dietary treatments were T1 (negative control), T2 (positive control-20 mg antibiotic BMD kg⁻¹ diet; BMD: bacitracin methylene disalicylate), T3 (0·1% MOS + 10⁶ CFU BFD per g feed), T4 (0·1% MOS + 10⁷ CFU BFD per g feed), T5 (0·2% MOS + 10⁶ CFU BFD per g feed) and T6 (0·2% MOS + 10⁷ CFU BFD per g feed). Significantly (P < 0·01) better growth performance and efficiency was observed in birds supplemented with 0·2% MOS along with 10⁶ CFU BFD per g of feed compared to BMD and control birds. Supplementation with 0·2% MOS along with either 10⁶ or 10⁷ CFU BFD per g feed reduced (P < 0·01) the gut coliform, Escherichia coli, total plate count, and Clostridium perfringens count and increased the Lactobacillus and Bifidobacterium count. Significantly (P < 0·01) higher serum and liver antioxidant enzyme pool, serum HDL cholesterol and lower serum glucose, triglyceride, total cholesterol, cardiac risk ratio, atherogenic coefficient and atherogenic index of plasma were observed in birds supplemented with 0·2% MOS along with 10⁶ CFU BFD per g of feed compared to control or BMD supplemented birds. Better production performance, gut microbial composition, serum biochemistry, antioxidant profile and health indices were depicted by broiler chicken supplemented with 0·2% MOS and 10⁶ CFU BFD per g of feed.     

p-Toluenesulfonyl Chloride Catalysed Facile Synthesis of O-benzyl-l-amino Acids and Their In Vitro Evaluation

International Journal of Peptide Research and Therapeutics - Protection and subsequent deprotection of amino acid functional groups play a key role in regioselective peptide synthesis. For...     

Unraveling the camel rumen microbiome through metaculturomics approach for agriculture waste hydrolytic potential

Archives of Microbiology - Cellulose is the most abundant natural polymer present on Earth in the form of agriculture waste. Hydrolysis of agriculture waste for simple fermentable reducing sugars...