In vitro antioxidant potential of some soil fungi: screening of functional compounds and their purification from Penicillium citrinum

Fungal isolates (Aspergillus wentii 1, A. wentii 2, Penicillium citrinum, Penicillium granulatum) were selected to study their in vitro antioxidant potential by various assay procedures. Czapek–Dox’s medium was selected for the growth of fungi as it supported the best antioxidant activity based on their EC₅₀ values, P. citrinum was the best followed by P. granulatum, A. wentii 1, and A. wentii 2. The chromatographic analyses showed several compounds possessing antioxidant activity in the fungal extracts. Two such compounds were partially purified from P. citrinum which demonstrated potent antioxidant activity, equally effective or better than some of the standard antioxidants.     

Compound prioritization methods increase rates of chemical probe discovery in model organisms

Preselection of compounds that are more likely to induce a phenotype can increase the efficiency and reduce the costs for model organism screening. To identify such molecules, we screened ~81,000 compounds in Saccharomyces cerevisiae and identified ~7500 that inhibit cell growth. Screening these growth-inhibitory molecules across a diverse panel of model organisms resulted in an increased phenotypic hit-rate. These data were used to build a model to predict compounds that inhibit yeast growth. Empirical and in silico application of the model enriched the discovery of bioactive compounds in diverse model organisms. To demonstrate the potential of these molecules as lead chemical probes, we used chemogenomic profiling in yeast and identified specific inhibitors of lanosterol synthase and of stearoyl-CoA 9-desaturase. As community resources, the ~7500 growth-inhibitory molecules have been made commercially available and the computational model and filter used are provided.     

Molecular dynamics simulations of CXCL-8 and its interactions with a receptor peptide, heparin fragments, and sulfated linked cyclitols

CXCL-8 (Interleukin 8) is a CXC chemokine with a central role in the human immune response. We have undertaken extensive in silico analyses to elucidate the interactions of CXCL-8 with its various binding partners, which are crucial for its biological function. Sequence and structure analyses showed that residues in the thirdq β-sheet and basic residues in the heparin binding site are highly variable, while residues in the second β-sheet are highly conserved. Molecular dynamics simulations in aqueous solution of dimeric CXCL-8 have been performed with starting geometries from both X-ray and NMR structures showed shearing movements between the two antiparallel C-terminal helices. Dynamic conservation analyses of these simulations agreed with experimental data indicating that structural differences between the two structures at quaternary level arise from changes in the secondary structure of the N-terminal loop, the 3(10)-helix, the 30s, 40s, and 50s loops and the third β-sheet, resulting in a different interhelical separation. Nevertheless, the observation of these different states indicates that CXCL-8 has the potential to undergo conformational changes, and it seems likely that this feature is relevant to the mode of binding of glycosaminoglycan (GAG) mimetics such as cyclitols. Simulations of the receptor peptide fragment-CXCL-8 complex identified several specific interactions of the receptor peptide with CXCL-8 that could be exploited in the structure-based design of competitive peptides and nonpeptidic molecules targeting CXCL-8 for combating inflammatory diseases. Simulations of the CXCL-8 dimer complexed with a 24-mer heparin fragment and of the CXCL-8-receptor peptide complex revealed that Arg60, Lys64, and Arg68 in the dimer bind to cyclitols in a horseshoe pattern, defining a region which is spatially distinct from the receptor binding site. There appears to be an optimum number of sulfates and an optimum length of alkyl spacers required for the interaction of cyclitol inhibitors with the dimeric form of CXCL-8. Calculation of the binding affinities of cyclitol inhibitors reflected satisfactorily the ranking of experimentally determined inhibitory potencies. The findings of these molecular modeling studies will help in the search for inhibitors which can modulate various CXCL-8 biological activities and serve as an excellent model system to study CXC-inhibitor interactions.     

Production of lantipeptides in Escherichia coli

Lantipeptides are ribosomally synthesized and posttranslationally modified peptides containing thioether cross-links. We describe the preparation of seven different lantipeptides in Escherichia coli and demonstrate that this methodology can be used to incorporate nonproteinogenic amino acids.     

Preparation and characterization of symmetrical bis[4-chloro-2-pyrimidyl] dichalcogenide (S, Se, Te) and unsymmetrical 4-chloro-2-(arylchalcogenyl) pyrimidine: X-ray crystal structure of 4-chloro-2-(phenylselanyl) pyrimidine and 2-(p-tolylselanyl)-4-chloropyrimidine

Synthesis of a novel class of multinucleate pyrimidine chalcogen (S/Se/Te) derivatives has been successfully attempted for the first time by the selective substitution of chlorine at the C-2 position of 2,4-dichloropyrimidine with nucleophilic dichalcogenide anion E₂²⁻ (E = S, Se, Te) to afford bis[4-chloro-2-pyrimidyl] dichalcogenide. The highly electrophilic nature of 2,4-dichloropyrimidine compared to aryl chlorides has been further exploited to prepare a variety of 4-chloro-2-(arylchalcogenyl) pyrimidine compounds by substituting the chlorine exclusively at the C-2 position of 2,4-dichloropyrimidine with a variety of chalcogen bearing aryl anions ArE⁻ (Ar = phenyl, 1-naphthyl, p-tolyl, 4,6-dimethyl-2-pyrimidyl, 2-pyridyl, 4-methyl-2-pyridyl). All the newly prepared symmetrical and unsymmetrical pyrimidyl chalcogen compounds have been thoroughly characterized with the help of various spectroscopic techniques viz., NMR (¹H, ¹³C, ⁷⁷Se), FT-IR and mass spectrometry (in representative cases). The crystal structures of 4-chloro-2-(phenylselanyl) pyrimidine and 2-(p-tolylselanyl)-4-chloropyrimidine have been determined by X-ray crystallography.     

miR-9 and let-7g enhance the sensitivity to ionizing radiation by suppression of NFκB1

The activation of nuclear factor-kappa B1 (NFkB1) in cancer cells may confer resistance to ionizing radiation (IR). To enhance the therapeutic efficiency of IR in lung cancer, we screened for microRNAs (miRNAs) that suppress NFkB1 and observed their effects on radiosensitivity in a human lung cancer cell line. From time series data of miRNA expression in γ-irradiated H1299 human lung cancer cells, we found that the expression of miR-9 was inversely correlated with that of NFκB1. Overexpression of miR-9 down-regulated the level of NFκB1 in H1299 cells, and the surviving fraction of γ-irradiated cells was decreased. Interestingly, let-7g also suppressed the expression of NFκB1, although there was no canonical target site for let-7g in the NFκB1 3' untranslated region. From these results, we conclude that the expression of miR-9 and let-7g could enhance the efficiency of radiotherapy for lung cancer treatment through the inhibition of NFκB1.     

Generalized slant Toeplitz operators on H2

For an integer k ≥ 2, k^th‐order slant Toeplitz operator U_φ [1] with symbol φ in L^∞(??), where ?? is the unit circle in the complex plane, is an operator whose representing matrixM = (α_ij ) is given by α_ij = 〈φ, z^ki–j〉, where 〈. , .〉 is the usual inner product in L²(??). The operator V_φ denotes the compression of U_φ to H²(??) (Hardy space). Algebraic and spectral properties of the operator V_φ are discussed. It is proved that spectral radius of V_φ equals the spectral radius of U_φ, if φ is analytic or co‐analytic, and if T_φ is invertible then the spectrum of V_φ contains a closed disc and the interior of the disc consists of eigenvalues of infinite multiplicities. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

On the production of slow particles in high energy heavy ion collisions

The mechanism for producing slow, target associated particles in high energy heavy ion collisions is investigated. It is shown that the same mechanism which was proposed for hadron induced interactions is likely to appear also for heavy-ion reactions. The results indicate however a much weaker correlation between impact parameter and yield of slow particles.     

Regioselective synthesis of symmetrical pyridyl selenium compounds by bromine–magnesium exchange of bromopyridines using isopropyl magnesium chloride: X‐ray crystal structure of 2,2′,5,5′‐tetrabromo‐3,3′‐dipyridyldiselenide

2,2′‐Dipyridyl‐3,3′‐dipyridyl,5,5′‐dipyridyl‐diselenides have been synthesized by a convenient method employing non‐cryogenic conditions. Various bromopyridines (2‐Bromopyridine, 2,5‐dibromopyridines and 2,3,5‐Tribromopyridines) undergo selective monobromine–magnesium exchange to yield the corresponding pyridyl magnesium chlorides at room temperature upon treatment with ⁱPrMgCl. The resulting pyridyl magnesium chloride is quenched with elemental selenium, which upon further oxidation affords the above diselenides in good yields. The compounds prepared using this methodology have been characterized by elemental analysis, IR, NMR (¹H, ¹³C, ⁷⁷Se) and mass spectral analysis. The molecular structure of 2,2′,5,5′‐Tetrabromo‐3,3′‐dipyridyldiselenide has been established by single‐crystal X‐ray diffraction analysis. It exists as a dimeric form due to the non‐bonding interactions between the selenium of one pyridine moiety and the hydrogen of the other. Copyright © 2004 John Wiley & Sons, Ltd.     

Performance of YBaCuO thick film rf SQUIDs at 77 K

RF SQUID behaviour has been observed at 77 K in YBaCuO thick films prepared by screen printing technique. A hole shunted with a microbridge type of geometry is patterned manually for observing rf SQUID behaviour. Flux noise spectrum is also studied and it is found to depend on the quality of the film. The spectral density of the flux noise in the white noise region is 1.7×10⁻³ Φ₀/√Hz at 77 K.