Ligand-independent oligomerization of TACI is controlled by the transmembrane domain and regulates proliferation of activated B cells.

In mature B cells, TACI controls class-switch recombination and differentiation into plasma cells during T cell-independent antibody responses. TACI binds the ligands BAFF and APRIL. Approximately 10% of patients with common variable immunodeficiency (CVID) carry TACI mutations, of which A181E and C172Y are in the transmembrane domain. Residues A181 and C172 are located on distinct sides of the transmembrane helix, which is predicted by molecular modeling to spontaneously assemble into trimers and dimers. In human B cells, these mutations impair ligand-dependent (C172Y) and -independent (A181E) TACI multimerization and signaling, as well as TACI-enhanced proliferation and/or IgA production. Genetic inactivation of TACI in primary human B cells impaired survival of CpG-activated cells in the absence of ligand. These results identify the transmembrane region of TACI as an active interface for TACI multimerization in signal transduction, in particular for ligand-independent signals. These functions are perturbed by CVID-associated mutations

Identification and characterization of antibacterial compound(s) of cockroaches (Periplaneta americana)

Infectious diseases remain a significant threat to human health, contributing to more than 17 million deaths, annually. With the worsening trends of drug resistance, there is a need for newer and more powerful antimicrobial agents. We hypothesized that animals living in polluted environments are potential source of antimicrobials. Under polluted milieus, organisms such as cockroaches encounter different types of microbes, including superbugs. Such creatures survive the onslaught of superbugs and are able to ward off disease by producing antimicrobial substances. Here, we characterized antibacterial properties in extracts of various body organs of cockroaches (Periplaneta americana) and showed potent antibacterial activity in crude brain extract against methicillin-resistant Staphylococcus aureus and neuropathogenic E. coli K1. The size-exclusion spin columns revealed that the active compound(s) are less than 10 kDa in molecular mass. Using cytotoxicity assays, it was observed that pre-treatment of bacteria with lysates inhibited bacteria-mediated host cell cytotoxicity. Using spectra obtained with LC-MS on Agilent 1290 infinity liquid chromatograph, coupled with an Agilent 6460 triple quadruple mass spectrometer, tissues lysates were analyzed. Among hundreds of compounds, only a few homologous compounds were identified that contained isoquinoline group, chromene derivatives, thiazine groups, imidazoles, pyrrole containing analogs, sulfonamides, furanones, flavanones, and known to possess broad-spectrum antimicrobial properties, and possess anti-inflammatory, anti-tumour, and analgesic properties. Further identification, characterization and functional studies using individual compounds can act as a breakthrough in developing novel therapeutics against various pathogens including superbugs

ARCHIV DER PHARMAZIE

A series of thiazolopyrimidine derivatives was designed and synthesized as aLeishmania majorpteridine reductase 1 (LmPTR1) enzyme inhibitor. TheirLmPTR1 inhibitor activities were evaluated using the enzyme produced byEscherichia coliin a recombinant way. The antileishmanial activity of the selected compounds was tested in vitro againstLeishmaniasp. Additionally, the compounds were evaluated for cytotoxic activity against the murine macrophage cell line RAW 264.7. According to the results, four compounds displayed not only a potent in vitro antileishmanial activity against promastigote forms but also low cytotoxicity. Among them, compoundL16exhibited an antileishmanial activity for both the promastigote and amastigote forms ofL. tropica, with IC(50)values of 7.5 and 2.69 mu M, respectively. In addition, molecular docking studies and molecular dynamics simulations were also carried out in this study. In light of these findings, the compounds provide a new potential scaffold for antileishmanial drug discovery

Evaluation of alkylating and intercalating properties of mannich bases for cytotoxic activity

A series of new "hybrid compounds", Mannich base derivatives of planar polycyclic/heterocyclic starting materials, was designed and synthesized. The structures of the compounds were confirmed by spectroscopic methods and elemental analysis. Cytotoxicity of compounds was investigated in three cancer cell lines (PC3, HeLa, and MCF7) and one non-tumoral cell line (293 HEK). We tested the DNA-intercalating capability of the molecules by ethidium bromide (EtBr) fluorescence displacement experiment. Compounds' alkylation potency was investigated via in vitro incubation test using 2-mercaptoethanol, a biomimetic nucleophile. The five of the compounds (7s, 9d, 10b, 11b, 12c) are reported for first time in the literature. Our results suggest that compound 9d has a biological activity close to the reference compound doxorubicin, an intercalating agent in clinical use. © 2014 Bentham Science Publishers

Looking around with your brain in a virtual world

IEEE Computational Intelligence SocietySymposium Series on Computational Intelligence, IEEE SSCI 2011 - 2011 IEEE Symposium on Computational Intelligence, Cognitive Algorithms, Mind, and Brain, CCMB 2011 -- 11 April 2011 through 15 April 2011 -- Paris -- 85913Offline analysis pipelines have been developed and evaluated for the detection of covert attention from electroen-cephalography recordings, and the detection of overt attention in terms of eye movement based on electrooculographic measurements. Some additional analysis were done in order to prepare the pipelines for use in a real-time system. This real-time system and a game application in which these pipelines are to be used were implemented. The game is set in a virtual environment where player is a wildlife photographer on an uninhabited island. Overt attention is used to adjust the angle of the first person camera, when the player is tracking animals. When making a photograph, the animal will flee when it notices it is looked at directly, so covert attention is required to get a good shot. Future work will entail user tests with this system to evaluate usability, user experience, and characteristics of the signals related to overt and covert attention when used in such an immersive environment. © 2011 IEEE

Characterization of mono- and mixed-culture Campylobacter jejuni biofilms

Campylobacter jejuni, one of the most common causes of human gastroenteritis, is a thermophilic and microaerophilic bacterium. These characteristics make it a fastidious organism, which limits its ability to survive outside animal hosts. Nevertheless, C. jejuni can be transmitted to both humans and animals via environmental pathways, especially through contaminated water. Biofilms may play a crucial role in the survival of the bacterium under unfavorable environmental conditions. The goal of this study was to investigate survival strategies of C. jejuni in mono- and mixed-culture biofilms. We grew monoculture biofilms of C. jejuni and mixed-culture biofilms of C. jejuni with Pseudomonas aeruginosa. We found that mono- and mixed-culture biofilms had significantly different structures and activities. Monoculture C. jejuni biofilms did not consume a measurable quantity of oxygen. Using a confocal laser scanning microscope (CLSM), we found that cells from monoculture biofilms were alive according to live/dead staining but that these cells were not culturable. In contrast, in mixed-culture biofilms, C. jejuni remained in a culturable physiological state. Monoculture C. jejuni biofilms could persist under lower flow rates (0.75 ml/min) but were unable to persist at higher flow rates (1 to 2.5 ml/min). In sharp contrast, mixed-culture biofilms were more robust and were unaffected by higher flow rates (2.5 ml/min). Our results indicate that biofilms provide an environmental refuge that is conducive to the survival of C. jejuni. © 2012, American Society for Microbiology

The interference of piperidinopropionaphthone hydrochloride in mammalian type I and type II DNA topoisomerase reactions

Majority of anti-cancer drugs were shown to exert their activities by interfering with DNA topoisomerase reactions. Since the identification of Camptothecin as the topoisomerase I targeting compound, these enzymes are widely utilized in biological assays to assess the pharmaceutical significance of the synthetic and natural agents. Because a considerable number of compounds were shown to have cytostatic activities via blocking topoisomerase reactions, we aimed to identify if the previously-reported physiological activities of acetonapthones involves the interference with topoisomerase reactions. We covered topoisomerase activity and cytostatic activity evaluation of piperidinopropionaphthone hydrochloride type Mannich base (MB) to compare its bioactivities to the starting propionaphtone in order to assess the contribution of aminomethyl moiety of the compound on its bioactivity. MB was synthesized and characterized in our laboratory. Supercoiled plasmid relaxation and decatenation assays were carried out to evaluate their biological activities in mammalian DNA topoisomerases. We also assayed the cytostatic activities using HeLa, MCF7 and A431 cell lines. Our data showed a considerable inhibition of MB on type I and type II DNA topoisomerases without a correlation to cytostatic assays. MB exerted a modest activity against the proliferation of MCF7 cells with an IC50 value of 27.62 μM. The presence of MB inhibited topo II decatenation activity as well. Results offer no direct explanation for the contradictory effects on the DNA topoisomerases and the proliferation of cancer cells in vitro. Our results are discussed in relation to potential significance of aminomethyl group of Mannich base in the course of drug-development studies. © 2015, Marmara University. All rights reserved