162 research outputs found
New findings on the d(TGGGAG) sequence: Surprising anti-HIV-1 activity
No full textThe biological relevance of tetramolecular G-quadruplexes especially as anti-HIV agents has been extensively reported in the literature over the last years. In the light of our recent results regarding the slow G-quadruplex folding kinetics of ODNs based on d(TGGGAG) sequence, here, we report a systematic anti-HIV screening to investigate the impact of the G-quadruplex folding on their anti-HIV activity. In particular, varying the single stranded concentrations of ODNs, it has been tested a pool of ODN sample solutions with different G-quadruplex concentrations. The anti-HIV assays have been designed favouring the limited kinetics involved in the tetramolecular G4-association based on the d(TGGGAG) sequence. Aiming to determine the stoichiometry of G-quadruplex structures in the same experimental conditions of the anti-HIV assays, a native gel electrophoresis was performed. The gel confirmed the G-quadruplex formation for almost all sample solutions while showing the formation of high order G4 structures for the more concentrated ODNs solutions. The most significant result is the discovery of a potent anti-HIV activity of the G-quadruplex formed by the natural d(TGGGAG) sequence (IC50 = 14 nM) that, until now, has been reported to be completely inactive against HIV infection
Hairpin oligonucleotides forming G-quadruplexes: New aptamers with anti-HIV activity
No full textWe describe the facile syntheses of new modified oligonucleotides based on d(TG3AG) that form bimolecular G-quadruplexes and possess a HEG loop as an inversion of polarity site 3′-3′ or 5′-5′ and aromatic residues conjugated to the 5′-end through phosphodiester bonds. The conjugated hairpin G-quadruplexes exhibited parallel orientation, high thermal stability, elevated resistance in human serum and high or moderate anti-HIV-1 activity with low cytotoxicity. Further, these molecules showed significant binding to HIV envelope glycoproteins gp120, gp41 and HSA, as revealed by SPR assays. As a result, these conjugated hairpins represent the first active anti-HIV-1 bimolecular G-quadruplexes based on the d(TG3AG) sequence
2-Aminothiophene-3-carboxylic acid ester derivatives as novel highly selective cytostatic agents
No full textCytostatic agents often do not discriminate in their cytostatic potential between different tumor cell types in vitro. In this study, several 2-aminothiophene-3-carboxylic acid ester derivatives were discovered that show an unusual cytostatic selectivity for several T-cell (but not B-cell) lymphoma, prostate cancer, kidney carcinoma and hepatoma cell lines. Their 50 % cytostatic concentrations were generally in the higher nanomolar range and were approximately 20- to 50-fold lower for these tumor cell types than for any other tumor cell line or non-tumorigenic cells. The tumor-selective compounds caused a more preferential suppression of protein synthesis than DNA or RNA synthesis and the prototype compound 3 resulted in an accumulation of prostate cancer cells in the G1 phase of their cell cycle. Compound 3 was also shown to induce apoptosis in prostate cancer cells. The 2-aminothiophene-3-carboxylic acid ester derivatives represent novel candidate cytostatic agents to be further explored for their tumor-selective potential.sponsorship: We are grateful to Mrs. C. Callebaut for dedicated editorial assistance and to Mrs. Lizette van Berckelaer, Kristien Minner and Ria Van Berwaer for excellent technical assistance. The research was supported by the KU Leuven (GOA 10/14). The study sponsors had no role in the writing of the manuscript nor the decision to submit the manuscript for publication. (KU Leuven|GOA 10/14)status: Publishe
The broad-spectrum anti-DNA virus agent cidofovir inhibits lung metastasis of virus-independent, FGF2-driven tumors.
No full textThe FDA-approved anti-DNA virus agent cidofovir (CDV) is being evaluated in phase II/III clinical trials for the treatment of human papillomavirus (HPV)-associated tumors. However, previous observations had shown that CDV also inhibits the growth of vascular tumors induced by fibroblast growth factor-2 (FGF2)-transformed FGF2-T-MAE cells. Here, we demonstrate that CDV inhibits metastasis induced by FGF2-driven, virus-independent tumor cells. Pre-treatment of luciferase-expressing FGF2-T-MAE cells with CDV reduced single cell survival and anchorage-independent growth in vitro and lung metastasis formation upon intravenous inoculation into SCID mice. This occurred in the absence of any effect on homing of FGF2-T-MAE cells to the lungs and on the growth of subconfluent cell cultures or subcutaneous tumors in mice. Accordingly, CDV protected against lung metastasis when given systemically after tumor cell injection. Lung metastases in CDV-treated mice showed reduced Ki67 expression and increased nuclear accumulation of p53, indicating that CDV inhibits metastasis by affecting single cell survival properties. The anti-metastatic potential of CDV was confirmed on B16-F10 melanoma cells, both in zebrafish embryos and mice. These findings suggest that CDV may have therapeutic potential as an anti-metastatic agent and warrants further study to select those tumor types that are most likely to benefit from CDV therapy
Influenza virus entry via the GM3 ganglioside-mediated platelet-derived growth factor receptor β signalling pathway
No full textThe possible resistance of influenza virus against existing antiviral drugs calls for new therapeutic concepts. One appealing strategy is to inhibit virus entry, in particular at the stage of internalization. This requires a better understanding of virus-host interactions during the entry process, including the role of receptor tyrosine kinases (RTKs). To search for cellular targets, we evaluated a panel of 276 protein kinase inhibitors in a multicycle antiviral assay in Madin-Darby canine kidney cells. The RTK inhibitor Ki8751 displayed robust anti-influenza A and B virus activity and was selected for mechanistic investigations. Ki8751 efficiently disrupted the endocytic process of influenza virus in different cell lines carrying platelet-derived growth factor receptor β (PDGFRβ), an RTK that is known to act at GM3 ganglioside-positive lipid rafts. The more efficient virus entry in CHO-K1 cells compared to the wild-type ancestor (CHO-wt) cells indicated a positive effect of GM3, which is abundant in CHO-K1 but not in CHO-wt cells. Entering virus localized to GM3-positive lipid rafts and the PDGFRβ-containing endosomal compartment. PDGFRβ/GM3-dependent virus internalization involved PDGFRβ phosphorylation, which was potently inhibited by Ki8751, and desialylation of activated PDGFRβ by the viral neuraminidase. Virus uptake coincided with strong activation of the Raf/MEK/Erk cascade, but not of PI3K/Akt or phospholipase C-γ. We conclude that influenza virus efficiently hijacks the GM3-enhanced PDGFRβ signalling pathway for cell penetration, providing an opportunity for host cell-targeting antiviral intervention
New Horizons in Stylistics ?La Stylistique en quête de nouveaux horizons.
No full textM. Frédéric & J.P. van Noppen: Avant-Propos. J.J. Lecercle: La stylistique est morte, vive la stylistique. J.M. Klinkenberg: Sénescences et jouvences des stylistiques: la stylistique fin-de-siècle dans le champ des sciences. L. Hickey: Stylistics, Pragmatics and Pragmastylistics. A. Mercier: La sémiotique en quête de nouveaux horizons: une rencontre avec la stylistique. M. Colas-Blaise & J.J. Weber: Sade between Labov and Greimas / Sade entre Labov et Greimas. A. Viala: Stylistique et sociologie: classe de postures. L. Rosier: De le stylistique sociologique, suivie d'une application pratique: discours direct, presse et objectivités. D. Saint-Jacques, D. Geisen & I. Greulich: Le style des lecteurs de best-sellers. D. O'Kelly & A. Joly: Pour une stylistique de la parole transcrite: analyse d'un fragment d'interview à la BBC. J.L. Martinez-Dueñas: Words, Women and Orders: the Stylistics of Anglican Discourse. J.M. Swales: Genre and Engagement. R. Tuffs: A Genre Approach to Writing in the Second Language Classroom. T. Bex: The Genre of Advertising. A. Meurman-Solin: The Author-Addressee Relationship and the Marking of Stance in the Characterization of Sixteenth- and Seventeenth- Century Genre Styles.Numéro spécial de la Revue Belge de Philologie et d'Histoire, 71 (1993) n° 3.info:eu-repo/semantics/publishe
When Everything Falls Apart:On Justified and False Appeals to Divine Providence
No full textDiscussion of how Christians appeal to the providence of God when facing climate change. It is shown from biblical exegesis that this appeal should not be made to evade human responsibility, but to maintain hope in the face of profound threats
Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface
No full textThough the bulk of the COVID-19 pandemic is behind, the search for effective and safe anti-SARS-CoV-2 drugs continues to be relevant. A highly pursued approach for antiviral drug development involves targeting the viral spike (S) protein of SARS-CoV-2 to prevent its attachment to the cellular receptor ACE2. Here, we exploited the core structure of polymyxin B, a naturally occurring antibiotic, to design and synthesize unprecedented peptidomimetics (PMs), intended to target contemporarily two defined, non-overlapping regions of the S receptor-binding domain (RBD). Monomers 1, 2, and 8, and heterodimers 7 and 10 bound to the S-RBD with micromolar affinity in cell-free surface plasmon resonance assays (KD ranging from 2.31 μM to 2.78 μM for dimers and 8.56 μM to 10.12 μM for monomers). Although the PMs were not able to fully protect cell cultures from infection with authentic live SARS-CoV-2, dimer 10 exerted a minimal but detectable inhibition of SARS-CoV-2 entry in U87.ACE2+ and A549.ACE2.TMPRSS2+ cells. These results validated a previous modeling study and provided the first proof-of-feasibility of using medium-sized heterodimeric PMs for targeting the S-RBD. Thus, heterodimers 7 and 10 may serve as a lead for the development of optimized compounds, which are structurally related to polymyxin, with improved S-RBD affinity and anti-SARS-CoV-2 potential
Automatic Extraction of Ridge Lines from Digital Elevation Models
No full textSecond-order Gaussian kernels have been utilized to develop three algorithms that could automatically extract ridge lines for hydrodynamic modelling. Isotropic second-order Gaussian kernels produce inaccurate lines at crossings and junctions. To avoid the malfunctioning of Second-order Gaussian kernels, one default and two alternative algorithms were developed. The first, default algorithm is based on isotropic kernels and non-maximum suppression. For the first alternative algorithm, isotropic and anisotropic kernels have been applied for the filter process. The third algorithm uses skeletonization instead of non-maximum suppression. A verification was applied to analyzed the performance of the algorithms. The Matthews correlation coefficient (MCC) of the default algorithm and the alternative algorithm that included anisotropic kernels was found to be 0.17. For the algorithm based on skeletonization a value of 0.08 was obtained. Hence it has been concluded that the algorithms that utilized non maximum suppression instead could more accurately detect ridge lines than the model based on skeletonization. However, the latter generated lines that contained less discontinuities. Furthermore this algorithm turned out to be computationally less demanding in comparison to the other two algorithms.TKI project: 'D-HYDRO Suite 1D2D ontwikkelingen'Civil Engineering | Hydraulic Engineerin
A feasibility study for a deep-water port in Haiphong, Vietnam
No full textCivil Engineering and Geoscience
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