238 research outputs found
Laser stripe measurements of near-wall solid fraction in channel flows of liquid-granular mixtures
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Design and synthesis of prostate specific antigen-activated prodrugs
No full textThe feasibility of targeted delivery of cytotoxic agents to prostate cancer cells via selective activation of peptide-linked prodrugs by prostate-specific antigen (PSA) has been previously demonstrated. PSA is a chymotryspin-like serine protease that uniquely cleaves after Gln. Using cleavage maps for its natural substrates, semenogelins I and II, the highly specific PSA substrate glutaryl-Hyp-Ala-Ser-Chg-Gln was discovered, and subsequently coupled to various cytotoxic agents as a promoiety to synthesize prodrugs with enhanced selectivity for prostate cancer cells. In order to obtain PSA peptide substrates with improved specificity and plasma stability from the known substrate sequence glutaryl-Hyp-Ala-Ser-Chg-Gln, we systematically replaced the N-terminal segment with D-retro-inverso-peptides and incorporated 7-amino-4-methylcoumarin (7-AMC) after Gln for convenient fluorometric determination and ranking of the PSA substrate activity. Based on PSA cleavage rate and resistance to hydrolysis in plasma, GABA←mGly-Ala-Ser-Chg-Gln and glutaryl-Ser-Ala-Ser-Chg-Gln were identified as optimal promoieties and coupled to doxorubicin or phosphoramide mustard as PSA-cleavable prodrugs, using various linkers. The doxorubicin conjugates demonstrated comparable PSA cleavage rates, equal or improved cytotoxic profiles in PSA-producing tumor cells compared to the prodrug L-377,202 (glutaryl-Ser-Ala-Ser-Chg-Gln-Ser-Leu-Dox). We found that human neprilysin rapidly cleaved L-377,202 through its Ser-Leu linker and may be responsible for prodrug instability in blood and normal tissues. Thus, in addition to enhancing prodrug selectivity against non-PSA-secreting prostate cancer cell lines, stability in normal tissues was improved. Our results indicated that enhanced tumor specificity of peptide prodrugs targeted for activation by PSA in prostate cancer tumors was achievable with peptide sequence and linker modifications.Ph.D.Includes bibliographical referencesby Herve Aloysiu
Performances of moment resisting frames with slender steel and composite sections in low and moderate seismic areas
No full textSpecific investigations have been carried out regarding typical beam profiles commonly used for steel and composite frames. In a first stage, experimental tests on class-3 and class-4 built up steel profiles and composite beam-to-column nodes were performed. The measurement results were evaluated with regard to the development of the hysteretic behavior with particular emphasis on the cyclic degradation. These test results have been used as reference for the calibration and validation of numerical models aiming at extending the scope of the experimental outcomes through appropriate parametric variations regarding the behavior of nodal connections as well as towards the global analysis and behavior of structures made of class 3 and 4 profiles. Based on the outcomes of these investigations, practical design recommendations are finally derived for moment resisting frames located in low and moderate seismicity regions.This research has been carried out with the support of the Research Fund for Coal and Steel (RFCS) of the European Commission under the grant agreement RFSR-CT-2013-00022.Degee, H (corresponding author), Hasselt Univ, Hasselt, Belgium
Correction to: Potassium Fertilizer Value of Raw and Hydrothermally Treated Igneous Rocks
No full textInternational audienceThe name of author Aaron Mbissik was presented incorrectly (as “Aaron Herve”) in this article as originally published
The discovery of SycO reveals a new function for type three secretion effector chaperones
Full text linkThe Type Three Secretion (T3S) system is a device used by many Gram-negative pathogens that allows bacteria to deliver effector proteins straight into the eukaryotic cell cytosol. These effectors interfere with various signaling pathways to subvert the host cell functions. The secretion machinery of the T3S system consist of a basal body spanning the bacterial inner and outer membrane followed by a stiff hollow needle outside the bacterium. The fully assembled secretion apparatus constitute a continuous hollow conduit that connects the bacteria to the eukaryotic target cell. After cell contact, virulence proteins -called effectors- are injected directly into the cytosol of the host cell via the T3S apparatus. Several effectors of the T3S system require the assistance of specific cytosolic chaperones to be efficiently exported. There are three classes of T3S chaperones. Effector proteins are assisted by Class I chaperones. Although Class I chaperones are well characterized, their main function is still a matter of controversy. In this thesis, we demonstrate that orf155 encodes a specific chaperone for the effector YopO that we called SycO. We showed that SycO enhances YopO secretion in vitro and is required for translocation of YopO into infected cells. By pulldown assay we demonstrated that residues 20 to 77 of YopO are required and sufficient for SycO binding. Using crosslinking experiments and size exclusion chromatography analysis, we determined the stoichiometry of purified SycO and YopO-SycO complexes. SycO alone forms dimers in solution and the YopO-SycO complex has a 1:2 stoichiometry. These results suggested that SycO is a typical chaperone of the Class I. YopO is a serine/theronine kinase that interacts with Rho and Rac and disrupts the cytoskeleton of the target cells. YopO has been shown to localize at the cell plasma-membrane. By transfection of YopO-EGFP hybrid proteins into HEK293T cells, we demonstrated that the chaperone-binding domain (CBD) coincides with the membrane localization domain of YopO. Nevertheless, the CBD was not needed for the kinase activity of YopO. By ultracentrifugation, we also showed that the CBD causes YopO aggregation in the bacteria, when SycO does not cover it. Further, we show that the CBD of YopE and YopT also caused aggregation in the bacteria in the absence of SycE and SycT respectively. YopE, YopT and T3S effectors in other systems also act at the membrane of the eukaryotic host cell. We propose a new hypothesis concerning the role of T3S chaperones. The sub-cellular localization domain of effectors is aggregation-prone and creates the need for a chaperone inside bacteria. We propose that masking such aggregation-prone localization domains may be a general function for type III effector chaperones
Self-similar evolution of semi-infinite alluvial channels with moving boundaries
No full textMathematical solutions are obtained for several sedimentary problems featuring semi-infinite alluvial channels evolving under diffusional sediment transport. Moving boundaries are considered at one end of the channels, and represent transitions between alluvial reaches and either bedrock-floored channels or bodies of standing water. Three elementary cases are considered: bedrock-alluvial transitions, lake breaches, and prograding deltas. It is shown that idealized formulations of all three problems share the same mathematical structure and admit exact similarity solutions. Elementary solutions can further be assembled to describe composite profiles. This is illustrated by the case of a natural lake undergoing simultaneous breaching and backfill. For both elementary and composite cases, the explicit solutions clarify the link between alluvial profile evolution and the migration of channel boundaries. For the case of lake breaching, for instance, the outlet channel profile is controlled simultaneously by downwards incision and upstream migration of the channel head. The pace of the resulting water-level drawdown in turn affects the form of the backfill deposits upstream of the lake
U-shaped steel plate dissipative connection for concentrically braced frames
No full textIn concentrically braced frames, the use of dissipative connections allows to efficiently dissipate the seismic energy in earthquake scenarios and subsequently, to reduce the costs in the rehabilitation of the structure. To this end, U-shaped steel plates are simple and efficient connection components where significant dissipation of seismic energy can take place through the inelastic flexural deformation of the plate. This paper presents experimental results on the isolated U-shaped steel plate connections and on single-story concentrically braced frame (real scale) including the U-shaped steel plate to connect braces to adjacent members. The executed tests considered both monotonic and cyclic loading. The results highlight the efficiency of the U-shape steel plate to dissipate the energy input through inelastic deformations. On the other hand, the cyclic tests show potential fatigue behavior, as the deformation capacity is significantly reduced with repeated loading and increasing stress amplitude, requiring thus specific attention in practical design situations.The research leading to these results has received funding from the European Union’s Research Fund for Coal and Steel (RFCS) research programme under CEC agreement N° 7210-PR-316 (The INERD project) and the grant agreement N° 709343 (INNOSEIS).Henriques, J (corresponding author), Univ Hasselt, Fac Engn Technol, CERG, Hasselt, Belgium
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