892 research outputs found
Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir
The current effectiveness of HAART in the management of HIV infection is compromised by the emergence of extensively cross-resistant strains of HIV-1, requiring a significant need for new therapeutic agents. Due to its crucial role in viral maturation and therefore HIV-1 replication and infectivity, the HIV-1 protease continues to be a major development target for antiretroviral therapy. However, new protease inhibitors must have higher thresholds to the development of resistance and cross-resistance. Research has demonstrated that the binding characteristics between a protease inhibitor and the active site of the HIV-1 protease are key factors in the development of resistance. More specifically, the way in which a protease inhibitor fits within the substrate consensus volume, or substrate envelope , appears to be critical. The currently available inhibitors are not only smaller than the native substrates, but also have a different shape. This difference in shape underlies observed patterns of resistance because primary drug-resistant mutations often arise at positions in the protease where the inhibitors protrude beyond the substrate envelope but are still in contact with the enzyme. Since all currently available protease inhibitors occupy a similar space (in spite of their structural differences) in the active site of the enzyme, the specific positions where the inhibitors protrude and contact the enzyme correspond to the locations where most mutations occur that give rise to multidrug-resistant HIV-1 strains. Detailed investigation of the structure, thermodynamics, and dynamics of the active site of the protease enzyme is enabling the identification of new protease inhibitors that more closely fit within the substrate envelope and therefore decrease the risk of drug resistance developing. The features of darunavir, the latest FDA-approved protease inhibitor, include its high binding affinity (Kd = 4.5 x 10-12 M) for the protease active site, the presence of hydrogen bonds with the backbone, and its ability to fit closely within the substrate envelope (or consensus volume). Darunavir is potent against both wild-type and protease inhibitor-resistant viruses in vitro, including a broad range of over 4,000 clinical isolates. Additionally, in vitro selection studies with wild-type HIV-1 strains have shown that resistance to darunavir develops much more slowly and is more difficult to generate than for existing protease inhibitors. Clinical studies have shown that darunavir administered with low-dose ritonavir (darunavir/ritonavir) provides highly potent viral suppression (including significant decreases in HIV viral load in patients with documented protease inhibitor resistance) together with favorable tolerability. In conclusion, as a result of its high binding affinity for and overall fit within the active site of HIV-1 protease, darunavir has a higher genetic barrier to the development of resistance and better clinical efficacy against multidrug-resistant HIV relative to current protease inhibitors. The observed efficacy, safety and tolerability of darunavir in highly treatment-experienced patients makes darunavir an important new therapeutic option for HIV-infected patients
Can thin-lipped mullet directly exploit the primary and detritic production of European macrotidal salt marshes?
Juveniles and adults (>100 mm) of Liza ramada colonize macrotidal salt marsh creeks of Mont Saint-Michel bay (France)between March and November, during spring tide floods (43% of the tides) and return to coastal waters during the ebb. This fish species actively feeds during its short stay in the creek (from 1 to 2 h). On average, each fish swallows sediment including living and inert organic matter, which amounts to 8% of its fresh body weight. Their diet is dominated by small benthic items (especially diatoms and salt marsh plant detritus), that correspond to the primary and detritic production of this macrotidal salt marsh creek. Despite very short submersion periods, mullets filter and ingest large quantities of sediment and concentrated organic matter (on average organic matter in stomach content is 31%) produced by these coastal wetlands. European salt marshes are thus shown to act as trophic areas for mullets, which are well adapted to this constraining habitat which is only flooded for short periods during spring tides
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Global morphogenetic flow is accurately predicted by the spatial distribution of myosin motors.
During embryogenesis tissue layers undergo morphogenetic flow rearranging and folding into specific shapes. While developmental biology has identified key genes and local cellular processes, global coordination of tissue remodeling at the organ scale remains unclear. Here, we combine in toto light-sheet microscopy of the Drosophila embryo with quantitative analysis and physical modeling to relate cellular flow with the patterns of force generation during the gastrulation process. We find that the complex spatio-temporal flow pattern can be predicted from the measured meso-scale myosin density and anisotropy using a simple, effective viscous model of the tissue, achieving close to 90% accuracy with one time dependent and two constant parameters. Our analysis uncovers the importance of a) spatial modulation of myosin distribution on the scale of the embryo and b) the non-locality of its effect due to mechanical interaction of cells, demonstrating the need for the global perspective in the study of morphogenetic flow
Ultrasonic tomography of green wood using a non-parametric imaging algorithm with reflected waves
International audience• Ultrasonic computed tomography in reflection was used to assess the integrity of green wood. Qualitative reflectivity images were obtained from back-scattered measurements by reflection tomography, like ultrasound in medical applications. • The reconstruction algorithm was designed using, in particular, a linear approximation of the forward problem (Born approximation) and based on the assumption that a transversal cross section of wood is isotropic. The experimental device was composed of only one rotating emitter–receiver transducer to record and compute the projections. In this specific case, a tomographic projection was directly associated with a recorded signal. The qualitative aspect of this imaging technique was validated by performing a numerical simulation and tested on a small diameter green wood (Picea abies) log. • The images obtained were geometrically accurate considering the internal inclusions. It was, however, not possible in the simulation to differentiate the object shape from the background (coupling medium) because the reflectivity value associated with the object was too low. The image obtained with the spruce sample mainly showed the position of the bark as indicated by a very high contrast area. The proportion of transmitted energy was, however, sufficient to reconstruct the artificial inclusion within the sample
Laser-induced fluorescence studies of HfF+ produced by autoionization
Autoionization of Rydberg states of HfF, prepared using the optical-optical
double resonance (OODR) technique, holds promise to create HfF+ in a particular
Zeeman level of a rovibronic state for an electron electric dipole moment
(eEDM) search. We characterize a vibronic band of Rydberg HfF at 54 cm-1 above
the lowest ionization threshold and directly probe the state of the ions formed
from this vibronic band by performing laser-induced fluorescence (LIF) on the
ions. The Rydberg HfF molecules show a propensity to decay into only a few ion
rotational states of a given parity and are found to preserve their orientation
qualitatively upon autoionization. We show empirically that we can create 30%
of the total ion yield in a particular |J+,M+> state and present a simplified
model describing autoionization from a given Rydberg state that assumes no
angular dynamics.Comment: 8 pages, 5 figure
Transport of indirect excitons in ZnO quantum wells
We report on spatially- and time-resolved emission measurements and
observation of transport of indirect excitons in ZnO/MgZnO wide single quantum
wells
Identification of the metallurgical parameters explaining the corrosion susceptibility in a 2050 aluminium alloy
The corrosion behaviour of a 2050 aluminium alloy was studied in a NaCl solution. The structure ofprecipitation did not fully explain the susceptibility to intergranular (in the -T34 state) and intragran-ular corrosion for the aged state (the -T8 state). A relationship between the nature of interfaces, thegrains characteristics (size, internal misorientation and orientation according to the plane exposed tothe electrolyte) on one hand and the corrosion susceptibility of the alloy on the other hand was clearlyestablished. Galvanic coupling between grains with different internal misorientations helped to explainthe intergranular corrosion susceptibility of the -T34 state
Optical microcavity with semiconducting single-wall carbon nanotubes
We report studies of optical Fabry-Perot microcavities based on
semiconducting single-wall carbon nanotubes with a quality factor of 160. We
experimentally demonstrate a huge photoluminescence signal enhancement by a
factor of 30 in comparison with the identical film and by a factor of 180 if
compared with a thin film containing non-purified (8,7) nanotubes. Futhermore,
the spectral full-width at half-maximum of the photo-induced emission is
reduced down to 8 nm with very good directivity at a wavelength of about 1.3
m. Such results prove the great potential of carbon nanotubes for photonic
applications
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