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41.
Bahar M Deng Y Zhu X He S Pandharkar T Drew ME Navarro-Vázquez A Anklin C Gil RR Doskotch RW Werbovetz KA Kinghorn AD 《Bioorganic & medicinal chemistry letters》2011,21(9):2606-2610
Treatment of diseases such as African sleeping sickness and leishmaniasis often depends on relatively expensive or toxic drugs, and resistance to current chemotherapeutics is an issue in treating these diseases and malaria. In this study, a new semi-synthetic berberine analogue, 5,6-didehydro-8,8-diethyl-13-oxodihydroberberine chloride (1), showed nanomolar level potency against in vitro models of leishmaniasis, malaria, and trypanosomiasis as well as activity in an in vivo visceral leishmaniasis model. Since the synthetic starting material, berberine hemisulfate, is inexpensive, 8,8-dialkyl-substituted analogues of berberine may lead to a new class of affordable antiprotozoal compounds. 相似文献
42.
The morphogenesis of poxviruses such as vaccinia virus (VACV) sees the virion shape mature from spherical to brick-shaped. Trimeric capsomers of the VACV D13 protein form a transitory, stabilizing lattice on the surface of the initial spherical immature virus particle. The crystal structure of D13 reveals that this major scaffolding protein comprises?a double β barrel "jelly-roll" subunit arranged as pseudo-hexagonal trimers. These structural features are characteristic of the major capsid proteins of?a lineage of large icosahedral double-stranded DNA viruses including human adenovirus and the bacteriophages PRD1 and PM2. Structure-based phylogenetic analysis confirms that VACV belongs to this lineage, suggesting that (analogously to higher organism embryogenesis) early poxvirus morphogenesis reflects their evolution from a lineage of viruses sharing a common icosahedral ancestor. 相似文献
43.
44.
Walker JC Ratcliffe MB Zhang P Wallace AW Fata B Hsu EW Saloner D Guccione JM 《American journal of physiology. Heart and circulatory physiology》2005,289(2):H692-H700
Tagged MRI and finite-element (FE) analysis are valuable tools in analyzing cardiac mechanics. To determine systolic material parameters in three-dimensional stress-strain relationships, we used tagged MRI to validate FE models of left ventricular (LV) aneurysm. Five sheep underwent anteroapical myocardial infarction (25% of LV mass) and 22 wk later underwent tagged MRI. Asymmetric FE models of the LV were formed to in vivo geometry from MRI and included aneurysm material properties measured with biaxial stretching, LV pressure measurements, and myofiber helix angles measured with diffusion tensor MRI. Systolic material parameters were determined that enabled FE models to reproduce midwall, systolic myocardial strains from tagged MRI (630 +/- 187 strain comparisons/animal). When contractile stress equal to 40% of the myofiber stress was added transverse to the muscle fiber, myocardial strain agreement improved by 27% between FE model predictions and experimental measurements (RMS error decreased from 0.074 +/- 0.016 to 0.054 +/- 0.011, P < 0.05). In infarct border zone (BZ), end-systolic midwall stress was elevated in both fiber (24.2 +/- 2.7 to 29.9 +/- 2.4 kPa, P < 0.01) and cross-fiber (5.5 +/- 0.7 to 11.7 +/- 1.3 kPa, P = 0.02) directions relative to noninfarct regions. Contrary to previous hypotheses but consistent with biaxial stretching experiments, active cross-fiber stress development is an integral part of LV systole; FE analysis with only uniaxial contracting stress is insufficient. Stress calculations from these validated models show 24% increase in fiber stress and 115% increase in cross-fiber stress at the BZ relative to remote regions, which may contribute to LV remodeling. 相似文献
45.
46.
Growing evidence supports the view that enzymatic activity results from a subtle interplay between chemical kinetics and molecular motions. A systematic analysis is performed here to delineate the type and level of coupling between catalysis and conformational mechanics. The dynamics of a set of 98 enzymes representative of different EC classes are analyzed with the Gaussian network model (GNM) and compared with experimental data. In more than 70% of the examined enzymes, the global hinge centers predicted by the GNM are found to be colocalized with the catalytic sites experimentally identified. Low translational mobility (< 7%) is observed for the catalytic residues, consistent with the fine-tuned design of enzymes to achieve precise mechanochemical activities. Ligand binding sites, while closely neighboring catalytic sites, enjoy a moderate flexibility to accommodate the ligand binding. These findings could serve as additional criteria for assessing drug binding residues and could lessen the computational burden of substrate docking searches. 相似文献
47.
Mohd Jaafar F Attoui H Bahar MW Siebold C Sutton G Mertens PP De Micco P Stuart DI Grimes JM De Lamballerie X 《Structure (London, England : 1993)》2005,13(1):17-28
Banna virus (BAV: genus Seadornavirus, family Reoviridae) has a double-shelled morphology similar to rotavirus and bluetongue virus. The structure of BAV outer-capsid protein VP9 was determined by X-ray crystallography at 2.6 A resolution, revealing a trimeric molecule, held together by an N-terminal helical bundle, reminiscent of coiled-coil structures found in fusion-active proteins such as HIV gp41. The major domain of VP9 contains stacked beta sheets with marked structural similarities to the receptor binding protein VP8 of rotavirus. Anti-VP9 antibodies neutralize viral infectivity, and, remarkably, pretreatment of cells with trimeric VP9 increased viral infectivity, indicating that VP9 is involved in virus attachment to cell surface and subsequent internalization. Sequence similarities were also detected between BAV VP10 and VP5 portion of rotavirus VP4, suggesting that the receptor binding and internalization apparatus, which is a single gene product activated by proteoloysis in rotavirus, is the product of two separate genome segments in BAV. 相似文献
48.
The present study provides insights on the dominant mechanisms of motions of the nucleosome core particle and the changes in its functional dynamics in response to histone variants. Comparative analysis of the global dynamics of nucleosomes with native and variant H2A histones, using normal mode analysis revealed that the dynamics of the nucleosome is highly symmetric, and its interaction with the nucleosomal DNA plays a vital role in its regulation. The collective dynamics of nucleosomes are predicted to be dominated by two types of large-scale motions: (1) a global stretching-compression of nucleosome along the dyad axis by which the nucleosome undergoes a breathing motion with a massive distortion of nucleosomal DNA, modulated by histone-DNA interactions; and (2) the flipping (or bending) of both the sides of the nucleosome in an out-of-plane fashion with respect to the dyad axis, originated by the highly dynamic N-termini of H3 and (H2A.Z-H2B) dimer in agreement with the experimentally observed perturbed dynamics of the particular N-terminus under physiological conditions. In general, the nucleosomes with variant histones exhibit higher mobilities and weaker correlations between internal motions compared to the nucleosome containing ordinary histones. The differences are more pronounced at the L1 and L2 loops of the respective monomers H2B and H2A, and at the N-termini of the monomers H3 and H4, all of which closely interact with the wrapping DNA. 相似文献
49.
The purpose of this research was to investigate the effects of different concentrations of polymer and sucrose stearate, aluminum
tristearate as dispersing agents on microsphere properties and performance. The yield values of microspheres were over the
78%, and the encapsulation efficiencies were found to be ∼735. Particle sizes of microspheres prepared with aluminum tristearate
were between 76 and 448 μm, while that of the microspheres containing sucrose stearate were between 521 and 2000 μm. Morphological
and physicochemical properties of microspheres were investigated by scanning electron micrography and differential scanning
calorimetry (DSC). DSC analysis indicated that verapamil hydrochloride formed a solid solution with acrylic polymers. In vitro
release studies were performed using the flow-through cell method. While ∼80% of drug was released from the microspheres containing
aluminum tristearate in 480 minutes, the same amount of drug was released from microspheres containing sucrose stearate in
only 60 minutes. Chemical structures and concentrations of the dispersing agents were clearly effective on the physical properties
of microspheres and their drug-release characteristics.
Published: February 24, 2006 相似文献
50.
The aerial parts of Crotalaria emarginella Vatke (Leguminosae) has afforded two triterpenes, characterized as 3alpha-hydroxy-arbor-12-ene-28-carboxylic acid, designated as crotalic acid (1), and 2beta,3beta,21-trihydroxy-arbor-12-ene-29-carboxylic acid, designated as emarginellic acid (2). The structures of the isolated products were elucidated on the basis of spectral and chemical studies. On screening the biological activity, the crotalic acid (1) exhibited a significant anti-inflammatory activity (dose: 10mg/kg), which showed 53% inhibitory effect. Whereas, the standard oxyphenyl butazone (100mg/kg) exhibited 69% inhibition with respect to carrageenan (0.05ml, 1%) used to cause inflammation in rat paw method. In addition, it also showed anti-hepatotoxic activity by 13-30% with respect to standard silybon-70 (35-57%) against CCl(4) induced toxicity in Wistar rats. 相似文献