38 research outputs found
Influence of the Accepted Concrete Deformation Diagrams on the Results of Calculating Bending Reinforced Concrete Elements
The article describes the influence of various types of concrete deformation diagrams on the accuracy of the deformational analysis of a bending concrete element. By analyzing different forms of diagrams, we get results with the help of the software "Beta 4.2 (5.0)". After getting the results, conclusions are drawn, according to particular qualities concerning the investigated element
Concerning the Question of Calculating a Beam with a Hinge-Rod Chain
We consider the calculation of a statically indeterminate combined system consisting of a beam and a hinge-rod chain of a general form for the action of an arbitrary vertical load. The qualitative regularities of the internal forces in the rods of the hinge-rod chain are established. Depending on the scheme of interaction of the chain with the beam, the calculation of combined systems with and without a horizontal reaction support is considered. Finite formulas are obtained for determining the internal forces in such systems
Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines.
Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is over expressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth and the di-methylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first co-crystal structure of G9a with a small molecule inhibitor, was obtained. Based on the structural insights revealed by this co-crystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison Ki = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date
A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells
Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation
A single active catalytic site is sufficient to promote transport in P-glycoprotein
P-glycoprotein (Pgp) is an ABC transporter responsible for
the ATP-dependent efflux of chemotherapeutic compounds from
multidrug resistant cancer cells. Better understanding of the
molecular mechanism of Pgp-mediated transport could promote
rational drug design to circumvent multidrug resistance. By
measuring drug binding affinity and reactivity to a
conformation-sensitive antibody we show here that nucleotide
binding drives Pgp from a high to a low substrate-affinity
state and this switch coincides with the flip from the
inward- to the outward-facing conformation. Furthermore, the
outward-facing conformation survives ATP hydrolysis: the
post-hydrolytic complex is stabilized by vanadate, and the
slow recovery from this state requires two functional
catalytic sites. The catalytically inactive double Walker A
mutant is stabilized in a high substrate affinity inward-open
conformation, but mutants with one intact catalytic center
preserve their ability to hydrolyze ATP and to promote drug
transport, suggesting that the two catalytic sites are
randomly recruited for ATP hydrolysis