The structural requirements of histone deacetylase (hdac) inhibitors: suberoylanilide hydroxamic acid (saha) analogues modified at c3, c6, and c7 positions enhance selectivity

Histone deacetylase (HDAC) proteins are targets for drug design towards the treatment of cancers since overexpression of HDAC is linked to cancer. Several HDAC inhibitors, including the FDA approved drug suberoylanilide hydroxamic acid (SAHA, Vorinostat), have cleared clinical trials and emerged as anti-cancer drugs. However, SAHA inhibits all of the 11 metal ion-dependent HDAC proteins. Therefore, we synthesized several libraries of small molecule HDAC inhibitors based on SAHA to help understand the structural requirements of inhibitory potency and isoform selectivity. In previous work, SAHA analogues functionalized at the C2 position (C2-SAHA analogues) near the metal binding hydroxamic acid displayed decreased inhibitory activity compared to the parent compound, SAHA. The lack of potency of the C2 library indicated that limited flexibility exists in the HDAC active site near the hydroxamic acid. Therefore, we theorized the substituents on the C3, C4, C5, C6, and C7 positions would display more potent inhibition compared to the C2-SAHA library due to the solvent exposed location. Interestingly, while the C2-SAHA analogues containing any substituents were poor potent, the C3-SAHA analogue with a methyl substituent displayed potency, . The potency of the remaining analogues decreased with increasing size of the C3 substituents. Moreover, the C6-SAHA phenyl analogue even displayed potency in the submicromolar range. Finally, most of the C7-SAHA analogues displayed equal or greater potency compared to SAHA. The results indicate that more flexibility in the HDAC active site exists closer to the capping group region near the C6 and C7 position, while only modest flexibility exists in the bottom of the active site near the C2 and C3 position. After analyzing the potency of SAHA analogues, isoform selective inhibition of the individual compounds was evaluated. Seven of the SAHA analogues demonstrated selectivity. The C3-SAHA ethyl-substituted analogue showed preference for HDAC6 over HDAC1 and HDAC3 even though it displayed decreased potency. The C6-SAHA analogues displayed diverse selectivity; the C6-SAHA methyl variant displayed preference for class I, t-butyl variant showed a dual-HDAC1 and HDAC6 selectivity, and 2-ethylhexyl variant showed HDAC3-selectivity. The C7-SAHA analogues displayed selective inhibition as well; the C7-SAHA pyridylmethyl and anthracenylmethyl variants displayed a dual-HDAC1 and HDAC6 selectivity, and naphthylmethyl variant showed HDAC3-selectivity. The interesting potency and selectivity of linker-modified SAHA analogues suggest that the linker region substituents can be exploited in the design of new anti-cancer drugs

A generic hybrid model for the simulation of three-dimensional bulk elastodynamics for use in nondestructive evaluation

A three-dimensional (3-D) generic hybrid model is developed for the simulation of elastic waves in applications in nondestructive evaluation (NDE) that efficiently links different solution strategies but, crucially, is independent of the particular schemes employed. This is an important step forward in facilitating rapid and accurate large-scale simulations, and this advances the two-dimensional (2-D) generic hybrid methodology recently developed by the authors. The hybrid model provides an efficient and effective tool for creating highly accurate simulations that model the wave propagation and scattering, enabling the interpretation of inspection data; the new methodology is verified against other numerical simulations. Furthermore, its deployment to simulate wave reflection from side-drilled holes (SDHs), comparing the results with experimental measurements, provides a realistic demonstration as well as further validation

An Intelligent Safety System for Human-Centered Semi-Autonomous Vehicles

Nowadays, automobile manufacturers make efforts to develop ways to make cars fully safe. Monitoring driver's actions by computer vision techniques to detect driving mistakes in real-time and then planning for autonomous driving to avoid vehicle collisions is one of the most important issues that has been investigated in the machine vision and Intelligent Transportation Systems (ITS). The main goal of this study is to prevent accidents caused by fatigue, drowsiness, and driver distraction. To avoid these incidents, this paper proposes an integrated safety system that continuously monitors the driver's attention and vehicle surroundings, and finally decides whether the actual steering control status is safe or not. For this purpose, we equipped an ordinary car called FARAZ with a vision system consisting of four mounted cameras along with a universal car tool for communicating with surrounding factory-installed sensors and other car systems, and sending commands to actuators. The proposed system leverages a scene understanding pipeline using deep convolutional encoder-decoder networks and a driver state detection pipeline. We have been identifying and assessing domestic capabilities for the development of technologies specifically of the ordinary vehicles in order to manufacture smart cars and eke providing an intelligent system to increase safety and to assist the driver in various conditions/situations.Comment: 15 pages and 5 figures, Submitted to the international conference on Contemporary issues in Data Science (CiDaS 2019), Learn more about this project at https://iasbs.ac.ir/~ansari/fara

Rough surface reconstruction of real surfaces for numerical simulations of ultrasonic wave scattering

The scattering of waves by rough surfaces plays a significant role in many fields of physical sciences including ultrasonics where failure surfaces are often rough and their accurate identification is critical. The prediction of the strength of scattering can be hampered when the roughness is not adequately characterised and this is a particular issue when the surface roughness is within an order of the incident wavelength. Here we develop a methodology to reconstruct, and accurately represent, rough surfaces using an AutoRegressive (AR) process that then allows for rapid numerical simulations of ultrasonic wave rough surface scattering in three dimensions. Gaussian, exponential and AR surfaces are reconstructed based on real surface data and the statistics of the surfaces are compared with each other. The statistics from the AR surfaces agree well with those from actual rough surfaces, taken from experimental samples, in terms of the heights as well as the gradients, which are the two main factors in accurately predicting the wave scattering intensities. Ultrasonic rough surface scattering is simulated numerically using the Kirchhoff approximation, and comparisons with Gaussian, exponential, AR and real sample surfaces are performed; scattering intensities found using AR surfaces show the best agreement with the real sample surfaces

Non-simply-laced Lie algebras via F theory strings

In order to describe the appearance in F theory of the non--simply--laced Lie algebras, we use the representation of symmetry enhancements by means of string junctions. After an introduction to the techniques used to describe symmetry enhancement, that is algebraic geometry, BPS states analysis and string junctions, we concentrate on the latter. We give an explicit description of the folding of D_{2n} to B_n of the folding of E_6 to F_4 and that of D_4 to G_2 in terms of junctions and Jordan strings. We also discuss the case of C_n, but we are unable in this case to provide a string interpretation.Comment: 24 pages, 3 figure

Growth and dislocation studies of β-HMX

Background: The defect structure of organic materials is important as it plays a major role in their crystal growth properties. It also can play a subcritical role in “hot-spot” detonation processes of energetics and one such energetic is cyclotetramethylene-tetranitramine, in the commonly used beta form (β-HMX). Results: The as-grown crystals grown by evaporation from acetone show prismatic, tabular and columnar habits, all with {011}, {110}, (010) and (101) faces. Etching on (010) surfaces revealed three different types of etch pits, two of which could be identified with either pure screw or pure edge dislocations, the third is shown to be an artifact of the twinning process that this material undergoes. Examination of the {011} and {110} surfaces show only one type of etch pit on each surface; however their natural asymmetry precludes the easy identification of their Burgers vector or dislocation type. Etching of cleaved {011} surfaces demonstrates that the etch pits can be associated with line dislocations. All dislocations appear randomly on the crystal surfaces and do not form alignments characteristic of mechanical deformation by dislocation slip. Conclusions: Crystals of β-HMX grown from acetone show good morphological agreement with that predicted by modelling, with three distinct crystal habits observed depending upon the supersaturation of the growth solution. Prismatic habit was favoured at low supersaturation, while tabular and columnar crystals were predominant at higher super saturations. The twin plane in β-HMX was identified as a (101) reflection plane. The low plasticity of β-HMX is shown by the lack of etch pit alignments corresponding to mechanically induced dislocation arrays. On untwinned {010} faces, two types of dislocations exist, pure edge dislocations with b = [010] and pure screw dislocations with b = [010]. On twinned (010) faces, a third dislocation type exists and it is proposed that these pits are associated with pure screw dislocations with b = [010]