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

A Corticothalamic Circuit Trades off Speed for Safety during Decision-Making under Motivational Conflict

Decisions to act while pursuing goals in the presence of danger must be made quickly but safely. Premature decisions risk injury or death, whereas postponing decisions risk goal loss. Here we show how mice resolve these competing demands. Using microstructural behavioral analyses, we identified the spatiotemporal dynamics of approach–avoidance decisions under motivational conflict in male mice. Then we used cognitive modeling to show that these dynamics reflect the speeded decision-making mechanisms used by humans and nonhuman primates, with mice trading off decision speed for safety of choice when danger loomed. Using calcium imaging in paraventricular thalamus and optogenetic inhibition of the prelimbic cortex to paraventricular thalamus pathway, we show that this speed-safety trade off occurs because increases in paraventricular thalamus activity increase decision caution, thereby increasing approach–avoid decision times in the presence of danger. Our findings demonstrate that a discrete brain circuit involving the paraventricular thalamus and its prefrontal input adjusts decision caution during motivational conflict, trading off decision speed for decision safety when danger is close. We identify the corticothalamic pathway as central to cognitive control during decision-making under conflict

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

Response of pulmonary artery intimal sarcoma to surgery, radiotherapy and chemotherapy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pulmonary artery intimal sarcoma is a rare disease with no characteristic symptoms. It is difficult to diagnose early and is frequently misdiagnosed as a pulmonary embolism.</p> <p>Case presentation</p> <p>Here we report a case of pulmonary artery intimal sarcoma in a 54-year-old woman presenting with complaints of shortness of breath on exertion. Echocardiography and a computed tomography scan showed that the right pulmonary artery trunk was blocked by a low-density mass. The patient was diagnosed with pulmonary artery intimal sarcoma by pathology and a complete mass resection was performed. After experiencing 10 months of disease-free survival, she was re-admitted because of the recurrence and metastasis of the tumor. Radiotherapy and chemotherapy were performed; however, only limited success was achieved. The patient died 15 months after the initial onset of symptoms.</p> <p>Conclusion</p> <p>Some patients with intimal sarcoma of the pulmonary artery can benefit from radiotherapy and chemotherapy as well as surgery.</p

The Microfloral Analysis of Secondary Caries Biofilm around Class I and Class II Composite and Amalgam Fillings

<p>Abstract</p> <p>Background</p> <p>Secondary caries is responsible for 60 percent of all replacement restorations in the typical dental practice. The diversity of the bacterial sources and the different types of filling materials could play a role in secondary caries. The aim of this study was to determine and compare the microbial spectrum of secondary caries biofilms around amalgam and composite resin restorations.</p> <p>Methods</p> <p>Clinical samples were collected from freshly extracted teeth diagnosed with clinical secondary caries. Samples were categorized into four groups according to the types of restoration materials and the classification of the cavity. Biofilms were harvested from the tooth-restoration interface using a dental explorer and after dilution were incubated on special agars. The bacteria were identified using the biochemical appraisal system. Statistical calculations were carried out using SPSS11.5 software to analyze the prevalence of the bacteria involved in secondary caries.</p> <p>Results</p> <p>Samples from a total of four groups were collected: two groups were collected from amalgam restorations, each had 21 samples from both Class I and Class II caries; and the other two groups were from composite resin restorations, each had 13 samples from both class I and class II caries. Our results showed: (1) Anaerobic species were dominant in both restoration materials. (2) In terms of the types of individual bacteria, no significant differences were found among the four groups according to the geometric mean of the detected bacteria (P > 0.05). However, there were significant differences among the detected bacteria within each group (P < 0.05). The composition of each bacterium had no statistical difference among the four groups (P > 0.05), but showed significant differences among the detected bacteria in each group (P < 0.05). (3) Among the four groups, there were no significant differences for the detection rate of each bacterium (P > 0.05), however, the detection rate of each bacterium within each group was statistically different among the detected bacteria (P < 0.05).</p> <p>Conclusions</p> <p>The proportion of obligatory anaerobic species was much greater than the facultative anaerobic species in the biofilm of secondary caries. Statistically, the materials of restoration and the location of secondary caries did not show any significant effects on the composition of the microflora.</p

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