TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.     

Comparison of calorimetric and IR-spectroscopic data for alcohols and alcoholic solutions

The heats of solution of alcohols in hexane can be considered as the energy necessary to break hydrogen bonds (H-bond). The amount of non H-bonded OH groups estimated from caloric data, are in good agreement with IR-spectroscopic data. Comparison of calorimetric and IR-spectroscopically determined H-bond energies permit the separation of intermolecular van der Waals effects from H-bond interactions. This separation shows that van der Waals interactions of alcohols or water should not be underestimated.     

含黄酮的三价铁配合物合成及其药理性质(英文)

3,3,4,7-四羟基黄酮与1,3-二环己基碳二亚胺在4-二甲胺吡啶存在下反应,得到2,2-双(3,3,4,7-四羟基黄酮)1,3-二环己基碳二亚胺。三价金属离子与上述合成得到的配体螯合,对此四面体结构的双核Fe(Ⅲ)配合物的血液学及病理学数据进行了讨论,同时研究了合成的配体作为螯合剂清除鼠肝胰组织中超载的铁的能力。结果表明作为口服药其作为双齿配体的螯合能力与市售用于治疗地中海贫血的药物"去铁敏"相近。     

Laser carbonitriding of alumina surface

Laser carbonitriding of alumina surfaces is examined. Temperature and stress fields developed during the laser heating of the substrate surface are predicted using the finite element method in line with the experimental conditions. The formation of Al(C, N) and AlN compounds in the surface region of irradiated workpiece is examined using X-ray Photoelectron Spectroscopy (XPS) and X-ray Diffraction (XRD). The microstructural and morphological changes in the laser irradiated region are examined using Scanning Electron Microscope (SEM). The microhardness of the resulting surface is measured and compared with the base material hardness. It is found that high temperature gradient is developed in the irradiated region, which in turn, results in high residual stress levels in this region. XPS and XRD data reveal the presence of Al (C, N) and AlN compounds in the surface region. The microhardness in the surface region of the laser treated workpiece increases significantly.     

An ILP and simulation model to optimize search and rescue helicopter operations

Maritime search and rescue (SAR) operations, conducted for rendering aid to the victims in need of help at sea, play a crucial role in dropping the number of causalities. Therefore, it is of high importance to organize SAR operations properly. In this paper, we compose a hybrid methodology which combines optimization and simulation to allocate SAR helicopters. First, we build an integer linear programming (ILP) model to provide an effective deployment plan and use it as an input to a simulation model which includes constraints that the ILP model cannot tackle. Next, using a rule-based algorithm, we generate alternative solutions and seek better plans that exist in the vicinity of the ILP model solution. We perform our methodology on the historical incident data in the Aegean Sea region. Results show that the hybrid methodology we adopted leads to a more effective utilization of resources than the optimization model alone.     

An analysis of p-median location problem: Effects of backup service level and demand assignment policy

Any solution to facility location problems will consider determining the best suitable locations with respect to certain criteria. Among different types of location problems, involving emergency service system (ESSs) are one of the most widely studied in the literature, and solutions to these problems will mostly aim to minimize the mean response time to demands. In practice, however, a demand may not be served from its nearest facility if that facility is engaged in serving other demands. This makes it a requirement to assign backup services so as to improve response time and service quality. The level of backup service is a key, strategic-level planning factor, and must be taken into consideration carefully. Moreover, in emergency service operations conducted in congested demand regions, demand assignment policy is another important factor that affects the system performance. Models failing to adopt sufficient levels of backup service and realistic demand assignment policies may significantly deteriorate the system performance.Considering the classic p-median problem (pMP) location model, this paper investigates the effects of backup service level, demand assignment policy, demand density, and number of facilities and their locations on the solution performance in terms of multiple metrics. For this purpose, we adopt a combined optimization and simulation approach. We will first modify the classic pMP to account for distances to backup services. Next, we employ a discrete event simulation to evaluate the performance of location schemes obtained from the deterministic mathematical model. Our results provide insights for decision-makers while planning ESS operations.     

Investigation of antioxidant vitamins (A, E, C) and lipid peroxidation levels in rats injected N-(1,3-benzothiazol-2-yl)-N-(4,5-dihydro-1H-imidazol-2-yl) amine

The present study examined the influence of synthetic N-(1,3-benzothiazol-2-yl)-N-(4,5-dihydro-1H-imidazol-2-yl) amine (2-Amdz) on levels of vitamins A, E and C and malondialdehyde (MDA) in rats. A total of 30 rats, divided into two groups, were used in the study. The control group was given only a subcutaneous injection of 250 microL 75% ethanol, every other day. The other group of rats was administered a subcutaneous injection of 2-Amdz (25 mg kg-1, dissolved in 250 microL of 75% ethanol). Injections were continued for 16 days. After the application of 2-Amdz for 16 days, the serum levels of vitamins A, E and C and malondialdehyde (MDA) were determined by HPLC. The serum vitamin A, E, and C levels decreased significantly compared to controls (p<0.05) whereas serum MDA levels were higher than control levels (p<0.005). As a result, it can be suggested that 2-Amdz induced a severe stress and more importantly, increased the amount of free radicals and significantly decreased the levels of serum antioxidant vitamins.