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.     

Synthesis,characterization, fluorescence and redox features of new <Emphasis Type="Italic">vic</Emphasis>-dioxime ligand bearing pyrene and its metal complexes

A new vic-dioxime ligand, N,N′-bis(aminopyreneglyoxime) (LH₂), and its copper(II), nickel(II) and cobalt(II) metal complexes were synthesized and characterized by elemental analyses, IR, UVVIS and ¹H and ¹³C NMR spectra (for the ligand). Mononuclear complexes were synthesized by a reaction of ligand (LH₂) and salts of Co(II), Ni(II), and Cu(II) in ethanol. The complexes have the metal-ligand ratio of 1: 2 and metals are coordinated by N,N′ atoms of vicinal dioximes. The ligand acts in a polydentate fashion bending through nitrogen atoms in the presence of a base, as do most vic-dioximes. Detection of a H-bonding in the Co(II), Ni(II), and Cu(II) complexes by IR revealed the square-planar MN₄ coordination of mononuclear complexes. Fluorescent properties of the ligand and its complexes arise from pyrene units conjugated with a vic-dioxime moiety. Fluorescence emission spectra of the ligand showed a drastic decrease in its fluorescence intensity upon metal binding. The electrochemical properties of the complexes were studied by the cyclic voltammetry technique. The nickel complex displayed an irreversible oxidation process while the copper complex exhibited a quasi-reversible oxidation and reduction processes based on the copper Cu(II)/Cu(III) and Cu(II)/Cu(I) couples, respectively.     

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.     

A novel approach to modelling counter-current chromatography

Literature lists a number of counter-current chromatography (CCC) models that can predict the retention time and to a certain extent the peak width of a solute eluting from a CCC column. The approach described in this paper distinguishes itself from previous reports by relating all model parameters directly to column dimensions and experimental settings. Most importantly, this model can predict a chromatogram from scratch without resorting to traditional calibration using empirical values. The model validation with experimental results obtained across a range of CCC instruments demonstrated that the solute retention time, peak width, and peak resolution could be predicted within reasonable accuracy. Additionally, the effect of several process parameters, such as mobile phase flow rate, rotational speed of the column or β-value, showed that the model is robust and applicable to a wide range of CCC instruments. Overall, this model proved to be a useful tool for parameter estimation and, most significantly, separation optimisation.     

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.