Development of Selective Inhibitors for Human Aldehyde Dehydrogenase 3A1 (ALDH3A1) for the Enhancement of Cyclophosphamide Cytotoxicity

Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in many cellular oxidative processes, including cancer chemoresistance, by metabolizing activated forms of oxazaphosphorine drugs such as cyclophosphamide (CP) and its analogues, such as mafosfamide (MF), ifosfamide (IFM), and 4‐hydroperoxycyclophosphamide (4‐HPCP). Compounds that can selectively target ALDH3A1 could permit delineation of its roles in these processes and could restore chemosensitivity in cancer cells that express this isoenzyme. Here we report the detailed kinetic and structural characterization of an ALDH3A1‐selective inhibitor, CB29, previously identified in a high‐throughput screen. Kinetic and crystallographic studies demonstrate that CB29 binds within the aldehyde substrate‐binding site of ALDH3A1. Cellular proliferation of ALDH3A1‐expressing lung adenocarcinoma (A549) and glioblastoma (SF767) cell lines, as well as ALDH3A1 non‐expressing lung fibroblast (CCD‐13Lu) cells, is unaffected by treatment with CB29 and its analogues alone. However, sensitivity toward the anti‐proliferative effects of mafosfamide is enhanced by treatment with CB29 and its analogue in the tumor cells. In contrast, the sensitivity of CCD‐13Lu cells toward mafosfamide was unaffected by the addition of these same compounds. CB29 is chemically distinct from the previously reported small‐molecule inhibitors of ALDH isoenzymes and does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2 isoenzymes at concentrations up to 250 μM . Thus, CB29 is a novel small molecule inhibitor of ALDH3A1, which might be useful as a chemical tool to delineate the role of ALDH3A1 in numerous metabolic pathways, including sensitizing ALDH3A1‐positive cancer cells to oxazaphosphorines.     

Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI.     

Multidisciplinary approach for investigating the hot corrosion behavior of thermal barrier coatings

Herein, we propose a new multidisciplinary approach for investigating the corrosion behavior of thermal barrier coatings, combining the thermal-gradient mechanical fatigue method with hot corrosion tests. Corrosive salts (Na₂SO₄; V₂O₅) of varying concentrations (10−20 mg/cm²) were deposited on the surface of yttria-stabilized zirconia (YSZ) coatings to evaluate the microstructural changes occurring during the reaction, via thermal graded mechanical fatigue tests. The tests were conducted at a surface temperature of 1150 °C in 10 min cycles and underwent applied uniaxial tensile loads. The corrosion tests show that the ZrV₂O₇ plays an important role as an intermediate in the collapse of the lamellar structures during the reaction, which results from the repetitive precipitation of V₂O₅ and m-ZrO₂ from the ZrV₂O₇. The microstructure of corroded YSZ coatings exhibited a different degradation mechanism under a thermomechanical environment, compared with the testing under isothermal atmospheric conditions.     

Polyaniline-graphene composites with a three-dimensional array-based nanostructure for high-performance supercapacitors

The ordered three-dimensional arrays conjugative polyaniline–graphene composites were fabricated through in-situ chemical oxidative polymerization of aniline in the presence of amino-functionalized graphene sheets (AFG), in which polyaniline (PANI) polymerization is initiated by those amino groups on graphene. Therefore, the resulting PANI nanorod arrays are integrated into a large conjugative frame based on chemical covalent bond incorporation. The structure and properties of these resulting composites were characterized and evaluated by combining Fourier transform infrared spectroscopy, Ultraviolet–visible absorption spectroscopy, Raman spectroscope, X-ray diffraction spectroscopy analyses and electrochemical techniques. Morphology was studied by scanning electron microscopy. It was found that the density and size of ordered PANI nanorod arrays can be manipulated by simply varying the amount of AFG. Such resultant composite exhibits high special capacitance, together with low electrical resistance and excellent cycling stability attributed to conjugative covalent bonds and ordered PANI nanorod arrays. Meanwhile, a new time-dependent heterogeneous nucleation mechanism was proposed and investigated in detail.     

直线电机伺服定位系统时间最优鲁棒控制

无铁心永磁同步直线电机伺服定位系统点位运动控制中Bang-Bang控制满足庞特里亚金极小值原理条件.为确定Bang-Bang控制中的切换时间,提出一种基于粒子群优化算法的切换时间计算方法.为保证电机系统的稳定性和鲁棒性,提出先用Bang-Bang控制后用快速终端滑模控制的两阶段控制方案.系统起始阶段采用Bang-Ban...     

Monitoring Biosensor Activity in Living Cells with Fluorescence Lifetime Imaging Microscopy

Live-cell microscopy is now routinely used to monitor the activities of the genetically encoded biosensor proteins that are designed to directly measure specific cell signaling events inside cells, tissues, or organisms. Most fluorescent biosensor proteins rely on Förster resonance energy transfer (FRET) to report conformational changes in the protein that occur in response to signaling events, and this is commonly measured with intensity-based ratiometric imaging methods. An alternative method for monitoring the activities of the FRET-based biosensor proteins is fluorescence lifetime imaging microscopy (FLIM). FLIM measurements are made in the time domain, and are not affected by factors that commonly limit intensity measurements. In this review, we describe the use of the digital frequency domain (FD) FLIM method for the analysis of FRET signals. We illustrate the methods necessary for the calibration of the FD FLIM system, and demonstrate the analysis of data obtained from cells expressing “FRET standard” fusion proteins. We then use the FLIM-FRET approach to monitor the changes in activities of two different biosensor proteins in specific regions of single living cells. Importantly, the factors required for the accurate determination and reproducibility of lifetime measurements are described in detail.     

Solvent-free selective oximation of aldehydes using facile and reusable heterogenous polyoxometalate

The efficiency of various heteropoly compounds as well-known solid acids was investigated and a new procedure was developed for synthesis of Z-isomers of aldoximes. This method consistently has the advantage of excellent yields and short reaction times. Furthermore, the catalyst could be easily recovered after completion of the reaction and reused without a considerable loss of its activity.     

Statistical characterization of a real video on demand service: User behaviour and streaming-media workload analysis

The video on demand service characterized in this article has surpassed 4 years of service, and the access log database stores information of more than 160,000 reproductions and 900 videos. The wide variety of subjects, the range of content lengths and a frequent update of contents (several new videos every day), clearly differentiate this study from other previous research limited to specific users, subjects or environments. We present a statistical study of user behaviour and streaming traffic, analyzing session characteristics, mistaken reproductions, amount of media delivered, number and length of pauses and jumps in the reproduction, popularity and daily access profile. The results of the analysis will allow us to develop simulation models and workload generators to evaluate different scenarios and situations of the service.     

Determination of Most Economical Scrapers Fleet

Scrapers are valuable construction equipment for large earthmoving operations. Their production rates vary widely as they depend on the equipment performance, operation’s travel time, and haul-road conditions. Determining the most economical selection of the size, model, and number of scrapers is a rather tedious process that involves repetitive calculations. A spreadsheet application was created in order to facilitate such calculations and select the most economical scraper from the list of available equipment for the job under consideration. The application is made of seven spreadsheets containing a scrapers’ database, performance charts, soil properties, and other supporting worksheets. The application provides a user interface to solicit all data entries specific to a project. Once the user enters the required data the system compares the production rate, time required for the job, determines the estimated unit cost for each scraper in the database, and recommends the most economical selection.