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1.
Water Resources Management - The water evaluation and planning (WEAP) approach and the invasive weed optimization algorithm (IWOA) are herein employed to determine the optimal operating policies in...  相似文献   
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Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.  相似文献   
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Polyethersulphone (PES) is an aromatic thermoplastic, at low environmental impact, evaluated in this work as a promising candidate for new polymer electrolytes in the PEMFCs technology. A sulfonation procedure has been tuned in order to graft sulfonic acid groups on the polymer chains (sPES) and to make it hydrophilic. Homogeneous membranes with different polymer's sulfonation degrees (SD%) have demonstrated excellent mechanical properties and very low permeability toward methanol (important in the DMFCs), even if low proton conductivity. Nanocomposite sPES membranes were prepared by dispersion of highly hydrophilic lamellar particles such as layered double hydroxide (LDH) in the polymer. Deep investigations performed by a combination of PFG-NMR, EIS, XRD, DMA, and scanning electron microscopy have evidenced the exfoliation of the lamellae in polymer matrix. However, a certain anisotropy was evidenced both in the morphology and molecular diffusion, favored in the longitudinal direction (parallel to surface), while completely inhibited in the cross-section. This finding is most likely induced by the polymer structure, therefore particular attention must be paid to the choice of the filler and preparation of the composites. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47884.  相似文献   
5.
The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies.  相似文献   
6.
Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp3 hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC50 value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.  相似文献   
7.
Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.  相似文献   
8.
Environmental factors such as oxygen, temperature, and microbial species may have significant effects on decomposition of biodegradable polymers. A representative biodegradable, thermoplastic polymer, poly(3‐hydroxybutyrate‐co‐hydroxyvalerate) (PHBV), was decomposed in an aqueous medium under controlled laboratory conditions by soil microbes for the intrinsic degradation kinetics and the effects of the environmental factors on polymer biodegradation. The amount of proteins, including the PHBV depolymerases, that attached to the polymer surfaces was quite constant during the period of significant mass loss of the polymer specimens. The microbial polymer degradation followed a zero‐order rate model, so the residual mass fraction of PHBV films declined linearly with time. The mixed aerobic microbial organisms from fertile soil showed a higher activity of polymer degradation than an aerobic PHBV‐producing bacterium and the mixed anaerobes in the same soil. The mixed anaerobic microorganisms from barren soil decomposed the polymer at a slower rate than the anaerobes from fertile soil, and this was attributed to fewer microbial cells in the barren soil instead of the difference in the microbial species. The temperature effect on PHBV degradation can be described with an Arrhenius equation, and the activation energy is around 16 kcal/mol. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 205–213, 2003  相似文献   
9.
Using an integrated process of data and modeling in HRA   总被引:1,自引:0,他引:1  
The paper describes an approach taken to estimate the probabilities of failure associated with various railroad tasks to prevent accidents (principally collisions and derailments). These probabilities were estimated using an expert elicitation process that used partially relevant data available from a variety of databases and that were filtered and scaled to make them more directly relevant to the analyses being performed. Extensive qualitative studies were performed prior to the elicitation process to identify relevant contexts under which the tasks can be performed.  相似文献   
10.
The planimetric shifts in channel location of large alluvial rivers are a critical component in the creation of diverse structures and functions in riverine habitats. Engineered management schemes must also compensate for this type of channel change to protect resources and maintain navigation channels. The stability of the Lower Mississippi River channel was assessed through an analysis of historical records of channel position produced and archived by the United States Army Corps of Engineers. Channel location was recorded for the years 1765, 1820, 1881, 1915, 1930, 1937, 1960 and 1970. Channel stability was measured by two introduced metrics on a cell‐by‐cell basis: (1) the standard deviation of Euclidean distance to a channel cell for the entire period of record, and (2) the rate of Euclidean distance change between years in the period of record. At a coarse spatial scale, channel instability increased in the downstream direction. The variability of channel stability also increased in the downstream direction. Analysis of this variability identified alternating areas of high and low stability occurring with greater frequency as distance downstream increased. These findings are validated by past studies of channel stability along the Lower Mississippi River. As a result, the proposed metrics provide a consistent, quantitative, efficient and cost‐effective means of identifying areas of channel instability at several spatial scales. Copyright © 2006 John Wiley & Sons, Ltd.  相似文献   
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