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1.
Lissy Z. F. Gross Mariana Sacerdoti Prof. Albrecht Piiper Prof. Stefan Zeuzem Dr. Alejandro E. Leroux Dr. Ricardo M. Biondi 《ChemMedChem》2020,15(18):1682-1690
Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID-19). Thus, ACE2 is a potential target for drugs that disrupt the interaction of human cells with SARS-CoV-2 to abolish infection. There is also interest in drugs that inhibit or activate ACE2, that is, for cardiovascular disorders or colitis. Compounds binding at alternative sites could allosterically affect the interaction with the spike protein. Herein, we review biochemical, chemical biology, and structural information on ACE2, including the recent cryoEM structures of full-length ACE2. We conclude that ACE2 is very dynamic and that allosteric drugs could be developed to target ACE2. At the time of the 2020 pandemic, we suggest that available ACE2 inhibitors or activators in advanced development should be tested for their ability to allosterically displace the interaction between ACE2 and the spike protein. 相似文献
2.
Marta Gabasa Marselina Arshakyan Alejandro Llorente Lourdes Chuli-Peris Irina Pavelescu Antoni Xaubet Javier Pereda Jordi Alcaraz 《International journal of molecular sciences》2020,21(22)
Pro-inflammatory cytokines like interleukin-1β (IL-1β) are upregulated during early responses to tissue damage and are expected to transiently compromise the mechanical microenvironment. Fibroblasts are key regulators of tissue mechanics in the lungs and other organs. However, the effects of IL-1β on fibroblast mechanics and functions remain unclear. Here we treated human pulmonary fibroblasts from control donors with IL-1β and used Atomic Force Microscopy to unveil that IL-1β significantly reduces the stiffness of fibroblasts concomitantly with a downregulation of filamentous actin (F-actin) and alpha-smooth muscle (α-SMA). Likewise, COL1A1 mRNA was reduced, whereas that of collagenases MMP1 and MMP2 were upregulated, favoring a reduction of type-I collagen. These mechanobiology changes were functionally associated with reduced proliferation and enhanced migration upon IL-1β stimulation, which could facilitate lung repair by drawing fibroblasts to sites of tissue damage. Our observations reveal that IL-1β may reduce local tissue rigidity by acting both intracellularly and extracellularly through the downregulation of fibroblast contractility and type I collagen deposition, respectively. These IL-1β-dependent mechanical effects may enhance lung repair further by locally increasing pulmonary tissue compliance to preserve normal lung distension and function. Moreover, our results support that IL-1β provides innate anti-fibrotic protection that may be relevant during the early stages of lung repair. 相似文献
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4.
Christian P. Romero Jonathan I. Avila Edgardo Cisternas Guerau B. Cabrera Alejandro L. Cabrera Kristiaan Temst Margriet J. Van Bael 《Journal of Materials Science》2007,42(18):7667-7672
Hydrogen desorption curves were obtained from a sample composed of a square arrangement of Co dots with average diameter of
4.4 μm, separated by a distance of 11.6 μm. A macroscopic sample of Co dots grown on a 2.5 × 2.5 cm Si substrate was made
by standard lithographic techniques and used in these experiments. Thermal programmed desorption (TPD) was performed under
ultra-high vacuum conditions. Hydrogen TPD curves were obtained from a 1 × 1 cm Co dots samples displaying a maximum of intensity
at 425 K. Hydrogen TPD curve was also obtained from 1 cm× 1 cm samples of Co films and Co foils for comparison. The hydrogen
TPD curves have decreasing intensity from the Co foils to the Co dots and finally to the Co films. This indicates that there
are more sites for hydrogen adsorption on the Co dots than in the Co films. This is a surprising result because there is approximately
8.7 times less Co atoms exposed in the Co dots that in the Co film sample. A desorption energy of 27 kcal/mol was obtained
for the Co dots suggesting that hydrogen is adsorbed on an hcp hollow site of the Co dot crystalline structure. 相似文献
5.
This paper shows a few possibilities for the application of Community OR in a Third World country based on experience in Venezuela. These possibilities are discussed in a framework of the relationship between the state and community organizations. Emphasis lies in showing that Community OR in Venezuela requires a deep critical commitment to emancipation in order to help community organizations develop in a rather hostile environment. Lastly, results in dealing with community organizations in Venezuela using the Interpretive Systemology approach are presented. 相似文献
6.
The hypothesis of Geisler (Brain Res. 212 (1981) 198-201), in which the different spontaneous-rate classes of primary auditory neurons were accounted for by the different sizes of uniquantal EPSPs relative to the gap between resting membrane and threshold potentials, was represented with an expanded model which included relative refractory effects. The spike rates generated by the expanded model, when plotted vs. estimated sound level, are qualitatively similar to those of experimentally obtained rate-level curves. The hypothesis is also consistent with recent ultrastructural data which suggest that average quantal-release rates for any particular primary auditory neuron are inversely related to its spontaneous rate. The model's recovery processes following spike generation (hazard functions) are also similar to those observed experimentally. 相似文献
7.
In this article, we analyze a co-operative multi-thread search-based optimization strategy, where each solver thread represents a different optimization algorithm (or the same one with different settings), and they are all controlled by a centralized co-ordinator. We also propose the use of memory to keep track of both the state of the individual threads and the obtained solutions. Based on this memory, a very simple fuzzy rule base is used to control the system behavior.We also present the results of three computational experiments. The first of these checks the strategy by comparing it with an independent search strategy and a sequential algorithm, and the superiority of the co-operative scheme is confirmed. The second analyzes how definition of the threads affects the quality of the results, and the importance of there being a balanced set between intensification and diversification is corroborated. The third explores the use of memory with two different fuzzy rules, and the results indicate that the best combination is to use memory together with two rules (solver dependent and solver independent ones) (although this combination should not be activated at the beginning of the search in order to avoid premature convergence). 相似文献
8.
9.
The Grid shows itself as a globally distributed computing environment, in which hardware and software resources are virtualized to transparently provide applications with vast capabilities. Just like the electrical power grid, the Grid aims at offering a powerful yet easy‐to‐use computing infrastructure to which applications can be easily ‘plugged’ and efficiently executed. Unfortunately, it is still very difficult to Grid‐enable applications, since current tools force users to take into account many details when adapting applications to run on the Grid. In this paper, we survey some of the recent efforts in providing tools for easy gridification of applications and propose several taxonomies to identify approaches followed in the materialization of such tools. We conclude this paper by describing common features among the proposed approaches, and by pointing out open issues and future directions in the research and development of gridification methods. Copyright © 2007 John Wiley & Sons, Ltd. 相似文献
10.
L Martinez de Haro P Parrilla A Ortiz G Morales J Cifuentes D Perez D Videla 《Canadian Metallurgical Quarterly》1993,88(4):525-529
The relationship between manometric and pH-metric data was studied in a group of 50 patients with symptoms of gastroesophageal reflux. Using a multiple regression analysis, we found that the total percentage of reflux was significantly correlated to the infradiaphragmatic length and resting pressure of the lower esophageal sphincter and also to the mean amplitude of the contractile waves of the distal esophagus, thus revealing the important role of these factors in the antireflux mechanism. When the patients were divided into groups according to their manometric characteristics and the values of the various pH-metric parameters between these groups compared using a one-way analysis of variance, we found that the amplitude of the contractile waves and the percentage of deglutitions without response were related not only to the total percentage of reflux but also to the number of reflux episodes of greater than 5 min duration and to the duration of the longest episode. This shows that prolonged exposure of the esophageal mucosa to the refluxed material may be due, in part, to an alteration in the capacity for esophageal clearing. 相似文献