ACE2, the Receptor that Enables Infection by SARS-CoV-2: Biochemistry,Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

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.     

Interleukin-1β Modulation of the Mechanobiology of Primary Human Pulmonary Fibroblasts: Potential Implications in Lung Repair

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.     

Hydrogen adsorption studies in micro-size cobalt dots

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.     

The Possibilities of Community OR in a Third World Country

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.     

A new family of heparin-binding growth/differentiation factors: increased midkine expression in Wilms' tumor and other human carcinomas

Midkine (MK) and heparin-binding growth-associated molecule/pleiotrophin form a new family of heparin-binding growth/differentiation factors. We studied MK gene expression in human tumors. In normal human reference tissues, MK was highly expressed in the mucosal tissue of the small intestine, moderately in the thyroid, weakly in the tissues of the lung, colon, stomach, kidney, and spleen, and not at all in the liver. All of 6 surgically removed specimens of Wilms' tumor highly expressed MK. Also, a moderate to intense level of MK expression was noted in the majority of surgically removed hepatocellular carcinomas. The MK mRNA level was analyzed in a number of cultured and nude mice-transplanted lines of human tumors. In stomach, colon, pancreatic, lung, and esophageal carcinomas, a moderate to high level of MK expression was found in the majority of them. These results suggest an important role of MK in the development and/or biological behavior of tumors and raised a possibility to use MK as a diagnostic marker. Heparin-binding growth associated molecule/pleiotrophin mRNA was low or scarcely detectable in samples analyzed thus far except for significant levels of the expression that were observed in PA-1 teratocarcinoma cells and in some surgical specimens of Wilms' tumor.     

Using memory and fuzzy rules in a co-operative multi-thread strategy for optimization

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).     

A survey on approaches to gridification

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.