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.     

Synergistic antimicrobial effect of lactocin AL705 and nisin combined with organic acid salts against Listeria innocua 7 in broth and a hard cheese

The effectiveness of antimicrobial mixtures against Listeria innocua 7, used as a L. monocytogenes surrogate, was investigated in broth and a food system. Synergistic effects were found for nisin (Nis), potassium sorbate (PS), calcium propionate (CP) and sodium lactate (SL), Nis + PS being the most effective binary mixture that exhibited listericidal activity in broth. To assess the effect of adding lactocin AL705 (AL705) to Nis + organic acid salt combinations, tridimensional isobolograms were generated. Sub-MIC combinations of the antimicrobials exerted bactericidal activity against L. innocua 7 after AL705 addition to the binary mixtures. However, when applied on Sardo cheese contaminated with L. innocua 7 (initial inoculum 4.45 ± 0.06 CFU g⁻¹), only Nis + PS + AL705 produced count reductions respect to the control, reaching 3.04 ± 0.35 CFU g⁻¹ counts after 15 days at 15 °C. Ternary combinations containing AL705 showed potential to reduce antimicrobial usages for L. innocua 7 inhibition.     

Combined differentiating therapy for myelodysplastic syndromes: a phase II study

An in vitro synergism between different inducers of AML cell differentiation has been previously observed. Therefore, we treated 53 myelodysplastic (MDS) patients with a low dose combination of cis-retinoic acid (cRA, 20-40 mg/day) and 1,25 alpha (OH)2 cholecalciferol [(OH)2D3, 1-1.5 micrograms/day] +/- intermittent 6-thioguanine (30 mg/m2/day). The latter was reserved for patients with bone marrow (BM) blast excess (> or = 5%). The treatment was well tolerated, without major toxicity. Among 25 patients with BM blasts less than 5%, we observed one complete, eight partial and four minor responses (response rate 52%) with a median response duration of 8 months (2 +/- 24). Median survival, which did not correlate with response, is projected at 76 months. Thirty-one patients with BM blast excess (> or = 5%), including three of the previous group who progressed to refractory anemia with excess of blasts (RAEB), were treated with the three-drug protocol. One complete, 12 partial and six minor responses were obtained (response rate 61%) with a median response duration of 6 months (2-29+). A significant difference in survival (P < 0.005) was observed between the 19 responders (median 25 months) and the 12 non-responders (median 9 months). A reduction in the transfusion need was observed in 41% of the transfusion-dependent patients with blast excess and in 53% of those without blast excess. Therefore, combined differentiating therapy seems more effective than previously reported single agent treatments and should be considered for a larger randomized study to assess its actual impact on survival of MDS patients.     

Carcinoembryonic antigen in diagnosis and monitoring of colorectal cancer]

Female SJL mice are more susceptible than male mice to experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP)-specific T lymphocytes. In the present study, we examined mechanisms involved in this gender-related difference in disease susceptibility. MBP-specific T lymphocytes derived from spleens of males during the effector phase of adoptive EAE produced significantly higher levels of IL-10, an anti-inflammatory cytokine in EAE. A protective effect of testosterone was then shown. Females implanted with dihydrotestosterone pellets demonstrated a significantly less severe course of EAE as compared with females implanted with placebo pellets. Finally, MBP-specific T lymphocytes derived from dihydrotestosterone-implanted females produced significantly higher levels of IL-10 than those from placebo. Together these data indicate that testosterone exerts a protective effect in EAE that is mediated at least in part by enhanced production of IL-10 by autoantigen-specific T lymphocytes.     

The impacts of a GTL plant on Brazil's oil products supply and refinery expansion

This paper assesses the impacts of a GTL plant on the expansion of Brazil's oil refining segment. The GTL plant (50,000 bpd) was sized to start up operations in 2015, producing diesel and naphtha through the indirect route (FT-synthesis). This plant will consume the non-associated natural gas production from the recent discoveries at the Santos Basin (around 419 Bm³), and the associated gas production from the Campos Basin. Both basins are located in the Southeast of Brazil, the most populated, rich and industrialized region of the country. Two different criteria for refinery expansion were simulated in order to meet oil product demand scenarios. Findings show that depending on the refinery expansion criteria considered GTL will play a fundamental hole to meet the oil product demand forecast to Brazil in the next 10 years.     

Dynamic vulcanisation of EPDM/PE-based thermoplastic vulcanisates studied along the extruder axis

Simple blending and dynamic vulcanisation of EPDM/PE blends using the resol/SnCl₂ system was studied in an extruder using a series of sampling devices. The melting of the PE pellets occurs just in front of and in the first kneading zone. Upon complete melting of the PE phase, the EPDM/PE blends reach very quickly their final morphology. Crosslinking of the EPDM phase to high levels occurs already when the PE phase is not yet fully molten. The higher the EPDM content, the higher the viscous dissipation, the higher the melt temperature and, consequently, the higher the crosslinking rate. For the EPDM/PE (50/50; w/w) TPV a transition from continuous via co-continuous to fully dispersed EPDM is observed, which is driven by crosslinking. Although the degree of crosslinking of the EPDM rubber is very high, this does not prevent phase inversion of the blend. The EPDM/PE interface is rather blurred, because PE crystalline lamellae are growing into the EPDM domains, probably because of the high compatibility between PE and EPDM (60 wt% of ethene). This study shows that dynamic vulcanisation in extruders proceeds quite differently from that in batch kneaders, where melting, mixing and crosslinking are separated in time. In extruders mass and heat transport, melting of the thermoplastic, morphology development (including dispersion and phase inversion), distribution and dissolution of (crosslinking) chemicals and crosslinking of the rubber do not occur as independent phenomena, but mutually and/or continuously interact.     

Influence of Cu<Superscript>2+</Superscript> ions on structural and magnetic properties of NiZn ferrites

The paper is devoted to the preparation of NiZn ferrite with small substitutions of copper by means of ceramic technology. The influence of small Cu substitution on the microstructural and magnetic properties of NiZn ferrites have been analysed by means of various experimental methods and interpreted from the point of view of preparation technology optimisation and possible applications of such materials. A strong correlation between the substituent content and resulting properties has been observed, thus allowing preparation of material with the properties tailored for any particular application.     

Inference, inquiry, evidence censorship, and explanation inconnectionist expert systems

The combination of the techniques of expert systems and neural networks has the potential of producing more powerful systems, for example, expert systems able to learn from experience. In this paper, we address the combinatorial neural model (CNM), a kind of fuzzy neural network able to accommodate in a simple framework the highly desirable property of incremental learning, as well as the usual capabilities of expert systems. We show how an interval-based representation for membership grades makes CNM capable of reasoning with several types of uncertainty: vagueness, ignorance, and relevance commonly found in practical applications. In addition, we show how basic functions of expert systems such as inference, inquiry, censorship of input information, and explanation may be implemented. We also report experimental results of the application of CNM to the problem of deforestation monitoring of the Amazon region using satellite images