1,724,263 research outputs found
The Effect of ACE2 Inhibitor MLN-4760 on the Interaction of SARS-CoV-2 Spike Protein with Human ACE2: A Molecular Dynamics Study
No full textA previous study shows that an ACE2 enzymatic activity inhibitor efficiently blocks the interaction of SARS-CoV spike protein with human ACE2 and may be effective in preventing the coronavirus membrane fusion and entry to human cells. The report suggests that potent ACE2 inhibitors can be used to treat hypertension as well as for controlling SARS-CoV infection. We here studied the effect of a selective and highly potent ACE2 inhibitor (MLN-4760) on the interaction of the SARS-CoV-2 spike receptor-binding domain (RBD) with human ACE2 by molecular dynamics (MD) simulation. To this end, we docked the RBD of SARS-CoV-2 to the human native ACE2 and the ACE2 complexed with MLN-4760, and analyzed the dynamics, protein-protein and ligand-protein interactions of the complexes by MD simulation in a simulated biological condition for 100 ns. Analyzing crystallographic structures of SARS-CoV-2 and SARS-CoV RBDs in the complexes with human ACE2 showed that RBD of SARS-CoV-2 binds to ACE2 with a higher affinity than that of SARS-CoV. Results also revealed that MLN-4760 binds to ACE2 at the enzymatic active site with a high affinity and significantly alters the ACE2 protein conformation. MLN-4760 also changes the binding site and the residues involved in hydrogen and hydrophobic binding between RBD and ACE2, however, it had no major effect on the binding affinity of the interaction between RDB and ACE2. Interestingly, binding RBD to the ACE2 complexed with MLN-4760 abrogated the inhibitory effect of MLN-4760 and rescued the conformation of the ACE2 enzymatic site by reforming the closed conformation to the open native conformation. This was due to the disassociation of MLN-4760 from the enzymatic active site of the ACE2 in the result of RBD binding. Overall, these results show that MLN-4760 does neither block nor increase the binding of SARS-CoV-2 spike RBD to human ACE2 and probably had no effect on the viral entry. However, binding the spike protein to ACE2 can rescue the enzymatic function of ACE2 from its inhibitor.</p
Block Card 4760 Thobe Road
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Cape Cod Style | Dwelling | 4760 Thobe Road (Toledo, Ohio) | Edgewood Addition (Toledo, Ohio) | Reynolds Corners Area (Toledo, Ohio
HD/PSYCH 4760/6760 Course Syllabus - Spring 2018
No full textSyllabus for HD/PSYCH 4760/6760 Quantative Methods 2 taught by Felix Thoemmes in Spring 2018
Linked collectors and determiners for: Staatliches Museum für Naturkunde Karlsruhe_Abteilung Biowissenschaften - Referat Zoologie_Oribatida_SMNK-Taxonomische Belegsammlung ORIB.
No full textNatural history specimen data linked to collectors and determiners held within, "Staatliches Museum für Naturkunde Karlsruhe_Abteilung Biowissenschaften - Referat Zoologie_Oribatida_SMNK-Taxonomische Belegsammlung ORIB". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/a7ab3af6-0f58-4760-9f74-19b4a6e75688">https://bionomia.net/dataset/a7ab3af6-0f58-4760-9f74-19b4a6e75688</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/a7ab3af6-0f58-4760-9f74-19b4a6e75688">https://gbif.org/dataset/a7ab3af6-0f58-4760-9f74-19b4a6e75688</a>. Formatted as a Frictionless Data package
Linked collectors and determiners for: The flattie spiders of the Selenops isopodus species group (Araneae: Selenopidae) with a review of Selenops records from Colombia.
No full textNatural history specimen data linked to collectors and determiners held within, "The flattie spiders of the Selenops isopodus species group (Araneae: Selenopidae) with a review of Selenops records from Colombia". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/19ec59cf-a6ba-4760-8a7f-dac3e88b0775">https://bionomia.net/dataset/19ec59cf-a6ba-4760-8a7f-dac3e88b0775</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/19ec59cf-a6ba-4760-8a7f-dac3e88b0775">https://gbif.org/dataset/19ec59cf-a6ba-4760-8a7f-dac3e88b0775</a>. Formatted as a Frictionless Data package
Vascular Effects of Low-Dose ACE2 Inhibitor MLN-4760—Benefit or Detriment in Essential Hypertension?
No full textSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects host cells through angiotensin-converting enzyme 2 (ACE2). Concurrently, the product of ACE2 action, angiotensin 1–7 (Ang 1–7), binds to Mas receptors within the cardiovascular system and provides protective effects. Therefore, it is crucial to reveal the role of ACE2 inhibition, especially within pre-existing cardiovascular pathologies. In our study, we imitated the action of SARS-CoV-2 in organisms using the low dose of the ACE2 inhibitor MLN-4760 with the aim of investigating to what degree ACE2 inhibition is detrimental to the cardiovascular system of spontaneously hypertensive rats (SHRs), which represent a model of human essential hypertension. Our study revealed the complex action of MLN-4760 in SHRs. On the one hand, we found that MLN-4760 had (1) (pro)obesogenic effects that negatively correlated with alternative renin-angiotensin system activity and Ang 1–7 in plasma, (2) negative effects on ACE1 inhibitor (captopril) action, (3) detrimental effects on the small arteries function and (4) anti-angiogenic effect in the model of chick chorioallantoic membrane. On the other hand, MLN-4760 induced compensatory mechanisms involving strengthened Mas receptor-, nitric oxide- and hydrogen sulfide-mediated signal transduction in the aorta, which was associated with unchanged blood pressure, suggesting beneficial action of MLN-4760 when administered at a low dose
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of Nfe2l2 Gene, Nitric Oxide and Hydrogen Sulfide
No full textReduced angiotensin 1–7 bioavailability due to inhibition of angiotensin-converting enzyme 2 (ACE2) may contribute to increased mortality in hypertensive individuals during COVID-19. However, effects of ACE2 inhibitor MLN-4760 in brain functions remain unknown. We investigated the selected behavioural and hemodynamic parameters in spontaneously hypertensive rats (SHRs) after a 2-week s.c. infusion of MLN-4760 (dose 1 mg/kg/day). The biochemical and molecular effects of MLN-4760 were investigated in the brainstem and blood plasma. MLN-4760 had no effects on hemodynamic and behavioural parameters. However, MLN-4760 increased plasma hydrogen sulfide (H2S) level and total nitric oxide (NO) synthase activity and conjugated dienes in the brainstem. Increased NO synthase activity correlated positively with gene expression of Nos3 while plasma H2S levels correlated positively with gene expressions of H2S-producing enzymes Mpst, Cth and Cbs. MLN-4760 administration increased gene expression of Ace2, Sod1, Sod2, Gpx4 and Hmox1, which positively correlated with expression of Nfe2l2 gene encoding the redox-sensitive transcription factor NRF2. Collectively, MLN-4760 did not exacerbate pre-existing hypertension and behavioural hyperactivity/anxiety in SHRs. However, MLN-4760-induced oxidative damage in brainstem was associated with activation of NO- and H2S-mediated compensatory mechanisms and with increased gene expression of antioxidant, NO- and H2S-producing enzymes that all correlated positively with elevated Nfe2l2 expression
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