Interaction of Spike protein and lipid membrane of SARS-CoV-2 with Ursodeoxycholic acid, an in-silico analysis.

Numerous repositioned drugs have been sought to decrease the severity of SARS-CoV-2 infection. It is known that among its physicochemical properties, Ursodeoxycholic Acid (UDCA) has a reduction in surface tension and cholesterol solubilization, it has also been used to treat cholesterol gallstones and viral hepatitis. In this study, molecular docking was performed with the SARS-CoV-2 Spike protein and UDCA. In order to confirm this interaction, we used Molecular Dynamics (MD) in "SARS-CoV-2 Spike protein-UDCA". Using another system, we also simulated MD with six UDCA residues around the Spike protein at random, naming this "SARS-CoV-2 Spike protein-6UDCA". Finally, we evaluated the possible interaction between UDCA and different types of membranes, considering the possible membrane conformation of SARS-CoV-2, this was named "SARS-CoV-2 membrane-UDCA". In the "SARS-CoV-2 Spike protein-UDCA", we found that UDCA exhibits affinity towards the central region of the Spike protein structure of - 386.35 kcal/mol, in a region with 3 alpha helices, which comprises residues from K986 to C1032 of each monomer. MD confirmed that UDCA remains attached and occasionally forms hydrogen bonds with residues R995 and T998. In the presence of UDCA, we observed that the distances between residues atoms OG1 and CG2 of T998 in the monomers A, B, and C in the prefusion state do not change and remain at 5.93 ± 0.62 and 7.78 ± 0.51 Å, respectively, compared to the post-fusion state. Next, in "SARS-CoV-2 Spike protein-6UDCA", the three UDCA showed affinity towards different regions of the Spike protein, but only one of them remained bound to the region between the region's heptad repeat 1 and heptad repeat 2 (HR1 and HR2) for 375 ps of the trajectory. The RMSD of monomer C was the smallest of the three monomers with a value of 2.89 ± 0.32, likewise, the smallest RMSF was also of the monomer C (2.25 ± 056). In addition, in the simulation of "SARS-CoV-2 membrane-UDCA", UDCA had a higher affinity toward the virion-like membrane; where three of the four residues remained attached once they were close (5 Å, to the centre of mass) to the membrane by 30 ns. However, only one of them remained attached to the plasma-like membrane and this was in a cluster of cholesterol molecules. We have shown that UDCA interacts in two distinct regions of Spike protein sequences. In addition, UDCA tends to stay bound to the membrane, which could potentially reduce the internalization of SARS-CoV-2 in the host cell.

The influence of hydrogen ions on coagulation in traumatic brain injury, explored by molecular dynamics.

Background: Patients in intensive care units with traumatic brain injuries (TBI) frequently present acid-base abnormalities and coagulability disorders, which complicate their condition.Objective: To identify protonation through in silico simulations of molecules involved in the process of coagulation in standard laboratory tests.Materials and methods: Ten patients with TBI were selected from the intensive care unit in addition to ten "healthy control subjects", and another nine patients as "disease control subjects"; the latter being a comparative group, corresponding to subjects with diabetes mellitus 2 (DM2). Fibrinogen, FVII, FVIII, FIX, FX, and D-dimer in the presence of acidification were evaluated in 20 healthy subjects in order to compare clinical results with molecular dynamics (MD), and to explain proton interactions and coagulation molecules.Results: The TBI group presented a slight, non-significant increase in D-dimer; but this was not present in "disease control subjects". Levels of fibrinogen, FVII, FIX, FX, and D-dimer were affected in the presence of acidification. We observed that various specific residues of coagulation factors "trap" ions.Conclusion: Protonation of tissue factor and factor VIIa may favor anticoagulant mechanisms, and protonation does not affect ligand binding sites of GPIIb/IIIa (PAC1) suggesting other causes for the low affinity to PAC1.

Analysis of SARS-CoV-2 mutations in Mexico, Belize, and isolated regions of Guatemala and its implication in the diagnosis.

The genomic sequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide are publicly available and are derived from studies due to the increase in the number of cases. The importance of study of mutations is related to the possible virulence and diagnosis of SARS-CoV-2. To identify circulating mutations present in SARS-CoV-2 genomic sequences in Mexico, Belize, and Guatemala to find out if the same strain spread to the south, and analyze the specificity of the primers used for diagnosis in these samples. Twenty three complete SARS-CoV-2 genomic sequences, available in the GISAID database from May 8 to September 11, 2020 were analyzed and aligned versus the genomic sequence reported in Wuhan, China (NC_045512.2), using Clustal Omega. Open reading frames were translated using the ExPASy Translate Tool and UCSF Chimera (v.1.12) for amino acid substitutions analysis. Finally, the sequences were aligned versus primers used in the diagnosis of COVID-19. One hundred and eighty seven distinct variants were identified, of which 102 are missense, 66 synonymous and 19 noncoding. P4715L and P5828L substitutions in replicase polyprotein were found, as well as D614G in spike protein and L84S in ORF8 in Mexico, Belize, and Guatemala. The primers design by CDC of United States showed a positive E value. The genomic sequences of SARS-CoV-2 in Mexico, Belize, and Guatemala present similar mutations related to a virulent strain of greater infectivity, which could mean a greater capacity for inclusion in the host genome and be related to an increased spread of the virus in these countries, furthermore, its diagnosis would be affected.

Molecules and Prostaglandins Related to Embryo Tolerance.

It is generally understood that the entry of semen into the female reproductive tract provokes molecular and cellular changes facilitating conception and pregnancy. We show a broader picture of the participation of prostaglandins in the fertilization, implantation and maintenance of the embryo. A large number of cells and molecules are related to signaling networks, which regulate tolerance to implantation and maintenance of the embryo and fetus. In this work, many of those cells and molecules are analyzed. We focus on platelets, polymorphonuclear leukocytes, and group 2 innate lymphoid cells involved in embryo tolerance in order to have a wider view of how prostaglandins participate. The combination of platelets and neutrophil extracellular traps (Nets), uterine innate lymphoid cells (uILC), Treg cells, NK cells, and sex hormones have an important function in immunological tolerance. In both animals and humans, the functions of these cells can be regulated by prostaglandins and soluble factors in seminal plasma to achieve an immunological balance, which maintains fetal-maternal tolerance. Prostaglandins, such as PGI2 and PGE2, play an important role in the suppression of the previously mentioned cells. PGI2 inhibits platelet aggregation, in addition to IL-5 and IL-13 expression in ILC2, and PGE2 inhibits some neutrophil functions, such as chemotaxis and migration processes, leukotriene B4 (LTB4) biosynthesis, ROS production, and the formation of extracellular traps, which could help prevent trophoblast injury and fetal loss. The implications are related to fertility in female when seminal fluid is deposited in the vagina or uterus.