Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy

SARS-CoV-2 is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. Because the molecular biology of this virus has been studied in such great detail, it represents an archetypal paradigm for research into new antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis of furin and 3CLpro cleavage sites that augment infection. Non-RBD and non-interfacial mutations assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Kappa, Lambda and Omicron variants, which stabilize the RBD-ACE2 complex, are investigated by free-energy computational approaches, as well as equilibrium and steered molecular dynamic simulations. Considered also are the structural hydropathy traits of the residues in the interface between SARS-CoV-2 RBD and ACE2 protein. Salt bridges and π-π interactions are critical forces that create stronger complexes between the RBD and ACE2. The trend of mutations is the replacement of non-polar hydrophobic interactions with polar hydrophilic interactions, which enhance binding of RBD with ACE2. However, this is not always the case, as conformational landscapes also contribute to a stronger binding. Arginine, the most polar and hydrophilic among the natural amino acids, is the most aggressive mutant amino acid for stronger binding. Arginine blockers, such as traditional sartans that bear anionic tetrazoles and carboxylates, may be ideal candidate drugs for retarding viral infection by weakening S-protein RBD binding to ACE2 and discouraging hydrolysis of cleavage sites. Based on our computational results it is suggested that a new generation of “supersartans”, called “bisartans”, bearing two anionic biphenyl-tetrazole pharmacophores, are superior to carboxylates in terms of their interactions with viral targets, suggesting their potential as drugs in the treatment of COVID-19. In Brief: This in silico study reviews our understanding of molecular driving forces that trigger mutations in the SARS-CoV-2 virus. It also reports further studies on a new class of “supersartans” referred to herein as “bisartans”, bearing two anionic biphenyltetrazole moieties that show potential in models for blocking critical amino acids of mutants, such as arginine, in the Delta variant. Bisartans may also act at other targets essential for viral infection and replication (i.e., ACE2, furin cleavage site and 3CLpro), rendering them potential new drugs for additional experimentation and translation to human clinical trials.     

Corifollitropin alfa compared with follitropin beta in GnRH-antagonist ovarian stimulation protocols in an unselected population undergoing IVF/ICSI

Recombinant DNA technologies have produced Corifollitropin alfa (CFa) used during IVF/ICSI in order to keep the circulating FSH levels above the threshold necessary to support multi-follicular growth for a week. In this prospective case-control study, we compared 70 participants treated with 150?μg CFa combined with 150?IU of follitropin beta (study group) with 70 subfertile participants with matching baseline characteristics, conforming with the same inclusion criteria and treated with an antagonist protocol using follitropin beta (control group). Live birth was the primary outcome, while secondary outcome measures were IVF/ICSI cycles characteristics, including adverse events and complications. Live birth was determined in reduced rates in the study compared to the control group, reaching statistical significance [6/70 versus 20/70, p?=?0.002], as also in the respective number of clinical pregnancies [9/70 versus 23/70, p?=?0.005], although the incidence of miscarriage was similar for both groups [6/70 versus 5/70, p?>?0.99]. Most of the secondary parameters examined were similar between groups. Logistic regression revealed that protocol and AFC had a direct impact on live birth. Ovarian stimulation with CFa does not seem to constitute an equally effective method as compared with follitropin beta to be offered in a general subfertile population seeking IVF/ICSI treatments.     

Methods of Preparation and Performance Evaluation of ABS/Mineral Microsphere Composites Produced through FDM and Compression Molding

The use of amorphous microspheres as filler in composites is promising due to their light weight, low cost, incombustibility, and the ability to alter relevant properties of the final composite. Contrary to glass spheres, perlite microspheres are much cheaper and can be tailor-made to facilitate purpose-oriented alteration of the final composite. We report the use of perlite microspheres for the preparation of: (1) composites, through a compression molding (hot pressing) technique; and (2) composite filaments, in a single screw extruder, as well as their use for sample printing through Fused Deposition Modeling (FDM). Proper characterization of the produced composites allows for their evaluation in terms of physical, thermal, and mechanical properties and with regards to the manufacturing technique, the filler fraction, and size. Composite samples of acceptable quality in terms of filler survival and dispersion as well as mechanical properties were produced through compression molding using fine expanded perlite microspheres (<90 μm) up to an infill ratio of 40 vol.%. Fine fillers (<90 μm) performed well in FDM, allowing printing of composite dogbone samples with a higher Young’s modulus and elongation and similar ultimate tensile strength compared to benchmark, up to an infill ratio of 20 vol.%. Composite samples present a slightly lower burning rate compared to those produced solely by ABS. Perlite microspheres present good workability in both applications, possessing satisfactory performance as filler in the composites, and can thus be assumed a promising multifunctional filler for various thermoplastics considering their low price, environmental impact, and fire rating.     

Sexual dysfunctions: classifications and definitions

Sexual classification systems are based on precise and understandable definitions of sexual dysfunctions and are needed for investigative research, determination of diagnostic standards, and delineation of treatment strategies. The four major categories of sexual dysfunctions include disorders of sexual desire/interest, arousal, orgasm, and sexual pain. The purpose of this article is to review the major features, differences, and similarities of the six classification systems widely used in sexual medicine, including the International Classification of Diseases, the Diagnostic and Statistical Manual of Mental Disorders, the National Institute of Health Consensus Conference on Impotence, the American Foundation for Urologic Diseases, International Consensus Conference on Women's Sexual Dysfunction, and the First and Second International Consultations on Sexual Dysfunctions.     

The value of transesophageal echocardiography in the investigation and management of cryptogenic cerebral ischemia: a single-center experience

The diagnostic utility of transesophageal echocardiography (TEE) has often been challenged in patients with cryptogenic stroke (CS). We estimated the prevalence of different findings on TEE examination of CS patients, their impact on secondary stroke prevention and the presence of potential age or gender disparities. We reviewed all TEE examinations that were performed in a single echocardiography laboratory during a 7-year-old period to identify CS patients that underwent investigation with TEE. Of the 518 total TEE examinations, we identified 88 CS patients. TEE revealed abnormal findings in 69.3 % of them. Patent foramen ovale (PFO) and atrial septal aneurysm (ASA) were identified in 30.6 and 22.7 % of the patients. Ascending aorta and aortic arch atheromatosis was present in 26.1 % of the patients, with complex atheromatosis diagnosed in 14.7 % of them. Cardiac myxomas were uncovered in 2.3 %. Thrombi in the left atrium and in cardiac valves were reported in 3.4 and 2.3 % of the patients, respectively. Based on TEE findings, the therapeutic management would be very likely modified in 9.1 % of the patients. Subgroup analysis revealed no gender disparities on the prevalence of TEE findings and in secondary stroke prevention, while linear regression analyses revealed significant associations of age with the prevalence of PFO, ASA, aorta atheromatosis and complex aorta atheromatosis. TEE examination should be included in the diagnostic work-up of all CS patients, irrespective of age and gender status, since it can reveal potential sources of embolism and has a significant impact for secondary stroke prevention.