Membrane-bound transcription factor site-1 protease (S1P) is an emerging clinical target due to its roles in lipogenesis, lysosomal biogenesis, unfolded protein response and viral glycoprotein processing. In this study, homology model of S1P was created in order to understand the structural basis for S1P inhibition by PF429242 using molecular docking, molecular dynamics simulation and in silico kinetics studies. PF429242 was docked (GlideScorePF429242=−5.20 kcal/mol) into the catalytic triad (D218, H249 and S414) and validated (R2=0.5686). The reversible binding kinetic parameter (Koff/Kon) was estimated at=7.28E-03 M with fully bound and apo-states interspersed by 3 transient ligand-bound states with unique binding signatures; water plays a major role in PF429242 dissociation from the catalytic site. Communication between key catalytic triad residues is altered in the presence of PF429242. In apo-S1P state, S414–S307/V216-D218 is the preferred route but in PF429242-bound state, S414-S417/V216-D218 is preferred. Communication between S414 and H249 is also shortened in PF429242 bound state; here, only L410 is required unlike apo-state, which requires P418, V256 and F252. Ligand binding did not alter the communication route between S414 and H249 as both recruited D244 and G220. In conclusion, PF429242 binds tightly but reversible to S1P and the details of this interaction has been presented to guide future efforts at developing novel inhibitors. Site-1-protease; PF429242; Kon/Koff; Network analysis

Lassa virus infection is clinically characterized by multiorgan failure in humans. Without an FDA‐approved vaccine, ribavirin is the frontline drug for the treatment but with attendant toxicities. 6‐Fluoro‐3‐hydroxy‐2‐pyrazinecarboxamide (T‐705) is an emerging alternative drug with proven anti‐Lassa virus activity in experimental model. One of the mechanisms of action is its incorporation into nascent single‐strand RNA (ssRNA) which forms complex with Lassa nucleoprotein (LASV‐NP). Here, using molecular dynamics simulation, the structural and electrostatics changes associated with LASV‐NP‐ssRNA complex have been studied when none, one, or four of its bases has been substituted with T‐705. The results demonstrated that glycosidic torsion angle χ (O4′‐C1′‐N1‐C2) rotated from high‐anti‐ (−110° and −60°) to the syn‐ conformation (+30) with increased T‐705 substitution. Similarly, increased T‐705 substitution resulted in increased splaying (55°–70°), loss of ssRNA‐LASV‐NP H‐bond interaction, increased water influx into the ssRNA‐binding pocket, and decreased electrostatic potentials of ssRNA pocket. Furthermore, strong positively correlated motion observed between α6 residues (aa: 128–145) and its contact ssRNA bases (5–7) is weakened in Apo biosystem and transitioned into anticorrelated motions in ssRNA‐bound LASV‐NP biosystem. Finally, LASV genome may become more accessible to cellular ribonuclease access with T‐705 incorporation due to loss of NP interaction.

Background: COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic affecting approximately 490,000 people and accounting for more than 22,000 deaths and has no generally cure. Here, the recently resolved 3D structure of SARS-CoV-2 receptor binding domain (RBD) in complex with its receptor-the angiotensin converting enzyme-2 (ACE-2) have provided the basis for screening chemical database for novel entry inhibitors. Methods: Molecular docking protocols have been used to rapidly screen FDA database for high affinity interaction at the SARS-CoV-2-RBD/ACE-2 interface. One of the top candidate ubrogepant has been using atomistic molecular dynamics simulation method. Results: Molecular docking result showed that ubrogepant (UBR) and darunavir have binding energies of -10.4 kcal/mol. MMPBSA free energy analyses of UBR bound to RBD, ACE-2 and RBD/ACE-2 revealed RBD/ACE-2 > ACE-2 > RBD preference. Network analysis showed that interaction captured in the crystal structure were disrupted in UBR-bound state, hydration of the interface and increased atomic fluctuation within the RBD oligomerization interface and ACE-2 zinc binding site. Conclusions: The ability of ubrogepant to rupture the interaction at the RBD/ACE-2 interface residues of SARS-CoV-2 RBD/ACE-2 complex may result in loss of protein function with direct implication on oligomerization formation in RBD and loss of function in ACE-2 thus, making binding, cellular receptor recognition impossible. General Significance: Ubrogepant represents a new therapeutic candidate in the fight against COVID-19, as it binds with relatively high affinity with free RBD, ACE-2 receptor and SARS-CoV-2 RBD/ACE-2 complex based on binding affinity calculations

Biblical worldview on the influenza investigation and the investigation's implication for the Liberty Culture. The research we conducted, everything from study design to our results, was done to improve people's lives. In this study, we were guided by the precedent that was set by Jesus during his ministry, to be lights of the gospel by seeking to prevent diseases and easing afflictions. Everywhere Christ went in his ministry he healed first, and then he spoke the gospel. Through his actions and teachings, Jesus asserted that caring for the health of the world should be a priority for Christians. In Luke 10 is a story of Jesus giving something like a mission briefing to his disciples before he sends them to do his work (with some of his godly power), Jesus said in Luke 10:1, "to cast [unclean spirits] out, and to heal every disease and affliction (ESV)." We believe this influenza investigation can make an influence on our community's health and God smiles when Christians spread health to those comforted in His name. This research investigation shines a light on a previously unknown fact about Liberty's campus, that both the low flu vaccination rates and high flu-like symptom prevalence need to be addressed. The overall vaccination prevalence of those surveyed was 14%, this is low; the overall flu vaccination prevalence of the country, from 2009 to 2014, for adults over the age of 18 is 42% (http://www.cdc.gov/flu/fluvaxview/coverage-1314estimates.htm#age-group-adults). This is three times less than the national average. For the prevalence of flu-like symptoms, Liberty students had higher rates than the national average, which is 31.7% (http://www.cdc.gov/nchs/fastats/flu.htm). These findings lead to three ways our study can influence Liberty culture. The first role is to increase flu education campaigns on campus. Learning about a problem or issue is often seen as the first step in addressing that problem. So, if more students learn that the flu is a reason students get sick on campus they may be more likely to get vaccinated. The second way this investigation can affect our community is through more people having the flu shot. We hope that when students see the research that it will spark their interest in getting the flu shot to prevent getting the flu. Finally, we hope that this study will prevent further student illness. No one likes to get sick, especially college students. They have many things to worry about: exams, paper, and balancing aspects of social life. Coming down with the flu can severely complicate college life, but we hope this study will be able to shine a light on the flu at Liberty's campus.

Background: Artificial inseminations of donor semen (AID) involve use of heterologous donated semen for conception in infertile couple when indicated or in a single woman desirous of pregnancy. Its practice often requires regulation to address possible ethical and legal issues which may arise. In formulating acceptable guidelines/policies, the perspectives of health professionals and the participants should be considered. Therefore, we sought to explore the knowledge and perception of semen donation for artificial insemination among health professionals.Methods: A cross sectional study conducted on consenting health workers in a single health institution using a structured questionnaire to assess their knowledge and perception on artificial insemination of donor semen (AID). Descriptive and analytical statistics were applied to the data collected with a statistically significant value of <0.05.Results: One hundred and twenty-one health professionals completed the questionnaires. The mean age of the respondents was 27.58±5.5years. Sixty of the respondents were males while 61 were females. Eighty-four of the respondents (69.4%) demonstrated good knowledge of AID while 37 (30.6%) had poor knowledge. Cadre of health professionals and marital status influenced the knowledge of respondents. Perceptions on AID varied among the respondents mostly influenced by psycho-social factors and possible legal disputes on third party reproductive process. None of the male respondents has ever donated semen and willingness to donate semen was low; with anonymity preferred by the willing donors.Conclusions: Substantial knowledge gap of AIDS existed among health professionals which were influenced by cadre and marital status. Psycho-social factors and possible legal disputes influenced their perceptions of AID.