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While worldwide efforts for improving COVID-19 vaccines are currently considered a top priority, the role of the genetic variants responsible for virus receptor protein stability is less studied. Angiotensin-converting enzyme-2 is the primary target of the SARS-CoV-1/SARS-CoV-2 spike (S) glycoprotein, enabling entry into the human body. Here, we applied computational saturation mutagenesis approaches to determine the folding energy caused by all possible mutations in ACE2 proteins within ACE2 - SARS-CoV-1-S/ACE2 - SARS-CoV-2-S complexes. We observed ACE2 mutations at residue D350 causing the most stabilizing effects on the protein. In addition, we identified ACE2 genetic variations in African Americans (rs73635825, rs766996587, and rs780574871), Latino Americans (rs924799658), and both groups (rs4646116 and rs138390800) affecting stability in the ACE2 - SARS-CoV-2-S complex. The findings in this study may aid in targeting the design of stable neutralizing peptides for treating minority patients.

 

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe pneumonia-like symptoms and is still pose a significant threat to global public health. A key component in the virulence of MERS-CoV is the Spike (S) protein, which binds with the host membrane receptor dipeptidyl peptidase 4 (DPP4). The goal of the present investigation is to examine the effects of missense mutations in the MERS-CoV S protein on protein stability and binding affinity with DPP4 to provide insight that is useful in developing vaccines to prevent coronavirus infection. We utilized a saturation mutagenesis approach to simulate all possible mutations in the MERS-CoV full-length S, S Receptor Binding Domain (RBD) and DPP4. We found the mutations in MERS-CoV S protein residues, G552, C503, C526, N468, G570, S532, S451, S419, S465, and S435, affect protein stability. We identified key residues, G538, E513, V555, S557, L506, L507, R511, M452, D537, and S454 in the S protein RBD region are important in the binding of MERS-CoV S protein to the DPP4 receptor. We investigated the effects of MERS-CoV S protein viral mutations on protein stability and binding affinity. In addition, we studied all DPP4 mutations and found the functional substitution R336T weakens both DPP4 protein stability and S-DPP4 binding affinity. We compared the S protein structures of MERS-CoV, SARS-CoV, and SARS-CoV-2 viruses and identified the residues like C526, C383, and N468 located in equivalent positions of these viruses have effects on S protein structure. These findings provide further information on how mutations in coronavirus S proteins effect protein function. 

Myeloperoxidase (MPO) is a heme peroxidase with microbicidal properties. MPO plays a role in the host’s innate immunity by producing reactive oxygen species inside the cell against foreign organisms. However, there is little functional evidence linking missense mutations to human diseases. We utilized in silico saturation mutagenesis to generate and analyze the effects of 10,811 potential missense mutations on MPO stability. Our results showed that ~71% of the potential missense mutations destabilize MPO, and ~8% stabilize the MPO protein. We showed that G402W, G402Y, G361W, G402F, and G655Y would have the highest destabilizing effect on MPO. Meanwhile, D264L, G501M, D264H, D264M, and G501L have the highest stabilization effect on the MPO protein. Our computational tool prediction showed the destabilizing effects in 13 out of 14 MPO missense mutations that cause diseases in humans. We also analyzed putative post-translational modification (PTM) sites on the MPO protein and mapped the PTM sites to disease-associated missense mutations for further analysis. Our analysis showed that R327H associated with frontotemporal dementia and R548W causing generalized pustular psoriasis are near these PTM sites. Our results will aid further research into MPO as a biomarker for human complex diseases and a candidate for drug target discovery. 

Community–academic partnerships (CAPs) are being increasingly used to study and address health disparity issues. CAPs help to create new bodies of knowledge and innovative solutions to community problems, which benefits the community and academia. Supported by a grant, a partnership was formed between an academic research team and a community health organization to analyze and interpret data collected from the caregivers of asthmatic African American children living in urban low-income households. Using a case study approach, we discuss how we built a healthy CAP and the lessons learned from the process. Our analysis was guided by the six main factors that facilitate success in developing collaborative relationships, including (1) environment; (2) membership; (3) process and structure; (4) communication; (5) purpose; and (6) resources. Based on these six factors, we describe our collaboration process, challenges, and areas for improvement. We aimed to provide a “points-to-consider” roadmap for academic and community partners to establish and maintain a mutually beneficial and satisfactory relationship. Collaborating with community members and organizations provides unique opportunities for researchers and students to apply their skills and knowledge from textbooks and the classroom, engage with community members, and improve real-life community needs. Building a constructive CAP involves efforts, energy, and resources from both parties. The six major themes derived from our project offer suggestions for building a healthy, collaborative, and productive relationship that best serves communities in the future. 

Neurexin-1 (NRXN1) is a membrane protein essential in synapse formation and cell signaling as a cell-adhesion molecule and cell-surface receptor. NRXN1 and its binding partner neuroligin have been associated with deficits in cognition. Recent genetics research has linked NRXN1 missense mutations to increased risk for brain disorders, including schizophrenia (SCZ) and autism spectrum disorder (ASD). Investigation of the structure–function relationship in NRXN1 has proven difficult due to a lack of the experimental full-length membrane protein structure. AlphaFold, a deep learning-based predictor, succeeds in high-quality protein structure prediction and offers a solution for membrane protein model construction. In the study, we applied a computational saturation mutagenesis method to analyze the systemic effects of missense mutations on protein functions in a human NRXN1 structure predicted from AlphaFold and an experimental Bos taurus structure. The folding energy changes were calculated to estimate the effects of the 29,540 mutations of AlphaFold model on protein stability. The comparative study on the experimental and computationally predicted structures shows that these energy changes are highly correlated, demonstrating the reliability of the AlphaFold structure for the downstream bioinformatics analysis. The energy calculation revealed that some target mutations associated with SCZ and ASD could make the protein unstable. The study can provide helpful information for characterizing the disease-causing mutations and elucidating the molecular mechanisms by which the variations cause SCZ and ASD. This methodology could provide the bioinformatics protocol to investigate the effects of target mutations on multiple AlphaFold structures. 

COVID-19, caused by SARS-CoV-2, is a systemic illness due to its multiorgan effects in patients. The disease has a detrimental impact on respiratory and cardiovascular systems. One early symptom of infection is anosmia or lack of smell; this implicates the involvement of the olfactory bulb in COVID-19 disease and provides a route into the central nervous system. However, little is known about how SARS-CoV-2 affects neurological or psychological symptoms. SARS-CoV-2 exploits host receptors that converge on pathways that impact psychological symptoms. This systemic review discusses the ways involved by coronavirus infection and their impact on mental health disorders. We begin by briefly introducing the history of coronaviruses, followed by an overview of the essential proteins to viral entry. Then, we discuss the downstream effects of viral entry on host proteins. Finally, we review the literature on host factors that are known to play critical roles in neuropsychiatric symptoms and mental diseases and discuss how COVID-19 could impact mental health globally. Our review details the host factors and pathways involved in the cellular mechanisms, such as systemic inflammation, that play a significant role in the development of neuropsychological symptoms stemming from COVID-19 infection. 

Severe Acute respiratory syndrome coronavirus (SARS-CoV-1) attaches to the host cell surface to initiate the interaction between the receptor-binding domain (RBD) of its spike glycoprotein (S) and the human Angiotensin-converting enzyme (hACE2) receptor. SARS-CoV-1 mutates frequently because of its RNA genome, which challenges the antiviral development. Here, we per-formed computational saturation mutagenesis of the S protein of SARS-CoV-1 to identify the residues crucial for its functions. We used the structure-based energy calculations to analyze the effects of the missense mutations on the SARS-CoV-1 S stability and the binding affinity with hACE2. The sequence and structure alignment showed similarities between the S proteins of SARS-CoV-1 and SARS-CoV-2. Interestingly, we found that target mutations of S protein amino acids generate similar effects on their stabilities between SARS-CoV-1 and SARS-CoV-2. For example, G839W of SARS-CoV-1 corresponds to G857W of SARS-CoV-2, which decrease the stability of their S glycoproteins. The viral mutation analysis of the two different SARS-CoV-1 isolates showed that mutations, T487S and L472P, weakened the S-hACE2 binding of the 2003–2004 SARS-CoV-1 isolate. In addition, the mutations of L472P and F360S destabilized the 2003–2004 viral isolate. We further predicted that many mutations on N-linked glycosylation sites would increase the stability of the S glycoprotein. Our results can be of therapeutic importance in the design of antivirals or vaccines against SARS-CoV-1 and SARS-CoV-2. 

Research has rarely examined how the COVID-19 pandemic may affect teens’ social media engagement and psychological wellbeing, and even less research has compared the difference between teens with and without mental health concerns. We collected and analyzed weekly data from January to December 2020 from teens in four Reddit communities (subreddits), including teens in r/Teenagers and teens who participated in three mental health subreddits (r/Depression, r/Anxiety, and r/SuicideWatch). The results showed that teens’ weekly subreddit participation, posting/commenting frequency, and emotion expression were related to significant pandemic events. Teen Redditors on r/Teenagers had a higher posting/commenting frequency but lower negative emotion than teen Redditors on the three mental health subreddits. When comparing posts/comments on r/Teenagers, teens who ever visited one of the three mental health subreddits posted/commented twice as frequently as teens who did not, but their emotion expression was similar. The results from the Interrupted Time Series Analysis (ITSA) indicated that both teens with and without mental health concerns reversed the trend in posting frequency and negative emotion from declining to increasing right after the pandemic outbreak, and teens with mental health concerns had a more rapidly increasing trend in posting/commenting. The findings suggest that teens’ social media engagement and emotion expression reflect the pandemic evolution. Teens with mental health concerns are more likely to reveal their emotions on specialized mental health subreddits rather than on the general r/Teenagers subreddit. In addition, the findings indicated that teens with mental health concerns had a strong social interaction desire that various barriers in the real world may inhibit. The findings call for more attention to understand the pandemic’s influence on teens by monitoring and analyzing social media data and offering adequate support to teens regarding their mental health wellbeing.