Protein Glycation in Plants-An Under-Researched Field with Much Still to Discover.

Recent research has identified glycation as a non-enzymatic post-translational modification of proteins in plants with a potential contributory role to the functional impairment of the plant proteome. Reducing sugars with a free aldehyde or ketone group such as glucose, fructose and galactose react with the N-terminal and lysine side chain amino groups of proteins. A common early-stage glycation adduct formed from glucose is N-fructosyl-lysine (FL). Saccharide-derived reactive dicarbonyls are arginine residue-directed glycating agents, forming advanced glycation endproducts (AGEs). A dominant dicarbonyl is methylglyoxal-formed mainly by the trace-level degradation of triosephosphates, including through the Calvin cycle of photosynthesis. Methylglyoxal forms the major quantitative AGE, hydroimidazolone MG-H1. Glucose and methylglyoxal concentrations in plants change with the developmental stage, senescence, light and dark cycles and also likely biotic and abiotic stresses. Proteomics analysis indicates that there is an enrichment of the amino acid residue targets of glycation, arginine and lysine residues, in predicted functional sites of the plant proteome, suggesting the susceptibility of proteins to functional inactivation by glycation. In this review, we give a brief introduction to glycation, glycating agents and glycation adducts in plants. We consider dicarbonyl stress, the functional vulnerability of the plant proteome to arginine-directed glycation and the likely role of methylglyoxal-mediated glycation in the activation of the unfolded protein response in plants. The latter is linked to the recent suggestion of protein glycation in sugar signaling in plant metabolism. The overexpression of glyoxalase 1, which suppresses glycation by methylglyoxal and glyoxal, produced plants resistant to high salinity, drought, extreme temperature and other stresses. Further research to decrease protein glycation in plants may lead to improved plant growth and assist the breeding of plant varieties resistant to environmental stress and senescence-including plants of commercial ornamental and crop cultivation value.Qatar University and HBKU, Qatar Foundatio

Vulnerabilities of the SARS-CoV-2 Virus to Proteotoxicity—Opportunity for Repurposed Chemotherapy of COVID-19 Infection

The global pandemic of COVID-19 disease caused by infection with the SARS-CoV-2 coronavirus, has produced an urgent requirement and search for improved treatments while effective vaccines are developed. A strategy for improved drug therapy is to increase levels of endogenous reactive metabolites for selective toxicity to SARS-CoV-2 by preferential damage to the viral proteome. Key reactive metabolites producing major quantitative damage to the proteome in physiological systems are: reactive oxygen species (ROS) and the reactive glycating agent methylglyoxal (MG); cysteine residues and arginine residues are their most susceptible targets, respectively. From sequenced-based prediction of the SARS-CoV-2 proteome, we found 0.8-fold enrichment or depletion of cysteine residues in functional domains of the viral proteome; whereas there was a 4.6-fold enrichment of arginine residues, suggesting SARS-CoV-2 is resistant to oxidative agents and sensitive to MG. For arginine residues of the SARS-CoV-2 coronavirus predicted to be in functional domains, we examined which are activated toward modification by MG – residues with predicted or expected low pKa by neighboring group in interactions. We found 25 such arginine residues, including 2 in the spike protein and 10 in the nucleoprotein. These sites were partially conserved in related coronaviridae: SARS-CoV and MERS. Finally, we identified drugs which increase cellular MG concentration to virucidal levels: antitumor drugs with historical antiviral activity, doxorubicin and paclitaxel. Our findings provide evidence of potential vulnerability of SARS-CoV-2 to inactivation by MG and a scientific rationale for repurposing of doxorubicin and paclitaxel for treatment of COVID-19 disease, providing efficacy and adequate therapeutic index may be established.- Qatar Foundation - PhD studentship. - Qatar Foundation - (project code QB-14). - Qatar University - COVID-19 research (project code QU ERG-CMED-2020-1)

Vulnerabilities of the SARS-CoV-2 virus to proteotoxicity - opportunity for repurposed chemotherapy of COVID-19 infection

The global pandemic of COVID-19 disease caused by infection with the SARS-CoV-2 coronavirus, has produce an urgent requirement and search for improved treatments whilst effective vaccines are developed. A strategy for improved drug therapy is to increase levels of endogenous reactive metabolites for selective toxicity to SARS-CoV-2 by preferential damage to the viral proteome. Key reactive metabolites producing major quantitative damage to the proteome in physiological systems are: reactive oxygen species (ROS) and the reactive glycating agent methylglyoxal (MG); cysteine residues and arginine residues are their most susceptible targets, respectively. From sequenced-based prediction of the SARS-CoV-2 proteome, we found 0.8-fold enrichment or depletion of cysteine residues in functional domains of the viral proteome; whereas there was a 4.6-fold enrichment of arginine residues, suggesting SARS-CoV-2 is resistant to oxidative agents and sensitive to MG. We examined activated arginine residues in functional domain with predicted low pKa by neighbouring group interaction in the SARS-CoV-2 We found 25 such arginine residues, including 2 in the spike protein and 10 in the nucleoprotein. These sites were partially conserved in related coronaviridae: SARS-COV and MERS. We also screened and identified drugs which increase cellular MG concentration to virucidal levels and found two antitumor drugs with historical antiviral activity, doxorubicin and paclitaxel were the best candidate for repurposing. Our findings provide evidence of potential vulnerability of SARS-CoV-2 to inactivation by MG and a scientific rationale for repurposing of doxorubicin and paclitaxel for treatment of COVID-19 disease, providing efficacy and adequate therapeutic index may be establishe

Prevalence and Determinants of Mental Health Problems and Mental Health Stigma Among Medical Students of Different Nationalities in Qatar

Introduction: Past studies have shown high prevalence of mental illness among medical students. This is often linked to the demands of the medical curriculum, and to mental health stigma that prevents students from seeking help. This study aimed to examine experiences of mental health problems among medical students of different nationalities in Qatar and to uncover sociodemographic factors related to their prevalence and associated stigma. Methods: A cross-sectional online survey was conducted with medical students in their second through fifth years at the College of Medicine at Qatar University. The survey began with a consent form, and those agreed to take the survey were directed to the questionnaire. The survey comprised 64 items across three sections. The first section collected sociodemographic data. The second section screened depressive symptoms using the PHQ-9; anxiety symptoms using GAD-7; and psychological distress symptoms using Kessler-6. The third section included 27 questions adopted from Schwenk et al, which evaluate students’ perceptions of stigma and their attitudes toward seeking help with their mental health. Results: One hundred and eighty-two students participated in the study. The prevalence of self-reported symptoms of severe depression, anxiety, and psychological distress was 4.4% (95% CI 2–9), 10.4% (95% CI 7–16), and 39.6% (95% CI 33–47), respectively; the prevalence of high stigma was 31.9% (95% CI 25–39). Parental education, repetition of an academic year, progress in medical studies, gender, and nationality had statistically significant correlations with mental health problems and stigma. Conclusion: In addition to the impact of the requirements of medical study, the high prevalence of reported mental illness among medical students is impacted by sociodemographic factors and the mental health stigma that constitutes a barrier to seeking help. Preventive wellbeing programs should be an essential component of medical curricula.The College of Medicine, Qatar University funded the publication fees of this study