Integrated multiomics implicates dysregulation of ECM and cell adhesion pathways as drivers of severe COVID-associated kidney injury (preprint)

COVID-19 has been a significant public health concern for the last four years; however, little is known about the mechanisms that lead to severe COVID-associated kidney injury. In this multicenter study, we combined quantitative deep urinary proteomics and machine learning to predict severe acute outcomes in hospitalized COVID-19 patients. Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrated predictive power for both discovery and validation set with 87% and 79% accuracy, respectively. These predictive urinary biomarkers were recapitulated in non-COVID acute kidney injury revealing overlapping injury mechanisms. We further combined orthogonal multiomics datasets to understand the mechanisms that drive severe COVID-associated kidney injury. Functional overlap and network analysis of urinary proteomics, plasma proteomics and urine sediment single-cell RNA sequencing showed that extracellular matrix and autophagy-associated pathways were uniquely impacted in severe COVID-19. Differentially abundant proteins associated with these pathways exhibited high expression in cells in the juxtamedullary nephron, endothelial cells, and podocytes, indicating that these kidney cell types could be potential targets. Further, single-cell transcriptomic analysis of kidney organoids infected with SARS-CoV-2 revealed dysregulation of extracellular matrix organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters showed significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids. Collectively, these data suggest that extracellular matrix degradation and adhesion-associated mechanisms could be a main driver of COVID-associated kidney injury and severe outcomes.

Investigating Ecotourism Opportunities Measurements in a Complex Adaptive System: A Systematic Literature Review

Identifying and quantifying ecotourism opportunities are critical processes in sustainable tourism planning, which is challenging, since ecotourism is a Complex Adaptive System (CAS). This study investigated Ecotourism Opportunities Measurements (EOMs) in the literature and mapped the research trends to provide practical implications for research in this area. A systematic quantitative literature review began with a scientometric analysis in CiteSpace to examine the existing knowledge and the state of the art in EOMs. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol was then applied to refine the initial search results, and snowballing was used to collect additional articles. The refined set was then thematically coded and quantitatively analyzed. Our findings show that existing studies on ecotourism opportunities predominantly focus on the impacts of ecotourism on the environment, stakeholders' contributions toward ecotourism development, sustainability, and responsible behavior of local communities in ecotourism promotion. In addition, five dimensions have been identified under which ecotourism opportunities can be measured, including nature, environmental education/protection, sustainability, socio-cultural benefits, and tourist satisfaction. Existing scales or indices assess potential destinations qualitatively rather than quantitatively. In contrast, an index-based approach might help to solve the challenges of evaluating ecotourism opportunities as a CAS, as well as to quantitatively assess potential destinations to support decision-making related to ecotourism promotion.

Pathogen spectrum in lower respiratory tracts of suspected case infected with SARS-CoV-2

Objective: To understand the pathogen spectrum in the lower respiratory tracts of 100 suspected cases infected with SARS-CoV-2 in Chaoyang district of Beijing from January to March, 2020.

Relation of Serum Copper Status to Survival in COVID-19 (preprint)

The trace element copper (Cu) is part of our nutrition and essentially needed for several cuproenzymes that control redox status and support the immune system. In blood, the ferroxidase ceruloplasmin (CP) accounts for the majority of circulating Cu and serves as transport protein. Both Cu and CP behave as positive, whereas serum selenium (Se) and its transporter selenoprotein P (SELENOP) behave as negative acute phase reactants. In view that coronavirus disease (COVID-19) causes systemic inflammation, we hypothesized that biomarkers of Cu and Se status are regulated inversely, in relation to disease severity and mortality risk. Serum samples from COVID-19 patients were analysed for Cu by total reflection X-ray fluorescence and CP was quantified by a validated sandwich ELISA. The two Cu biomarkers correlated positively in serum from patients with COVID-19 (R=0.42, p<0.001). Surviving patients showed higher mean serum Cu and CP concentrations in comparison to non-survivors ([mean+/-SEM], Cu; 1475.9+/-22.7 vs. 1317.9+/-43.9 µg/L; p<0.001, CP; 547.2.5 +/- 19.5 vs. 438.8+/-32.9 mg/L, p=0.086). In contrast to expectations, total serum Cu and Se concentrations displayed a positive linear correlation in the patient samples analysed (R=0.23, p=0.003). Serum CP and SELENOP levels were not interrelated. Applying receiver operating characteristics (ROC) curve analysis, the combination of Cu and SELENOP with age outperformed other combinations of parameters for predicting risk of death, yielding an AUC of 95.0%. We conclude that the alterations in serum biomarkers of Cu and Se status in COVID-19 are not compatible with a simple acute phase response, and that serum Cu and SELENOP levels contribute to a good prediction of survival. Adjuvant supplementation in patients with diagnostically proven deficits in Cu or Se may positively influence disease course, as both increase in survivors and are of crucial importance for the immune response and antioxidative defence systems.

The Pivotal Role of SOD1 for Prediction of COVID-19 Progression Revealed by Proteomic and Bioinformatic Strategies (preprint)

Background: Severe acute respiratory distress syndrome-associated coronavirus-2 (SARS-CoV-2) is still threatening the whole human population worldwide. Patients infected with SARS-CoV-2 present diverse symptoms regarding to the severity of the disease. Determining the proteome changes associated with diverse symptoms and in different infection stages is beneficial for clinical diagnosis and management. Methods: We performed a TMT labeling proteomic study on the plasma of healthy controls and COVID-19 patients, including those with asymptomatic infection (NS), mild syndrome (MS), and severe syndrome in the early phase (SSEP) and later phase (SSLP). Bioinformatic and ELISA were used for the data analysis and identification. Findings: Hundreds of proteins were dysregulated in the plasma of COVID-19 patients including all the clinical symptoms. Bioinformatics analysis of the dysregulated proteins revealed that oxidative stress, complement activation and glycolysis-related proteins were affected after infection with SARS-CoV-2. ELISA analysis confirmed that SOD1, PRDX2 and LDHA levels were increased along with severe symptoms and did not change after recovery compared with those in healthy controls. Both GSEA and ROC analysis indicated that SOD1 could be a pivotal player in the progression of COVID-19. Interpretation: Our results indicated that plasma proteome changes differed based on symptoms and disease stages and SOD1 could be an important protein for indicating COVID-19 progression. These results may also provide new understanding for COVID-19 diagnosis and treatment. Funding: This project is supported by Shenzhen Bay Laboratory Opening Fund, Shenzhen Key Medical Discipline Construction Fund, Guangdong Natural Science Foundation, Sanming Project of Medicine in Shenzhen.Declaration of Interests: All the authors declared there are no conflicts of interest exist.Ethics Approval Statement: This research was approved by the ethics committee of the Shenzhen Center for Disease Control and Prevention [Approval number: 2020-025A].

Selenium Deficiency is Associated with Mortality Risk from COVID-19 (preprint)

SARS-CoV-2 infections underlie the current Coronavirus disease (COVID-19) pandemic and are causative for a high death toll particularly among elderly subjects and those with comorbidities. Selenium (Se) is an essential trace element of high importance for human health and particularly for a well-balanced immune response. Mortality risk from severe disease like sepsis or polytrauma is inversely related to Se status. We hypothesized that this relation also applies to COVID-19. Serum samples (n=166) from COVID-19 patients (n=33) were collected consecutively and analysed for total Se by X-ray fluorescence and selenoprotein P (SELENOP) by a validated ELISA. Both biomarkers showed the expected strong correlation (r=0.7758, p<0.001), pointing to an insufficient Se status for optimal selenoprotein expression. In comparison to reference data from a European cross sectional analysis (EPIC, n=1915), the patients showed a pronounced deficit in total serum Se (mean±SD, 50.8±15.7 vs. 84.4±23.4 µg/L) and SELENOP (3.0±1.4 vs. 4.3±1.0 mg/L). A Se status below the 2.5th percentile of the reference population, i.e., [Se] < 45.7 µg/L and [SELENOP] < 2.56 mg/L was present in 43.4% and 39.2% of COVID samples, respectively. The Se status was significantly higher in samples from surviving COVID patients as compared to non-survivors (Se; 53.3±16.2 vs. 40.8±8.1 µg/L, SELENOP; 3.3±1.3 vs. 2.1±0.9 mg/L). We conclude that Se status analysis in COVID patients provides diagnostic information. However, causality remains unknown due to the observational nature of this study. Nevertheless, the findings strengthen the notion on a relevant role of Se for COVID convalescence, and support the discussion on adjuvant Se supplementation in severely diseased and Se-deficient patients.