关键词： Complement system   alternative pathway   COVID-19   SARS-CoV-2   immunology   hemostasis  

摘要： Background: Severe coronavirus disease 2019 (COVID-19) is characterized by impaired type I interferon activity and a state of hyperinflammation leading to acute respiratory distress syndrome. The complement system has recently emerged as a key player in triggering and maintaining the inflammatory state, but the role of this molecular cascade in severe COVID-19 is still poorly characterized. Objective: We aimed at assessing the contribution of complement pathways at both the protein and transcriptomic levels. Methods: To this end, we systematically assessed the RNA levels of 28 complement genes in the circulating whole blood of patients with COVID-19 and healthy controls, including genes of the alternative pathway, for which data remain scarce. Results: We found differential expression of genes involved in the complement system, yet with various expression patterns: whereas patients displaying moderate disease had elevated expression of classical pathway genes, severe disease was associated with increased lectin and alternative pathway activation, which correlated with inflammation and coagulopathy markers. Additionally, properdin, a pivotal positive regulator of the alternative pathway, showed high RNA expression but was found at low protein concentrations in patients with a severe and critical disease, suggesting its deposition at the sites of complement activation. Notably, low properdin levels were significantly associated with the use of mechanical ventilation (area under the curve = 0.82;P = .002). Conclusion: This study sheds light on the role of the alternative pathway in severe COVID-19 and provides additional rationale for the testing of drugs inhibiting the alternative pathway of the complement system.

关键词： immunogene-related alternative splicing   tumor microenvironment   prognosis signatures   immuno   chemotherapy   breast cancer  

摘要： Simple Summary Aberrant immunogene-related alternative splicing (IGAS) pattern plays a pivotal role in pathogenesis, progression, and tumor microenvironment. However, the IGAS pattern of post-transcriptional mechanisms in breast cancer remains limited. Here, we performed a systematic analysis of IGAS patterns in breast cancer to assess the association between aberrant IGAS events, prognosis signatures, AS regulatory network, immune cell infiltration level and its marker gene expression, sensitivity to immunotherapy and chemotherapy, and heterogeneity of IGAS clusters. Generally, we demonstrated the prognostic signatures for IGAS events and immune cells, which were valuable information for breast cancer patients in predicting survival and directing immunotherapy and chemotherapy. Alternative splicing (AS) plays a crucial role in tumor development and tumor microenvironment (TME) formation. However, our current knowledge about AS, especially immunogene-related alternative splicing (IGAS) patterns in cancers, remains limited. Herein, we identified and characterized post-transcriptional mechanisms of breast cancer based on IGAS, TME, prognosis, and immuno/chemotherapy. We screened the differentially spliced IGAS events and constructed the IGAS prognostic model (p-values < 0.001, AUC = 0.939), which could be used as an independent prognostic factor. Besides, the AS regulatory network suggested a complex cooperative or competitive relationship between splicing factors and IGAS events, which explained the diversity of splice isoforms. In addition, more than half of the immune cells displayed varying degrees of infiltration in the IGAS risk groups, and the prognostic characteristics of IGAS demonstrated a remarkable and consistent trend correlation with the infiltration levels of immune cell types. The IGAS risk groups showed substantial differences in the sensitivity of immunotherapy and chemotherapy. Finally, IGAS clusters defined by unsupervised cluster analysis had dist

关键词： cheese alternative   meat alternative   micronutrients   Nutri-Score   online market analysis  

摘要： In recent decades, the demand, supply, and consumption of plant-based (pb) alternative products have increased worldwide. The objective of this study was to characterize pb meat and cheese products and compare them with their respective animal-based products. Data were collected in online market analyses (2019/2021). Nutritional data, Nutri-Score, and analysis of micronutrients are presented in this article. The number of products has grown in all categories, with the largest increase of 110% in pb cheese. The main protein sources in pb meat were soy and wheat, followed by an increasing use of peas. Pb meat generally contained less energy and total and saturated fat, but more carbohydrates and sugars than meat. In pb cheese, the protein content was lower than that of cheese. In 3 of 17 food groups, the salt content of pb alternatives was lower than in animal products. The daily requirement for iron could be covered better by pb alternatives than previously anticipated as well as the need for the vitamins E and K. The calculated Nutri-Score was generally lower for pb meat and higher for pb cheese than for the respective animal products. The trend towards consumption of pb alternative products is increasing, but the high level of processing, wide range of nutrients, and high salt content indicate the need for nutritional guidelines for these products.

关键词： postprandial hyperglycemia   insulin resistance   insulin secretion   chrononutrition   dietary interventions   exercise  

摘要： As years progress, we are found more often in a postprandial than a postabsorptive state. Chrononutrition is an integral part of metabolism, pancreatic function, and hormone secretion. Eating most calories and carbohydrates at lunch time and early afternoon, avoiding late evening dinner, and keeping consistent number of daily meals and relative times of eating occasions seem to play a pivotal role for postprandial glycemia and insulin sensitivity. Sequence of meals and nutrients also play a significant role, as foods of low density such as vegetables, salads, or soups consumed first, followed by protein and then by starchy foods lead to ameliorated glycemic and insulin responses. There are several dietary schemes available, such as intermittent fasting regimes, which may improve glycemic and insulin responses. Weight loss is important for the treatment of insulin resistance, and it can be achieved by many approaches, such as low-fat, low-carbohydrate, Mediterranean-style diets, etc. Lifestyle interventions with small weight loss (7-10%), 150 min of weekly moderate intensity exercise and behavioral therapy approach can be highly effective in preventing and treating type 2 diabetes. Similarly, decreasing carbohydrates in meals also improves significantly glycemic and insulin responses, but the extent of this reduction should be individualized, patient-centered, and monitored. Alternative foods or ingredients, such as vinegar, yogurt, whey protein, peanuts and tree nuts should also be considered in ameliorating postprandial hyperglycemia and insulin resistance. This review aims to describe the available evidence about the effects of diet, chrononutrition, alternative dietary interventions and exercise on postprandial glycemia and insulin resistance.

关键词： glucagon‐   like peptide‐   1 receptor   high‐   throughput screening   nonpeptide agonist   positive allosteric modulator   type 2 diabetes   β   ‐   cell  

摘要： Glucagon-like peptide-1 (GLP-1) receptors belong to the pharmaceutically important Class B family of GPCRs and are involved in many biologically significant signalling pathways. Its incretin peptide ligand GLP-1 analogues are effective treatments for Type 2 diabetes. Although developing non-peptide low MW drugs targeting GLP-1 receptors remains elusive, considerable progress has been made in discovering non-peptide agonists and positive allosteric modulators (PAMs) of GLP-1 receptors with demonstrated efficacy. Many of these compounds induce biased signalling in GLP-1 receptor-mediated functional pathways. High-quality structures of GLP-1 receptors in both inactive and active states have been reported, revealing detailed molecular interactions between GLP-1 receptors and non-peptide agonists or PAMs. These progresses raise the exciting possibility of developing non-peptide drugs of GLP-1 receptors as alternative treatments for Type 2 diabetes. The insight into the interactions between the receptor and the non-peptide ligand is also useful for developing non-peptide ligands targeting other Class B GPCRs.

关键词： modernity   white supremacy   western empires   racial hierarchies   colonization   slavery   Jim Crow   patriarchy   resistance movements   Du Bois   emancipatory sociology  

摘要： This article derives from my 2021 ASA presidential address. I examine how sociologists including Karl Marx, Emile Durkheim, Max Weber, and white American sociologists have omitted key determinants of modernity in their accounts of this pivotal development in world history. Those determinants are white supremacy, western empires, racial hierarchies, colonization, slavery, Jim Crow, patriarchy, and resistance movements. This article demonstrates that any accounts omitting these determinants will only produce an anemic and misleading analysis of modernity. The central argument maintains that the sociologist W. E. B. Du Bois developed a superior analysis of modernity by analytically centering these determinants. I conclude by making a case for the development of an emancipatory sociology in the tradition of Du Boisian critical sociological thought.

摘要： Severe cases of coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) are characterized by hyperinflammation and multiorgan dysfunction. Although the incidence and mortality of these illnesses are low in the pe-diatric population, they occur with enough frequency to necessitate well-defined treat-ment strategies with demonstrated clinical efficacy. Biologic medications include small molecules or monoclonal antibodies that target specific receptors, enzymes or other proteins that play key roles in human disease. Biologic medications that inhibit proin-flammatory cytokines and signaling pathways represent an emerging and valuable tool for the treatment of both severe COVID-19 and MIS-C in pediatric patients. This article discusses current theories regarding the pathogenesis of both diseases, and it will sum-marize the latest evidence supporting each biologic medication used for their treatment.

关键词： agricultural policy   economic welfare analysis   input subsidies   Malawi  

摘要： Most studies that have evaluated the welfare impacts of agricultural input subsidy programmes (ISPs) in developing countries have focused on measuring their effects on various outcomes of interest such as agricultural productivity. I estimate the consumer surplus accrued by direct and indirect beneficiaries of ISPs in Malawi. Malawi's Farm Input Subsidy Programme (FISP), introduced in 2005, is the largest such scheme in sub-Saharan Africa. I find that the programme provides low direct benefits compared to the public costs of the programme. At the national level, the benefit-cost ratio (BCR) is up to 0.37 for FISP households with no option to resell the fertiliser accessed through the programme. When reselling of the fertiliser is allowed for, the BCR increases to 0.64 including spillover benefits to direct non-beneficiaries of FISP. I also found 60% of all fertiliser vouchers and benefits accrued to farm households with above the median wealth level. Many farmers demand 25 kg of fertiliser or less at the subsidised price. Thus, when resource poor direct beneficiaries have the option to buy 25 kg bags of fertiliser in addition to the 50 kg bags currently being offered under FISP, their benefits increase by about 53% compared to the status quo. Overall, my results suggest that a more flexible redemption of the fertiliser vouchers as well as complementary investments such as improved access to credit could increase the programme's contribution to farmers' welfare.

关键词： PEGylation   L-asparaginase   Reducing agents   Pyridine borane   Pegaspargase  

摘要： PEGylation is a reductive alkylation of a protein N-terminal/alpha-amine of protein with mPEG chain by reducing agent. To obtain quantitative and site-specific PEGylation, sodium cyanoborohydride is commonly used as a reducing agent. The reduction process of sodium cyanoborohydride produces highly poisonous hydrogen cyanide, which may render the final product toxic. Herein, we have studied various reducing agents such as dimethylamine borane, triethylamine borane, trimethylamine borane, pyridine borane, morpholine borane, 2-picoline borane, and 5-ethyl-2-methyl-pyridine borane were tested as alternatives to sodium cyanoborohydride for the PEGylation of L-asparaginase. The characterization of reacted pegaspargase was carried out by SDS-PAGE, Western blotting, SEC-HPLC, RP-HPLC, SEC-MALS, CD, enzyme activity, and cell proliferation assays using with lymphoblast cells and MTS/PMS as substrate. Pyridine borane was determined to be the best acceptable reducing agent for PEGylation in terms of purity and activity. As a result, instead of sodium cyanoborohydride, pyridine borane can be employed.