ABSTRACT
The COVID-19 pandemic has pushed healthcare systems globally to a breaking point. The urgent need for effective and affordable COVID-19 treatments calls for repurposing combinations of approved drugs. The challenge is to identify which combinations are likely to be most effective and at what stages of the disease. Here, we present the first disease-stage executable signalling network model of SARS-CoV-2-host interactions used to predict effective repurposed drug combinations for treating early- and late-stage severe disease. Using our executable model, we performed in silico screening of 9870 pairs of 140 potential targets and have identified 12 new drug combinations. Camostat and Apilimod were predicted to be the most promising combination in effectively supressing viral replication in the early stages of severe disease and were validated experimentally in human Caco-2 cells. Our study further demonstrates the power of executable mechanistic modelling to enable rapid pre-clinical evaluation of combination therapies tailored to disease progression. It also presents a novel resource and expandable model system that can respond to further needs in the pandemic.
ABSTRACT
SARS-CoV-2 infection triggers highly variable host responses and causes varying degrees of illness in humans. We sought to harness the peripheral blood mononuclear cell (PBMC) response over the course of illness to provide insight into COVID-19 physiology. We analyzed PBMCs from subjects with variable symptom severity at different stages of clinical illness before and after IgG seroconversion to SARS-CoV-2. Prior to seroconversion, PBMC transcriptomes did not distinguish symptom severity. In contrast, changes in chromatin accessibility were associated with symptom severity. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif occupancy for individual PBMC cell types. The most extensive remodeling occurred in CD14+ monocytes where sub-populations with distinct chromatin accessibility profiles were associated with disease severity. Our findings indicate that pre-seroconversion chromatin remodeling in certain innate immune populations is associated with divergence in symptom severity, and the identified transcription factors, regulatory elements, and downstream pathways provide potential prognostic markers for COVID-19 subjects. One sentence summaryChromatin accessibility in immune cells from COVID-19 subjects is remodeled prior to seroconversion to reflect disease severity.
ABSTRACT
Community acquired pneumonia (CAP) is an important cause of death in children under five years old.Viruses and bacteria are common causes.At present, accurate diagnosis of the pathogen of cap in children is still a clinical challenge.Clinical diagnosis of pathogens mainly through the collection of various samples (such as nasopharyngeal swab, sputum, blood, body fluids, etc.) for pathogen detection (such as antigen, antibody, culture, polymerase chain reaction (PCR) detection). Different samples and different detection methods have their own advantages and disadvantages, especially in the diagnosis of viral pneumonia and bacterial pneumonia, which lead to great differences in treatment measures.In order to identify different pathogens early and reduce the irrational use of antibiotics, clinicians and researchers are still exploring methods regarding early accurate pathogen diagnosis.Metabonomics is a rapidly developing field, which aims to identify and quantify the concentration changes of all metabolites or metabonomics in model systems.Most disease states are related with metabolic homeostasis.Metabonomics can provide clues for the discovery of new biomarkers, and also be used for the study of infections caused by different pathogens.Non targeted metabonomics analysis provides a new diagnostic approach for the etiology of cap in children.
ABSTRACT
Objective To investigate the enhanced effect of polysaccharide from B.jiangsiensis(PBJ) on the immune hypofunction mouse models and its dose-effect relationship.Methods The immune hypofunction mouse models were made by hypodermic injection with cyclophosphamide(Cy) in mice.PBJ's effect on hemolysin content in mouse body induced by chicken erythrocytes and the delayed-type hypersensitivity(DTH) induced by dinitrochlorobenzene in mice were observed and contrasted in the different mouse groups treated with Cy in vivo by hypodermic injection together with PBJ at doses of 400mg/kg,200mg/kg and 50mg/kg,respectively.Results The test showed that the index of hemolysin,hemolytic plaque formation and delayed hypersensitivity reaction in model group markedly decreased while the indexes of hemolysin test in the control group,high and middle dose groups increased(P
ABSTRACT
Objective To study the therapeutic effect of tianluo decoction against hepatitis B virus(HBV) in vivo and vitro.Methods The inhibitive effect were observed in the duplication process of hepatitis B virus by fluorescence quantitative PCR(FQ-PCR) in vitro test and duck's hepatitis B animal model in vivo test.Results FQ-PCR in vitro test demonstrated that tianluo decoction had biological function to inhibit from duplication of hepatitis B virus,and there were significant difference in inhibit hepatitis B virus from duplicating in distilled water and tianluo decoction group(median:6.9?108/ml vs 2.6?104/ml,u=2.76,P
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Objective To investigate the relationship among the expressions of CD44v6,nm23 and MMP-9 and lymph node metastasis,differentiated degree as well as invasion depth in primary gastric carcinoma.Methods Seventy cases of gastric carcinoma,20 cases of chronic superficial gastritis,20 cases of large intesinal metaplasia and 20 cases of atipical hyperplasia were investigated using antibodies to CD44v6,MMP-9 and nm23 by S-P immunohistochemical technique.Results The positivity rates of CD44v6,MMP-9 and nm23 in gastric cancer were 64.3%,60.0%,57.1%,respectively.The positivity rates of CD44v6 and MMP-9 in gastric carcinoma were higher than that in the control groups.The positivity rates of nm23 in gastric carcinoma were lower than that in the control groups.The difference between the expression of CD44v6,MMP-9 and nm23 and lymph node metastasis was statistically significant.There was statistically significant difference between the expression of MMP-9,nm23 and the depth of invasion.CD44v6 expression in gastric cancer was positively correlated with MMP-9 expression(P
