This paper proposes a mathematical model based on probability graphs and an algorithm of iterative reasoning,which is an automatic interactive question-and-answer mathematical model based on the classic TCM syndrome differentiation system and the theory of prescription and syndrome correspondence.It is used for TCM online interactive consultation and automatic syndrome differentiation analysis to improve the effectiveness of remote TCM clinical consultation and help TCM artificial intelligence assist syndrome differentiation.This model can express the clinician's experience in syndrome differentiation,and reflect his ability to accumulate and apply knowledge of ancient Chinese books,which is conducive to the inheritance and development of TCM physicians'personal experience.The model is scalable and configurable,and can continuously accumulate experience in dialectics and knowledge of traditional Chinese medicine.The use of iterative reasoning algorithm can realize the automatic analysis and reasoning of more optimized syndrome analysis results through brief interactive question and answer,providing more efficient and convenient practical assistance for clinical diagnosis and treatment of traditional Chinese medicine,which is conducive to accelerating the inheritance and promotion of traditional Chinese medicine,and is conducive to the expansion of Chinese medicine.The mass basis and market supply of medical diagnosis and treatment services have far-reaching social benefits.

Ulcerative colitis （UC） is a commonly seen digestive system disease with unclear pathogenesis. The condition is complex and variable， often chronic， and has a long treatment period with no specific cure. Currently， the treatment of UC often involves the use of corticosteroids， aminosalicylates， and biologics in western medicine， which provide fast-acting and definite efficacy in the short term. However， with prolonged medication， some patients may develop drug resistance and worsening of the disease， leading to the occurrence of colon cancer. Research has found that oxidative stress is one of the important pathogenic factors in UC and influences its onset and development. Oxidative stress is a state of imbalance between oxidative products and the antioxidant system in the body， characterized by overexpression of oxidative products such as malondialdehyde （MDA）， reactive oxygen species （ROS）， nitric oxide （NO）， or deficiency of antioxidant enzymes such as superoxide dismutase （SOD）， catalase （CAT）， and glutathione （GSH）. It is worth noting that traditional Chinese medicine （TCM）， as a unique characteristic medicine of China， has achieved significant efficacy in the treatment of UC. Studies have shown that TCM effectively inhibits the occurrence of UC by suppressing the accumulation of metabolites and antagonizes the development of UC by enhancing the antioxidant system. Therefore， using TCM to regulate the oxidative balance as a diagnostic and therapeutic approach may be a new method and direction for the treatment of UC in the future. Based on the above research， this article summarized the mechanisms of key pathogenic proteins in oxidative stress and the occurrence and development of UC， and compiled the effective ingredients of Chinese medicine， single drugs， prescriptions， and acupuncture and moxibustion in regulating upstream and downstream target proteins of oxidative stress. These interventions can reduce pathological damage to the intestinal mucosa， lower the colon injury index， enrich the intestinal microbiota， increase colon length， and improve clinical symptoms of UC. The article is expected to expand the application of TCM in the treatment of UC and provide a reliable scientific theoretical basis.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

A fundamental challenge that arises in biomedicine is the need to characterize compounds in a relevant cellular context in order to reveal potential on-target or off-target effects. Recently, the fast accumulation of gene transcriptional profiling data provides us an unprecedented opportunity to explore the protein targets of chemical compounds from the perspective of cell transcriptomics and RNA biology. Here, we propose a novel Siamese spectral-based graph convolutional network (SSGCN) model for inferring the protein targets of chemical compounds from gene transcriptional profiles. Although the gene signature of a compound perturbation only provides indirect clues of the interacting targets, and the biological networks under different experiment conditions further complicate the situation, the SSGCN model was successfully trained to learn from known compound-target pairs by uncovering the hidden correlations between compound perturbation profiles and gene knockdown profiles. On a benchmark set and a large time-split validation dataset, the model achieved higher target inference accuracy as compared to previous methods such as Connectivity Map. Further experimental validations of prediction results highlight the practical usefulness of SSGCN in either inferring the interacting targets of compound, or reversely, in finding novel inhibitors of a given target of interest.
Drug Delivery Systems ; Proteins ; Transcriptome

Analysis of Variance ; Humans

Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATP-competitive inhibitor of PGK1 with an affinity of K _d = 99.08 nmol/L. DC-PGKI stabilizes PGK1 in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition, DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated macrophages. Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2 (nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium (DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.

With the rapid development of sequencing technology and bioinformatics analysis, the application of high-throughput sequencing (NGS) technology in precision medicine has been deepening, mainly in genetic disease diagnosis, tumor gene detection and concomitant diagnosis, as well as infectious disease detection. Compared with the traditional clinical tests, NGS analysis are more complicated with tedious operation steps and complex workflow, and they have high requirements for data analysis and variant interpretation. NGS approaches were reviewed in clinical diagnosis for constitutional disorders, cancer, infectious diseases as well as current issues in these clinical applications. Finally some suggestions for the quality management of laboratories were discussed.

Objective:To ascertain the endemic status of paragonimiasis in Zhejiang Province.Methods:From 2005 to 2020, 2-3 villages in 1-2 counties (cities, districts, hereinafter refferred to as counties) in historical endemic areas of paragonimiasis in Zhejiang Province were selected for monitoring each year. In each village, 50 to 150 local residents were selected as monitoring subjects, venous blood samples were collected, and serum Paragonimus antibody was detected by enzyme-linked immunosorbent assay (ELISA). Fifty to 100 intermediate hosts crabs or crayfish were collected in each village, and the infection of Paragonimus metacercaria was detected by crushing precipitation. Results:The positive rate of Paragonimus antibody was 2.9% (94/3 297); 3 929 crabs or crayfish were divided into 2 749 groups, 790 of which were found to have Paragonimus metacercaria infection, with a Paragonimus metacercaria infection rate of 28.7%. Conclusions:Paragonimus transmission chain exists in some counties of Zhejiang Province, which still has the potential risk of Paragonimus epidemic. Therefore, it is necessary to strengthen monitoring and carry out extensive health education to improve residents' self-protection awareness.

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-

A total of 280 patients with varicose veins of lower extremities who were prescribed stretch socks as pressure therapy in the outpatient clinic of Beijing Chaoyang Hospital from September 2019 to November 2019 were included in the study. Among 280 patients 208 were followed up for one year(74.3%), 139 cases (66.8%) gave up wearing stretch socks and 69 cases (33.2%) insisted to wear. The main reasons for giving up wearing were feeling too tight (23.1%), too much troubles (17.7%), symptom improvement (15.1%), poor effect (10.8%) and so on. The compliance of wearing stretch socks as pressure therapy in outpatients with varicose veins of lower extremities is poor with a variety of reasons, the data may provide a reference for improving clinical compliance in the future.