Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.

Actionable druggable genome-wide Mendelian randomization identifies repurposingopportunities for COVID-19

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization (MR) analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2: P=1.6x10-6, IFNAR2: P=9.8x10-11, and IL-10RB: P=1.9x10-14) using cis-eQTL genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared eQTL signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

The predictive model of birth defect risk based on evidence-based medicine / 中华疾病控制杂志

Objective The Rothman-Keller model was used to establish a predictive model for the risk of birth defects on the basis of evidence-based medicine, which so as to provide the basis for pertinent interventions in China. Methods First, the odds ratio (OR) value of risk factors for birth defects was obtained by evaluating the literature of meta-analysis, and the risk score table of the Rothman-Keller model was constructed. Then the simulation data was used to build the model, the risk boundary value of risk prediction, and finally the actual data to was used for verification. Results The main risk factors for 20 birth defects were collected through 17 articles. In the actual data of Shanxi Province, the actual incidence rate of high-risk populations screened by Rothman-Keller model was 10.9%, and it was statistically different from other groups ( 2 =147.58，P<0.001). In addition, the rothman-keller model identified all patients with a family history of birth defects as high-risk. Conclusions Through the meta-analysis literature on birth defects in China, the study find the main risk factors and construct a risk prediction model. It can be used to predict the risk of birth defects and help screen high-risk groups. At the same time, it provides ideas for predicting the risk of other diseases.

Influence of different frequencies of acupuncture on therapeutic effect in patients with cerebral infarction at convalescence / 中国针灸

<p><b>OBJECTIVE</b>To observe the influence of different frequencies of acupuncture on the therapeutic effect in patients with cerebral infarction at convalescence.</p><p><b>METHODS</b>Ninety-seven cases were randomly divided into an observation group I (n = 50) and an observation group II (n = 47). They were treated with same Chinese drugs and western medicine and electroacupuncture at Jiquan (HT 1), Quchi (LI 11), Hegu (LI 4), Huantiao (GB 30), etc. The observation group I was treated twice each day and the observation group II once each day. After treatment of 30 days, their therapeutic effects were observed.</p><p><b>RESULTS</b>The total effective rate of 94.0% for improvement of limb activity in the observation group I was better than 78.7% in the observation group II (P < 0.05); the therapeutic effects for choking when taking water, dysphagia, vague mind and slurred speech were similar in the two groups (P > 0.05).</p><p><b>CONCLUSION</b>The therapeutic effect of acupuncture twice each day on cerebral infarction at convalescence is superior to that of once daily.</p>

Synthesis and antitumor activity of nitrogen-based thiocolchicine derivatives / 药学学报

<p><b>AIM</b>To search for colchicine derivatives which have high efficacy and low toxicity.</p><p><b>METHODS</b>Colchicine was firstly converted into thiocolchicine, and then it was hydrolyzed to get 7-(N-deacetylthiocolchicine). At last, 7-(N-deacetylthiocolchicine) was amidated to get the target compounds. The chemical structure of these new derivatives was confirmed with 1H NMR, IR, MS, and HR-MS. The cytotoxicity of the compounds was tested by MTT assay. Their in vivo antitumor activity was evaluated against mice tumor H22 and U14.</p><p><b>RESULTS</b>Twelve thiocolchicine derivatives are new compounds.</p><p><b>CONCLUSION</b>In vitro antitumor activity has showed that some of these thiocolchicines possessed cytotoxic activity superior to colchicine. However, in vivo antitumor activity indicated that these derivatives have poor efficacy in mice.</p>

Effect of benflumetol on DNA content and pH value of the lysosome of Plasmodium berghei / 军事医学科学院院刊

Objective:To study the antimalarial mechanism of benflumetol (B). Methods: Flow cytometry (FCM) was used to analyze the effects of B and chloroquine (CQ) on DNA content of Plasmodium berghei and pH value of the lysosome of malarial parasites. Results: DNA content of the plasmodia not treated with any drugs was not changed in 24 hours,while benflumetol could decrease the DNA content: the DNA content began to decrease 2 h after the drug administration and reached the minimum by 16 h, but somewhat increased at 24 h after administration. The pH in the lysosome increased 1 h and restored premedication level 4 h after benflumetol administration. Chloroquine had the same effects on DNA and lysosome pH of malarial parasites.Conclusions: The antimalarial mechanism of benflumetol is directly related to its effect to inhibit the synthesis of DNA.