Emetine, an isoquinoline alkaloid that is enriched at high concentrations in the lung, has shown potent in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to better understand the effectiveness of low-dose emetine for patients with coronavirus disease 2019 (COVID-19).In this real-world study, 63 patients with mild or common COVID-19 were recruited from Wuhan Fangcang Shelter Hospital and five COVID-19-designated hospitals in Anhui Province, China from February to March 2020. Thirty-nine patients from Wuhan Fangcang Shelter Hospital were assigned to a pragmatic randomized controlled clinical trial, and 24 patients from the 5 COVID-19-designated hospitals in Anhui Province underwent a real-world study. The medication course of emetine was less than 10 days. The main symptoms and adverse reactions of all patients were observed and recorded. The primary outcome measure was the time required for a negative SARS-CoV-2 RNA result or the negative result rate on day 10. Secondary outcomes included axillary temperature, transcutaneous oxygen saturation, and respiratory frequency recovery. The study was approved by the Ethics Committee of The First Affiliated Hospital of Anhui Medical University on February 20, 2019 (approval No. PJ2020-03-19) and was registered with the Chinese Clinical Trial Registry on February 20, 2019 (registration number: ChiCTR2000030022).The oxygen saturation values were higher in the treatment group than in the control group on the first day after enrollment for patients treated at Fangcang Shelter Hospital. The axillary body temperature, respiratory rate, and oxygen saturation among patients in Fangcang Shelter Hospital were related to the time effect but not to the intervention measures. The respiratory rate and oxygen saturation of patients in the Anhui designated hospitals were related to the intervention measures but not to the time effect. The axillary body temperature of patients in Anhui designated hospitals was related to the time effect but not to the intervention measures.Our preliminary study shows that low-dose emetine combined with basic conventional antiviral drugs improves clinical symptoms in patients with mild and common COVID-19 without apparent adverse effects, suggesting that moderately increased doses of emetine may have good potential for treatment and prevention of COVID-19.
Abstract Familial Dilated cardiomyopathy (DCM) is a genetic cardiomyopathy with reduced left ventricle function or systolic function. Fifty-one DCM genes have been reported, most of which are inherited in an autosomal dominant manner, while those caused by a recessive manner are rarely observed. Here we identified an autosome recessive and evolutionarily conserved missense variant, c.2429G>A: p.Arg810His, in bicaudal D homolog 2 ( BICD2 ), which was segregated with the disease phenotype in a consanguineous family with DCM. Furthermore, we confirmed the presence of BICD2 variants in 3 of 210 sporadic cases, highlighting its candidate causative role. Interestingly, we discovered that BICD2 expressed higher in cardiomyocytes from DCM than that from control by reanalyzing published scRNA-seq dataset, implicating its possible involvement in cardiac function. We next explored BICD2 function in zebrafish model at both embryonic and adult stages. Knockout of bicd2 resulted in partial embryonic lethality in homozygotes, suggesting a vital role for bicd2 in embryogenesis. We performed zebrafish echocardiography to detect indices of ventricular size at the adult zebrafish stage. Intriguingly, dilated hearts, decreased ejection fraction, cardiac output and stroke volume were observed, suggesting a phenotype similar to human DCM in bicd2 -knockout homozygotes. Furthermore, RNA-seq confirmed the largest transcriptome shift in bicd2 homozygotes. Gene Set Enrichment Analysis(GSEA) of bicd2 -deficient fish showed altered gene expression enriched in cardiac pathways and mitochondrial energy metabolism. In conclusion, we found for the first time that an autosomal recessive BICD2 variant is associated with familial DCM, providing further insight into the molecular pathological mechanism of DCM.
Some lipoxygenase (LOX) isoenzymes can co-oxidize carotenoids. Carotenoids are collectors of light energy for photosynthesis and can protect plants from reactive oxygen species and coloration. This study isolated the cucumber (Cucumis sativus L.) yellow-green leaf mutant (ygl1), which had yellow-green leaves with decreased chlorophyll synthesis, increased relative carotenoid content, and delayed chloroplast development. Genetic analysis demonstrated that the phenotype of ygl1 was caused by a recessive mutation in a nuclear gene. The bulked segregants were resequenced, and the candidate ygl1 locus identified was mapped to the 9.2 kb region of the chromosome 4. Sequence analysis revealed that ygl1 encodes the tandem 13-LOX genes in a cluster. Four missense mutations were found in four tandem 13-LOX genes (Csa4M286960, Csa4M287550, Csa4M288070, and Csa4M288080) in the ygl1 mutant, and the four 13-LOX genes showed high similarity with one another. The transient RNA interference and virus-induced gene silencing of these genes simultaneously resulted in yellow-green leaves with a reduced amount of chloroplasts and increased relative carotenoid content, which were observed in the ygl1 mutant. This evidence supported the non-synonymous SNPs (Single Nucleotide Polymorphism) in the four tandem 13-LOX genes as being the causative mutation for the yellow-green leaves. Furthermore, this study provides a new allele for breeding cucumbers with yellow-green leaves and serves as an additional resource for studying carotenoid biosynthesis.
As an important wild relative of wheat, Agropyron cristatum has been successfully used for wheat improvement. Currently, a few useful agronomic traits of A. cristatum, such as high grain number per spike and resistance to diseases, have been transferred into common wheat. However, the effective detection of small A. cristatum segmental introgressions in common wheat is still difficult. The objective of this study was to identify A. cristatum-specific single nucleotide polymorphisms (SNPs) for the detection of small alien segments in wheat. The transcriptome sequences of A. cristatum were aligned against wheat coding DNA sequences (CDS) for SNP calling. As a result, we discovered a total of 167,613 putative SNPs specific to the P genome of A. cristatum compared with the common wheat genomes. Among 230 selected SNPs with functional annotations related to inflorescence development and stress resistance, 68 were validated as P genome-specific SNPs in multiple wheat backgrounds using Kompetitive Allele Specific PCR (KASP) assays. Among them, 55 SNPs were assigned to six homoeologous groups of the P genome using wheat-A. cristatum addition lines, and 6P-specific SNP markers were further physically mapped on different segments of chromosome 6P in 6P translocation lines. The P genome-specific SNPs were also validated by Sanger sequencing and used to detect the P chromatin in wheat-A. cristatum cryptic introgression lines. Two SNP markers (Unigene20217-182 and Unigene20307-1420) were detected in two wheat-A. cristatum introgression lines that showed enhanced grain number per spike and high resistance to powdery mildew. Together, the developed P genome-specific SNP markers will accelerate the detection of large numbers of wheat-A. cristatum derivatives and will be helpful for marker-assisted transfer of desirable traits from A. cristatum into adapted wheat cultivars in wheat breeding programs.
Spontaneous clearance of hepatitis B virus (HBV) is frequent in adults (95%) but rare in infants (5%), emphasizing the critical role of age-related hepatic immunocompetence. However, the underlying mechanisms of hepatocyte-specific immunosurveillance and age-dependent HBV clearance remain unclear. Here, we identified PGLYRP2 as a hepatocyte-specific pattern recognition receptor with age-dependent expression, and demonstrated that phase separation of PGLYRP2 was a critical driver of spontaneous HBV clearance in hepatocytes. Mechanistically, PGLYRP2 recognized and potentially eliminated covalently closed circular DNA (cccDNA) via phase separation, coordinated by its intrinsically disordered region and HBV DNA-binding domain (PGLYRP2IDR/209-377) in the nucleus. Additionally, PGLYRP2 suppressed HBV capsid assembly by directly interacting with the viral capsid, mediated by its PGRP domain. This interaction promoted the nucleocytoplasmic translocation of PGLYRP2 and subsequent secretion of the PGLYRP2-HBV capsid complex, thereby bolstering the hepatic antiviral response. Pathogenic variants or deletions in PGLYRP2 impaired its ability to inhibit HBV replication, highlighting its essential role in hepatocyte-intrinsic immunity. These findings suggest that targeting the PGLYRP2-mediated host-virus interaction may offer a potential therapeutic strategy for the development of anti-HBV treatments, representing a promising avenue for achieving a functional cure for HBV infection.
A 32-year-old female with systemic lupus erythematosus (SLE) for more than 7 years, and long-term treatment with cyclophosphamide, cyclosporine, methotrexate, and tacrolimus, later found to be combined with hypertrophic cardiomyopathy (HCM) for one year. The patient denied a family history of cardiomyopathy and sudden cardiac death (SCD). Echocardiography suggested that uneven thickening of the left ventricle (LV), mainly in the lower middle segment. Cardiac magnetic resonance (CMR) showed that the walls of the left ventricular (LV) were significantly thickened, as about 21 mm, mainly in the middle and lower segments. Genetic tests showed no known or suspected pathogenic variations were found and no significant enhancement in CMR, so secondary HCM was diagnosed clinically. After symptomatic treatment, the patient was discharged, and long-term follow-up was conducted. The diagnosis of HCM, which combined with SLE or second to usage of tacrolimus, was based on symptoms, echocardiography, and CMR; no endomyocardial biopsies were performed.
Abstract Background: In mice, liver fibrosis is the most serious pathologic change during Schistosoma japonicum ( S. japonicum ) infection. Schistosomiasis is mainly characterized by schistosome egg-induced granulomatous fibrosis. Hepatic stellate cells (HSCs) are mainly responsible for the net accumulation of collagens and fibrosis formation in the liver. Activated HSCs regulated by transforming growth factor-β1 (TGF-β1)/Smad signaling have emerged as the critical regulatory pathway in hepatitis virus or carbon tetrachloride-induced liver fibrosis. However, the detailed mechanism of HSCs activation in schistosome-induced liver fibrosis remains not well-elucidated. Methods: S. japonicum -induced murine models and control group were generated by abdominal infecting with 15 (±1) cercariae. The purity of cultured primary HSCs was evaluated by immunocytochemistry. The histopathological changes of the liver in i nfected mice were estimated by hematoxylin-eosin and Masson staining. Dynamic expression of pro-fibrotic molecules and microRNAs were detected by quantitative Real-time PCR (RT-qPCR). Mainly members involved in TGF-β1/Smad signaling pathway were examined via RT-qPCR and Western blot. Results: The egg-induced granulomatous inflammation formed at 4 weeks post-infection (wpi) and kept a progressive development. Alpha-smooth muscle actin (α-SMA), Collagen Ⅰ, Collagen Ⅲ, TGF-β1, Smad2, Smad3, and Smad4 showed a significant increase in mRNA and protein expression compared with the control group at 7 weeks and 9 wpi, while observed an opposite effect on Smad7. In addition, the mRNA expression of microRNA-21 (miRNA-21) was significantly increased at 7 wpi, and the mRNA expression of miRNA-454 was decreased starting from 4 wpi. Conclusion: Our present findings uncovered that HSCs regulated by TGF-β1/Smad signaling pathway play an important role in liver fibrosis of S. japonicum -infected mice, which may provide proof-of-concept for liver fibrosis in Schistosomiasis.
ObjectivesHypertrophic cardiomyopathy (HCM) is the most common hereditary cardiomyopathy. However, few studies have investigated the prognosis of familial HCM (FHCM) through clinical data. The purpose of this study was to compare the clinical outcomes of FHCM and non-FHCM through propensity score matching analysis.Methods and resultsThe cohort study included 1243 patients with HCM between 1996 and 2013 in Fuwai Hospital, Chinese Academy of Medical Sciences, among whom 125 patients had FHCM. During a mean follow-up of 7.6 ± 3.8 years (interquartile range: (IQR) 5.0–10.0 years), 217 (16.57%) of the 1243 patients had died, including 3 patients who underwent cardiac transplantation. Using 30 demographic and clinical variables, a 4:1 propensity score matched cohort for FHCM was established. The stepwise variable selection procedure for the Cox proportional hazards model was performed to identify the factors associated with mortality and competing risk regression analysis was performed to analyze the competitive risk of cardiovascular and non-cardiovascular mortality. The results showed that FHCM patients had a higher risk of cardiovascular mortality/cardiac transplantation (log-rank χ2 = 6.8, P = 0.0084) and an increased tendency of sudden cardiac death (SCD) (log-rank χ2 = 3.2, P = 0.074) compared with non-FHCM patients, but there was no difference in all-cause mortality (log-rank χ2 = 2.7, P = 0.1) between the two groups. Moreover, the Cox model showed that FHCM was an independent prognostic predictor for cardiovascular mortality/cardiac transplantation in HCM patients.ConclusionFHCM patients had a higher risk of cardiovascular mortality/cardiac transplantation and a higher tendency of SCD than non-FHCM patients, but there was no difference in all-cause mortality. Moreover, FHCM was an independent prognostic predictor for cardiovascular mortality/cardiac transplantation in HCM patients.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)