Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CL pro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CL pro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CL pro . We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

The formation of –OOH groups and their high reactivity for As(iii) oxidation under visible light and alkaline conditions are demonstrated.

Characterization of the genetic properties of maize inbred lines is beneficial not only for increasing knowledge of genetic diversity, but also for maize breeding. In the present study, a panel of 240 maize inbred lines commonly used in China, including three foundation parents Dan340, Mo17, and Huangzao4, and their derivatives, was genotyped using the MaizeSNP50 BeadChip, which contains 56,110 single-nucleotide polymorphism (SNP) markers. As a result, 40,757 SNPs with unique physical positions were successfully recalled in this panel with an average coverage of 50 kb per SNP. Five subgroups including Lan, LRC, PB, Reid, and SPT were inferred using 4000 SNPs with minor allele frequency C0.200, a result that was largely consistent with the pedigree information for these 240 inbred lines. With a cutoff value of r 2 \ 0.100, linkage disequilibrium (LD) decay distances along the ten chromosomes of maize ranged from 397 to 819 kb, with an average of 643 kb. A subtotal of 26, 35, and 23 identity-by-descent segments, which were longer than both the average LD decay distance on the corresponding chromosomes and the local LD decay distance of r 2 \ 0.100, were identified in the Dan340, Huangzao4, and Mo17 derivatives, respectively. Three lower peaks for Tajima's D overlapped with three major quantitative trait loci (qkrn7, scmv1, and qHS2.09) in these derivatives. Elucidating the genetic properties of this panel provides information for investigating the genetic architecture of agronomic traits and heterotic grouping during maize breeding.

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Examination stress occurs so frequently in the lives of students. The neural mechanisms of attentional bias induced by examination stress in test-anxious individuals remain unclear. Accordingly, we investigated the attentional bias toward test-related threatening words in selected high and low test-anxious participants under the stress of final examinations by using an event-related potential (ERP) technique. A classic dot-probe paradigm was adopted with a test-related/test-unrelated threatening word and a neutral word pair as cues. Results showed attention bias and enhanced N200 amplitude toward test-related threat in high test-anxious individuals, whereas avoidance of test-related threat and decreased N200 amplitude were shown in low test-anxious individuals. Additionally, ERP data revealed the relatively enhanced LPP amplitude in low test-anxious participants compared with that in high test-anxious participants. No attentional bias toward test-unrelated threat was found. In conclusion, examination stress resulted in attentional bias and functional perturbations of a brain circuitry that reacted rapidly to test-related threat in high test-anxious individuals.

Background Epigenetic alternation is a common contributing factor to neoplastic transformation. Although previous studies have reported a cluster of aberrant promoter methylation changes associated with silencing of tumor suppressor genes, little is known concerning their sequential DNA methylation changes during the carcinogenetic process. The aim of the present study was to address a genome-wide search for identifying potentially important methylated changes and investigate the onset and pattern of methylation changes during the progression of colorectal neoplasia. Methods A three-phase design was employed in this study. In the screening phase, DNA methylation profile of 12 pairs of colorectal cancer (CRC) and adjacent normal tissues was analyzed by using the Illumina MethylationEPIC BeadChip. Significant CpG sites were selected based on a cross-validation analysis from The Cancer Genome Atlas (TCGA) database. Methylation levels of candidate CpGs were assessed using pyrosequencing in the training dataset (tumor lesions and adjacent normal tissues from 46 CRCs) and the validation dataset (tumor lesions and paired normal tissues from 13 hyperplastic polyps, 129 adenomas, and 256 CRCs). A linear mixed-effects model was used to examine the incremental changes of DNA methylation during the progression of colorectal neoplasia. Results The comparisons between normal and tumor samples in the screening phase revealed an extensive CRC-specific methylomic pattern with 174,006 (21%) methylated CpG sites, of which 22,232 (13%) were hyermethylated and 151,774 (87%) were hypomethylated. Hypermethylation mostly occurred in CpG islands with an overlap of gene promoters, while hypomethylation tended to be mapped far away from functional regions. Further cross validation analysis from TCGA dataset confirmed 265 hypermethylated promoters coupling with downregulated gene expression. Among which, hypermethylated changes in MEEPD2 promoter was successfully replicated in both training and validation phase. Significant hypermethylation appeared since precursor lesions with an extensive modification in CRCs. The linear mixed-effects modeling analysis found that a cumulative pattern of MPPED2 methylation changes from normal mucosa to hyperplastic polyp to adenoma, and to carcinoma ( P < 0.001). Conclusions Our findings indicate that epigenetic alterations of MPPED2 promoter region appear sequentially during the colorectal neoplastic progression. It might be able to serve as a promising biomarker for early diagnosis and stage surveillance of colorectal tumorigenesis. Electronic supplementary material The online version of this article (10.1186/s13148-019-0628-y) contains supplementary material, which is available to authorized users.

Background:Several studies have revealed that high shock index (SI) is a risk factor for acute myocardial infarction (AMI) patients. These studies do not give a systematic review in this issue. Therefore, we conducted a systematic review and meta-analysis to determine the effect of high SI on the prognosis of AMI patients.Methods:We did a systematic search of PubMed, Embase, and the Cochrane Library, using various combinations of keywords such as “shock index,” “shock-index,” “acute myocardial infarction,” “ST elevation myocardial infarction,” “non-ST segment elevation myocardial infarction,” “STEMI,” “NSTEMI,” “AMI,” and “MI” for eligible studies published up to December 23, 2016. The 3 primary outcomes for this analysis were all-cause in-hospital mortality, short-term adverse outcomes, and long-term adverse outcomes.Results:Database searches retrieved 226 citations. Finally, 8 studies enrolling 20,404 patients were eventually included in the analysis. High SI was associated with an increased in-hospital mortality (pooled RR = 10.96, 95% CI: 2.00–59.94, P = .01). Adverse outcomes were significantly higher in the high SI group compared to the low SI group (pooled RR = 1.93, 95% CI: 1.10–3.39, P = .02; I2 = 95%). Individuals with high SI had an increased risk of long-term adverse outcomes (pooled RR = 2.31, 95% CI: 1.90–2.81, P < .001) compared to low SI.Conclusion:High SI may increase the in-hospital mortality, short-term, and long-term adverse outcomes in AMI patients.

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