m6A-related lncRNAs as potential biomarkers and the lncRNA ELFN1-AS1/miR-182-5p/BCL-2 regulatory axis in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid subtype. However, unsatisfactory survival outcomes remain a major challenge, and the underlying mechanisms are poorly understood. N6-methyladenosine (m6A), the most common internal modification of eukaryotic mRNA, participates in cancer pathogenesis. In this study, m6A-associated long non-coding RNAs (lncRNA) were retrieved from publicly available databases. Univariate, LASSO, and multivariate Cox regression analyses were performed to establish an m6A-associated lncRNA model specific to DLBCL. Kaplan-Meier curves, principal component analysis, functional enrichment analyses and nomographs were used to study the risk model. The underlying clinicopathological characteristics and drug sensitivity predictions against the model were identified. Risk modelling based on the three m6A-associated lncRNAs was an independent prognostic factor. By regrouping patients using our model-based method, we could differentiate patients more accurately for their response to immunotherapy. In addition, prospective compounds that can target DLBCL subtypes have been identified. The m6A-associated lncRNA risk-scoring model developed herein holds implications for DLBCL prognosis and clinical response prediction to immunotherapy. In addition, we used bioinformatic tools to identify and verify the ceRNA of the m6A-associated lncRNA ELFN1-AS1/miR-182-5p/BCL-2 regulatory axis. ELFN1-AS1 was highly expressed in DLBCL and DLBCL cell lines. ELFN1-AS1 inhibition significantly reduced the proliferation of DLBCL cells and promoted apoptosis. ABT-263 inhibits proliferation and promotes apoptosis in DLBCL cells. In vitro and in vivo studies have shown that ABT-263 combined with si-ELFN1-AS1 can inhibit DLBCL progression.

Exploration of shared gene signatures and molecular mechanisms between type 2 diabetes and osteoporosis.

Type 2 diabetes mellitus (T2D) and osteoporosis (OP) are systemic metabolic diseases and often coexist. The mechanism underlying this interrelationship remains unclear. We downloaded microarray data for T2D and OP from the Gene Expression Omnibus (GEO) database. Using weighted gene co-expression network analysis (WGCNA), we identified co-expression modules linked to both T2D and OP. To further investigate the functional implications of these associated genes, we evaluated enrichment using ClueGO software. Additionally, we performed a biological process analysis of the genes unique in T2D and OP. We constructed a comprehensive miRNA-mRNA network by incorporating target genes and overlapping genes from the shared pool. Through the implementation of WGCNA, we successfully identified four modules that propose a plausible model that elucidates the disease pathway based on the associated and distinct gene profiles of T2D and OP. The miRNA-mRNA network analysis revealed co-expression of PDIA6 and SLC16A1; their expression was upregulated in patients with T2D and islet ß-cell lines. Remarkably, PDIA6 and SLC16A1 were observed to inhibit the proliferation of pancreatic ß cells and promote apoptosis in vitro, while downregulation of PDIA6 and SLC16A1 expression led to enhanced insulin secretion. This is the first study to reveal the significant roles of PDIA6 and SLC16A1 in the pathogenesis of T2D and OP, thereby identifying additional genes that hold potential as indicators or targets for therapy.

M6A-mediated upregulation of circMDK promotes tumorigenesis and acts as a nanotherapeutic target in hepatocellular carcinoma.

BACKGROUND: Emerging evidence suggest the critical role of circular RNAs (circRNAs) in disease development especially in various cancers. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) is still largely unknown. METHODS: RNA sequencing was performed to identify significantly upregulated circRNAs in paired HCC tissues and non-tumor tissues. CCK-8 assay, colony formation, transwell, and xenograft mouse models were used to investigate the role of circRNAs in HCC proliferation and metastasis. Small interfering RNA (siRNA) was used to silence gene expression. RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assay and western blot were used to explore the underlying molecular mechanisms. RESULTS: Hsa_circ_0095868, derived from exon 5 of the MDK gene (named circMDK), was identified as a new oncogenic circRNA that was significantly upregulated in HCC. The upregulation of circMDK was associated with the modification of N6-methyladenosine (m6A) and poor survival in HCC patients. Mechanistically, circMDK sponged miR-346 and miR-874-3p to upregulate ATG16L1 (Autophagy Related 16 Like 1), resulting to the activation of PI3K/AKT/mTOR signaling pathway to promote cell proliferation, migration and invasion. Poly (ß-amino esters) (PAEs) were synthesized to assist the delivery of circMDK siRNA (PAE-siRNA), which effectively inhibited tumor progression without obvious adverse effects in four liver tumor models including subcutaneous, metastatic, orthotopic and patient-derived xenograft (PDX) models. CONCLUSIONS: CircMDK could serve as a potential tumor biomarker that promotes the progression of HCC via the miR-346/874-3p-ATG16L1 axis. The PAE-based delivery of siRNA improved the stability and efficiency of siRNA targeting circMDK. The PAE-siRNA nanoparticles effectively inhibited HCC proliferation and metastasis in vivo. Our current findings offer a promising nanotherapeutic strategy for the treatment of HCC.

CircRNA-001241 mediates sorafenib resistance of hepatocellular carcinoma cells by sponging miR-21-5p and regulating TIMP3 expression.

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and its incidence is on the rise, closely related to advanced liver disease. Sorafenib chemotherapy is one of the main treatment options for patients with advanced HCC. Despite several reports on HCC multidrug resistance, the underlying regulatory mechanisms are still unclear. In this study, we found circ-001241 was significantly upregulated in HCC tissues and cells. Knockdown of circ-001241 markedly inhibited HCC cell proliferation and decreased sorafenib-resistance. More importantly, circRNA acts as a ceRNA to suppress the expression and activity of miR-21-5p, leading to the increase in TIMP3 expression. In addition, circRNA-001241 facilitated HCC sorafenib-resistance by regulating the miR-21-5p/TIMP3 axis. Taken together, our study elucidated the oncogenic role of circ-001241 in mediating sorafenib resistance in HCC, providing insights and opportunities to overcome sorafenib resistance in patients with advanced hepatocellular carcinoma.

Truncated tests for combining evidence of summary statistics.

To date, thousands of genetic variants to be associated with numerous human traits and diseases have been identified by genome-wide association studies (GWASs). The GWASs focus on testing the association between single trait and genetic variants. However, the analysis of multiple traits and single nucleotide polymorphisms (SNPs) might reflect physiological process of complex diseases and the corresponding study is called pleiotropy association analysis. Modern day GWASs report only summary statistics instead of individual-level phenotype and genotype data to avoid logistical and privacy issues. Existing methods for combining multiple phenotypes GWAS summary statistics mainly focus on low-dimensional phenotypes while lose power in high-dimensional cases. To overcome this defect, we propose two kinds of truncated tests to combine multiple phenotypes summary statistics. Extensive simulations show that the proposed methods are robust and powerful when the dimension of the phenotypes is high and only part of the phenotypes are associated with the SNPs. We apply the proposed methods to blood cytokines data collected from Finnish population. Results show that the proposed tests can identify additional genetic markers that are missed by single trait analysis.

Phase transition and higher order analysis of Lq regularization under dependence.

We study the problem of estimating a [Formula: see text]-sparse signal [Formula: see text] from a set of noisy observations [Formula: see text] under the model [Formula: see text], where [Formula: see text] is the measurement matrix the row of which is drawn from distribution [Formula: see text]. We consider the class of [Formula: see text]-regularized least squares (LQLS) given by the formulation [Formula: see text], where [Formula: see text]  [Formula: see text] denotes the [Formula: see text]-norm. In the setting [Formula: see text] with fixed [Formula: see text] and [Formula: see text], we derive the asymptotic risk of [Formula: see text] for arbitrary covariance matrix [Formula: see text] that generalizes the existing results for standard Gaussian design, i.e. [Formula: see text]. The results were derived from the non-rigorous replica method. We perform a higher-order analysis for LQLS in the small-error regime in which the first dominant term can be used to determine the phase transition behavior of LQLS. Our results show that the first dominant term does not depend on the covariance structure of [Formula: see text] in the cases [Formula: see text] and [Formula: see text] which indicates that the correlations among predictors only affect the phase transition curve in the case [Formula: see text] a.k.a. LASSO. To study the influence of the covariance structure of [Formula: see text] on the performance of LQLS in the cases [Formula: see text] and [Formula: see text], we derive the explicit formulas for the second dominant term in the expansion of the asymptotic risk in terms of small error. Extensive computational experiments confirm that our analytical predictions are consistent with numerical results.

Bidirectional crosstalk between the epithelial-mesenchymal transition and immunotherapy: A bibliometric study.

Immunotherapy has recently attracted considerable attention. However, currently, a thorough analysis of the trends associated with the epithelial-mesenchymal transition (EMT) and immunotherapy is lacking. In this study, we used bibliometric tools to provide a comprehensive overview of the progress in EMT-immunotherapy research. A total of 1,302 articles related to EMT and immunotherapy were retrieved from the Web of Science Core Collection (WOSCC). The analysis indicated that in terms of the volume of research, China was the most productive country (49.07%, 639), followed by the United States (16.89%, 220) and Italy (3.6%, 47). The United States was the most influential country according to the frequency of citations and citation burstiness. The results also suggested that Frontiers in Immunotherapy can be considered as the most influential journal with respect to the number of articles and impact factors. "Immune infiltration," "bioinformatics analysis," "traditional Chinese medicine," "gene signature," and "ferroptosis" were found to be emerging keywords in EMT-immunotherapy research. These findings point to potential new directions that can deepen our understanding of the mechanisms underlying the combined effects of immunotherapy and EMT and help develop strategies for improving immunotherapy.

Phthalate and gallstones: the mediation of insulin.

Background: Exposure to a mixture of environmental chemicals may cause gallstone, but the evidence remains equivocal. The current study aims to investigate the association between phthalate metabolites and gallstones, and to explore their mediators. Methods: Data from the National Health and Nutrition Examination Survey 2017-2018 on U.S. adults (≥20 years) were analyzed to explore the association between phthalate metabolites and gallstones by employed survey-weighted logistic regression, restricted cubic spline (RCS), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR). Mediation analyses examined the role of oxidative stress markers, inflammatory markers, metabolic syndrome, body composition, diabetes, and insulin. Results: The current study included 1,384 participants, representing 200.6 million U.S. adults. Our results indicated a significant association between phthalate metabolites, particularly high molecular weight metabolites such as Di(2-ethylhexyl) phthalate (DEHP) and 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH), and gallstones. Furthermore, mediation analyses indicated that phthalate metabolites may play a role in the development of gallstones by influencing insulin secretion. Subgroup analyses did not reveal significant interaction. Conclusion: The association between exposure to phthalates and the occurrence of gallstones, potentially mediated by hyperinsulinemia from a nationally representative epidemiological perspective. These insights contribute to a better understanding of the potential health implications of plasticizers, emphasizing the need for proactive management measures.

Association between biological aging and diabetic retinopathy.

The impact of aging on diabetic retinopathy (DR) remains underestimated. The current study aimed to investigate the association between biological aging and DR, in contrast to chronological age (CA). Using the National Health and Nutrition Survey data from 2005 to 2008. Biological aging was evaluated through the biological age (BA) and phenotypic age (PA), which were calculated from clinical markers. DR was identified in participants with diabetes mellitus (DM) when they exhibited one or more retinal microaneurysms or retinal blot hemorrhages under retinal imaging, with or without the presence of more severe lesions. Survey-weighted multivariable logistic regression was performed, and the regression model was further fitted using restricted cubic splines. The discriminatory capability and clinical utility of the model were evaluated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Based on weighted analyses, of the 3100 participants included in this study, of which 162 had DR. In the adjusted model, BA (odds ratio [OR] = 1.12, 95% CI, 1.06-1.18) and PA (OR = 1.11, 95% CI, 1.07-1.14) were associated with DR, while CA was not significantly (OR = 1.01, 95% CI, 0.99-1.03). Narrowing the analysis to DM participants and adjusting for factors like insulin showed similar results. ROC and DCA analyses indicate that BA/PA predicted DR better than CA and offer greater clinical utility. The positive association between BA/PA and DR was consistent across subgroups despite potential interactions. Biological aging heightens DR risk, with BA/PA showing a stronger association than CA. Our findings underscored the importance of timely anti-aging interventions for preventing DR.

Association between Flavonoid Intake and Rheumatoid Arthritis among US Adults.

BACKGROUND: Basic research shows that flavonoids have anti-inflammatory effects that influence rheumatoid arthritis (RA) in rats. Investigating potential dietary interventions for RA helps prevent the onset and progression of the disease. Clinical evidence on the association of- flavonoid and subclass intake with RA is lacking. METHODS: Using three survey cycles of 2007-2008, 2009-2010 and 2017-2018 from the National Health and Nutrition Survey and the United States Department of Agriculture's Food and Nutrient Database for Dietary Studies (FNDDS), we analyzed 7,419 American adults (≥20 years old). The values of flavonoid and subclass intake were calculated using FNDDS. The status questions for self-reported RA were from the NHANES codebook. RESULTS: Weighted analyses, revealed that among the 7,419 participants included in this study (mean age of 44.69 years [standard error, 0.40] and3,584 [48.31%] were female), 408 met the classification criteria for RA. According to the multivariable logistic regression model, compared with the risk of RA in the first quartile (Q1), the risks of RA in the second quartile (Q2), the third quartile (Q3) and the fourth quartile (Q4))were lower (Q2: OR=0.55, 95% CI: 0.38-0.80; Q3: OR=0.66, 95% CI: 0.44-0.97; Q4: OR=0.64, 95% CI: 0.46-0.89;trend: P=0.03). The association between total flavonoids and RA remained significant after full consideration of confounding factors. With regard to the subclasses of flavonoids, high flavanones intake was associated with low RA prevalence in Model 3 (Q3: OR= 0.60, 95% CI:0.39-0.92; Q4: OR = 0.56 95% CI: 0.32-0.99, trend:P =0.02) but no such association was found in the other subclasses. Total flavonoids intake protected against RA, and the risk of developing RA decreased significantly with increasing intake of total flavonoids. CONCLUSION: Total flavonoids and flavanones were significantly associated with reduced RA risk for the American adult population. We highlighted the importance of employing diverse methodologies to assess the health effects of flavonoids.

Cuproptosis-related lncRNAs as potential biomarkers of AML prognosis and the role of lncRNA HAGLR/miR-326/CDKN2A regulatory axis in AML.

Acute myeloblastic leukemia (AML) is the most prevalent form of AML in adults. Despite the availability of various treatment options, including radiotherapy and chemotherapy, many patients fail to respond to treatment or relapse. Copper is a necessary cofactor for all organisms; however, it turns toxic when concentrations reach a certain threshold maintained by homeostatic systems that have been conserved through evolution. However, the mechanism through which excess copper triggers cell death remains unknown. In this study, data on long non-coding RNAs (lncRNAs) related to cuproptosis were retrieved from publicly available databases. LASSO and univariate and multivariate Cox regression analyses were performed to establish an lncRNA model associated with cuproptosis specific to AML. To investigate the risk model, the Kaplan-Meier curve, principal component analysis, functional enrichment analysis, and nomographs were employed. The underlying clinicopathological characteristics were determined, and drug sensitivity predictions against the model were identified. Six cuproptosis-related lncRNA-based risk models were identified as the independent prognostic factors. By regrouping patients using a model-based method, we were able to more accurately differentiate patients according to their responses to immunotherapy. In addition, prospective compounds targeting AML subtypes have been identified. Using qRT-PCR, we examined the expression levels of six cuproptosis-associated lncRNAs in 30 clinical specimens. The cuproptosis-associated lncRNA risk-scoring model developed herein has implications in monitoring AML prognosis and in the clinical prediction of the response to immunotherapy. Furthermore, we identified and verified the ceRNA of the cuproptosis-related lncRNA HAGLR/miR-326/CDKN2A regulatory axis using bioinformatic tools. HAGLR is highly expressed in AML and AML cell lines. HAGLR inhibition significantly reduced the proliferation of AML cells and promoted apoptosis. Elesclomol promotes the degradation of CDKN2A and inhibits the proliferation of AML cells. Elesclomol combined with si-HAGLR inhibited the AML progression of AML both in vitro and in vivo.

Exosomal circRNA-001264 promotes AML immunosuppression through induction of M2-like macrophages and PD-L1 overexpression.

Exosomes can help to effectively regulate the crosstalk between cancer cells and normal cells in the tumor microenvironment. They also regulate cancer cell proliferation and apoptosis by virtue of their cargo molecules. Transmission electron microscopy (TEM) together with differential ultracentrifugation served for verifying the presence of exosomes. In vivo and in vitro assays served for determining the role of exosomal circ_001264. RNA pull-down and dual-luciferase reporter assays assisted in the classification of the mechanism of exosomal circ_001264-mediated regulation of the crosstalk between Acute myeloid leukemia (AML) cells and M2 macrophages. Furthermore, we adopted a programmed death ligand 1 antibody (aPD-L1) in combination with exosomal circ_001264 siRNA for antitumor treatment in vitro and in vivo mouse models served for validating the in vivo outcomes. Out study illustrated the aberrant overexpression of circ_001264 in AML patients and its correlation with poor patient prognosis. AML cell-derived exosomal circ_001264 regulated the RAF1 expression and activated the p38-STAT3 signaling pathway, thereby inducing the M2 macrophage polarization. Polarized M2 macrophages can induce PD-L1 overexpression by secreting PD-L1. Here, a programmed death ligand (aPD-L1) was adopted for preventing the immunosuppression, which was able to achieve the desired therapeutic effect at the tumor site. Indeed, in the mouse model, leukemia tumor load decreased remarkably in the exosomal circ_001264 siRNA plus aPD-L1 combination group. Taken together, our study contributed to a theoretical basis for AML treatment. The co-administration of exosomal circ_001264 siRNA and aPD-L1 exhibited an obvious anti-cancer effectiveness in AML.

Immunological significance of prognostic markers for breast cancer based on alternative splicing.

OBJECTIVES: Breast cancer (BC) currently has the highest incidence rate. Epigenetic regulation could alter gene expression and is closely related to BC initiation. This study aimed to develop an alternative splicing (AS)-based prognostic signature and clarify its relevance to the tumor immune microenvironment (TIME) status and immunotherapy of BC. METHODS: Cox regression analysis was conducted to screen for prognosis-related AS events. Thereafter, LASSO with Cox regression analyses was designed to construct a prognostic signature model. Kaplan-Meier survival analysis, receiver operating characteristic curves, and proportional hazard model were then utilized to confirm the prognostic value. Multiple methods were employed to reveal the context of TIME in BC. QPCR, western blotting and immunofluorescence microscopy were carried out to detect myc-associated zinc finger protein (MAZ) expression in different cell lines, and BC and paracancerous tissues. RESULTS: A total of 1,787 prognosis-related AS events were screened. Eight AS prognostic signatures were constructed with robust predictive accuracy based on the splicing subtypes. Furthermore, the establishment of a quantitative prognostic nomogram and consolidated signature was significantly correlated with TIME diversity and immune checkpoint blockade-related genes. MAZ was detected to be upregulated in BC. Finally, a newly constructed splicing regulatory network model revealed the potential functions of splicing factors. CONCLUSIONS: AS-splicing factor networks may enable a new approach to investigating potential regulatory mechanisms. Moreover, pivotal players in AS events with regards to TIME and efficiency of immunotherapy were uncovered and could facilitate clinical decision-making and individual determination of BC prognosis.

Ferroptosis synergistically sensitizes wee1 inhibitors: a bibliometric study.

Synthetic lethality (SL) is a lethal phenomenon with an important role in cancer treatment. This study was conducted to analyze the hotspots and frontiers in SL research. The Web of Science Core Collection (WOSCC) was used to identify the 100 top-cited articles related to SL research. Additionally, wee1 inhibitors combined with erastin were used to determine the effectiveness of SL in vitro and in vivo. Relevant articles were published mainly from 2009 to 2021, reaching a peak in 2020; articles published in 2010 were most frequently cited among the 100-top cited papers. Most studies (54%) were performed in the United States. Articles in Nature Chemical Biology were cited more frequently than articles in other journals, whereas Nature published the largest number of reports on SL. Among the 88 corresponding authors, CJ Lord was the most productive. Overlay visualization of keyword analysis revealed that the hotspots in SL research were PARP inhibitors, BRCA mutations, DNA damage repair, and carcinogenesis. CRISPR, ferroptosis, wee1, double-strand break (dsb) repair, myc, immunotherapy, and replication stress are emerging topics in SL research, whereas ovarian cancer, prostate stress, acute myeloid leukemia, and other topics have been used as disease models in recent years. The application and therapeutic strategy of SL in cancer is an emerging trend. Significantly, experiments verified that the wee1 inhibitor AZD1775 and ferroptosis activator erastin have synergistic effects on ovarian cancer in vitro and in vivo. Combining bibliometric analysis with experimental verification is a useful approach for SL research.

A simple method for lodging resistance evaluation of maize in the field.

The increase of planting density is a dominant approach for the higher yield of maize. However, the stalks of some varieties are prone to lodging under high density conditions. Much research has been done on the evaluation of maize lodging resistance. But there are few comprehensive reports on the determination of maize lodging resistance in situ without injury under field conditions. This study introduces a non-destructive in situ tester to determine the lodging resistance of the different maize varieties in the field. The force value can be obtained by pulling the stalk to different angles with this instrument, which is used to evaluate the lodging resistance of maize varieties. From 2018 to 2020, a total of 1,172 sample plants from 113 maize varieties were tested for the lodging resistance of plants. The statistical results show that the values of force on maize plants at 45° inclination angles (F45) are appropriate to characterize maize lodging resistance in situ by nondestructive testing in the field. According to the F45 value, the maximum lodging resistance Fmax can be inferred. The formula is: Fmax =1.1354 F45 - 0.3358. The evaluation results of lodging resistance of different varieties of this study are basically consistent with the test results of three-point bending method, moving wind tunnel and other methods. Therefore, the F45 value is the optimal index for nondestructive evaluation of maize stalk-lodging resistance under the field-planting conditions.

Research on real time detection of departure angle for the laser beam through atmospheric channels.

The precision of departure angle detection for the laser beam can be improved by optimizing algorithms by which the high precision and stability of the laser beam pointing and tracking would be obtained, namely, improving the performance and accommodation of the free space optical communications. Atmospheric turbulence-induced optical intensity scintillations have a strong impact on the location precision of the laser spot through the atmospheric channels. Consequently, new requests come into view for the optimization of the algorithms. In the paper, the advantages and disadvantages of the traditional centroid method are analyzed. In terms of variations of laser spot, combined with the requests for real-time detection of departure angle, we proposed a new detection method. The edge of the laser spot on the detection sensor was redefined, and then the redefined spot was used to calculate the departure angle of the laser beam. The results of the simulations and experiments show that the precision of departure angle detection has been improved by more than 16%, which could reduce the effect of detection errors on the tracking procedure.

Directional-sum test for nonparametric Behrens-Fisher problem with applications to the dietary intervention trial.

For a nonparametric Behrens-Fisher problem, a directional-sum test is proposed based on division-combination strategy. A one-layer wild bootstrap procedure is given to calculate its statistical significance. We conduct simulation studies with data generated from lognormal, t and Laplace distributions to show that the proposed test can control the type I error rates properly and is more powerful than the existing rank-sum and maximum-type tests under most of the considered scenarios. Applications to the dietary intervention trial further show the performance of the proposed test.

Upgrade of far infrared three-wave polarimeter-interferometer system on Joint-TEXT.

The far infrared polarimeter-interferometer system (POLARIS) on the Joint-TEXT has been upgraded recently. A new support structure has been applied to the mixer array of the POLARIS for adjusting the position of the mixers precisely. Five detection chords have been added to the system on the low field side by optimizing the utilization efficiency of the laser beams on both sides of the beam splitting grid. The spatial resolution can be improved from 3 to 1.5 cm. A better measurement on plasma electron density and current density has been obtained after the system is upgraded. The initial experimental result will be introduced along with the upgrade details.

Epigallocatechin-3-gallate, an active ingredient of Traditional Chinese Medicines, inhibits the 3CLpro activity of SARS-CoV-2.

SARS-CoV-2 is the etiological agent responsible for the ongoing pandemic of coronavirus disease 2019 (COVID-19). The main protease of SARS-CoV-2, 3CLpro, is an attractive target for antiviral inhibitors due to its indispensable role in viral replication and gene expression of viral proteins. The search of compounds that can effectively inhibit the crucial activity of 3CLpro, which results to interference of the virus life cycle, is now widely pursued. Here, we report that epigallocatechin-3-gallate (EGCG), an active ingredient of Chinese herbal medicine (CHM), is a potent inhibitor of 3CLpro with half-maximum inhibitory concentration (IC50) of 0.874 ± 0.005 µM. In the study, we retrospectively analyzed the clinical data of 123 cases of COVID-19 patients, and found three effective Traditional Chinese Medicines (TCM) prescriptions. Multiple strategies were performed to screen potent inhibitors of SARS-CoV-2 3CLpro from the active ingredients of TCMs, including network pharmacology, molecular docking, surface plasmon resonance (SPR) binding assay and fluorescence resonance energy transfer (FRET)-based inhibition assay. The SPR assay showed good interaction between EGCG and 3CLpro with KD ~6.17 µM, suggesting a relatively high affinity of EGCG with SARS-CoV-2 3CLpro. Our results provide critical insights into the mechanism of action of EGCG as a potential therapeutic agent against COVID-19.

A Semismooth Newton Algorithm for High-Dimensional Nonconvex Sparse Learning.

The smoothly clipped absolute deviation (SCAD) and the minimax concave penalty (MCP)-penalized regression models are two important and widely used nonconvex sparse learning tools that can handle variable selection and parameter estimation simultaneously and thus have potential applications in various fields, such as mining biological data in high-throughput biomedical studies. Theoretically, these two models enjoy the oracle property even in the high-dimensional settings, where the number of predictors p may be much larger than the number of observations n . However, numerically, it is quite challenging to develop fast and stable algorithms due to their nonconvexity and nonsmoothness. In this article, we develop a fast algorithm for SCAD- and MCP-penalized learning problems. First, we show that the global minimizers of both models are roots of the nonsmooth equations. Then, a semismooth Newton (SSN) algorithm is employed to solve the equations. We prove that the SSN algorithm converges locally and superlinearly to the Karush-Kuhn-Tucker (KKT) points. The computational complexity analysis shows that the cost of the SSN algorithm per iteration is O(np) . Combined with the warm-start technique, the SSN algorithm can be very efficient and accurate. Simulation studies and a real data example suggest that our SSN algorithm, with comparable solution accuracy with the coordinate descent (CD) and the difference of convex (DC) proximal Newton algorithms, is more computationally efficient.