scholarly journals Transcriptome Analysis Reveals Possible Immunomodulatory Activity Mechanism of Chlorella sp. Exopolysaccharides on RAW264.7 Macrophages

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 217
Author(s):  
Siwei Wu ◽  
Hongquan Liu ◽  
Siyu Li ◽  
Han Sun ◽  
Xiumiao He ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Enrichment Analysis ◽  
Immunomodulatory Activity ◽  
Pathway Enrichment Analysis ◽  
Immune Activity ◽  
Lectin Receptor ◽  
Chlorella Sp ◽  
Raw264.7 Macrophages ◽  
Immune Related Genes ◽  
The Impact

In this study, the exopolysaccharides of Chlorella sp. (CEP) were isolated to obtain the purified fraction CEP4. Characterization results showed that CEP4 was a sulfated heteropolysaccharide. The main monosaccharide components of CEP4 are glucosamine hydrochloride (40.8%) and glucuronic acid (21.0%). The impact of CEP4 on the immune activity of RAW264.7 macrophage cytokines was detected, and the results showed that CEP4 induced the production of nitric oxide (NO), TNF-α, and IL-6 in a dose-dependent pattern within a range of 6 μg/mL. A total of 4824 differentially expressed genes (DEGs) were obtained from the results of RNA-seq. Gene enrichment analysis showed that immune-related genes such as NFKB1, IL-6, and IL-1β were significantly upregulated, while the genes RIPK1 and TLR4 were significantly downregulated. KEGG pathway enrichment analysis showed that DEGs were significantly enriched in immune-related biological processes, including toll-like receptor (TLR) signaling pathway, cytosolic DNA-sensing pathway, and C-type lectin receptor signaling pathway. Protein–protein interaction (PPI) network analysis showed that HSP90AB1, Rbx1, ISG15, Psmb6, Psmb3, Psmb8, PSMA7, Polr2f, Rpsa, and NEDD8 were the hub genes with an essential role in the immune activity of CEP4. The preliminary results of the present study revealed the potential mechanism of CEP4 in the immune regulation of RAW264.7 macrophages, suggesting that CEP4 is a promising immunoregulatory agent.

scholarly journals Mechanistic Insight Into the Regulation of Immune-Related Genes Expression in Autism Spectrum Disorder

2021 ◽  
Vol 8 ◽  
Author(s):  
Hani Sabaie ◽  
Hossein Dehghani ◽  
Shadi Shiva ◽  
Mohammad Reza Asadi ◽  
Omidvar Rezaei ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Pathway Enrichment Analysis ◽  
Cerna Network ◽  
Immune Related Genes ◽  
Rna Interaction

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder featuring impairment in verbal and non-verbal interactions, defects in social interactions, stereotypic behaviors as well as restricted interests. In recent times, the incidence of ASD is growing at a rapid pace. In spite of great endeavors devoted to explaining ASD pathophysiology, its precise etiology remains unresolved. ASD pathogenesis is related to different phenomena associated with the immune system; however, the mechanisms behind these immune phenomena as well as the potential contributing genes remain unclear. In the current work, we used a bioinformatics approach to describe the role of long non-coding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) in the peripheral blood (PB) samples to figure out the molecular regulatory procedures involved in ASD better. The Gene Expression Omnibus database was used to obtain the PB microarray dataset (GSE89594) from the subjects suffering from ASD and control subjects, containing the data related to both mRNAs and lncRNAs. The list of immune-related genes was obtained from the ImmPort database. In order to determine the immune-related differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs), the limma package of R software was used. A protein-protein interaction network was developed for the immune-related DEmRNAs. By employing the Human MicroRNA Disease Database, DIANA-LncBase, and DIANA-TarBase databases, the RNA interaction pairs were determined. We used the Pearson correlation coefficient to discover the positive correlations between DElncRNAs and DEmRNAs within the ceRNA network. Finally, the lncRNA-associated ceRNA network was created based on DElncRNA-miRNA-DEmRNA interactions and co-expression interactions. In addition, the KEGG enrichment analysis was conducted for immune-related DEmRNAs found within the constructed network. This work found four potential DElncRNA-miRNA-DEmRNA axes in ASD pathogenesis, including, LINC00472/hsa-miR-221-3p/PTPN11, ANP32A-IT1/hsa-miR-182-5p/S100A2, LINC00472/hsa-miR-132-3p/S100A2, and RBM26-AS1/hsa-miR-182-5p/S100A2. According to pathway enrichment analysis, the immune-related DEmRNAs were enriched in the “JAK-STAT signaling pathway” and “Adipocytokine signaling pathway.” An understanding of regulatory mechanisms of ASD-related immune genes would provide novel insights into the molecular mechanisms behind ASD pathogenesis.

Systematic Investigation of Quercetin for Treating Cardiovascular Disease Based on Network Pharmacology

2019 ◽  
Vol 22 (6) ◽  
pp. 411-420 ◽  
Author(s):  
Xian-Jun Wu ◽  
Xin-Bin Zhou ◽  
Chen Chen ◽  
Wei Mao
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Signaling Pathway ◽  
Kegg Pathway ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Therapeutic Effects ◽  
Pathway Enrichment ◽  
Compound Target

Aim and Objective: Cardiovascular disease is a serious threat to human health because of its high mortality and morbidity rates. At present, there is no effective treatment. In Southeast Asia, traditional Chinese medicine is widely used in the treatment of cardiovascular diseases. Quercetin is a flavonoid extract of Ginkgo biloba leaves. Basic experiments and clinical studies have shown that quercetin has a significant effect on the treatment of cardiovascular diseases. However, its precise mechanism is still unclear. Therefore, it is necessary to exploit the network pharmacological potential effects of quercetin on cardiovascular disease. Materials and Methods: In the present study, a novel network pharmacology strategy based on pharmacokinetic filtering, target fishing, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, compound-target-pathway network structured was performed to explore the anti- cardiovascular disease mechanism of quercetin. Results:: The outcomes showed that quercetin possesses favorable pharmacokinetic profiles, which have interactions with 47 cardiovascular disease-related targets and 12 KEGG signaling pathways to provide potential synergistic therapeutic effects. Following the construction of Compound-Target-Pathway (C-T-P) network, and the network topological feature calculation, we obtained top 10 core genes in this network which were AKT1, IL1B, TNF, IL6, JUN, CCL2, FOS, VEGFA, CXCL8, and ICAM1. KEGG pathway enrichment analysis. These indicated that quercetin produced the therapeutic effects against cardiovascular disease by systemically and holistically regulating many signaling pathways, including Fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, MAPK signaling pathway, IL-17 signaling pathway and PI3K-Akt signaling pathway.

scholarly journals MicroRNA expression profiling involved in Borax-induced anti-tumor effect using gene-chip analysis

2020 ◽  
Author(s):  
Lun Wu ◽  
Ying Wei ◽  
Wen-Bo Zhou ◽  
Jiao Zhou ◽  
Li-Hua Yang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hepg2 Cells ◽  
Enrichment Analysis ◽  
Gene Chip ◽  
Differentially Expressed ◽  
Control Group ◽  
Pathway Enrichment Analysis ◽  
Ras Signaling ◽  
Therapeutic Benefits ◽  
Differentially Expressed Mirnas

Abstract Background Borax, a boron compound, which is becoming widely recognized for its biological effects, including antioxidant activity, cytotoxicity, and potential therapeutic benefits. However, the specific molecular mechanisms underlying borax-induced anti-tumor effect still remain to be to further elucidated. MicroRNAs (miRNAs) may play key roles in cellular processes including tumor progression, cell apoptosis and cytotoxicity. Thus, this study aimed to investigate, whether miRNAs were involved in the borax-mediated anti-tumor effect using miRNA profiling of a human liver cancer cell line (HepG2) using gene-chip analysis.Methods Total RNA was extracted and purified from HepG2 cells that were treated with 4 mM borax for either 2 or 24 h. The samples underwent microarray analysis using an Agilent Human miRNA Array. Differentially expressed miRNAs were analysed by volcano plot and heatmap, and were validated using real-time fluorescent quantitative PCR (qPCR).ResultsAmong this, 2- or 24-h exposure to borax significantly altered the expression level of miRNAs in HepG2 cells, 4 or 14 were upregulated and 3 were downregulated compared with the control group, respectively (≥2-fold; P<0.05). GO enrichment analysis and KEGG pathway enrichment analysis revealed that target genes of differentially expressed miRNAs in HepG2 cells predominantly participated in MAPK signaling pathway, TGF-beta signaling pathway, NF-kappa B signaling pathway, etc; in 2-h borax treatment group, while Ras signaling pathway, FoxO signaling pathway, Cellular senescence, etc; involved in 24-h treatment group.Conclusions Result indicates that borax-induced anti-tumor effect may be associated with alterations in miRNAs.

scholarly journals Comprehensive Analysis of the Immune and Prognostic Implication of MMP14 in Lung Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Chun-long Zheng ◽  
Qiang Lu ◽  
Nian Zhang ◽  
Peng-yu Jing ◽  
Ji-peng Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signaling Pathway ◽  
Lung Squamous Cell Carcinoma ◽  
Enrichment Analysis ◽  
Cell Receptor ◽  
Risk Scores ◽  
Pathway Enrichment Analysis ◽  
Receptor Signaling ◽  
Immune Infiltration ◽  
Receptor Signaling Pathway

More and more studies have indicated an association between immune infiltration in lung cancer and clinical outcomes. Matrix metalloproteinase 14 (MMP14) has been reported to be dysregulated in many types of tumors and involved in the development and progression of tumors. However, its contribution to cancer immunity was rarely reported. In the study, we found that MMP14 expression was distinctly upregulated in lung cancer specimens compared with nontumor lung specimens. High MMP14 expression predicted a poor prognosis of lung squamous cell carcinoma (LUSC) patients. Increased MMP14 expressions were observed to be positively related to high immune infiltration levels in most of the immune cells. A pathway enrichment analysis of 32 MMP14-associated immunomodulators indicated the involvement of T cell receptor signaling pathway and Toll-like receptor signaling pathway. Based on MMP14-associated immunomodulators, we applied multivariate assays to construct multiple-gene risk prediction signatures. We observed that risk scores were independently associated with overall survival. These data highlighted that MMP14 was involved in tumor immunity, indicating that MMP14 could serve as a novel prognostic biomarker and therapeutic target for lung cancer. Our data suggest that the four genes identified in this study may serve as valuable biomarkers of lung cancer patient outcomes.

scholarly journals Integrating Network Pharmacology with Molecular Docking to Unravel the Active Compounds and Potential Mechanism of Simiao Pill Treating Rheumatoid Arthritis

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Mengshi Tang ◽  
Xi Xie ◽  
Pengji Yi ◽  
Jin Kang ◽  
Jiafen Liao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Docking ◽  
Signaling Pathway ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Binding Activity ◽  
New Combination ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Potential Mechanism

Objective. To explore the main components and unravel the potential mechanism of simiao pill (SM) on rheumatoid arthritis (RA) based on network pharmacological analysis and molecular docking. Methods. Related compounds were obtained from TCMSP and BATMAN-TCM database. Oral bioavailability and drug-likeness were then screened by using absorption, distribution, metabolism, and excretion (ADME) criteria. Additionally, target genes related to RA were acquired from GeneCards and OMIM database. Correlations about SM-RA, compounds-targets, and pathways-targets-compounds were visualized through Cytoscape 3.7.1. The protein-protein interaction (PPI) network was constructed by STRING. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed via R packages. Molecular docking analysis was constructed by the Molecular Operating Environment (MOE). Results. A total of 72 potential compounds and 77 associated targets of SM were identified. The compounds-targets network analysis indicated that the 6 compounds, including quercetin, kaempferol, baicalein, wogonin, beta-sitosterol, and eugenol, were linked to ≥10 target genes, and the 10 target genes (PTGS1, ESR1, AR, PGR, CHRM3, PPARG, CHRM2, BCL2, CASP3, and RELA) were core target genes in the network. Enrichment analysis indicated that PI3K-Akt, TNF, and IL-17 signaling pathway may be a critical signaling pathway in the network pharmacology. Molecular docking showed that quercetin, kaempferol, baicalein, and wogonin have good binding activity with IL6, VEGFA, EGFR, and NFKBIA targets. Conclusion. The integrative investigation based on bioinformatics/network topology strategy may elaborate on the multicomponent synergy mechanisms of SM against RA and provide the way out to develop new combination medicines for RA.

scholarly journals Immunostimulation by Lactobacillus kefiri S-layer proteins with distinct glycosylation patterns requires different lectin partners

2020 ◽  
Vol 295 (42) ◽  
pp. 14430-14444 ◽  
Author(s):  
Mariano Malamud ◽  
Gustavo J. Cavallero ◽  
Adriana C. Casabuono ◽  
Bernd Lepenies ◽  
María de los Ángeles Serradell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Protein Glycosylation ◽  
Immunomodulatory Activity ◽  
Glycosylation Pattern ◽  
Immunostimulatory Activity ◽  
Lectin Receptors ◽  
Lectin Receptor ◽  
Raw264.7 Macrophages ◽  
Lactobacillus Kefiri

S-layer (glyco)-proteins (SLPs) form a nanostructured envelope that covers the surface of different prokaryotes and show immunomodulatory activity. Previously, we have demonstrated that the S-layer glycoprotein from probiotic Lactobacillus kefiri CIDCA 8348 (SLP-8348) is recognized by Mincle (macrophage inducible C-type lectin receptor), and its adjuvanticity depends on the integrity of its glycans. However, the glycan's structure has not been described so far. Herein, we analyze the glycosylation pattern of three SLPs, SLP-8348, SLP-8321, and SLP-5818, and explore how these patterns impact their recognition by C-type lectin receptors and the immunomodulatory effect of the L. kefiri SLPs on antigen-presenting cells. High-performance anion-exchange chromatography–pulse amperometric detector performed after β-elimination showed glucose as the major component in the O-glycans of the three SLPs; however, some differences in the length of hexose chains were observed. No N-glycosylation signals were detected in SLP-8348 and SLP-8321, but SLP-5818 was observed to have two sites carrying complex N-glycans based on a site-specific analysis and a glycomic workflow of the permethylated glycans. SLP-8348 was previously shown to enhance LPS-induced activation on both RAW264.7 macrophages and murine bone marrow–derived dendritic cells; we now show that SLP-8321 and SLP-5818 have a similar effect regardless of the differences in their glycosylation patterns. Studies performed with bone marrow–derived dendritic cells from C-type lectin receptor–deficient mice revealed that the immunostimulatory activity of SLP-8321 depends on its recognition by Mincle, whereas SLP-5818's effects are dependent on SignR3 (murine ortholog of human DC-SIGN). These findings encourage further investigation of both the potential application of these SLPs as new adjuvants and the protein glycosylation mechanisms in these bacteria.

scholarly journals Ganghuo Kanggan Decoction in Influenza: Integrating Network Pharmacology and In Vivo Pharmacological Evaluation

2020 ◽  
Vol 11 ◽  
Author(s):  
Yanni Lai ◽  
Qiong Zhang ◽  
Haishan Long ◽  
Tiantian Han ◽  
Geng Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Influenza A ◽  
Target Prediction ◽  
Enrichment Analysis ◽  
New Drugs ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Active Components ◽  
Compound Screening

Background: Ganghuo Kanggan decoction (GHKGD) is a clinical experience prescription used for the treatment of viral pneumonia in the Lingnan area of China, and its clinical effect is remarkable. However, the mechanism of GHKGD in influenza is still unclear.Objective: To predict the active components and signaling pathway of GHKGD and to explore its therapeutic mechanism in influenza and to verified it in vivo using network pharmacology.Methods: The potential active components and therapeutic targets of GHKGD in the treatment of influenza were hypothesized through a series of network pharmacological strategies, including compound screening, target prediction and pathway enrichment analysis. Based on the target network and enrichment results, a mouse model of influenza A virus (IAV) infection was established to evaluate the therapeutic effect of GHKGD on influenza and to verify the possible molecular mechanism predicted by network pharmacology.Results: A total of 116 candidate active compounds and 17 potential targets were identified. The results of the potential target enrichment analysis suggested GHKGD may involve the RLR signaling pathway to reduce inflammation in the lungs. In vivo experiments showed that GHKGD had a protective effect on pneumonia caused by IAV-infected mice. Compared with the untreated group, the weight loss in the GHKGD group in the BALB/c mice decreased, and the inflammatory pathological changes in lung tissue were reduced (p &lt; 0.05). The expression of NP protein and the virus titers in lung were significantly decreased (p &lt; 0.05). The protein expression of RIG-I, NF-kB, and STAT1 and the level of MAVS and IRF3/7 mRNA were remarkably inhibited in GHKGD group (p &lt; 0.05). After the treatment with GHKGD, the level of Th1 cytokines (IFN-γ, TNF-α, IL-2) was increased, while the expression of Th2 (IL-5, IL4) cytokines was reduced (p &lt; 0.05).Conclusion: Through a network pharmacology strategy and in vivo experiments, the multi-target and multi-component pharmacological characteristics of GHKGD in the treatment of influenza were revealed, and regulation of the RLR signaling pathway during the anti-influenza process was confirmed. This study provides a theoretical basis for the research and development of new drugs from GHKGD.

scholarly journals A Network Pharmacology Approach to Uncover the Mechanisms of Shen-Qi-Di-Huang Decoction against Diabetic Nephropathy

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Sha Di ◽  
Lin Han ◽  
Qing Wang ◽  
Xinkui Liu ◽  
Yingying Yang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Protein Protein Interaction ◽  
Regulation Of Blood Pressure ◽  
Protein Protein Interaction Network

Shen-Qi-Di-Huang decoction (SQDHD), a well-known herbal formula from China, has been widely used in the treatment of diabetic nephropathy (DN). However, the pharmacological mechanisms of SQDHD have not been entirely elucidated. At first, we conducted a comprehensive literature search to identify the active constituents of SQDHD, determined their corresponding targets, and obtained known DN targets from several databases. A protein-protein interaction network was then built to explore the complex relations between SQDHD targets and those known to treat DN. Following the topological feature screening of each node in the network, 400 major targets of SQDHD were obtained. The pathway enrichment analysis results acquired from DAVID showed that the significant bioprocesses and pathways include oxidative stress, response to glucose, regulation of blood pressure, regulation of cell proliferation, cytokine-mediated signaling pathway, and the apoptotic signaling pathway. More interestingly, five key targets of SQDHD, named AKT1, AR, CTNNB1, EGFR, and ESR1, were significant in the regulation of the above bioprocesses and pathways. This study partially verified and predicted the pharmacological and molecular mechanisms of SQDHD on DN from a holistic perspective. This has laid the foundation for further experimental research and has expanded the rational application of SQDHD in clinical practice.

scholarly journals Identification of novel genes and pathways in carotid atheroma using integrated bioinformatic methods

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Wenqing Nai ◽  
Diane Threapleton ◽  
Jingbo Lu ◽  
Kewei Zhang ◽  
Hongyuan Wu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Transforming Growth Factor Β ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Pathway Enrichment Analysis ◽  
Atheromatous Plaques

Abstract Atherosclerosis is the primary cause of cardiovascular events and its molecular mechanism urgently needs to be clarified. In our study, atheromatous plaques (ATH) and macroscopically intact tissue (MIT) sampled from 32 patients were compared and an integrated series of bioinformatic microarray analyses were used to identify altered genes and pathways. Our work showed 816 genes were differentially expressed between ATH and MIT, including 443 that were up-regulated and 373 that were down-regulated in ATH tissues. GO functional-enrichment analysis for differentially expressed genes (DEGs) indicated that genes related to the “immune response” and “muscle contraction” were altered in ATHs. KEGG pathway-enrichment analysis showed that up-regulated DEGs were significantly enriched in the “FcεRI-mediated signaling pathway”, while down-regulated genes were significantly enriched in the “transforming growth factor-β signaling pathway”. Protein-protein interaction network and module analysis demonstrated that VAV1, SYK, LYN and PTPN6 may play critical roles in the network. Additionally, similar observations were seen in a validation study where SYK, LYN and PTPN6 were markedly elevated in ATH. All in all, identification of these genes and pathways not only provides new insights into the pathogenesis of atherosclerosis, but may also aid in the development of prognostic and therapeutic biomarkers for advanced atheroma.

scholarly journals Identification of Potential Prognostic Competing Triplets in High-Grade Serous Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jian Zhao ◽  
Xiaofeng Song ◽  
Tianyi Xu ◽  
Qichang Yang ◽  
Jingjing Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Throughput Sequencing ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Sequencing Data ◽  
P53 Signaling ◽  
Oocyte Meiosis ◽  
The Difference ◽  
Division Cell ◽  
The Impact

Increasing lncRNA-associated competing triplets were found to play important roles in cancers. With the accumulation of high-throughput sequencing data in public databases, the size of available tumor samples is becoming larger and larger, which introduces new challenges to identify competing triplets. Here, we developed a novel method, called LncMiM, to detect the lncRNA–miRNA–mRNA competing triplets in ovarian cancer with tumor samples from the TCGA database. In LncMiM, non-linear correlation analysis is used to cover the problem of weak correlations between miRNA–target pairs, which is mainly due to the difference in the magnitude of the expression level. In addition, besides the miRNA, the impact of lncRNA and mRNA on the interactions in triplets is also considered to improve the identification sensitivity of LncMiM without reducing its accuracy. By using LncMiM, a total of 847 lncRNA-associated competing triplets were found. All the competing triplets form a miRNA–lncRNA pair centered regulatory network, in which ZFAS1, SNHG29, GAS5, AC112491.1, and AC099850.4 are the top five lncRNAs with most connections. The results of biological process and KEGG pathway enrichment analysis indicates that the competing triplets are mainly associated with cell division, cell proliferation, cell cycle, oocyte meiosis, oxidative phosphorylation, ribosome, and p53 signaling pathway. Through survival analysis, 107 potential prognostic biomarkers are found in the competing triplets, including FGD5-AS1, HCP5, HMGN4, TACC3, and so on. LncMiM is available at https://github.com/xiaofengsong/LncMiM.

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