Screening Mutations of the Monogenic Syndromic High Myopia by Whole Exome Sequencing From MAGIC Project.

Purpose: This observational study aimed to identify mutations in monogenic syndromic high myopia (msHM) using data from reported samples (n = 9370) of the Myopia Associated Genetics and Intervention Consortium (MAGIC) project. Methods: The targeted panel containing 298 msHM-related genes was constructed and screening of clinically actionable variants was performed based on whole exome sequencing. Capillary sequencing was used to verify the identified gene mutations in the probands and perform segregation analysis with their relatives. Results: A total of 381 candidate variants in 84 genes and 85 eye diseases were found to contribute to msHM in 3.6% (335/9370) of patients with HM. Among them, the 22 genes with the most variations accounted for 62.7% of the diagnostic cases. In the genotype-phenotype association analysis, 60% (201/335) of suspected msHM cases were recalled and 25 patients (12.4%) received a definitive genetic diagnosis. Pathogenic variants were distributed in 18 msHM-related diseases, mainly involving retinal dystrophy genes (e.g. TRPM1, CACNA1F, and FZD4), connective tissue disease genes (e.g. FBN1 and COL2A1), corneal or lens development genes (HSF4, GJA8, and MIP), and other genes (TEK). The msHM gene mutation types were allocated to four categories: nonsense mutations (36%), missense mutations (36%), frameshift mutations (20%), and splice site mutations (8%). Conclusions: This study highlights the importance of thorough molecular subtyping of msHM to provide appropriate genetic counselling and multispecialty care for children and adolescents with HM.

In-depth mining of single-cell transcriptome reveals the key immune-regulated loops in age-related macular degeneration.

Introduction: Age-related macular degeneration (AMD), an ever-increasing ocular disease, has become one of the leading causes of irreversible blindness. Recent advances in single-cell genomics are improving our understanding of the molecular mechanisms of AMD. However, the pathophysiology of this multifactorial disease is complicated and still an ongoing challenge. To better understand disease pathogenesis and identify effective targets, we conducted an in-depth analysis of the single-cell transcriptome of AMD. Methods: The cell expression specificity of the gene (CESG) was selected as an index to identify the novel cell markers. A computational framework was designed to explore the cell-specific TF regulatory loops, containing the interaction of gene pattern signatures, transcription factors regulons, and differentially expressed genes. Results: Three potential novel cell markers were DNASE1L3 for endothelial cells, ABCB5 for melanocytes, and SLC39A12 for RPE cells detected. We observed a notable change in the cell abundance and crosstalk of fibroblasts cells, melanocytes, schwann cells, and T/NK cells between AMD and controls, representing a complex cellular ecosystem in disease status. Finally, we identified six cell type related and three disease-associated ternary loops and elaborated on the robust association between key immune-pathway and AMD. Discussion: In conclusion, this study facilitates the optimization of screening for AMD-related receptor ligand pathways and proposes to further improve the interpretability of disease associations from single-cell data. It illuminated that immune-related regulation paths could be used as potential diagnostic markers for AMD, and in the future, also as therapeutic targets, providing insights into AMD diagnosis and potential interventions.

Sequencing of 19,219 exomes identifies a low-frequency variant in FKBP5 promoter predisposing to high myopia in a Han Chinese population.

High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. Here, we report a whole-exome sequencing (WES) study in 9,613 HM cases and 9,606 controls of Han Chinese ancestry to pinpoint HM-associated risk variants. Single-variant association analysis identified three newly identified -genetic loci associated with HM, including an East Asian ancestry-specific low-frequency variant (rs533280354) in FKBP5. Multi-ancestry meta-analysis with WES data of 2,696 HM cases and 7,186 controls of European ancestry from the UK Biobank discerned a newly identified European ancestry-specific rare variant in FOLH1. Functional experiments revealed a mechanism whereby a single G-to-A transition at rs533280354 disrupted the binding of transcription activator KLF15 to the promoter of FKBP5, resulting in decreased transcription of FKBP5. Furthermore, burden tests showed a significant excess of rare protein-truncating variants among HM cases involved in retinal blood vessel morphogenesis and neurotransmitter transport.

Impact of the RNA allosteric effect triggered by single nucleotide polymorphisms on the splicing process.

The susceptibility single nucleotide polymorphisms (SNPs) obtained by genome-wide association studies leave some thorny questions, such as prioritization, false positives and unknown pathogenesis. Previous studies suggested that genetic variation may perturb the RNA secondary structure, influence protein recruitment and binding and ultimately affect splicing processes. Therefore, exploring the perturbation of SNPs to structure-function correlations may provide an effective bridge toward understanding the genetic contribution to diseases. Here, aiming to decipher the regulatory mechanism of myopia susceptibility variants, we systematically evaluated the roles of SNP-induced structural changes during splicing. In addition, 7.53% of myopia-related SNPs exhibited significant global structural changes, 19.53% presented noteworthy local structural disturbance and there were wide-ranging structural perturbations in the splice-related motifs. We established a comprehensive evaluation system for structural disturbance in the splicing-related motifs and gave the priority ranking for the SNPs at RNA structural level. These high-priority SNPs were revealed to widely disturb the molecular interaction properties between splicing-related proteins and pre-mRNAs by HDOCK. Moreover, mini-gene assays confirmed that structural perturbation could influence splicing efficiency through structural remodelling. This study deepens our understanding of the potential molecular regulatory mechanisms of susceptible SNPs in myopia and contributes to personalized diagnosis, personalized medicine, disease-risk prediction and functional verification study by guiding the prioritization of the susceptibility SNPs.

RNAsmc: A integrated tool for comparing RNA secondary structure and evaluating allosteric effects.

RNA structure plays a crucial role in gene regulation, in RNA stability and the essential biological processes. RNA secondary structure (RSS) motifs are the basic building blocks for investigating the biological mechanisms of structure. Here, we present a strategy for structural motif-based dynamic alignment, namely, RNA secondary-structural motif-comparing (RNAsmc), to identify structural motifs and quantitatively evaluate their underlying molecular functions. RNAsmc also has strong robustness to sequence length, folding protocol and RNA structural profile by chemical probing. Notably, it is also applicable to quantify structural variation in special RNA editing events (SNVs or SNPs, fragment insertion or deletion, etc.). The findings indicate that RNAsmc can uncover the heterogeneity of RNA secondary structure and score for similarities among components, which provides an impetus to cluster RNA families and evaluate allosteric effects. We find that RNAsmc exhibits remarkable detection efficiency for experimentally-derived RiboSNitches. Finally, the pipeline was assembled into an R software package to serve as an automated toolkit to explore, align, and cluster RSS. It is freely available for download at https://CRAN.R-project.org/package=RNAsmc.

Simulations to Assess the Performance of Multifactor Risk Scores for Predicting Myopia Prevalence in Children and Adolescents in China.

Background: Myopia is the most common visual impairment among Chinese children and adolescents. The purpose of this study is to explore key interventions for myopia prevalence, especially for early-onset myopia and high myopia. Methods: Univariate and multivariate analyses were conducted to evaluate potential associations between risk factor exposure and myopia. LASSO was performed to prioritize the risk features, and the selected leading factors were used to establish the assembled simulation model. Finally, two forecasting models were constructed to predict the risk of myopia and high myopia. Results: Children and adolescents with persistently incorrect posture had a high risk of myopia (OR 7.205, 95% CI 5.999-8.652), which was 2.8 times higher than that in students who always maintained correct posture. In the cohort with high myopia, sleep time of less than 7 h per day (OR 9.789, 95% CI 6.865-13.958), incorrect sitting posture (OR 8.975, 95% CI 5.339-15.086), and siblings with spherical equivalent <-6.00 D (OR 8.439, 95% CI 5.420-13.142) were the top three risk factors. The AUCs of integrated simulation models for myopia and high myopia were 0.8716 and 0.8191, respectively. Conclusion: The findings illustrate that keeping incorrect posture is the leading risk factor for myopia onset, while the onset age of myopia is the primary factor affecting high myopia progression. The age between 8 and 12 years is the crucial stage for clinical intervention, especially for children with parental myopia.

Design, methodology, and baseline of whole city-million scale children and adolescents myopia survey (CAMS) in Wenzhou, China.

BACKGROUND: Myopia is the most common visual impairment in children and adolescents worldwide. This study described an economical and effective population-based screening pipeline and performed the project of a million scale children and adolescents myopia survey (CAMS), which will shed light on the further study of myopia from the level of epidemiology and precision medicine. METHODS: We developed a novel population-based screening pattern, an intelligent screening process and internet-based information transmission and analysis system to carry out the survey consisting of school children in Wenzhou, China. The examination items include unaided distance visual acuity, presenting distance visual acuity, and non-cycloplegic autorefraction. Myopia and high myopia were defined as spherical equivalent (SE) ≤ - 1.00 diopters (D) and SE ≤ - 6.00 D, respectively. Next, the reports of the vision checking were automatically sent to parents and the related departments. The CAMS project will be done two to four times annually with the support of the government. An online eyesight status information management system (OESIMS) was developed to construct comprehensive and efficient electronic vision health records (EVHRs) for myopia information inquiry, risk pre-warning, and further study. RESULTS: The CAMS completed the first-round of screening within 30 days for 99.41% of Wenzhou students from districts and counties, in June 2019. A total of 1,060,925 participants were eligible for CAMS and 1,054,251 (99.37% participation rate) were selected through data quality control, which comprised 1305 schools, and 580,609, 251,050 and 170,967 elementary, middle, and high school students. The mean age of participants was 12.21 ± 3.32 years (6-20 years), the female-to-male ratio was 0.82. The prevalence of myopia in elementary, middle, and high school students was 38.16%, 77.52%, and 84.00%, respectively, and the high myopia incidence was 0.95%, 6.90%, and 12.98%. CONCLUSIONS: The CAMS standardized myopia screening model involves automating large-scale information collection, data transmission, data analysis and early warning, thereby supporting myopia prevention and control. The entire survey reduced 90% of staff, cost, and time consumption compared with previous surveys. This will provide new insights for decision support for public health intervention.

Ten Years of EWAS.

Epigenome-wide association study (EWAS) has been applied to analyze DNA methylation variation in complex diseases for a decade, and epigenome as a research target has gradually become a hot topic of current studies. The DNA methylation microarrays, next-generation, and third-generation sequencing technologies have prepared a high-quality platform for EWAS. Here, the progress of EWAS research is reviewed, its contributions to clinical applications, and mainly describe the achievements of four typical diseases. Finally, the challenges encountered by EWAS and make bold predictions for its future development are presented.

Association of Myopia and Genetic Variants of TGFB2-AS1 and TGFBR1 in the TGF-ß Signaling Pathway: A Longitudinal Study in Chinese School-Aged Children.

BACKGROUND: Myopia is a complex multifactorial condition which involves several overlapping signaling pathways mediated by distinct genes. This prospective cohort study evaluated the associations of two genetic variants in the TGF-ß signaling pathway with the onset and progression of myopia and ocular biometric parameters in Chinese school-aged children. METHODS: A total of 556 second grade children were examined and followed up for 3.5 years. Non-cycloplegic refraction and ocular biometric parameters were measured annually. Multivariate regression analysis was used to assess the effect of the TGFBR1 rs10760673 and TGFB2-AS1 rs7550232 variants on the occurrence and progression of myopia. A 10,000 permutations test was used to correct for multiple testing. Functional annotation of single nucleotide polymorphisms (SNPs) was performed using RegulomeDB, HaploReg, and rVarBase. RESULTS: A total of 448 children were included in the analysis. After adjustments for gender, age, near work time and outdoor time with 10,000 permutations, the results indicated that the C allele and the AC or CC genotypes of rs7550232 adjacent to TGFB2-AS1 were associated with a significantly increased risk of the onset of myopia in two genetic models (additive: P' = 0.022; dominant: P' = 0.025). Additionally, the A allele and the AA or AG genotypes of rs10760673 of TGFBR1 were associated with a significant myopic shift (additive: P' = 0.008; dominant: P' = 0.028; recessive: P' = 0.027). Furthermore, rs10760673 was associated with an increase in axial length (AL) (P' = 0.013, ß = 0.03) and a change in the ratio of AL to the corneal radius of curvature (AL/CRC) (P' = 0.031, ß = 0.003). Analysis using RegulomeDB, HaploReg, and rVarBase indicated that rs7550232 is likely to affect transcription factor binding, any motif, DNase footprint, and DNase peak. CONCLUSION: The present study indicated that rs10760673 and rs7550232 may represent susceptibility loci for the progression and onset of myopia, respectively, in school-aged children. Associations of the variants of the TGFBR1 and TGFB2-AS1 genes with myopia may be mediated by the TGF-ß signaling pathway; this hypothesis requires validation in functional studies. This trial was registered as ChiCTR1900020584 at www.Chictr.org.cn.

Contribution of structural accessibility to the cooperative relationship of TF-lncRNA in myopia.

Transcriptional regulation is associated with complicated mechanisms including multiple molecular interactions and collaborative drive. Long noncoding RNAs (lncRNAs) have highly structured characteristics and play vital roles in the regulation of transcription in organisms. However, the specific contributions of conformation feature and underlying molecular mechanisms are still unclear. In the present paper, a hypothesis regarding molecular structure effect is presented, which proposes that lncRNAs fold into a complex spatial architecture and act as a skeleton to recruit transcription factors (TF) targeted binding, and which is involved in cooperative regulation. A candidate set of TF-lncRNA coregulation was constructed, and it was found that structural accessibility affected molecular binding force. In addition, transcription factor binding site (TFBS) regions of myopia-related lncRNA transcripts were disturbed, and it was discovered that base mutations affected the occurrence of significant molecular allosteric changes in important elements and variable splicing regions, mediating the onset and development of myopia. The results originated from structureomics and interactionomics and created conditions for systematic research on the mechanisms of structure-mediated TF-lncRNA coregulation in transcriptional regulation. Finally, these findings will help further the understanding of key regulatory roles of molecular allostery in cell physiological and pathological processes.

Identification of the RNase-binding site of SARS-CoV-2 RNA for anchor primer-PCR detection of viral loading in 306 COVID-19 patients.

The pandemic of coronavirus disease 2019 (COVID-19) urgently calls for more sensitive molecular diagnosis to improve sensitivity of current viral nuclear acid detection. We have developed an anchor primer (AP)-based assay to improve viral RNA stability by bioinformatics identification of RNase-binding site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and implementing AP dually targeting the N gene of SARS-CoV-2 RNA and RNase 1, 3, 6. The arbitrarily primed polymerase chain reaction (AP-PCR) improvement of viral RNA integrity was supported by (a) the AP increased resistance of the targeted gene (N gene) of SARS-CoV-2 RNA to RNase treatment; (b) the detection of SARS-CoV-2 RNA by AP-PCR with lower cycle threshold values (-2.7 cycles) compared to two commercially available assays; (c) improvement of the viral RNA stability of the ORF gene upon targeting of the N gene and RNase. Furthermore, the improved sensitivity by AP-PCR was demonstrated by detection of SARS-CoV-2 RNA in 70-80% of sputum, nasal, pharyngeal swabs and feces and 36% (4/11) of urine of the confirmed cases (n = 252), 7% convalescent cases (n = 54) and none of 300 negative cases. Lastly, AP-PCR analysis of 306 confirmed and convalescent cases revealed prolonged presence of viral loading for >20 days after the first positive diagnosis. Thus, the AP dually targeting SARS-CoV-2 RNA and RNase improves molecular detection by preserving SARS-CoV-2 RNA integrity and reveals the prolonged viral loading associated with older age and male gender in COVID-19 patients.

SARS-CoV-2 and Three Related Coronaviruses Utilize Multiple ACE2 Orthologs and Are Potently Blocked by an Improved ACE2-Ig.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused >20 million infections and >750,000 deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, has been found closely related to the bat coronavirus strain RaTG13 (Bat-CoV RaTG13) and a recently identified pangolin coronavirus (Pangolin-CoV-2020). Here, we first investigated the ability of SARS-CoV-2 and three related coronaviruses to utilize animal orthologs of angiotensin-converting enzyme 2 (ACE2) for cell entry. We found that ACE2 orthologs of a wide range of domestic and wild mammals, including camels, cattle, horses, goats, sheep, cats, rabbits, and pangolins, were able to support cell entry of SARS-CoV-2, suggesting that these species might be able to harbor and spread this virus. In addition, the pangolin and bat coronaviruses, Pangolin-CoV-2020 and Bat-CoV RaTG13, were also found able to utilize human ACE2 and a number of animal-ACE2 orthologs for cell entry, indicating risks of spillover of these viruses into humans in the future. We then developed potently anticoronavirus ACE2-Ig proteins that are broadly effective against the four distinct coronaviruses. In particular, through truncating ACE2 at its residue 740 but not 615, introducing a D30E mutation, and adopting an antibody-like tetrameric-ACE2 configuration, we generated an ACE2-Ig variant that neutralizes SARS-CoV-2 at picomolar range. These data demonstrate that the improved ACE2-Ig variants developed in this study could potentially be developed to protect from SARS-CoV-2 and some other SARS-like viruses that might spillover into humans in the future.IMPORTANCE The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the currently uncontrolled coronavirus disease 2019 (COVID-19) pandemic. It is important to study the host range of SARS-CoV-2, because some domestic species might harbor the virus and transmit it back to humans. In addition, insight into the ability of SARS-CoV-2 and SARS-like viruses to utilize animal orthologs of the SARS-CoV-2 receptor ACE2 might provide structural insight into improving ACE2-based viral entry inhibitors. In this study, we found that ACE2 orthologs of a wide range of domestic and wild animals can support cell entry of SARS-CoV-2 and three related coronaviruses, providing insights into identifying animal hosts of these viruses. We also developed recombinant ACE2-Ig proteins that are able to potently block these viral infections, providing a promising approach to developing antiviral proteins broadly effective against these distinct coronaviruses.

Detection of Allosteric Effects of lncRNA Secondary Structures Altered by SNPs in Human Diseases.

Recent studies have shown that structuralized long non-coding RNAs (lncRNAs) play important roles in genetic and epigenetic processes. The spatial structures of most lncRNAs can be altered by distinct in vivo and in vitro cellular environments, as well as by DNA structural variations, such as single-nucleotide polymorphisms (SNPs) and variants (SNVs). In the present study, we extended candidate SNPs that had linkage disequilibria with those significantly associated with lung diseases in genome-wide association studies in order to investigate potential disease mechanisms originating from SNP structural changes of host lncRNAs. Following accurate alignments, we recognized 115 ternary-relationship pairs among 41 SNPs, 10 lncRNA transcripts, and 1 type of lung disease (adenocarcinoma of the lung). Then, we evaluated the structural heterogeneity induced by SNP alleles by developing a local-RNA-structure alignment algorithm and employing randomized strategies to determine the significance of structural variation. We identified four ternary-relationship pairs that were significantly associated with SNP-induced lncRNA allosteric effects. Moreover, these conformational changes disrupted the interactive regions and binding affinities of lncRNA-HCG23 and TF-E2F6, suggesting that these may represent regulatory mechanisms in lung diseases. Taken together, our findings support that SNP-induced changes in lncRNA conformations regulate many biological processes, providing novel insight into the role of the lncRNA "structurome" in human diseases.

Nc2Eye: A Curated ncRNAomics Knowledgebase for Bridging Basic and Clinical Research in Eye Diseases.

Eye diseases (EDs) represent a group of disorders affecting the visual system, most of which can lead to visual impairment and blindness. Accumulating evidence reveals that non-coding RNAs (ncRNAs) are closely associated with a wide variety of EDs. However, abundant associations between ncRNAs and EDs are scattered across the published literature, obstructing a global view of ncRNA-ED associations. A public resource of high-quality manually curated ncRNAomics knowledge associated with EDs remains unavailable. To address this gap, we thus developed Nc2Eye (http://nc2eye.bio-data.cn/), which is the first knowledgebase dedicated to providing a comprehensive ncRNAomics resource for bridging basic and clinical research in EDs. Through a comprehensive review of more than 2400 published papers, Nc2Eye catalogs 7088 manually curated ncRNA-ED associations involving 4363 ncRNAs across eight species. We also provide detailed descriptions and annotation information for each ncRNA-disease association such as ncRNA categories, experimental methods, expression pattern and related clinical drugs. To further expand the pathogenic ncRNAs, we also collected more than 90 high-throughput EDs-related transcriptome datasets. Furthermore, a user-friendly interface was constructed for convenient and flexible data browsing, querying, and retrieving. We believe that Nc2Eye is a timely and valuable knowledgebase for significantly improving and useful for discovery of new diagnostic and therapeutic biomarkers.

Identification of tumor immune infiltration-associated lncRNAs for improving prognosis and immunotherapy response of patients with non-small cell lung cancer.

BACKGROUND: Increasing evidence has demonstrated the functional relevance of long non-coding RNAs (lncRNAs) to immunity regulation and the tumor microenvironment in non-small cell lung cancer (NSCLC). However, tumor immune infiltration-associated lncRNAs and their value in improving clinical outcomes and immunotherapy remain largely unexplored. METHODS: We developed a computational approach to identify an lncRNA signature (TILSig) as an indicator of immune cell infiltration in patients with NSCLC through integrative analysis for lncRNA, immune and clinical profiles of 115 immune cell lines, 187 NSCLC cell lines and 1533 patients with NSCLC. Then the influence of the TILSig on the prognosis and immunotherapy in NSCLC was comprehensively investigated. RESULTS: Computational immune and lncRNA profiling analysis identified an lncRNA signature (TILSig) consisting of seven lncRNAs associated with tumor immune infiltration. The TILSig significantly stratified patients into the immune-cold group and immune-hot group in both training and validation cohorts. These immune-hot patients exhibit significantly improved survival outcome and greater immune cell infiltration compared with immune-cold patients. Multivariate analysis revealed that the TILSig is an independent predictive factor after adjusting for other clinical factors. Further analysis accounting for TILSig and immune checkpoint gene revealed that the TILSig has a discriminatory power in patients with similar expression levels of immune checkpoint genes and significantly prolonged survival was observed for patients with low TILSig and low immune checkpoint gene expression implying a better response to immune checkpoint inhibitor (ICI) immunotherapy. CONCLUSIONS: Our finding demonstrated the importance and value of lncRNAs in evaluating the immune infiltrate of the tumor and highlighted the potential of lncRNA coupled with specific immune checkpoint factors as predictive biomarkers of ICI response to enable a more precise selection of patients.

Location deviations of DNA functional elements affected SNP mapping in the published databases and references.

The recent extensive application of next-generation sequencing has led to the rapid accumulation of multiple types of data for functional DNA elements. With the advent of precision medicine, the fine-mapping of risk loci based on these elements has become of paramount importance. In this study, we obtained the human reference genome (GRCh38) and the main DNA sequence elements, including protein-coding genes, miRNAs, lncRNAs and single nucleotide polymorphism flanking sequences, from different repositories. We then realigned these elements to identify their exact locations on the genome. Overall, 5%-20% of all sequence element locations deviated among databases, on the scale of kilobase-pair to megabase-pair. These deviations even affected the selection of genome-wide association study risk-associated genes. Our results implied that the location information for functional DNA elements may deviate among public databases. Researchers should take care when using cross-database sources and should perform pilot sequence alignments before element location-based studies.

Landscape of SNPs-mediated lncRNA structural variations and their implication in human complex diseases.

An increasing number of functional studies shows that long noncoding RNAs (lncRNAs) are involved in many aspects of cellular physiology and fulfills a wide variety of regulatory roles at almost every stage of gene expression. A major feature of lncRNAs is the highly folded modular domains in transcripts. With improved modeling and definition, it is now feasible to explore and gain novel insights into the structural-functional relationship of lncRNAs and their association with complex human diseases. In this study, we utilized an automatic computational pipeline to scan lncRNA architecture at the genome-wide scale and to obtain a landscape of functional domains. An accurate alignment algorithm was performed to identify 40 triple pairs between single-nucleotide polymorphisms (SNPs), lncRNAs and diseases. In order to detect the potential contribution of a lncRNA's modular character, we estimated and evaluated structural rearrangements, which were derived from disease-associated SNPs. In addition, we focused on annotating and comparing the global and local heterogeneity of the wild-type and mutant lncRNAs. Assessing lncRNA architecture has yielded how variations in structured regions impact the molecular mechanisms of lncRNAs and how SNPs disturb binding and recruiting ability. These observations are the first glimpse of the 'lncRNA structurome' and make it possible to robustly explore and assemble intricate space conformation and their stress variation. This result also successfully demonstrates that lncRNA transcripts contain a complex structural landscape and highlights the proposed contribution of lncRNA structure in controlling RNA functions and disease mechanisms.

Evaluation of drug efficacy based on the spatial position comparison of drug-target interaction centers.

The spatial position and interaction of drugs and their targets is the most important characteristics for understanding a drug's pharmacological effect, and it could help both in finding new and more precise treatment targets for diseases and in exploring the targeting effects of the new drugs. In this work, we develop a computational pipeline to confirm the spatial interaction relationship of the drugs and their targets and compare the drugs' efficacies based on the interaction centers. First, we produce a 100-sample set to reconstruct a stable docking model of the confirmed drug-target pairs. Second, we set 5.5 Å as the maximum distance threshold for the drug-amino acid residue atom interaction and construct 3-dimensional interaction surface models. Third, by calculating the spatial position of the 3-dimensional interaction surface center, we develop a comparison strategy for estimating the efficacy of different drug-target pairs. For the 1199 drug-target interactions of the 649 drugs and 355 targets, the drugs that have similar interaction center positions tend to have similar efficacies in disease treatment, especially in the analysis of the 37 targeted relationships between the 15 known anti-cancer drugs and 10 target molecules. Furthermore, the analysis of the unpaired anti-cancer drug and target molecules suggests that there is a potential application for discovering new drug actions using the sampling molecular docking and analyzing method. The comparison of the drug-target interaction center spatial position method better reflect the drug-target interaction situations and could support the discovery of new efficacies among the known anti-cancer drugs.

EWASdb: epigenome-wide association study database.

DNA methylation, the most intensively studied epigenetic modification, plays an important role in understanding the molecular basis of diseases. Furthermore, epigenome-wide association study (EWAS) provides a systematic approach to identify epigenetic variants underlying common diseases/phenotypes. However, there is no comprehensive database to archive the results of EWASs. To fill this gap, we developed the EWASdb, which is a part of 'The EWAS Project', to store the epigenetic association results of DNA methylation from EWASs. In its current version (v 1.0, up to July 2018), the EWASdb has curated 1319 EWASs associated with 302 diseases/phenotypes. There are three types of EWAS results curated in this database: (i) EWAS for single marker; (ii) EWAS for KEGG pathway and (iii) EWAS for GO (Gene Ontology) category. As the first comprehensive EWAS database, EWASdb has been searched or downloaded by researchers from 43 countries to date. We believe that EWASdb will become a valuable resource and significantly contribute to the epigenetic research of diseases/phenotypes and have potential clinical applications. EWASdb is freely available at http://www.ewas.org.cn/ewasdb or http://www.bioapp.org/ewasdb.