A review of disease risk prediction methods and applications in the omics era.

Risk prediction and disease prevention are the innovative care challenges of the 21st century. Apart from freeing the individual from the pain of disease, it will lead to low medical costs for society. Until very recently, risk assessments have ushered in a new era with the emergence of omics technologies, including genomics, transcriptomics, epigenomics, proteomics, and so on, which potentially advance the ability of biomarkers to aid prediction models. While risk prediction has achieved great success, there are still some challenges and limitations. We reviewed the general process of omics-based disease risk model construction and the applications in four typical diseases. Meanwhile, we highlighted the problems in current studies and explored the potential opportunities and challenges for future clinical practice.

Effects of genetic variation on the structure of RNA and protein.

Changes in the structure of RNA and protein, have an important impact on biological functions and are even important determinants of disease pathogenesis and treatment. Some genetic variations, including copy number variation, single nucleotide variation, and so on, can lead to changes in biological function and increased susceptibility to certain diseases by changing the structure of RNA or protein. With the development of structural biology and sequencing technology, a large amount of RNA and protein structure data and genetic variation data resources has emerged to be used to explain biological processes. Here, we reviewed the effects of genetic variation on the structure of RNAs and proteins, and investigated their impact on several diseases. An online resource (http://www.onethird-lab.com/gems/) to support convenient retrieval of common tools is also built. Finally, the challenges and future development of the effects of genetic variation on RNA and protein were discussed.

Genome-wide identification of m6A-associated single nucleotide polymorphisms in complex diseases of nervous system.

N6-methyladenosine (m6A) is one of the most abundant chemical modifications on RNA and can affect the occurrence and development of diseases. Some studies have shown that the expressions of some m6A-related genes are significantly regulated by single nucleotide variants (SNV). However, the function of m6A-associated single nucleotide polymorphisms (m6A-SNP) remains unclear in multiple sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Here, we identified the disease-associated m6A-SNPs by integrating genome-wide association study (GWAS) and m6A-SNPs from the RMVar database, and confirmed the relationship between these identified m6A-SNPs and their target genes in eQTL analysis and gene differential expression analysis. Finally, 26 genes corresponding to 20 m6A-SNPs with eQTL signals were identified and differentially expressed (P < 0.05) in MS, 15 genes corresponding to 12 m6A-SNPs (P < 1e-04) were differentially expressed in AD, and 27 PD-associated m6A-SNPs that regulated the expression of 31 genes were identified. There were 5 HLA genes with eQTL signals (HLA-DQB1, HLA-DRB1, HLA-DQA1, HLA-DQA2 and HLA-DQB1-AS1) to be detected in the three diseases. In summary, our study provided new insights into understanding the potential roles of these m6A-SNPs in disease pathogenesis as well as therapeutic target.

Epigenome-wide methylation haplotype association analysis identified HLA-DRB1, HLA-DRB5 and HLA-DQB1 as risk factors for rheumatoid arthritis.

The aim of this study was to compare nonrandom associations between physically adjacent single methylation polymorphism loci among rheumatoid arthritis (RA) and normal subjects for investigating RA-risk methylation haplotypes (meplotype). With 354 ACPA-positive RA patients and 335 normal controls selected from a case-control study based on Swedish population, we conducted the first RA epigenome-wide meplotype association study using our software EWAS2.0, mainly including (i) converted the ß value to methylation genotype (menotype) data, (ii) identified methylation disequilibrium (MD) block, (iii) calculated frequent of each meplotypes in MD block and performed case-control association test and (iv) screened for RA-risk meplotypes by odd ratio (OR) and p-values. Ultimately, 545 meplotypes on 334 MD blocks were identified significantly associated with RA (p-value < .05). These meplotypes were mapped to 329 candidate genes related to RA. Subsequently, combined with gene optimization, eight RA-risk meplotypes were identified on three risk genes: HLA-DRB1, HLA-DRB5 and HLA-DQB1. Our results reported the relationship between DNA methylation pattern on HLA-DQB1 and the risk of RA for the first time, demonstrating the co-demethylation of 'cg22984282' and 'cg13423887' on HLA-DQB1 gene (meplotype UU, p-value = 2.90E - 6, OR = 1.68, 95% CI = [1.35, 2.10]) may increase the risk of RA. Our results demonstrates the potential of methylation haplotype analysis to identify RA-related genes from a new perspective and its applicability to the study of other disease.

RABC: Rheumatoid Arthritis Bioinformatics Center.

Advances in sequencing technologies have led to the rapid growth of multi-omics data on rheumatoid arthritis (RA). However, a comprehensive database that systematically collects and classifies the scattered data is still lacking. Here, we developed the Rheumatoid Arthritis Bioinformatics Center (RABC, http://www.onethird-lab.com/RABC/), the first multi-omics data resource platform (data hub) for RA. There are four categories of data in RABC: (i) 175 multi-omics sample sets covering transcriptome, epigenome, genome, and proteome; (ii) 175 209 differentially expressed genes (DEGs), 105 differentially expressed microRNAs (DEMs), 18 464 differentially DNA methylated (DNAm) genes, 1 764 KEGG pathways, 30 488 GO terms, 74 334 SNPs, 242 779 eQTLs, 105 m6A-SNPs and 18 491 669 meta-mQTLs; (iii) prior knowledge on seven types of RA molecular markers from nine public and credible databases; (iv) 127 073 literature information from PubMed (from 1972 to March 2022). RABC provides a user-friendly interface for browsing, searching and downloading these data. In addition, a visualization module also supports users to generate graphs of analysis results by inputting personalized parameters. We believe that RABC will become a valuable resource and make a significant contribution to the study of RA.

Treatments and regulatory mechanisms of acoustic stimuli on mood disorders and neurological diseases.

Acoustic stimuli such as music or ambient noise can significantly affect physiological and psychological health in humans. We here summarize positive effects of music therapy in premature infant distress regulation, performance enhancement, sleep quality control, and treatment of mental disorders. Specifically, music therapy exhibits promising effects on treatment of neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). We also highlight regulatory mechanisms by which auditory intervention affects an organism, encompassing modulation of immune responses, gene expression, neurotransmitter regulation and neural circuitry. As a safe, cost-effective and non-invasive intervention, music therapy offers substantial potential in treating a variety of neurological conditions.

A novel immunochemotherapy based on immunogenicity-activated and immunosuppression-reversed biomimetic nanoparticles.

Studies show that infiltrated myeloid-derived suppressor cells (MDSCs) are vital in the immunosuppressive tumor microenvironment and account for lymphoma refractoriness and recurrence. Here, we developed a biomimetic nanoplatform (PM-PLGA-DOX/GEM) in which platelet membranes (PM) wrap PLGA nanoparticles co-loaded with doxorubicin (DOX) and gemcitabine (GEM). PM-PLGA-DOX/GEM would accumulate in tumor tissues because of the enhanced permeation and retention (EPR) effect and the tumor cell-induced platelet aggregation (TCIPA) effect. GEM could eliminate the MDSCs in tumor tissues, thereby reversing the immunosuppressive tumor microenvironment. Furthermore, DOX could invoke the immunogenic cell death (ICD) of lymphoma cells. Consequently, numerous T cells were recruited and activated to improve the therapeutic effects. This study will offer a potential platform for clinical treatment of lymphoma and other solid tumors.

Mobile-Based and Self-Service Tool (iPed) to Collect, Manage, and Visualize Pedigree Data: Development Study.

BACKGROUND: Pedigree data (family history) are indispensable for genetics studies and the assessment of individuals' disease susceptibility. With the popularity of genetics testing, the collection of pedigree data is becoming more common. However, it can be time-consuming, laborious, and tedious for clinicians to investigate all pedigree data for each patient. A self-service robot could inquire about patients' family history in place of professional clinicians or genetic counselors. OBJECTIVE: The aim of this study was to develop a mobile-based and self-service tool to collect and visualize pedigree data, not only for professionals but also for those who know little about genetics. METHODS: There are 4 main aspects in the iPed construction, including interface building, data processing, data storage, and data visualization. The user interface was built using HTML, JavaScript libraries, and Cascading Style Sheets (version 3; Daniel Eden). Processing of the submitted data is carried out by PHP programming language. MySQL is used to document and manage the pedigree data. PHP calls the R script to accomplish the visualization. RESULTS: iPed is freely available to all users through the iPed website. No software is required to be installed, no pedigree files need to be prepared, and no knowledge of genetics or programs is required. The users can easily complete their pedigree data collection and visualization on their own and through a dialogue with iPed. Meanwhile, iPed provides a database that stores all users' information. Therefore, when the users need to construct new pedigree trees for other genetic traits or modify the pedigree trees that have already been created, unnecessary duplication of operations can be avoided. CONCLUSIONS: iPed is a mobile-based and self-service tool that could be used by both professionals and nonprofessionals at any time and from any place. It reduces the amount of time required to collect, manage, and visualize pedigree data.

Gestational diabetes mellitus is associated with antenatal hypercoagulability and hyperfibrinolysis: a case control study of Chinese women.

BACKGROUND: To determine the relationship between gestational diabetes mellitus (GDM) and coagulation/fibrinolysis abnormality in antenatal Chinese women. METHODS: Case control study: 50 women had GDM and 132 did not (the NGDM group) grouping by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Maternal plasma biochemistry and previous medical history were collected from perinatal health records. Antenatal coagulation/fibrinolysis activity (CFA) parameters were assessed using thromboelastography and routine CFA parameters, respectively. Univariate and multiple regression analyses were used to evaluate the associations between GDM and CFA parameters. Maternal age, platelet, ALT, ALP, urea nitrogen, and previous history of abortion were taken as the covariables. RESULTS: The women with GDM were significantly older than those without GDM (30.3 vs. 28.6 years, p = .012). Compared with the NGDM group, the GDM group had a significantly higher prevalence of cesarean delivery (56.0 vs. 37.9%, p = .027) and higher values of fibrinogen (FIB; 4.7 vs. 4.3 g/L, p = .001), activated partial thromboplastin time (APTT; 30.9 vs. 29.5 s, p = .010).There were no significant differences in the prevalence of maternal thrombotic events or neonatal events. GDM was significantly associated with higher APTT (ß =1.41 s, 95% CI: 0.29-2.53), higher FIB (ß = 0.38 g/L, 95% CI: 0.14-0.61), and higher percentage reduction in clot lysis after 30 min (LY30; ß = 1.14%, 95% CI: 0.15-2.13) after adjustment for potential confounding factors. CONCLUSIONS: GDM is significantly associated with hypercoagulability and hyperfibrinolysis in these antenatal Chinese women.

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.

Liraglutide Attenuates Nonalcoholic Fatty Liver Disease by Modulating Gut Microbiota in Rats Administered a High-Fat Diet.

This study aimed to determine whether modulation of the gut microbiota structure by liraglutide helps improve nonalcoholic fatty liver disease (NAFLD) in rats on a high-fat diet (HFD). Rats were administered an HFD for 12 weeks to induce NAFLD and then administered liraglutide for 4 additional weeks. Next-generation sequencing and multivariate analysis were performed to assess structural changes in the gut microbiota. Liraglutide attenuated excessive hepatic ectopic fat deposition, maintained intestinal barrier integrity, and alleviated metabolic endotoxemia in HFD rats. Liraglutide significantly altered the overall structure of the HFD-disrupted gut microbiota and gut microbial composition in HFD rats in comparison to those on a normal diet. An abundance of 100 operational taxonomic units (OTUs) were altered upon liraglutide administration, with 78 OTUs associated with weight gain or inflammation. Twenty-three OTUs positively correlated with hepatic steatosis-related parameters were decreased upon liraglutide intervention, while 5 OTUs negatively correlated with hepatic steatosis-related parameters were increased. These results suggest that liraglutide-mediated attenuation of NAFLD partly results from structural changes in gut microbiota associated with hepatic steatosis.

Platelet-mimicking nanoparticles co-loaded with W18O49 and metformin alleviate tumor hypoxia for enhanced photodynamic therapy and photothermal therapy.

W18O49-mediated photodynamic therapy (PDT) and photothermal therapy (PTT) are limited by the easily oxidized property and tumor hypoxia. Here, we report the development of platelet membranes as nanocarriers to co-load W18O49 nanoparticles (NPs) and metformin (PM-W18O49-Met NPs). Platelet membranes can protect W18O49 from oxidation and immune evasion, and increase the accumulation of W18O49 in tumor sites via the passive EPR effect and active adhesion between platelets and cancer cells. The introduction of metformin (Met), a typical anti-diabetic drug, can alleviate the tumor hypoxia through reducing oxygen consumption. As a result, ROS and heat generation are both greatly increased, as revealed by ROS/hypoxia imaging in vitro, IR thermal imaging in vivo and PET imaging in vivo. PM-W18O49-Met NPs show the improved therapeutic effects with greatly inhibited tumor growth and induced tumor cell apoptosis. Therefore, our work provides a novel strategy for simultaneous enhanced PDT and PTT, which is promising in bioapplication. STATEMENTE OF SIGNIFICANCE: W18O49-mediated photodynamic therapy and photothermal therapy are limited by the poor delivery of nanoparticles to tumors, the easily oxidized property, and tumor hypoxia environment, which will induce tumor treatment failure. Herein, we report the development of platelet membranes as nanocarriers to co-load W18O49 nanoparticles and metformin (PM-W18O49-Met NPs). Platelet membranes can protect W18O49 from oxidation and immune evasion, and increase the accumulation of W18O49 in tumor sites via the passive EPR effect and active adhesion. Metformin can alleviate the tumor hypoxia through reducing oxygen consumption. Hence, ROS and heat generation are both greatly increased. PM-W18O49-Met NPs show the improved therapeutic effects with greatly inhibited tumor growth and induced apoptosis. Therefore, our work provides a novel strategy in bioapplication.

Modulation of gut microbiota contributes to curcumin-mediated attenuation of hepatic steatosis in rats.

BACKGROUND: Structural disruption of gut microbiota contributes to the development of non-alcoholic fatty liver disease (NAFLD) and modulating the gut microbiota represents a novel strategy for NAFLD prevention. Although previous studies have demonstrated that curcumin alleviates hepatic steatosis, its effect on the gut microbiota modulation has not been investigated. METHODS: Next generation sequencing and multivariate analysis were utilized to evaluate the structural changes of gut microbiota in a NAFLD rat model induced by high fat-diet (HFD) feeding. RESULTS: We found that curcumin attenuated hepatic ectopic fat deposition, improved intestinal barrier integrity, and alleviated metabolic endotoxemia in HFD-fed rats. More importantly, curcumin dramatically shifted the overall structure of the HFD-disrupted gut microbiota toward that of lean rats fed a normal diet and altered the gut microbial composition. The abundances of 110 operational taxonomic units (OTUs) were altered by curcumin. Seventy-six altered OTUs were significantly correlated with one or more hepatic steatosis associated parameters and designated 'functionally relevant phylotypes'. Thirty-six of the 47 functionally relevant OTUs that were positively correlated with hepatic steatosis associated parameters were reduced by curcumin. CONCLUSION: These results indicate that curcumin alleviates hepatic steatosis in part through stain-specific impacts on hepatic steatosis associated phylotypes of gut microbiota in rats. GENERAL SIGNIFICANCE: Compounds with antimicrobial activities should be further investigated as novel adjunctive therapies for NAFLD.