ObjectiveThe study utilized human transcriptome microarray to explore biomarkers for diagnosing drug-induced liver injury （DILI） caused by anti-tuberculosis drugs.MethodsA 6-month follow-up study was ...conducted on 152 patients treated with anti-tuberculosis drugs in designated hospitals in Shanghai. The blood samples were collected at the 0， 2， 4， 8， 12 and 24 weeks after treatment. According to the clinical biochemical indicators， the research subjects were divided into DILI cases （34 cases） and Control cases （118 cases）. Single factor analysis was conducted on the influencing factors between the two groups. In a 1∶1 matched DILI-control study， RNA samples of 13 pairs of cases were sequenced by the whole transcript expression mRNA array. Differentially expressed genes （DEGs） were screened by Hotelling's T2 value sequencing and the expression trend analysis of genes by STEM （short-time series expression miner）， and the functional enrichment and pathway analysis of DEGs were carried out.ResultsIn total 152 clin
Niemann–Pick disease type C (NPC) is an autosomal recessive disorder with progressive neurodegeneration. Although the causative genes were previously identified, NPC has unclear pathophysiological ...aspects, and patients with NPC present various symptoms and onset ages. However, various novel biomarkers and metabolic alterations have been investigated; at present, few comprehensive proteomic alterations have been reported in relation to NPC. In this study, we aimed to elucidate proteomic alterations in NPC and perform a global proteomics analysis for NPC model cells. First, we developed two NPC cell models by knocking out NPC1 using CRISPR/Cas9 (KO1 and KO2). Second, we performed a label-free (LF) global proteomics analysis. Using the LF approach, more than 300 proteins, defined as differentially expressed proteins (DEPs), changed in the KO1 and/or KO2 cells, while the two models shared 35 DEPs. As a bioinformatics analysis, the construction of a protein–protein interaction (PPI) network and an enrichment analysis showed that common characteristic pathways such as ferroptosis and mitophagy were identified in the two model cells. There are few reports of the involvement of NPC in ferroptosis, and this study presents ferroptosis as an altered pathway in NPC. On the other hand, many other pathways and DEPs were previously suggested to be associated with NPC, supporting the link between the proteome analyzed here and NPC. Therapeutic research based on these results is expected in the future.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Multiple myeloma (MM) is a severely debilitating and fatal B-cell neoplastic disease. The discovery of disease-associated proteins with causal genetic evidence offers a chance to uncover ...novel therapeutic targets. Methods First, we comprehensively investigated the causal association between 2994 proteins and MM through two-sample mendelian randomization (MR) analysis using summary-level data from public genome-wide association studies of plasma proteome (N = 3301 healthy individuals) and MM (598 cases and 180,756 controls). Sensitivity analyses were performed for these identified causal proteins. Furthermore, we pursued the exploration of enriched biological pathways, prioritized the therapeutic proteins, and evaluated their druggability using the KEGG pathway analysis, MR-Bayesian model averaging analysis, and cross-reference with current databases, respectively. Results We identified 13 proteins causally associated with MM risk (false discovery rate corrected P < 0.05). Six proteins were positively associated with the risk of MM, including nicotinamide phosphoribosyl transferase (NAMPT; OR 95% CI: 1.35 1.18, 1.55), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1; 1.14 1.06, 1.22), neutrophil cytosol factor 2 (NCF2; 1.27 1.12, 1.44), carbonyl reductase 1, cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D), platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2). Seven proteins were inversely associated with MM, which referred to suppressor of cytokine signaling 3 (SOCS3; 0.90 0.86, 0.94), Fc-gamma receptor III-B (FCGR3B; 0.75 0.65,0.86), glypican-1 (GPC1; 0.69 0.58,0.83), follistatin-related protein 1, protein tyrosine phosphatase non-receptor type 4 (PTPN4), granzyme B, complement C1q subcomponent subunit C (C1QC). Three of the causal proteins, SOCS3, FCGR3B, and NCF2, were enriched in the osteoclast differentiation pathway in KEGG enrichment analyses while GPC1 (marginal inclusion probability (MIP):0.993; model averaged causal effects (MACE): - 0.349), NAMPT (MIP:0.433; MACE: - 0.113), and NCF2 (MIP:0.324; MACE:0.066) ranked among the top three MM-associated proteins according to MR-BMA analyses. Furthermore, therapeutics targeting four proteins are currently under evaluation, five are druggable and four are future breakthrough points. Conclusions Our analysis revealed a set of 13 novel proteins, including six risk and seven protective proteins, causally linked to MM risk. The discovery of these MM-associated proteins opens up the possibility for identifying novel therapeutic targets, further advancing the integration of genome and proteome data for drug development. Keywords: Plasma proteome, Multiple myeloma, Drug target, Bayesian model, Mendelian randomization, Enrichment pathway analysis
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Women with uterine adenomyosis seeking assisted reproduction have been associated with compromised endometrial receptivity to embryo implantation. To understand the mechanisms involved in this ...process, we aimed to compare endometrial transcriptome profiles during the window of implantation (WOI) between women with and without adenomyosis.
We obtained endometrial biopsies LH-timed to the WOI from women with sonographic features of adenomyosis (n=10) and controls (n=10). Isolated RNA samples were subjected to RNA sequencing (RNA-seq) by the Illumina NovaSeq 6000 platform and endometrial receptivity classification with a molecular tool for menstrual cycle phase dating (beREADY®, CCHT). The program language R and Bioconductor packages were applied to analyse RNA-seq data in the setting of the result of accurate endometrial dating. To suggest robust candidate pathways, the identified differentially expressed genes (DEGs) associated with the adenomyosis group in the receptive phase were further integrated with 151, 173 and 42 extracted genes from published studies that were related to endometrial receptivity in healthy uterus, endometriosis and adenomyosis, respectively. Enrichment analyses were performed using Cytoscape ClueGO and CluePedia apps.
Out of 20 endometrial samples, 2 were dated to the early receptive phase, 13 to the receptive phase and 5 to the late receptive phase. Comparison of the transcriptomics data from all 20 samples provided 909 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group but only 4 enriched pathways (Bonferroni p value < 0.05). The analysis of 13 samples only dated to the receptive phase provided suggestive 382 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group, leading to 33 enriched pathways (Bonferroni p value < 0.05). These included pathways were already associated with endometrial biology, such as "Expression of interferon (IFN)-induced genes" and "Response to IFN-alpha". Data integration revealed pathways indicating a unique effect of adenomyosis on endometrial molecular organization (e.g., "Expression of IFN-induced genes") and its interference with endometrial receptivity establishment (e.g., "Extracellular matrix organization" and "Tumour necrosis factor production").
Accurate endometrial dating and RNA-seq analysis resulted in the identification of altered response to IFN signalling as the most promising candidate of impaired uterine receptivity in adenomyosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although bipolar disorder is highly heritable, the identification of specific genetic variations is limited because of the complex traits underlying the disorder. We performed a genome-wide ...association study of bipolar disorder using a subphenotype that shows hypersomnia symptom during a major depressive episode. We investigated a total of 2,191 cases, 1,434 controls, and 703,012 single nucleotide polymorphisms (SNPs) in the merged samples obtained from the Translational Genomics Institute and the Genetic Association Information Network. The gene emerging as the most significant by statistical analysis was rs1553441 (odds ratio=0.4093; p=1.20×10(-5); Permuted p=6.0×10(-6)). However, the 5×0(-8) threshold for statistical significance required in a genome-wide association study was not achieved. The functional enrichment pathway analysis showed significant enrichments in the adhesion, development-related, synaptic transmission-related, and cell recognition-related pathways. For further evaluation, each gene of the enriched pathways was reviewed and matched with genes that were suggested to be associated with psychiatric disorders by previous genetic studies. We found that the cadherin 13 and hypocretin (orexin) receptor 2 genes may be involved in the hypersomnia symptom during a major depressive episode of bipolar disorder.
Waldenström macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is rare but a clinicopathologically distinct B-cell malignancy. This study assessed differentially expressed genes (DEGs) ...to identify potential WM biomarkers and uncover the underlying the molecular mechanisms of WM progression using gene expression profiles from the Gene Expression Omnibus database. DEGs were identified using the LIMMA package and their potential functions were then analyzed by using the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and the protein-protein interaction (PPI) network analysis by using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Data showed that among 1,756 DEGs, 926 were upregulated and 830 were downregulated by comparing WM BM CD19+ with normal PB CD19+ B cell samples, whereas 241 DEGs (95 upregulated and 146 downregulated) were identified by comparing WM BM CD138+ with normal BM CD138+ plasma cell samples. The DEGs were enriched in different GO terms and pathways, including the apoptotic process, cell cycle arrest, immune response, cell adhesion, mitogen-activated protein kinase signaling pathway, toll-like receptor signaling pathway, and the gonadotropin-releasing hormone signaling pathway. Hub nodes in the PPI network included CDK1, JUN, CREBBP, EP300, CAD, CDK2, and MAPK14. Bioinformatics analysis of the GSE9656 dataset identified 7 hub genes that might play an important role in WM development and progression. Some of the candidate genes and pathways may serve as promising therapeutic targets for WM.
Neural differentiation as a major process during neural cell therapy is one of the main issues that is not fully characterized. This study focuses on the major deconstruction of the transcriptional ...networks that regulate cell fate determination during neural differentiation under the influence of RA signalling. In our studies, we used four different microarray datasets containing a total of 15,660 genes to determine which genes were differentially expressed during neural differentiation from pluripotent stem cells (P19), among the 17 samples from four different datasets that were integrated via meta-analysis approaches. Of the 15,660 gene expression in our data integration, 443 DEGs are induced during neural differentiation. Upstream dissection of these 443 DEGs revealed a network of protein-protein interactions (PPIs) from TFs and kinases, as well as intermediate proteins between them, which are indicated by three (POU51, NANOG, and FOXO1) down-expression genes and one PAX6 up-expression gene playing roles in up-stream of these 443 induced DEGs during neural differentiation. The constructed network from the PPIs database revealed that four novel sub-networks play major roles in neuron differentiation in cluster 3, retinol metabolism in cluster 4, Rap1 signalling pathways in cluster 2, and axonogenesis in cluster 6. These four clusters have revealed very useful information about how neural characterization will be created from pluripotent stem cells.
This research reveals a plethora of information on the neural differentiation process, including cell commitment and neural differentiation, and lays the groundwork for future research into particular pathways involving protein-protein interactions in neurogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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