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Immune thrombocytopenia (ITP), an acquired autoimmune disease, is characterized by immune-mediated platelet destruction. A biomarker is a biological entity that contributes to disease pathogenesis and reflects disease activity. Metabolic alterations are reported to be associated with the occurrence of various diseases. As metabolic biomarkers for ITP have not been identified. This study aimed to identify metabolism-related differentially expressed genes as potential biomarkers for pathogenesis of ITP using bioinformatic analyses.The microarray expression data of the peripheral blood mononuclear cells were downloaded from the Gene Expression Omnibus database (GSE112278 download link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112278). Key module genes were intersected with metabolism-related genes to obtain the metabolism-related key candidate genes. The hub genes were screened based on the degree function in the coytoscape sofware. The key ITP-related genes were subjected to functional enrichment analysis. Immune infiltration analysis was performed using a single-sample gene set enrichment analysis algorithm to evaluate the differential infiltration levels of immune cell types between ITP patient and control. Molecular subtypes were identified based on the expression of hub genes. The expression of hub genes in the ITP patients was validated using quantitative real-time polymerase chain reaction analysis. This study identified five hub genes (ADH4, CYP7A1, CYP1A2, CYP8B1, and NR1H4), which were be associated with the pathogenesis of ITP, and two molecular subtypes of ITP. Among these hub genes, CYP7A1 and CYP8B1 involved in cholesterol metabolism,were further verified in clinical samples. [ABSTRACT FROM AUTHOR]

GDP-l-galactose phosphorylase (GGP) is a key rate-limiting enzyme in plant ascorbic acid synthesis, which plays an important role in plant growth and development as well as stress response. However, the presence of GGP and its function in potato and pepper are not known. In this study, we first identified two GGP genes in each potato and pepper genomes using a genome-wide search approach. We then analyzed their physicochemical properties, conserved domains, protein structures and phylogenetic relationships. Phylogenetic tree analysis revealed that members of the potato and pepper GGP gene families are related to eggplant (Solanum melongena L.), Arabidopsis (Arabidopsis thaliana L.), tobacco (Nicotiana tabacum L.) and tomato (Solanum lycopersicum L.), with tomato being the most closely related. The promoter sequences mainly contain homeopathic elements such as light-responsive, hormone-responsive and stress-responsive, with light-responsive elements being the most abundant. By analyzing the structure of the genes, it was found that there is no transmembrane structure or signal peptide in the GGP gene family of potatoes and peppers, and that all of its members are hydrophilic proteins. The expression profiles of different tissues show that StGGP1 has the highest expression levels in leaves, StGGP2 has the highest expression levels in stamens, and CaGGPs have the highest expression levels in the early stages of fruit development (Dev1). It was found that StGGPs and CaGGPs genes showed different response to phytohormones and abiotic stresses. Abscisic acid (ABA) treatment induced the most significant change in the expression of StGGPs, while the expression of CaGGPs showed the most pronounced change under methyl jasmonate (MeJA) treatment. StGGPs responded mainly to dark treatment, whereas CaGGPs responded mainly to NaCl stress. These results provide an important basis for a detailed study about the functions of GGP homologous genes in potato and pepper in response to abiotic stresses. [ABSTRACT FROM AUTHOR]

Jujubae Fructus, the fruit of Ziziphus jujuba Mill has been used as one of the medicine food homology species for thousands of years in China. Studies have shown that the active ingredients of Jujubae Fructus have a variety of biological effects, but its role in the aging process still lacks knowledge. Here, we investigated the effect of Jujubae Fructus extract (JE) on Caenorhabditis elegans lifespan and its potential mechanism. The lifespan of C. elegans treated with JE was signifificantly increased in a dose-dependent manner. In addition, JE treatment prolonged the reproductive period and increased normal activity during aging in C. elegans. Similarly, JE supplementation also enhanced the resistance to heat and oxidative stress in C. elegans. Furthermore, the mutant worms' lifespan assays demonstrated that JE requires daf-16 to prolong lifespan. DAF-16::GFP analysis of TJ356 showed that JE treatment translocates DAF-16::GFP to nucleus in transgenic worms. By analyzing the downstream of daf-16, we identify that JE may regulate sod3 downstream of daf-16. Mutant worms' lifespan and transgenic reporter gene expression assays revealed that increasing SOD-3 expression was critical for extending longevity in C. elegans with JE therapy. Collectively, these data indicate that JE may have an important role in C. elegans longevity that is dependent on DAF-16 and SOD-3. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease marked by inflammatory cell infiltration and joint damage. The Chinese government has approved the prescription medication sinomenine (SIN), an effective anti-inflammation drug, for treating RA. This study evaluated the possible anti-inflammatory actions of SIN in RA based on bioinformatics analysis and experiments. Six microarray datasets were acquired from the gene expression omnibus (GEO) database. We used R software to identify differentially expressed genes (DEGs) and perform function evaluations. The CIBERSORT was used to calculate the abundance of 22 infiltrating immune cells. The weighted gene co-expression network analysis (WGCNA) was used to discover genes associated with M1 macrophages. Four public datasets were used to predict the genes of SIN. Following that, function enrichment analysis for hub genes was performed. The cytoHubba and least absolute shrinkage and selection operator (LASSO) were employed to select hub genes, and their diagnostic effectiveness was predicted using the receiver operator characteristic (ROC) curve. Molecular docking was undertaken to confirm the affinity between the SIN and hub gene. Furthermore, the therapeutic efficacy of SIN was validated in LPS-induced RAW264.7 cells line using Western blot and Enzyme-linked immunosorbent assay (ELISA). The matrix metalloproteinase 9 (MMP9) was identified as the hub M1 macrophages-related biomarker in RA using bioinformatic analysis and molecular docking. Our study indicated that MMP9 took part in IL-17 and TNF signaling pathways. Furthermore, we found that SIN suppresses the MMP9 protein overexpression and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the LPS-induced RAW264.7 cell line. In conclusion, our work sheds new light on the pathophysiology of RA and identifies MMP9 as a possible RA key gene. In conclusion, the above findings demonstrate that SIN, from an emerging research perspective, might be a potential cost-effective anti-inflammatory medication for treating RA. [ABSTRACT FROM AUTHOR]

Extreme high temperature has deleterious impact on the yield and quality of tea production, which has aroused the attention of growers and breeders. However, the mechanisms by which tea plant varieties respond to extreme environmental heat is not clear. In this study, we analyzed physiological indices, metabolites and transcriptome differences in three different heat-tolerant tea plant F1 hybrid progenies. Results showed that the antioxidant enzyme activity, proline, and malondialdehyde were significantly decreased in heat-sensitive 'FWS' variety, and the accumulation of reactive oxygen molecules such as H2O2 and O2− was remarkably increased during heat stress. Metabolomic analysis was used to investigate the metabolite accumulation pattern of different varieties in response to heat stress. The result showed that a total of 810 metabolites were identified and more than 300 metabolites were differentially accumulated. Transcriptional profiling of three tea varieties found that such genes encoding proteins with chaperon domains were preferentially expressed in heat-tolerant varieties under heat stress, including universal stress protein (USP32, USP-like), chaperonin-like protein 2 (CLP2), small heat shock protein (HSP18.1), and late embryogenesis abundant protein (LEA5). Combining metabolomic with transcriptomic analyses discovered that the flavonoids biosynthesis pathway was affected by heat stress and most flavonols were up-regulated in heat-tolerant varieties, which owe to the preferential expression of key FLS genes controlling flavonol biosynthesis. Take together, molecular chaperons, or chaperon-like proteins, flavonols accumulation collaboratively contributed to the heat stress adaptation in tea plant. The present study elucidated the differences in metabolite accumulation and gene expression patterns among three different heat-tolerant tea varieties under extreme ambient high temperatures, which helps to reveal the regulatory mechanisms of tea plant adaptation to heat stress, and provides a reference for the breeding of heat-tolerant tea plant varieties. [ABSTRACT FROM AUTHOR]

Necroptosis is a recently identified caspase-independent form of cell death which plays a significant role in the onset and progression of cancer. MicroRNAs (miRNAs) are vital for the development of uterine corpus endometrial carcinoma (UCEC) because they are an important regulatory component in necroptosis. This study developed a new necroptosis-related miRNAs profile to predict the prognosis of patients with UCEC. The TCGA-UCEC cohort's RNA sequencing data, consisting of 534 tumor samples and 33 normal samples, was downloaded. Ten differentially expressed miRNAs related to necroptosis were identified. A prediction model for necroptosis-related miRNAs was then created through COX regression and nomograms analysis. Clinical and pathological parameters were integrated to construct a nomogram and evaluate the model. Prognosis-related miRNAs were further used to predict target genes, and functional analysis was conducted to explore the potential mechanisms of these target genes. Subsequently, immune infiltration analysis was performed using transcriptome data to identify immune genes associated with prognosis, and the expression levels of target gene was validated using UCEC tissues. We identified 7 up-regulated miRNAs (hsa-miR-577, hsa-miR-7-5p, hsa-miR-210-3p, hsa-miR-210-5p, hsa-miR-200a-5p, hsa-miR-141-3p, hsa-miR-425-5p) and 3 down-regulated miRNAs (hsa-miR-7-2-3p, hsa-miR-383-5p, hsa-miR-29a-3p). The risk signature was based on univariate and multivariate COX analyses, constructed using 2 independent prognostic factors and miRNAs (hsa-miR-425-5p, hsa-miR-7-5p) associated with necroptosis. Nomograms demonstrated the prognostic value of risk level, age, FIGO stage, and histological type. Kaplan–Meier analysis revealed significant differences in overall survival (OS) outcomes associated with the expression of hsa-miR-425-5p (P < 0.001) and hsa-miR-7-5p (P = 0.015). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) investigations indicated that these miRNAs play crucial roles in tumor development, metastasis, and prognosis. Immune infiltration analysis showed decreased infiltration of CD8+ T cells, CD8+ T cells, NK cells, and M1 macrophages in normal tissues. Subsequently, a necroptosis-related immune gene significantly associated with prognosis (THRB) was identified, western blot and immunohistochemical staining confirmed the differential expression of THRB in normal endometrial tissues and tumor. Our findings demonstrate a close association between necroptosis and UCEC. The two necroptosis-related miRNAs used in this study may serve as valuable prognostic markers for UCEC patients, and are associated with immune cell infiltration. This suggests that necroptosis may be involved in the development of UCEC through its interaction with immune responses. [ABSTRACT FROM AUTHOR]

Despite numerous reports indicating the significant impact of RNA modification on malignant glioblastoma (GBM) cell behaviors such as proliferation, invasion and therapy efficacy, its specific involvement in glioblastoma (GBM) angiogenesis is remains unclear and is currently under investigation. In this study, we aimed to investigate the relevance between RNA modification regulators and GBM angiogenesis. Our study employed bioinformatic analyses, including Gene Set Enrichment Analysis (GSEA), differential expression analysis, and Kaplan–Meier survival analysis, to identify regulators of angiogenesis-associated RNA modification (RM). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to identify the enrichment of angiogenesis associated signatures in ALKBH5-high expression GBMs. We also utilized Western blot to verify the upregulation of ALKBH5 in clinical GBM samples. By a series of in vitro and in vivo assays, including plasmid transfection, wound healing, transwell invasion test, tube formation, RT-qPCR, ELISA assays and xenograft mice model, we validated the angiogenesis regulation ability of ALKBH5 in GBM. The N6-methyladenosine (m6A) modification "erase" ALKBH5 emerged as a candidate regulator associated with angiogenesis, demonstrating elevated expression and robust prognostic predictive ability in GBM patients. We also revealed enrichment of vasculature development biological process in GBMs with high ALKBH5 expression. Subsequently, we validated the elevated the expression of ALKBH5 in clinical GBM and paired adjacent tissues through western blot. Additionally, we knocked down the expression of ALKBH5 using sh-RNAs in U87 GBM cells to access the angiogenesis induction ability in U87 cells. In vitro experiments, Human Umbilical Vein Endothelial Cells (HUVECs) were used to perform wound healing, transwell migration and tube formation analysis, results indicated that ALKBH5 knock-down of U87 cells could decrease the pro-angiogenesis ability of U87 GBM cells. Further validation of our bioinformatic findings confirmed that ALKBH5 knockdown impaired VEGFA secretion in both in vitro and in vivo settings in U87 cells. These results comprehensively affirm the crucial role of ALKBH5 in regulating GBM-induced angiogenesis, both in vitro and in vivo. ALKBH5 not only emerges as a promising prognostic factor for GBM patients, but also plays a pivotal role in sustaining GBM progression by promoting angiogenesis. [ABSTRACT FROM AUTHOR]

Cuproptosis is a manner of cell death which is related to the homeostasis of copper ions in the cellular environment and is expected to open a new direction of anti-tumor therapy. However, the studies on cuproptosis and copper homeostasis in lung adenocarcinoma (LUAD) are still limited. In this study, we identified new cuproptosis and copper homeostasis related genes (CHRGs) which were effective in stratifying genotyping clusters with survival differences based on transcriptomic data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Weighted Gene Co-expression Network Analysis (WGCNA) further expands the screening boundary of CHRGs, and finally we established a 10-CHRGs-based prognostic signature using lasso-penalized cox regression method, which were validated in GSE30219. Comprehensive bioinformatics analysis revealed these genes are potential regulators of modulating immunotherapy efficacy, drug resistance, tumor microenvironment infiltration, and tumor mutation patterns. Lastly, the scRNA-seq datasets GSE183219 and GSE203360 offers the evidences that CHRGs signature are mainly distributed in cancer epithelial cells, real time quantitative polymerase chain reaction (RT-qPCR) also confirmed the differential expression of these genes between normal lung cell line and lung adenocarcinoma cell lines. Collectively, our findings revealed new cuproptosis and copper homeostasis related genotyping clusters and genes which may play important roles in predicting prognosis, influencing tumor microenvironment and drug efficacy in LUAD patients. [ABSTRACT FROM AUTHOR]

Colon adenocarcinoma (COAD), one of the common clinical cancers, exhibits high morbidity and mortality, and its pathogenesis and treatment are still underdeveloped. Numerous studies have demonstrated the involvement of bile acids in tumour development, while the potential role of their metabolism in the tumor microenvironment (TME) has not been explored. A collection of 481 genes related to bile acid metabolism were obtained, and The Cancer Genome Atlas-based COAD risk model was developed using the least absolute shrinkage selection operator (LASSO) regression analysis. The Gene Expression Omnibus dataset was used to validate the results. The predictive performance of the model was verified using column line plots, principal component analysis and receiver operating characteristic curves. Then, we analysed the differences between the high- and low-risk groups from training set based on clinical characteristics, immune cell infiltration, immune-related functions, chemotherapeutic drug sensitivity and immunotherapy efficacy. Additionally, we constructed a protein–protein interaction network to screen for target genes, which were further investigated in terms of differential immune cell distribution. A total of 234 bile acids-related differentially expressed genes were obtained between normal and tumour colon tissues. Among them, 111 genes were upregulated and 123 genes were down-regulated in the tumour samples. Relying on the LASSO logistic regression algorithm, we constructed a model of bile acid risk score, comprising 12 genes: CPT2, SLCO1A2, CD36, ACOX1, CDKN2A, HADH, GABRD, LEP, TIMP1, MAT1A, SLC6A15 and PPARGC1A. This model was validated in the GEO-COAD set. Age and risk score were observed to be independent prognostic factors in patients with COAD. Genes related to bile acid metabolism in COAD were closely related to bile secretion, intestinal transport, steroid and fatty acid metabolism. Furthermore, the high-risk group was more sensitive to Oxaliplatin than the low-risk group. Finally, the three target genes screened were closely associated with immune cells. We identified a set of 12 genes (CPT2, SLCO1A2, CD36, ACOX1, CDKN2A, HADH, GABRD, LEP, TIMP1, MAT1A, SLC6A15, and PPARGC1A) associated with bile acid metabolism and developed a bile acid risk score model using LASSO regression analysis. The model demonstrated good predictive performance and was validated using an independent dataset. Our findings revealed that the bile acid risk score were independent prognostic factors in COAD patients. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor. Conventional treatments have not achieved breakthroughs in improving survival. Therefore, novel molecular targets and biomarkers need to be identified. As signal transduction docks on the cell membrane, tetraspanins (TSPANs) are associated with various tumors; however, research on their role in GBM remains extremely scarce. Gene expression and clinicopathological characteristic data were obtained from GEPIA, CGGA, HPA, cBioPortal, and GSCA databases to analyze the mRNA and protein expression levels, prognostic value, clinical relevance, mutation status, and targeted drug sensitivity of TSPANs in GBM. Gene set enrichment analysis (GSEA), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used for biological process enrichment. Data from TCGA and TCIA were used to construct the tumor immune microenvironment landscape of TSPANs. Different R software algorithms were used to analyze the immune score, immune cell infiltration, and immune checkpoint correlation. Univariate and multivariate analyses were performed for TSPAN4, which had the most significant predictive prognostic value, and a nomogram model was constructed to predict individual outcomes. The expression and function of TSPAN4 were verified in vitro. TSPAN3/4/6/11/12/18/23/24/25/26/27/28/29/30/31expressions were significantly upregulated in GBM, and TSPAN3/4/6/11/18/24/25/26/29/30 were strongly correlated with prognosis. The expression of multiple TSPANs significantly correlated with 1p/19q co-deletion status, IDH mutation status, recurrence, age, and tumor grade. GSEA and GO analyses revealed the potential contribution of TSPANs in cell adhesion and migration. Immune correlation analysis revealed that TSPANs are related to the formation of the GBM tumor microenvironment (TME) and may influence immunotherapy outcomes. TSPAN4 is an independent prognostic factor and TSPAN4 knockdown has been demonstrated to strongly inhibit glioma cell proliferation, invasion, and migration in vitro. We comprehensively elaborated the prognostic value and potential role of differentially expressed TSPANs in GBM, including molecules that scientists have previously overlooked. This study provides a novel and comprehensive perspective on the pathological mechanisms of GBM and the future direction of individualized tumor immunotherapy, which may be a critical link between GBM malignant progression and TME remodeling. [ABSTRACT FROM AUTHOR]

This study is the first to investigate the process of osteoclast (OCL) differentiation, its potential functions, and the associated mRNA and signalling pathways in embryonic palatal bone. Our findings suggest that OCLs are involved in bone remodelling, bone marrow cavity formation, and blood vessel formation in embryonic palatal bone. We observed TRAP-positive OCLs at embryonic day 16.5 (E16.5), E17.5, and E18.5 at the palatal process of the palate (PPP) and posterior and anterior parts of the palatal process of the maxilla (PPMXP and PPMXA, respectively), with OCL differentiation starting 2 days prior to TRAP positivity. By comparing the key periods of OCL differentiation between PPMX and PPP (E14.5, E15.5, and E16.5) using RNA-seq data of the palates, we found that the PI3K-AKT and MAPK signalling pathways were sequentially enriched, which may play critical roles in OCL survival and differentiation. Csf1r, Tnfrsff11a, Ctsk, Fos, Tyrobp, Fcgr3, and Spi1 were significantly upregulated, while Pik3r3, Tgfbr1, and Mapk3k7 were significantly downregulated, in both PPMX and PPP. Interestingly, Tnfrsff11b was upregulated in PPMX but downregulated in PPP, which may regulate the timing of OCL appearance. These results contribute to the limited knowledge regarding mRNA-specific steps in OCL differentiation in the embryonic palatal bone. [ABSTRACT FROM AUTHOR]

Abnormal expression of the potassium channel tetramerization domain containing 12 (KCTD12) is closely related to the occurrence and development of various tumors, but a pan-cancer analysis of KCTD12 has not yet been conducted. We explored the association between KCTD12 and more than 30 human malignancies using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. First, the mRNA and protein levels of KCTD12 were examined and their correlations with tumor stage and survival were explored. Second, we analyzed the infiltration of CD8+ and CD4+ T cells and cancer-associated fibroblasts in tumors and explored the correlation between KCTD12 expression and tumor cell stemness, genomic heterogeneity, and diagnostic specificity. Finally, we explored the molecular mechanisms associated with KCTD12 using KEGG/GO analysis. The results showed that KCTD12 mRNA and protein expression levels decreased in most tumors was significantly associated with the prognosis of tumor patients, and the phosphorylation level of KCTD12 decreased in several tumors, such as S200 and T196, pancreatic adenocarcinoma (PAAD), lung adenocarcinoma (LUAD), and breast invasive cancer (BRCA). The expression of KCTD12 was positively correlated with the degree of cancer-associated fibroblasts infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), PAAD, and stomach adenocarcinoma (STAD). The relationship between KCTD12 expression and CD8+ and CD4+ T cell infiltration was also clarified. KCTD12 showed high diagnostic sensitivity for various types of tumors and may be involved in tumor cell biology by affecting tumor cell stemness, tumor burden, and other characteristics. Finally, we analyzed the molecular functions of KCTD12 and possible KEGG/GO signaling pathways. In this study, we developed a biological marker for diagnosis, prognosis, and immune infiltration of the pan-cancers. [ABSTRACT FROM AUTHOR]

Homeobox A13 (HOXA13) has been verified as an oncogen in some malignancies. However, its role in nasopharyngeal carcinoma (NPC) is still unclear. This study aims to explore the role of HOXA13 in NPC and its underlying mechanism. The mRNA expression of HOXA13 in NPC was obtained from the GSE53819 and GSE64634 datasets in the Gene Expression Omnibus (GEO) database. MTT, colony formation and transwell assays and xenograft tumour models were used to investigate the effects of HOXA13 on NPC HNE1 cells in vitro and in vivo. The expression of HOXA13, epithelial-mesenchymal transition-transcription factor (EMT-TF) Snail and matrix metalloproteinase 2 (MMP-2) was detected by immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The results showed that HOXA13 was upregulated in NPC. Silencing HOXA13 suppressed the proliferation, migration, and invasion of HNE1 cells, which inhibited tumour growth, while overexpression of HOXA13 induced the opposite effects. In addition, the expression of Snail and MMP-2 at the transcriptional and protein levels was associated with the expression of HOXA13. In summary, our results suggest that HOXA13 plays a role as a cancer-promoting gene in NPC. The underlying mechanism may be related to the upregulation of Snail and MMP-2. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) are clinically and molecularly heterogeneous diseases. We utilized clustering and integrative network analyses to elucidate roles for microRNAs (miRNAs) and miRNA isoforms (isomiRs) in COPD and ILD pathogenesis. Short RNA sequencing was performed on 351 lung tissue samples of COPD (n = 145), ILD (n = 144) and controls (n = 64). Five distinct subclusters of samples were identified including 1 COPD-predominant cluster and 2 ILD-predominant clusters which associated with different clinical measurements of disease severity. Utilizing 262 samples with gene expression and SNP microarrays, we built disease-specific genetic and expression networks to predict key miRNA regulators of gene expression. Members of miR-449/34 family, known to promote airway differentiation by repressing the Notch pathway, were among the top connected miRNAs in both COPD and ILD networks. Genes associated with miR-449/34 members in the disease networks were enriched among genes that increase in expression with airway differentiation at an air–liquid interface. A highly expressed isomiR containing a novel seed sequence was identified at the miR-34c-5p locus. 47% of the anticorrelated predicted targets for this isomiR were distinct from the canonical seed sequence for miR-34c-5p. Overexpression of the canonical miR-34c-5p and the miR-34c-5p isomiR with an alternative seed sequence down-regulated NOTCH1 and NOTCH4. However, only overexpression of the isomiR down-regulated genes involved in Ras signaling such as CRKL and GRB2. Overall, these findings elucidate molecular heterogeneity inherent across COPD and ILD patients and further suggest roles for miR-34c in regulating disease-associated gene-expression. [ABSTRACT FROM AUTHOR]

Leucism, a widespread occurrence observed in Northern snakehead (Channa argus), bestows a striking white jade-like body coloration upon affected individuals and has gained substantial popularity in commercial breeding. While the visible manifestation of leucism in snakeheads is primarily limited to body coloration, it is crucial to explore the potential influence of leucism on organ development and elucidate the underlying molecular mechanisms. Through a comparative analysis of growth differences, our study revealed that at 150 days post-fertilization, the white variety exhibited an 8.5% higher liver index and intestinal index, but experienced a 20% and 38% decreased in spleen index and renal interstitial index, respectively, suggesting an enlarged digestive area but relatively smaller immune tissues. Nonetheless, no significant differences were observed in the intestinal flora between the two varieties, suggesting the exclusion of any exogenous impacts from symbiotic flora on the growth and development of the white variety. Importantly, transcriptome analysis demonstrated that the white variety exhibited higher expression levels of innate immune genes. Furthermore, annotation of the gene sets expressed in the liver and spleen revealed 76 and 35 genes respectively, with the white variety displaying lower expression in genes associated with "Viral protein interaction with cytokine and cytokine receptor", "Protein processing in endoplasmic reticulum", and "TNF signaling pathway", while exhibiting higher expression in "Estrogen signaling pathway". Notably, three genes, namely pcdhf 4, nlrc3 card 15-like, and a pol-like were identified in both the liver and spleen, indicating their potential involvement in altering the development and innate immunity of the white variety. This study reveals the systemic impact of leucism that extends beyond mere pigmentation alterations, highlighting the prominent characteristics of this phenotype and providing a foundation for future molecular breeding programs aimed at enhancing this variety. [ABSTRACT FROM AUTHOR]

Hyperlipidemia, a common metabolic disease, is a risk factor for cardiovascular diseases, Poria cocos (PC) and Alismatis rhizoma (AR) serve as a potential treatment. A systematic approach based on transcriptome sequencing analysis and bioinformatics methods was developed to explore the synergistic effects of PC–AR and identify major compounds and potential targets. The phenotypic characteristics results indicated that the high dose (4.54 g/kg) of PC–AR reduced total cholesterol (TC), elevated high-density lipoprotein cholesterol (HDL-C) levels, and improved hepatocyte morphology, as assessed via hematoxylin and eosin (H&E) staining. Transcriptomic profiling processing results combined with GO enrichment analysis to identify the overlapping genes were associated with inflammatory responses. The cytokine-cytokine receptor interaction pathway was found as a potential key pathway using geneset enrichment analysis. Core enrichment targets were selected according to the PC–AR's fold change versus the model. Real-time quantitative PCR analysis validated that PC–AR significantly downregulated the expression of Cxcl10, Ccl2, Ccl4, Cd40 and Il-1β mRNA (P < 0.05). Molecular docking analysis revealed the significant compounds of PC–AR and the potential binding patterns of the critical compounds and targets. This study provides further evidence that the therapeutic effects of PC–AR on hyperlipidemia in rats through the regulation of inflammation-related targets. [ABSTRACT FROM AUTHOR]

Cortical and subcortical structural alteration has been extensively reported in schizophrenia, including the unusual expansion of gray matter volumes (GMVs) of basal ganglia (BG), especially putamen. Previous genome-wide association studies pinpointed kinectin 1 gene (KTN1) as the most significant gene regulating the GMV of putamen. In this study, the role of KTN1 variants in risk and pathogenesis of schizophrenia was explored. A dense set of SNPs (n = 849) covering entire KTN1 was analyzed in three independent European- or African-American samples (n = 6704) and one mixed European and Asian Psychiatric Genomics Consortium sample (n = 56,418 cases vs. 78,818 controls), to identify replicable SNP-schizophrenia associations. The regulatory effects of schizophrenia-associated variants on the KTN1 mRNA expression in 16 cortical or subcortical regions in two European cohorts (n = 138 and 210, respectively), the total intracranial volume (ICV) in 46 European cohorts (n = 18,713), the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258), and the surface areas (SA) and thickness (TH) of whole cortex and 34 cortical regions in 50 European cohorts (n = 33,992) and eight non-European cohorts (n = 2944) were carefully explored. We found that across entire KTN1, only 26 SNPs within the same block (r2 > 0.85) were associated with schizophrenia across ≥ 2 independent samples (7.5 × 10–5 ≤ p ≤ 0.048). The schizophrenia-risk alleles, which increased significantly risk for schizophrenia in Europeans (q < 0.05), were all minor alleles (f < 0.5), consistently increased (1) the KTN1 mRNA expression in 12 brain regions significantly (5.9 × 10–12 ≤ p ≤ 0.050; q < 0.05), (2) the ICV significantly (6.1 × 10–4 ≤ p ≤ 0.008; q < 0.05), (3) the SA of whole (9.6 × 10–3 ≤ p ≤ 0.047) and two regional cortices potentially (2.5 × 10–3 ≤ p ≤ 0.042; q > 0.05), and (4) the TH of eight regional cortices potentially (0.006 ≤ p ≤ 0.050; q > 0.05), and consistently decreased (1) the BG GMVs significantly (1.8 × 10–19 ≤ p ≤ 0.050; q < 0.05), especially putamen GMV (1.8 × 10–19 ≤ p ≤ 1.0 × 10–4; q < 0.05, (2) the SA of four regional cortices potentially (0.010 ≤ p ≤ 0.048), and (3) the TH of four regional cortices potentially (0.015 ≤ p ≤ 0.049) in Europeans. We concluded that we identified a significant, functional, and robust risk variant block covering entire KTN1 that might play a critical role in the risk and pathogenesis of schizophrenia. [ABSTRACT FROM AUTHOR]

Colon adenocarcinoma (COAD) is a type of cancer that arises from the glandular epithelial cells that produce mucus in the colon. COAD is influenced by various factors, including genetics, environment and lifestyle. The outcome of COAD is determined by the tumor stage, location, molecular characteristics and treatment. Disulfidptosis is a new mode of cell death that may affect cancer development. We discovered genes associated with disulfidptosis in colon adenocarcinoma and proposed them as novel biomarkers and therapeutic targets for COAD. We analyzed the mRNA expression data and clinical information of COAD patients from The Cancer Genome Atlas (TCGA) database and Xena databases, extracted disulfidptosis-related genes from the latest reports on disulfidptosis. We used machine learning to select key features and build a signature and validated the risk model using data from the Gene Expression Omnibus (GEO) database and Human Protein Atlas (HPA). We also explored the potential biological functions and therapeutic implications of the disulfidptosis-related genes using CIBERSORTx and GDSC2 databases. We identified four disulfidptosis-related genes: TRIP6, OXSM, MYH3 and MYH4. These genes predicted COAD patient survival and modulated the tumor microenvironment, drug sensitivity and immune microenvironment. Our study reveals the importance of disulfidptosis-related genes for COAD prognosis and therapy. Immune infiltration and drug susceptibility results provide important clues for finding new personalized treatment options for COAD. These findings may facilitate personalized cancer treatment. [ABSTRACT FROM AUTHOR]

Recurrent pregnancy loss (RPL) is a complex reproductive disorder. The incompletely understood pathophysiology of RPL makes early detection and exact treatment difficult. The purpose of this work was to discover optimally characterized genes (OFGs) of RPL and to investigate immune cell infiltration in RPL. It will aid in better understanding the etiology of RPL and in the early detection of RPL. The RPL-related datasets were obtained from the Gene Expression Omnibus (GEO), namely GSE165004 and GSE26787. We performed functional enrichment analysis on the screened differentially expressed genes (DEGs). Three machine learning techniques are used to generate the OFGs. A CIBERSORT analysis was conducted to examine the immune infiltration in RPL patients compared with normal controls and to investigate the correlation between OFGs and immune cells. Between the RPL and control groups, 42 DEGs were discovered. These DEGs were found to be involved in cell signal transduction, cytokine receptor interactions, and immunological response, according to the functional enrichment analysis. By integrating OFGs from the LASSO, SVM-REF, and RF algorithms (AUC > 0.880), we screened for three down-regulated genes: ZNF90, TPT1P8, FGF2, and an up-regulated FAM166B. Immune infiltration study revealed that RPL samples had more monocytes (P < 0.001) and fewer T cells (P = 0.005) than controls, which may contribute to RPL pathogenesis. Additionally, all OFGs linked with various invading immune cells to varying degrees. In conclusion, ZNF90, TPT1P8, FGF2, and FAM166B are potential RPL biomarkers, offering new avenues for research into the molecular mechanisms of RPL immune modulation and early detection. [ABSTRACT FROM AUTHOR]

Extensive evidence has explored the involvement of microRNAs (miRNAs) in osteosarcoma (OS). Limitedly, the concrete function of microRNA-18b-5p (miR-18b-5p) in OS remains unexplored and largely elusive. Here, we validated that miR-18b-5p significantly elevated in OS via analyzing the data from GEO database. The results showed that miR-18b-5p was overexpressed in human OS tissues and cell lines. The clinical evidence suggested that high level of miR-18b-5p was negatively correlated with the poor prognosis of OS. Meanwhile, miR-18b-5p upregulation facilitated the proliferation and metastasis of OS cells in vitro and in vivo. The mechanism exploration demonstrated that miR-18b-5p acted as a potential inhibitor of PHF2, a tumor suppressor gene, at post-transcriptional level. Moreover, hypoxia induced gene expression of miR-18b-5p was clarified to be transcriptionally mediated by HIF-1α. The clinicopathological analysis in samples of OS patients further supported that miR-18b-5p had a positive correlation with HIF-1α expression, and negative correlation with PHF2. Collectively, the present study uncovered a new molecular mechanism of OS tumorigenesis and development and miR-18b-5p might be a prognostic biomarker and potential therapeutic target for OS treatment. [ABSTRACT FROM AUTHOR]

Angelica dahurica (Fisch. ex Hoffm.) Benth.et Hook.f.var.formosana (Boiss.) Shan et Yuan (A. dahurica) is a well-known medicinal plant that has a wide range of applications in the pharmaceutical, food, cosmetic, and other industries. However, the issue of early bolting has emerged as a major hindrance to its production. This problem not only reduces the yield of A. dahurica, but also has an impact on its active ingredients. To date, the molecular factors that contribute to early bolting and its impact on the growth of A. dahurica have not been thoroughly investigated. Therefore, we conducted a transcriptome study using the Illumina NovaSeq 6000 on two developmental types: early-bolting and non-bolting (normal) roots of A. dahurica. We obtained 2,185 up-regulated and 1,414 down-regulated genes in total. Many of the identified transcripts were related to genes involved in early bolting. The gene ontology analysis revealed several differentially expressed genes that are crucial in various pathways, primarily associated with cellular, molecular, and biological processes. Additionally, the morphological characteristics and coumarin content in the early bolting roots of A. dahurica were significantly altered. This study provides insight into the transcriptomic regulation of early bolting in A. dahurica, which can potentially be utilized to enhance its medicinal properties. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous tumor that is highly aggressive and ranks fifth among the most common cancers worldwide. Although, the researches that attempted to construct a diagnostic model were deficient in HNSCC. Currently, the gold standard for diagnosing head and neck tumors is pathology, but this requires a traumatic biopsy. There is still a lack of a noninvasive test for such a high—incidence tumor. In order to screen genetic markers and construct diagnostic model, the methods of random forest (RF) and artificial neural network (ANN) were utilized. The data of HNSCC gene expression was accessed from Gene Expression Omnibus (GEO) database; we selected three datasets totally, and we combined 2 datasets (GSE6631 and GSE55547) for screening differentially expressed genes (DEGs) and chose another dataset (GSE13399) for validation. Firstly, the 6 DEGs (CRISP3, SPINK5, KRT4, MMP1, MAL, SPP1) were screened by RF. Subsequently, ANN was applied to calculate the weights of 6 genes. Besides, we created a diagnostic model and nominated it as neuralHNSCC, and the performance of neuralHNSCC by area under curve (AUC) was verified using another dataset. Our model achieved an AUC of 0.998 in the training cohort, and 0.734 in the validation cohort. Furthermore, we used the Cell-type Identification using Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm to investigate the difference in immune cell infiltration between HNSCC and normal tissues initially. The selected 6 DEGs and the constructed novel diagnostic model of HNSCC would make contributions to the diagnosis. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most prevalent one in the world among the most common malignant tumors. Numerous studies have shown that butyrate has demonstrated promise as an antitumor agent in a variety of human cancer types. However, butyrate remains understudied in CRC tumorigenesis and progression. In this study, we explored therapeutic strategies to treat CRC by examining the role of butyrate metabolism. First, from the Molecular Signature Database (MSigDB), we identified 348 butyrate metabolism-related genes (BMRGs). Next, we downloaded 473 CRC and 41 standard colorectal tissue samples from The Cancer Genome Atlas (TCGA) database and the transcriptome data of GSE39582 dataset from Gene Expression Omnibus (GEO) database. Then we evaluated the expression patterns of butyrate metabolism-related genes with difference analysis in CRC. Through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analysis, a prognostic model was constructed based on differentially expressed BMRGs. In addition, we discovered an independent prognostic marker for CRC patients. According to the expression levels and coefficients of identified BMRGs, the risk scores of all CRC samples were calculated. Utilizing differentially expressed genes in the high- and low-risk groups, we also constructed a Protein–Protein Interaction (PPI) network to visualize the interactions between proteins. Through the results of PPI network, we screened out differentially expressed target butyrate metabolism-related genes from ten hub genes. Finally, we performed clinical correlation analysis, immune cell infiltration analysis, and mutation analysis for these target genes. One hundred and seventy three differentially expressed butyrate metabolism-related genes were screened out in all the CRC samples. The prognostic model was established with univariate Cox regression and LASSO regression analysis. CRC patients' overall survival was significantly lower in the high-risk group than in the low-risk group for both training and validation set. Among the ten hub genes identified from the PPI network, four target butyrate metabolism-related genes were identified containing FN1, SERPINE1, THBS2, and COMP, which might provide novel markers or targets for treating CRC patients. Eighteen butyrate metabolism-related genes were used to develop a risk prognostic model that could be helpful for doctors to predict CRC patients' survival rate. Using this model, it is beneficial to forecast the response of CRC patients to immunotherapy and chemotherapy, thus making it easier to custom tailor cancer chemotherapy and immunotherapy to the individual patient. [ABSTRACT FROM AUTHOR]

The poor prognosis of gliomas necessitates the search for biomarkers for predicting clinical outcomes. Recent studies have shown that PANoptosis play an important role in tumor progression. However, the role of PANoptosis in in gliomas has not been fully clarified.Low-grade gliomas (LGGs) from TCGA and CGGA database were classified into two PANoptosis patterns based on the expression of PANoptosis related genes (PRGs) using consensus clustering method, followed which the differentially expressed genes (DEGs) between two PANoptosis patterns were defined as PANoptosis related gene signature. Subsequently, LGGs were separated into two PANoptosis related gene clusters with distinct prognosis based on PANoptosis related gene signature. Univariate and multivariate cox regression analysis confirmed the prognostic values of PANoptosis related gene cluster, based on which a nomogram model was constructed to predict the prognosis in LGGs. ESTIMATE algorithm, MCP counter and CIBERSORT algorithm were utilized to explore the distinct characteristics of tumor microenvironment (TME) between two PANoptosis related gene clusters. Furthermore, an artificial neural network (ANN) model based on machine learning methods was developed to discriminate distinct PANoptosis related gene clusters. Two external datasets were used to verify the performance of the ANN model. The Human Protein Atlas website and western blotting were utilized to confirm the expression of the featured genes involved the ANN model. We developed a machine learning based ANN model for discriminating PANoptosis related subgroups with drawing implications in predicting prognosis in gliomas. [ABSTRACT FROM AUTHOR]

Previous literatures have suggested the importance of inflammatory response during lung adenocarcinoma (LUAD) development. This study aimed at exploring the inflammation-related genes and developing a prognostic signature for predicting the prognosis of LUAD. Survival‑associated inflammation-related genes were identified by univariate Cox regression analysis in the dataset of The Cancer Genome Atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) penalized Cox regression model was used to derive a risk signature which is significantly negatively correlated with OS and divide samples into high-, medium- and low-risk group. Univariate and multivariate Cox analyses suggested that the level of risk group was an independent prognostic factor of the overall survival (OS). Time-dependent receiver operating characteristic (ROC) curve indicated the AUC of 1-, 3- and 5-years of the risk signature was 0.715, 0.719, 0.699 respectively. A prognostic nomogram was constructed by integrating risk group and clinical features. The independent dataset GSE30219 of Gene Expression Omnibus (GEO) was used for verification. We further explored the differences among risk groups in Gene set enrichment analysis (GSEA), tumor mutation and tumor microenvironment. Furthermore, Single Sample Gene Set Enrichment Analysis (ssGSEA) and the results of Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) suggested the status of immune cell infiltration was highly associated with risk groups. We demonstrated the prediction effect of CTLA-4 and PD-1/PD-L1 inhibitors in the low-risk group was better than that in the high-risk group using two methods of immune score include immunophenoscore from The Cancer Immunome Atlas (TCIA) and TIDE score from Tumor Immune Dysfunction and Exclusion (TIDE). In addition, partial targeted drugs and chemotherapy drugs for lung cancer had higher drug sensitivity in the high-risk group. Our findings provide a foundation for future research targeting inflammation-related genes to predictive prognosis and some reference significance for the selection of immunotherapy and drug regimen for lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Fish culture in paddy fields is a traditional aquaculture mode, which has a long history in East Asia. Large-scale loach (Paramisgurnus dabryanus) fast growth is suitable for paddy fields aquaculture in China. The objective of this study was to identify differential expression genes (DEGs) in the brain, liver and muscle tissues between large (LG, top 5% of maximum total length) and small (SG, top 5% of minimum total length) groups using RNA-seq. In total, 150 fish were collected each week and 450 fish were collected at twelfth week from three paddy fields for all the experimental. Histological observation found that the muscle fibre diameter of LG loaches was greater than that of SG loaches. Transcriptome results revealed that the high expression genes (HEGs) in LG loaches (fold change ≥ 2, p < 0.05) were mainly concentrated in metabolic pathways, such as "Thyroid hormone signalling pathway", "Citrate cycle (TCA cycle)", "Carbon metabolism", "Fatty acid metabolism", and "Cholesterol metabolism", and the HEGs in SG loaches were enriched in the pathways related to environmental information processing such as "Cell adhesion molecules (CAMs)", "ECM− receptor interaction" and "Rap1 signalling pathway"; cellular processes such as "Tight junction", "Focal adhesion", "Phagosome" and "Adherens junction". Furthermore, IGFs gene family may play an important role in loach growth for their different expression pattern between the two groups. These findings can enhance our understanding about the molecular mechanism of different growth and development levels of loaches in paddy fields. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is the malignant tumor arising from the nasopharynx epithelium with ethnic and geographical distribution preference. Y-box binding protein-1 (YB1) is the highly expressed DNA/RNA-binding protein with cold shock domain, and enhanced YB1 expression was proved to be associated with many kinds of malignant tumors. There is no systematic study about the regulation of YB1 and cell proliferation, migration, invasion and stress granules (SGs) in NPC, and the relationship between YB1 expression and clinical characteristics and prognosis of NPC patients. We analyzed the mRNA expression of YBX1 in head and neck squamous carcinoma (HNSC) and NPC in databases, investigated the functions of YB1 in cell proliferation, migration and invasion and SGs formation of NPC cells, and detected expression of YB1 protein in a large scale of NPC samples and analyzed their association with clinicopathological features and prognostic significance of NPC patients. YBX1 mRNA was significantly high expression in HNSC and NPC by bioinformatic analysis, and higher expression of YBX1 mRNA indicated poorer prognosis of HNSC patients. Clinically, the expression of YB1 in NPC tissues was significantly higher than these in the control nasopharyngeal epithelial tissues. We further found that the expression of YB1 had an evidently positive relation with advanced clinical stages of patients with NPC. The overall survival rates (OS) were significantly lower for NPC patients with positive expression of YB1. Multivariate analysis confirmed that positive expression of YB1 was the independent poorer prognostic factor for patients with NPC. Moreover, compared with the immortalized nasopharyngeal epithelial cell line (NP69), the basal level of YB1 in NPC cell lines was significantly higher. Knocking down YB1 may inhibit Akt/mTOR pathway in NPC cells. Knocking down YB1 by small interfering RNAs can reduce the ability of proliferation, migration, invasion and SGs formation of NPC cells. The expression of YB1 in NPC cell lines or patients with NPC was significantly higher. The high expression of YB1 protein may act as one valuable independent biomarker to predict poor prognosis for patients with NPC. Knocking down YB1 may release the malignant phenotype of NPC cells. [ABSTRACT FROM AUTHOR]

Graph: Figure 4 IGF-1R is experimentally validated as a co-target of miR-99b-5p and miR-203a-3p in GC cells. (A) Putative miR-99b-5p/203a-3p-binding sites in the IGR-1R 3'UTRs, mutations were generated in the IGF-1R 3'UTR sequences by mutating 4 nt for the seed region of miR-99b-5p/203a-3p, as indicated. [Extracted from the article]

Osteosarcoma (OS) is the most common type of primary malignant bone tumor. The high-throughput sequencing technology has shown potential abilities to illuminate the pathogenic genes in OS. This study was designed to find a powerful gene signature that can predict clinical outcomes. We selected OS cases with gene expression and survival data in the TARGET-OS dataset and GSE21257 datasets as training cohort and validation cohort, respectively. The univariate Cox regression and Kaplan–Meier analysis were conducted to determine potential prognostic genes from the training cohort. These potential prognostic genes underwent a LASSO regression, which then generated a gene signature. The harvested signature's predictive ability was further examined by the Kaplan–Meier analysis, Cox analysis, and receiver operating characteristic (ROC curve). More importantly, we listed similar studies in the most recent year and compared theirs with ours. Finally, we performed functional annotation, immune relevant signature correlation identification, and immune infiltrating analysis to better study he functional mechanism of the signature and the immune cells' roles in the gene signature's prognosis ability. A seventeen-gene signature (UBE2L3, PLD3, SLC45A4, CLTC, CTNNBIP1, FBXL5, MKL2, SELPLG, C3orf14, WDR53, ZFP90, UHRF2, ARX, CORT, DDX26B, MYC, and SLC16A3) was generated from the LASSO regression. The signature was then confirmed having strong and stable prognostic capacity in all studied cohorts by several statistical methods. We revealed the superiority of our signature after comparing it to our predecessors, and the GO and KEGG annotations uncovered the specifically mechanism of action related to the gene signature. Six immune signatures, including PRF1, CD8A, HAVCR2, LAG3, CD274, and GZMA were identified associating with our signature. The immune-infiltrating analysis recognized the vital roles of T cells CD8 and Mast cells activated, which potentially support the seventeen-gene signature's prognosis ability. We identified a robust seventeen-gene signature that can accurately predict OS prognosis. We identified potential immunotherapy targets to the gene signature. The T cells CD8 and Mast cells activated were identified linked with the seventeen-gene signature predictive power. [ABSTRACT FROM AUTHOR]

Heart failure with reduced ejection fraction (HFrEF) constitutes 50% of HF hospitalizations and is characterized by high rates of mortality. To explore the underlying mechanisms of HFrEF etiology and progression, we studied the molecular and cellular differences in four chambers of non-failing (NF, n = 10) and HFrEF (n = 12) human hearts. We identified 333 genes enriched within NF heart subregions and often associated with cardiovascular disease GWAS variants. Expression analysis of HFrEF tissues revealed extensive disease-associated transcriptional and signaling alterations in left atrium (LA) and left ventricle (LV). Common left heart HFrEF pathologies included mitochondrial dysfunction, cardiac hypertrophy and fibrosis. Oxidative stress and cardiac necrosis pathways were prominent within LV, whereas TGF-beta signaling was evident within LA. Cell type composition was estimated by deconvolution and revealed that HFrEF samples had smaller percentage of cardiomyocytes within the left heart, higher representation of fibroblasts within LA and perivascular cells within the left heart relative to NF samples. We identified essential modules associated with HFrEF pathology and linked transcriptome discoveries with human genetics findings. This study contributes to a growing body of knowledge describing chamber-specific transcriptomics and revealed genes and pathways that are associated with heart failure pathophysiology, which may aid in therapeutic target discovery. [ABSTRACT FROM AUTHOR]