Enrichment Of Genes Research Articles

Establishment of potential lncRNA-related hub genes involved competitive endogenous RNA in lung adenocarcinoma

Long non-coding RNAs (lncRNAs) have a notable role in the diagnosis and prognosis of cancer. However, the associations between lncRNA-related hub genes (LRHGs) expression and the corresponding outcomes have not been fully understood in lung adenocarcinoma (LUAD). Here, a total of 71 patients diagnosed with LUAD and 60 healthy volunteers at The First Affiliated Hospital of Huzhou University from April, 2023 to December, 2023 were enrolled in the present study. A LRHGs model was established using least absolute shrinkage and selection operator analyses of The Cancer Genome Atlas-LUAD datasets. The underlying mechanisms of the LRHGs were investigated via Gene Set Enrichment Analysis and Gene Set Variation Analysis. Additionally, the diagnostic role of serum HOXD cluster antisense RNA 2 (HOXD-AS2) was assessed by receiver operating characteristic (ROC) curve analysis. Lastly, TCGA-LUAD samples were divided into high- and low-HOXD-AS2 expression groups based on the median expression. The associations between HOXD-AS2 expression and miR-4538 as well as Calmodulin-Dependent Protein Kinase Type II subunit Beta (CAMK2B) levels were conducted through Pearson correlation analysis. A comprehensive analysis identified 141 differentially expressed lncRNAs between 539 LUAD tissues and 59 normal samples. A prognostic marker for overall survival was established by constructing a predictive signature consisting of 9 LRHGs. Subsequently, 474 LUAD samples were categorized into a high or low-risk group based on the median of the risk score. An independent prognostic model was constructed to confirm the validity of this categorization. Further comparisons of the clinicopathological features and LRHG-related pathways were performed between the two groups. Examinations of LRHG expression in two LUAD clusters and of the association between LRHG expression and immune infiltration were also conducted. HOXD-AS2 expression was shown to be elevated in LUAD tissues compared with matched normal tissues, and the serum HOXD-AS2 level was also notably increased in LUAD samples compared with healthy controls. The results of the ROC analysis indicated that the sensitivity and specificity of HOXD-AS2 were higher than that of cytokeratin-19 fragment (CYFRA21-1), which is a serum marker for LUAD. Pearson analyses indicated that miR-4538 level was negatively associated with HOXD-AS2 expression, but CAMK2B level showed positive correlation in LUAD. The results of the present study therefore indicated that the constructed LRHG model, particularly HOXD-AS2, could independently diagnose and predict the prognosis of LUAD, which suggested the underlying mechanism of the HOXD-AS2/miR-4538/CAMK2B, and might offer efficient strategies for LUAD treatment.

Genome-wide local ancestry and the functional consequences of admixture in African and European cattle populations.

Bos taurus (taurine) and Bos indicus (indicine) cattle diverged at least 150,000 years ago and, since that time, substantial genomic differences have evolved between the two lineages. During the last two millennia, genetic exchange in Africa has resulted in a complex tapestry of taurine-indicine ancestry, with most cattle populations exhibiting varying levels of admixture. Similarly, there are several Southern European cattle populations that also show evidence for historical gene flow from indicine cattle, the highest levels of which are found in the Central Italian White breeds. Here we use two different software tools (MOSAIC and ELAI) for local ancestry inference (LAI) with genome-wide high- and low-density SNP array data sets in hybrid African and residually admixed Southern European cattle populations and obtained broadly similar results despite critical differences in the two LAI methodologies used. Our analyses identified genomic regions with elevated levels of retained or introgressed ancestry from the African taurine, European taurine, and Asian indicine lineages. Functional enrichment of genes underlying these ancestry peaks highlighted biological processes relating to immunobiology and olfaction, some of which may relate to differing susceptibilities to infectious diseases, including bovine tuberculosis, East Coast fever, and tropical theileriosis. Notably, for retained African taurine ancestry in admixed trypanotolerant cattle we observed enrichment of genes associated with haemoglobin and oxygen transport. This may reflect positive selection of genomic variants that enhance control of severe anaemia, a debilitating feature of trypanosomiasis disease, which severely constrains cattle agriculture across much of sub-Saharan Africa.

Overexpression of CDCA8 predicts poor prognosis and drug insensitivity in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) accounts for the highest proportion of lung cancers; however, specific biomarkers are lacking for diagnosis, treatment, and prognostic assessment. Cell division cycle-associated 8 (CDCA8) is a cell cycle regulator with elevated expression in various cancers. However, the association between CDCA8 expression and LUAD prognosis remains unclear.MethodsThe association between CDCA8 and LUAD prognosis was evaluated based on the The Cancer Genome Atlas (TCGA) dataset, and CDCA8 related functions were determined using gene enrichment and gene ontology analyses. We also analyzed the association between CDCA8 expression and immune cell infiltration. Immunohistochemistry was used to determine the differential expression of CDCA8 in tumors and controls. Finally, we evaluated the differences in the sensitivity of different levels of CDCA8 to different anticancer drugs in LUAD.ResultsCDCA8 expression was significantly higher in primary LUAD tumors than in normal tissues (P < 0.001). Moreover, Kaplan–Meier survival analysis demonstrated that high CDCA8 expression predicted poor survival in patients with LUAD (P = 0.006). The receiver operating characteristic (ROC) curves indicated that CDCA8 was an effective guide for the diagnosis of LUAD. Functional annotation indicated that CDCA8 might be involved in functions such as p53 stabilization, nucleotide metabolism, RNA-mediated gene silencing, and the G2/M phase checkpoint. Immune infiltration results suggested that CDCA8 was positively correlated with Th2 cells and Tgd and negatively correlated with Eosinophils and Mast cells (P < 0.01). In addition, elevated expression of CDCA8 may increase the sensitivity of patients to certain anticancer drugs.ConclusionsCDCA8 upregulation is significantly associated with poor survival and immune infiltration in patients with LUAD. Our study suggests that CDCA8 can be used as a biomarker for LUAD prognosis and a reference for personalized medication.Graphical

Ischemia/Reperfusion Upregulates Genes Related to PANoptosis in Human Lung Transplants.

Activation of multiple programmed cell death (PCD) pathways has been reported in cellular and animal studies of ischemia/reperfusion injury in lung transplantation. However, the status of these pathways in human lung transplants remains unknown. This study investigates the involvement of PCD pathways and their relationship with inflammation and signaling pathways in human lung transplants. Transcriptomic analysis was conducted on 54 paired human lung tissue samples at the end of cold preservation time and 2 h after reperfusion, collected between 2008 and 2011. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA were used to examine the activation of genes in 6 PCD pathways. The relationships between PCD pathways and inflammation, as well as signaling pathways, were assessed via single-gene GSEA. GSEA results indicated that apoptosis and necroptosis were significantly upregulated after reperfusion in human lung transplants, whereas the gene sets related to pyroptosis, ferroptosis, autophagy, and cuproptosis were not significantly upregulated. Notably, single-sample GSEA demonstrated an intricate interplay among pyroptosis, apoptosis, and necroptosis, collectively referred to as PANoptosis, which is further supported by enrichment of genes related to PANoptosome, inflammatory response, and nuclear factor-κB and interferon signaling pathways, via single-gene GSEA assays. This study demonstrated the genes of PANoptosis are upregulated in human lung grafts during reperfusion. The discovery of PANoptosis as an underlying mechanism of cell death in human lung grafts implies that effective therapeutics to prevent or reduce PANoptosis may alleviate ischemia/reperfusion injury and improve clinical lung transplant outcomes.

Ocular adverse events associated with GLP-1 receptor agonists: a real-world study based on the FAERS database and network pharmacology

ABSTRACT Objective This study evaluates the risk of ocular adverse events (AEs) associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) using data from the FDA Adverse Event Reporting System (FAERS) and network pharmacology methods. Methods FAERS data from 2004 to 2024 were analyzed for ocular AEs linked to GLP-1 RA treatments. Disproportionality analysis (Reporting Odds Ratio, ROR) was used to identify signals, and a drug-gene interaction network explored potential mechanisms. Results Among 17,785,793 FAERS reports, semaglutide and lixisenatide were significantly associated with ocular AEs, with RORs of 1.25 (95% CI, 1.20-1.31) and 1.96 (95% CI, 1.70-2.27), respectively. Commonly reported AEs included blurred vision, visual impairment, and diabetic retinopathy, with some AEs occurring as early as 10 days after treatment initiation. Gene enrichment analysis highlighted potential links between GLP-1-related genes and ocular AEs. Conclusion The widespread use of GLP-1 RAs has raised concerns regarding their ophthalmic safety. This study contributes new evidence from real-world data, suggesting that semaglutide and lixisenatide are associated with significant risks of ocular AEs. Further experimental studies are warranted to elucidate the underlying mechanisms and confirm these associations.

Identification of Key Candidate Genes Involved in Aluminum Accumulation in the Sepals of Hydrangea macrophylla

Hydrangea macrophylla (H. macrophylla), a species in the genus Hydrangea in the family Hydrangeaceae, is widely valued for its ornamental qualities in both domestic and international markets. Notably, H. macrophylla is known for its ability to accumulate aluminum (Al). Moreover, aluminum ions (Al3+) participate in sepal bluing. However, the underlying mechanisms of Al accumulation in the sepals remain unclear. In this study, we utilized transcriptome data from two cultivars to identify genes associated with Al accumulation. In total, 154 differentially expressed isoforms between the CK and Tr groups in the sepals of both cultivars were screened. Through gene enrichment analysis and similarity identification in the CDS (coding sequence) region, 43 differentially expressed genes were identified, including 30 upregulated and 13 downregulated genes, in the sepals of the Al treatment group. Further analysis revealed that seven of these upregulated genes are related to Al accumulation in sepals. Among the seven, the gene HmALS3.1 was identified as a potential key player in Al transport within the sepals of H. macrophylla. This study lays the groundwork for further exploration into the mechanisms by which HmALS3.1 regulates Al accumulation in H. macrophylla.

Yigu decoction regulates plasma miRNA in postmenopausal osteoporosis patients: a randomized controlled trial

BackgroundPostmenopausal osteoporosis (PMOP) is a serious condition that affects elderly individuals. Our previous study revealed that Yigu decoction (YGD) effectively improved bone mineral density (BMD) in elderly individuals, but the mechanism underlying this effect remains unclear. In this study, we investigated the relationships among YGD, microRNAs (miRNAs), and bone metabolism by assessing the effects of YGD on the miRNA levels in patient plasma to provide a scientific basis for treating PMOP with YGD.MethodsIn this clinical trial, 60 patients were randomly assigned to the YGD group or the control group (ratio of 1:1) and treated for 3 months. The primary outcome measure was BMD, and the secondary outcome measures included plasma miRNA levels, visual analogue scale (VAS) scores, alkaline phosphatase (ALP) levels, anti-tartrate acid phosphatase (TRACP-5b) levels and traditional Chinese medicine (TCM) syndrome scores. We assessed the regulatory roles of miRNAs in PMOP patients by analysing publicly available data from the Gene Expression Omnibus (GEO) database. Bioinformatics methods were also used to explore the mechanism by which YGD regulates miRNAs that are involved in bone metabolism.ResultsCompared with those before treatment, the BMD, ALP levels, TRACP-5b levels, TCM syndrome scores and VAS scores improved in both groups after 3 months of treatment (P &amp;lt; 0.05). A total of 82 miRNAs differed between the groups. After analysing data from the GEO database, we confirmed that miR-133a-3p is the key molecule that mediates the effects of YGD intervention on PMOP. GO analysis of key genes suggested that gene enrichment was more pronounced in response to hormones, cellular response to growth factor stimulation, and positive regulation of physiological and metabolic processes. KEGG analysis revealed that these genes were enriched mainly in the PI3K-Akt, FOXO, and JAK-STAT pathways and other pathways. The results of the protein‒protein interaction (PPI) network analysis revealed that epidermal growth factor receptor (EGFR), Insulin-like growth factor 1 (IGF-1), Caveolin-1 (Cav-1) and others were core proteins.ConclusionThis study demonstrated that YGD is beneficial in the treatment of PMOP, ameliorating clinical symptoms and bone turnover indices. Moreover, the inhibition of miR-133a-3p expression may be the key mechanisms by which YGD regulates bone metabolism in the treatment of PMOP, although YGD regulates bone metabolism in a multitarget and multipathway manner.

Genomic signal selection analysis reveals genes related to the lambing trait of Hotan sheep.

Lambing in ewes is a complex and crucial aspect of sheep production that directly influences economic viability and production efficiency. In the present study, we analyzed the genomes of single lamb (SLE) and twin lamb (TLE) Hotan sheep to elucidate the genetic mechanisms underlying lamb production in Hotan sheep. In this study, we used genome-wide resequencing to analyze the genomes of Hotan sheep exhibiting SLE and TLE traits. To identify the population genetic structure and linkage disequilibrium associated with SLE and TLE traits, we employed two complementary genome selection signals: the interpopulation genetic differentiation index (FST) and nucleotide diversity (Pi). Subsequently, we performed gene annotation and enrichment analyses of the selected regions of the obtained genome. Our analysis generated 801 Gb of sequence data, from which 31,864,651 high-quality single nucleotide polymorphic loci were identified. We identified 290 selected regions and 332 genes across the Hotan sheep genome by using two widely adopted selective scanning detection methods (FST statistics and Piratio). Functional annotation and enrichment analysis of these genes identified 13 genes associated with the lambing rate, which were enriched in pathways such as the transforming growth factor-β (TGF-β) signaling pathway (BMPR2, ID2, SMAD7, THBS1, and RBX1), renal cell carcinoma (PAK1, ELOC), inositol phosphate metabolism (PLCZ), non-homologous terminal junction (RAD50), ABC transporters (ABCC4), and the NET pathway (H2B, H4, and H2A). This study employed selective elimination analysis to identify candidate genes involved in the regulation of lambing trait in Hotan sheep. By investigating the molecular mechanisms underlying lambing rate in Hotan sheep, we developed molecular markers for twin lambing to enhance reproductive performance and promote the conservation and development of outstanding genetic resources in local Xinjiang sheep.

In silico exploration of phytochemicals as inhibitors for acute myeloid leukemia by targeting LIN28A gene: A cheminformatics study

BackgroundRecent discoveries have illustrated that Lin28A is an oncogene in various cancers, particularly acute myeloid leukemia (AML). The upregulation of Lin28A can actively contribute to tumorigenesis and migration processes in multiple organs. Hence, the inhibition of Lin28A can be achieved by applying phytochemical herbals and targeting Lin28A protein using a computer-aided drug design (CAAD) approach. MethodsIn this study, we comprehensively applied several bioinformatics tools, including gene ontologies, gene enrichment analysis, and protein-protein interactions (PPI), to determine the biological pathways, functional gene ontology, and biological pathway. Furthermore, we investigated a list of phytochemical herbs as a candidate drug by applying a computation technique involving molecular docking, density functional theory (DFT), molecular dynamics simulation (MDs), and pharmacokinetic and physiochemical properties by applying the SwissADME, pkCSM, and Molsoft LLC web-servers. ResultsThe Lin28A gene is related to two significant enrichment pathways, including proteoglycans in cancer and the pluripotency of stem cells through interactions with different genes such as MAPK12, MYC, MTOR, and PIK3CA. Interestingly, limonin, 18β Glycyrrhetic Acid, and baicalein have the highest binding energy scores of −8.4, −8.2, and −7.3 kcal/mol, respectively. The DFT study revealed that baicalein has a higher reactivity than limonin and 18β-Glycyrrhetic due to a small energy gap between LUMO and HUMO. Molecular dynamics simulation exhibited that baicalein complex with Lin28A protein is more stable than other complexes during simulation time due to low fluctuation with simulation periods as compared with other complexes, which indicated that baicalein was more fitting to docking and combining in the protein cave because of the largest number of H-bonds available for the docking simulation process. Furthermore, the drug-likeness and ADMET profiles revealed the activity of limonin, baicalein, and 18β-glycyrrhizic Acid, which possess significant inhibiting Lin28A proteins. ConclusionThis study elucidated that baicalein, 18β-glycyrrhizic, and limonin may be applied as potential candidates for targeting Lin28A as an active oncogene for acute myeloid leukemia.

Evaluation of Bayesian Linear Regression models for gene set prioritization in complex diseases.

Genome-wide association studies (GWAS) provide valuable insights into the genetic architecture of complex traits, yet interpreting their results remains challenging due to the polygenic nature of most traits. Gene set analysis offers a solution by aggregating genetic variants into biologically relevant pathways, enhancing the detection of coordinated effects across multiple genes. In this study, we present and evaluate a gene set prioritization approach utilizing Bayesian Linear Regression (BLR) models to uncover shared genetic components among different phenotypes and facilitate biological interpretation. Through extensive simulations and analyses of real traits, we demonstrate the efficacy of the BLR model in prioritizing pathways for complex traits. Simulation studies reveal insights into the model's performance under various scenarios, highlighting the impact of factors such as the number of causal genes, proportions of causal variants, heritability, and disease prevalence. Comparative analyses with MAGMA (Multi-marker Analysis of GenoMic Annotation) demonstrate BLR's superior performance, especially in highly overlapped gene sets. Application of both single-trait and multi-trait BLR models to real data, specifically GWAS summary data for type 2 diabetes (T2D) and related phenotypes, identifies significant associations with T2D-related pathways. Furthermore, comparison between single- and multi-trait BLR analyses highlights the superior performance of the multi-trait approach in identifying associated pathways, showcasing increased statistical power when analyzing multiple traits jointly. Additionally, enrichment analysis with integrated data from various public resources supports our results, confirming significant enrichment of diabetes-related genes within the top T2D pathways resulting from the multi-trait analysis. The BLR model's ability to handle diverse genomic features, perform regularization, conduct variable selection, and integrate information from multiple traits, genders, and ancestries demonstrates its utility in understanding the genetic architecture of complex traits. Our study provides insights into the potential of the BLR model to prioritize gene sets, offering a flexible framework applicable to various datasets. This model presents opportunities for advancing personalized medicine by exploring the genetic underpinnings of multifactorial traits.

Germline copy number variants and endometrial cancer risk.

Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10-63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.

MiR-107 and Its Association With House Dust Mite Sensitisation: Implications for Asthma.

MicroRNAs (miRNAs) have been linked to allergic diseases but their effects on sensitisation to allergens in individuals with asthma are unknown. We aimed to identify miRNAs associated with house dust mite (HDM) sensitisation in childhood asthma. Serum samples from 1126 children with asthma who participated in the Genetics of Asthma in Costa Rica Study (GACRS) were profiled for 304 miRNAs. We first divided according to HDM sensitisation and then tested whether miRNAs were differentially expressed (DE) between the two groups. Gene enrichment analysis for target genes of the DE miRNAs was then performed to identify potential causal pathways. Replication analysis was performed in the Childhood Asthma Management Program (CAMP), in which expression data of 258 miRNAs in 491 children were available. A mediation analysis was conducted to discern relationships between miRNA and phenotype differences according to HDM sensitisation in GACRS cohort. There were 906 (80.5%) and 220 (19.5%) subjects in the GACRS HDM+ and HDM- groups. Compared with HDM- participants, those in the HDM+ group were more likely to be severe in variables including pulmonary function, oral corticosteroid use and blood tests. A total of 17 miRNAs were DE (p < 0.05) between the two groups, with miR-642a-3p, let-7c-5p and miR-107 most significantly associated with HDM sensitisation. In CAMP, there were 39 DE miRNAs, and increased expression of miR-107 in HDM+ children was replicated in this cohort. In both GACRS and CAMP, the cadherin-binding pathway was enriched in an analysis of target genes for DE miRNA. In a mediation analysis, miR-107 showed significant indirect effects on eosinophil count and total IgE that were mediated by HDM sensitisation. In children with asthma, miR-107 is associated with HDM sensitisation. Furthermore, miR-107 was indirectly associated with total IgE and eosinophil count through HDM sensitisation.

Tracing ALS Degeneration: Insights from Spinal Cord and Cortex Transcriptomes

Background/Objectives: Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Key factors contributing to neuronal death include mitochondrial energy damage, oxidative stress, and excitotoxicity. The frontal cortex is crucial for action initiation, planning, and voluntary movements whereas the spinal cord facilitates communication with the brain, walking, and reflexes. By investigating transcriptome data from the frontal cortex and spinal cord, we aim to elucidate common pathological mechanisms and pathways involved in ALS for understanding the disease progression and identifying potential therapeutic targets. Methods: In this study, we quantified gene and transcript expression patterns, predicted variants, and assessed their functional effects using computational tools. It also includes predicting variant-associated regulatory effects, constructing functional interaction networks, and performing a gene enrichment analysis. Results: We found novel genes for the upregulation of immune response, and the downregulation of metabolic-related and defective degradation processes in both the spinal cord and frontal cortex. Additionally, we observed the dysregulation of histone regulation and blood pressure-related genes specifically in the frontal cortex. Conclusions: These results highlight the distinct and shared molecular disruptions in ALS, emphasizing the critical roles of immune response and metabolic dysfunction in neuronal degeneration. Targeting these pathways may provide new therapeutic avenues to combat neurodegeneration and preserve neuronal health.

Brain single-cell transcriptomics highlights comorbidity-related cell type-specific changes of Parkinson’s disease with major depressive disorder after paraquat exposure

Paraquat (PQ), a commonly used herbicide, is a potent environmental neurotoxin associated with Parkinson’s disease (PD) and major depressive disorder (MDD). While the involvement of various brain cell types in the etiology of each disorder is well recognized, the specific cell subtypes implicated in the comorbidity of PD and MDD, especially under PQ neurotoxicity, remain poorly understood. In this study, we used single-cell RNA sequencing (scRNA-seq) to analyze brain tissues from mice with PQ-induced PD with MDD. By integrating genomic data with scRNA-seq profiles, we identified differences in cellular heterogeneity related to the pathogenesis of PD and MDD under PQ exposure. Our analysis of risk enrichment in genes with cell type-specific expression patterns revealed that astrocytes are predominantly linked to the comorbidity of PQ-induced PD and MDD. Furthermore, we identified a specific astrocyte subtype that plays a major role in the comorbidity-related changes observed in PQ-induced PD and MDD. This subtype appears to interact with and potentially transform into MDD-specific and PD-specific subtypes. Additionally, pathways related to chemical synaptic function and neuro-projection development were involved in all key stages of PD and MDD co-occurrence. We also identified RNF7 and MTCH2 as shared diagnostic hub genes for PD and MDD, which changed significantly in astrocytes following PQ exposure. These genes may serve as potential markers for astrocyte-specific prognostic diagnosis of PQ-induced PD with MDD. In summary, this study provides the first scRNA-seq profile of comorbidity in a PQ-exposed model. It highlights the heterogeneity of astrocytes in comorbidity and elucidates potential mechanisms underlying the co-occurrence of PD and MDD. These findings emphasize the need for further research into the pathogenesis of PD comorbid with MDD and offer novel insights into PQ neurotoxicity.

RUNX2 is stabilised by TAZ and drives pulmonary artery calcification and lung vascular remodelling in pulmonary hypertension due to left heart disease.

Calcification is common in chronic vascular disease, yet its role in pulmonary hypertension due to left heart disease is unknown. Here, we probed for the role of runt-related transcription factor-2 (RUNX2), a master transcription factor in osteogenesis, and its regulation by the HIPPO pathway transcriptional coactivator with PDZ-binding motif (TAZ) in the osteogenic reprogramming of pulmonary artery smooth muscle cells and vascular calcification in patients with pulmonary hypertension due to left heart disease. We similarly examined its role using an established rat model of pulmonary hypertension due to left heart disease induced by supracoronary aortic banding. Pulmonary artery samples were collected from patients and rats with pulmonary hypertension due to left heart disease. Genome-wide RNA sequencing was performed, and pulmonary artery calcification assessed. Osteogenic signalling via TAZ and RUNX2 was delineated by protein biochemistry. In vivo, the therapeutic potential of RUNX2 or TAZ inhibition by CADD522 or verteporfin was tested in the rat model. Gene ontology term analysis identified significant enrichment in ossification and osteoblast differentiation genes, including RUNX2, in pulmonary arteries of patients and lungs of rats with pulmonary hypertension due to left heart disease. Pulmonary artery calcification was evident in both patients and rats. Both TAZ and RUNX2 were upregulated and activated in pulmonary artery smooth muscle cells of patients and rats. Co-immunoprecipitation revealed a direct interaction of RUNX2 with TAZ in pulmonary artery smooth muscle cells. TAZ inhibition or knockdown decreased RUNX2 abundance due to accelerated RUNX2 protein degradation rather than reduced de novo synthesis. Inhibition of either TAZ or RUNX2 attenuated pulmonary artery calcification, distal lung vascular remodelling and pulmonary hypertension development in the rat model. Pulmonary hypertension due to left heart disease is associated with pulmonary artery calcification that is driven by TAZ-dependent stabilisation of RUNX2, causing osteogenic reprogramming of pulmonary artery smooth muscle cells. The TAZ-RUNX2 axis may present a therapeutic target in pulmonary hypertension due to left heart disease.

Comparison of the Distribution Patterns of Microsatellites Across the Genomes of Reptiles

ABSTRACTMicrosatellites or simple sequence repeats (SSRs) are prevalent across various organisms' genomes. However, their distribution patterns and evolutionary dynamics in reptile genomes are rarely studied systematically. We herein conducted a comprehensive analysis of SSRs in the genomes of 36 reptile species. Our findings revealed that the total number of SSRs ranged from 1,840,965 to 7,664,452, accounting for 2.16%–8.19% of the genomes analyzed. The relative density ranged from 21,567.82 to 81,889.41 bp per megabase (Mbp). The abundance of different SSR categories followed the pattern of imperfect SSR (I‐SSR) &gt; perfect SSR (P‐SSR) &gt; compound SSR (C‐SSR). A significant positive correlation was observed between the number of SSRs and genome size (p = 0.0034), whereas SSR frequency (p = 0.013) or density (p = 0.0099) showed a negative correlation with genome size. Furthermore, no correlation was found between SSR length and genome size. Mononucleotide repeats were the most common P‐SSRs in crocodilians and turtles, whereas mononucleotides, trinucleotides, or tetranucleotides were the most common P‐SSRs in snakes, lizards, and tuatara. P‐SSRs of varying motif sizes showed nonrandom distribution across different genic regions, with AT‐rich repeats being predominant. The genomic SSR content of the squamate lineage ranked the highest in abundance and variability, whereas crocodilians and turtles showed a slowly evolving and reduced microsatellite landscape. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that genes harboring P‐SSRs in the coding DNA sequence regions were primarily involved in the regulation of transcription and translation processes. The SSR dataset generated in this study provides potential candidates for functional analysis and calls for broader‐scale analyses across the evolutionary spectrum.

A novel chitosan/biochar-modified eco-concrete with balanced mechanical, planting, and water purification performance for riparian restoration

The blocking between terrestrial and riverine ecosystems by impermeable concrete can cause negative impacts on plant growth, water quality, and biodiversity in riparian zones. Herein, pursuing a balance among mechanical, planting, and water purification property, chitosan/biochar-modified eco-concrete (CBEC) was prepared as a new sustainable alternative for riparian protection, ecological restoration and water quality improvement. Compressive strength of CBEC with an optimized chitosan/biochar content of 6% could reach up to 14.05 MPa, meeting the requirements for stabilizing riparian slopes. Micromorphology characterization and porosity measurement (29.63%) confirmed the abundantly porous structure of CBEC, facilitating the soil-water nutrient exchange, plant growth and microbial attachment. The 30-d water tank cultivation observed that the physiological parameters of T. orientalis planted in CBEC, including biomass, chlorophyll, protein and starch, were greatly improved compared to unmodified eco-concrete (EC). Moreover, compared to EC, biochar-modified EC and chitosan-modified EC, the planting CBEC could most effectively decrease the levels of TN, NH4+-N, TP, and COD by 53.82%, 62.50%, 88.31%, and 57.95%, respectively. Specially, the planting CBEC could degrade a common but recalcitrant pesticide nitenpyram (NTP) by 32.83% into low-toxic substances, recognized by LC-MS analysis. Microbiological analysis revealed that CBEC greatly promoted the proliferation of both nutrient-transforming bacteria (e.g., Nitrospira and Pseudomonas) and some specific species dominating NTP degradation (e.g., Rhodococcus and Bacillus). Also, PICRUSt2 prediction results identified the enrichment of functional genes related to nitrogen and phosphorus transformation. Our findings can not only develop a superior multi-performance eco-concrete material but also provide a promising strategy for sustainable riparian restoration.

Comprehensive gene set enrichment and variation analyses identify SUV39H1 as a potential prognostic biomarker for glioblastoma immunorelevance

Glioblastoma (GBM) is the most common intracranial malignancy. SUV39H1 encodes a histone H3 lysine 9 methyltransferase that acts as an oncogene in several cancers; however, its role in GBM remains unknown. We obtained GBM transcriptome and clinical data from The Cancer Genome Atlas (TCGA) database on the UCSC Xena platform to perform differential and enrichment analyses of genes in the SUV39H1 high- and low-expression groups to construct a prognostic risk model. Analysis of SUV39H1 related biological processes in GBM was performed by gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). High- and low-risk subgroup mutation signatures were analyzed using maftools. Immune infiltration was evaluated using IOBR and CIBERSORT algorithms. We analyzed the cell types and intercellular communication networks in glioma stem cells (GSCs) using scRNA-seq. The effects on GBM cells and GSCs after inhibition of SUV39H1 were investigated in vitro. SUV39H1 was significantly overexpressed in GBM and associated with poor prognosis. SUV39H1-related differentially expressed genes were enriched in immune and inflammation related pathways, and GSEA revealed that these genes were significantly enriched in signaling pathways such as IL-18, oxidative phosphorylation, and regulation of TP53 activity. Mutational analysis revealed frequent alterations in TP53 and PTEN expression. In addition, the infiltration abundances of the five immune cell types were significantly different between the high- and low-expression groups. Analysis of cellular communication networks by scRNA-seq revealed a strong interaction between CRYAB-GSC and PTPRZ1-GSC in GSCs. In vitro experiments verified that knockdown of SUV39H1 inhibited the viability and proliferation of U87 and U251 glioblastoma cells and downregulated the expression of stemness markers Nestin and SOX2 in CSC1589 and TS576 GSC lines. Increased SUV39H1 expression is associated with immune cell infiltration and poor prognosis in patients with GBM. Inhibition of SUV39H1 restrains GBM growth and reduces the stem cell properties of GSC. Thus, SUV39H1 might be a prognostic predictor and immunotherapeutic target in patients with GBM.

Cholestatic insult triggers alcohol-associated hepatitis in mice.

Alcohol-associated hepatitis (AH) is a severe, potentially life-threatening form of alcohol-associated liver disease with limited therapeutic options. Existing evidence shows that biliary dysfunction and cholestasis are common in patients with AH and are associated with poorer prognosis. However, the role of cholestasis in the development of AH is largely unknown. We aimed to examine the hypothesis that cholestasis can be an important etiology factor for AH. To study the interaction of cholestasis and alcohol, chronically ethanol (EtOH)-fed mice were challenged with a subtoxic dose of α-naphthylisothiocyanate (ANIT), a well-studied intrahepatic cholestasis inducer. Liver injury was measured by biochemical and histological methods. RNAseq was performed to determine hepatic transcriptomic changes. The impact of inflammation was assessed using an anti-LY6G antibody to deplete the neutrophils and DNase I to degrade neutrophil extracellular traps. ANIT synergistically enhanced liver injury following a 4-week EtOH feeding with typical features of AH, including increased serum levels of ALT, AST, and total bile acids, cholestasis, necrosis, neutrophil infiltration, and accumulation of neutrophil extracellular traps. RNAseq revealed multiple genes uniquely altered in the livers of EtOH/ANIT-treated mice. Analysis of differentially expressed genes suggested an enrichment of genes related to inflammatory response. Anti-LY6G antibody or DNase I treatment significantly inhibited liver damage in EtOH/ANIT-treated mice. Our results support the hypothesis that cholestasis can be a critical contributor to the pathogenesis of AH. A combined treatment of EtOH and ANIT in mice presents biochemical, histological, and molecular features similar to those found in patients with AH, suggesting that this treatment scheme can be a useful model for studying Alcohol-associated Cholestasis and Hepatitis (AlChoHep).

Single-cell RNA sequencing analysis reveals the role of TXNDC5 in keloid formation

Objective: Thioredoxin domain-containing protein 5 (TXNDC5) is associated with fibrosis in a variety of organs, but its mechanism of action in keloid is unclear. In this study, we aimed to investigate the mechanism of TXNDC5 in keloid. Material and Methods: Single-cell RNA sequencing data of keloid and normal scar samples obtained from public databases were normalized and clustered using the Seurat package. Pathway enrich analysis was conducted using biological process enrichment analysis and Gene Set Enrichment Analysis (GSEA). In addition, TXNDC5 expression and its effects on migration and invasion of keloid fibroblasts (KFs) were validated based on cell function experiments. Results: A total of five cell types were obtained. The KF clusters were further clustered into two fibroblast subtypes (Fibroblast cells 1 and Fibroblast cells 2). Biological process enrichment analysis showed that transforming growth factor beta (TGF-β) signaling pathway was enriched in the two fibroblast subtypes. GSEA analysis demonstrated that genes in TGF-β signaling pathway were mainly enriched in Fibroblast cells 1, and that genes involved in cell proliferation, migration, and the TGF-β signaling pathway were all high-expressed in fibroblast cells 1. TXNDC5 was positively correlated with fibroblast proliferation, migration and TGF-β signaling pathway, and AUCell score. The cellular experiment confirmed that the messenger RNA and protein levels of TXNDC5 and TGF-β1 were high-expressed in KFs cells (P&lt;0.001), and that knockdown of TXNDC5 downregulated TGF-β1 expression and inhibited migration and invasion of KFs (P&lt;0.0001). Conclusion: Our study indicated that TGF-β signaling pathway was enriched in fibroblast cells, and TXNDC5 was positively correlated with proliferation, migration, and TGF-β signaling pathway. Cellular experiment demonstrated that knocking down TXNDC5 downregulated TGF-β1 expression, and suppressed migration and invasion of KFs. The current discoveries provided a new therapeutic strategy for the treatment of keloid.