Analysis Of Gene Expression Profiles Research Articles

Enhanced vascular contraction induced by exposure to angiotensin II mediated by endothelin-1 biosynthesis following PKCβ activation.

Protein kinase C (PKC) reportedly plays a role in the pathogenesis of many vascular dysfunction-related conditions. In this study, we investigated whether PKCβ is associated with vascular contractile changes induced by angiotensin II (Ang II) exposure. Long-term (24 h) treatment of rat aortae and mesenteric arteries in Ang II-containing culture medium enhanced 5-hydroxytrypatamine (5-HT)-induced vascular contraction in a dose-dependent manner, in association with enhanced phosphorylation of PKCβ S660. Increased contraction induced by Ang II treatment was also observed in endothelium-denuded aorta. Enhanced contraction induced by Ang II was markedly diminished by knockout of the PKCβ gene or treatment with LY333531 and CGP53353 (PKCβ inhibitors). Cycloheximide (protein synthesis inhibitor) blocked the Ang II-induced enhanced contraction. Gene expression profiling and real-time PCR analyses showed marked upregulation of endothelin-1 (ET-1) expression in Ang II-treated aorta, but was not observed in PKCβ-knockout aorta. Ang II increased the secretion of ET-1 peptide in endothelium-intact and -denuded aortae. Ang II-induced enhancement of vascular contraction was diminished by BQ-123 (ETAR blocker). In vivo treatment with Ang II (250 ng/kg/min) for 7 days increased phosphorylation of PKCβ S660 in rat vascular tissue and increased the in vitro contractile responses to 5-HT and in vivo systolic blood pressure, but these changes were largely absent in PKCβ-knockout experiments. These data suggest that long-term exposure to Ang II increases vascular smooth muscle contraction and blood pressure elevation, mediated by activation of PKCβ and subsequent biosynthesis of ET-1 in vascular smooth muscle cells.

Molecular landscape of CD8+ T cells in pure red cell aplasia.

The aberrant function of lymphocytes is considered a significant contributing factor to pure red cell aplasia (PRCA), but the precise mechanism by which T lymphocytes induce erythroid development stagnation remains unclear. In our study, the CD8+ T lymphocytes were isolated from bone marrow aspirates of acquired PRCA patients and healthy controls. RNA sequencing (RNA-Seq) was performed to analyze gene expression profiles. Additionally, the expression levels of key molecules and transcription factors were assessed at the transcription and protein levels. The RNA-Seq analysis revealed a significant upregulation of genes associated with the PI3K/AKT/mTOR pathway in CD8+ T lymphocytes from patients with PRCA, compared to healthy controls. The mRNA expression of AKT, mTOR and key transcription factors T-bet were significantly upregulated in CD8+ T cells from patients with PRCA. Treatment with rapamycin, an mTOR inhibitor, attenuated the activation of CD8+ T lymphocytes in PRCA patients. Our findings demonstrate the activation of the PI3K/AKT/mTOR signaling pathway in CD8+ T lymphocytes of PRCA patients, suggesting its involvement in PRCA pathogenesis. Targeting this pathway may offer a potential therapeutic strategy for PRCA characterized by CD8+ T cell dysregulation.

P1193 Cross-Disease Analysis Unveils CXCL6 as a Shared Immune Mediator in Ulcerative Colitis and Periodontitis: Novel Insights from Bioinformatics

Abstract Background Emerging evidence underscores a pathological bidirectional relationship between ulcerative colitis (UC) and periodontitis (PD) through the oral-gut axis, highlighting a complex interplay with significant implications for patient health. However, the shared molecular features underlying this interaction have yet to be explored. Methods In this study, we initially established a potential link between periodontitis and ulcerative colitis based on Mendelian randomization. Following this, we analyzed gene expression profiles from the Gene Expression Omnibus (GEO) for both UC and PD, identifying overlapping genes between UC-differentially expressed genes (DEGs) and PD-DEGs. Results Functional enrichment analysis revealed associations with various immune pathways, underscoring the immunological relevance of these genes. Intersection with immune-related genes (IRGs) yielded 25 candidate genes, among which CXCL6 emerged as a central hub gene identified through three machine learning methods: LASSO, RF, and SVM-RFE. Subgroup analysis based on CXCL6 expression demonstrated that the CXCL6-high group exhibited increased immune cell infiltration and enhanced immune function. Moreover, our investigation of CXCL6 in relation to biological therapies in UC patients indicated a reduction in CXCL6 levels following treatment, suggesting potential benefits of biological therapies. Finally, we validated the expression of CXCL6 in a rat model of dual diseases. Conclusion In summary, CXCL6 is identified as a diagnostic biomarker and potential therapeutic target for UC combined with PD, warranting further investigation into its clinical significance and associated mechanisms.

Mitochondrial oxidative stress related LncRNA predict cervical cancer prognosis and immunotherapy response: Molecular structure and protein interaction of ribosomal protein L34.

The purpose of this study was to investigate the predictive value of mitochondrial oxidative stress-related LncRNA in cancer prognosis and immunotherapy response, and to further analyze the molecular structure of ribosomal protein L34 and its interaction mechanism with the protein. We screened lncrnas associated with mitochondrial oxidative stress, evaluated their expression patterns in different cancer types, and analyzed the three-dimensional structure of ribosomal protein L34 and its interaction network with other proteins. In this study, public databases were used to screen out lncrnas associated with mitochondrial oxidative stress. Bioinformatic analysis, including gene expression profile analysis, survival analysis and functional enrichment analysis, was used to evaluate the expression patterns of these lncrnas in different cancer types and their relationship with prognosis. The interacting proteins of ribosomal protein L34 were identified by proteomic techniques. The three-dimensional structure of ribosomal protein L34 and its binding mode with interacting proteins were studied by molecular docking and dynamic simulation methods. The results showed that the screened lncrnas showed significant expression differences in multiple cancer types and were closely related to the survival rate of patients. The three-dimensional structure of ribosomal protein L34 reveals key amino acid residues and binding sites for its interactions with specific proteins. Functional enrichment analysis showed that these lncrnas may affect the development of cancer through regulating oxidative stress response, cell cycle and apoptosis. The interaction network of ribosomal protein L34 reveals its central role in protein synthesis and cellular stress response.

Uncovering the Regulatory Role of Long Non-Coding RNAs in Colorectal Cancer Progression and Liver Metastasis: Implications for Therapeutic and Diagnostic Targeting

Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, largely due to metastasis, particularly to the liver, and the limited understanding of the molecular mechanisms underlying this process. In this study, we aimed to investigate the role of long non-coding Methods: RNAs (lncRNAs) are key regulatory factors in CRC progression and metastasis to liver tissues. Using high-throughput sequencing and microarray approaches, we analyzed gene expression profiles from two independent lncRNA datasets to identify potential players involved in liver metastasis. Results: Our findings revealed five lncRNAs—PROX1-AS1, SOX9-AS1, LINC01594, LINC01555, and APOA1-AS—previously known for their roles in CRC progression, now identified as being involved in the liver metastatic process. Additionally, 20 other lncRNAs, including VCAN-AS1, SYP-AS1, SMIM2-IT1, NCOA7-AS1, and LINC01449, were also identified as potential contributors to CRC liver metastasis. Notably, two lncRNAs—SATB2-AS1 and LINC01116—emerged as common candidates across both datasets, suggesting their significant role in promoting CRC metastasis to the liver. These two lncRNAs hold promise as molecular targets for therapeutic and diagnostic development. Conclusion: Our study uncovers a novel layer of regulatory mechanisms involving lncRNAs in CRC liver metastasis. These findings advance our understanding of the molecular behaviors that drive CRC progression and offer new avenues for targeted therapeutic strategies and diagnostic tools, particularly for liver metastasis in CRC.

The expansion and loss of specific olfactory genes in relatives of parasitic lice, the stored-product psocids (Psocodea: Liposcelididae)

BackgroundBooklice, belonging to the genus Liposcelis (Psocodea: Liposcelididae), commonly known as psocids, infest a wide range of stored products and are implicated in the transmission of harmful microorganisms such as fungi and bacteria. The olfactory system is critical for insect feeding and reproduction. Elucidating the molecular mechanisms of the olfactory system in booklice is crucial for developing effective control strategies. In this study, we aim to bridge this knowledge gap by leveraging the transcriptome and genome data from five Liposcelis species.ResultUsing HMMER method and manual annotation, we have identified common gene families associated with olfactory processes, including odorant binding proteins (OBPs), chemosensory proteins (CSPs), odorant receptors (ORs), ionotropic receptors (IRs), and sensory neuron membrane proteins (SNMPs). Specifically, we identified 94, 118, 26, 47, and 34 olfactory-related genes in L. bostrychophila, L. tricolor, L. entomophila, L. decolor, and L. yangi, respectively. Comparison of quantities revealed that the number of ORs and IRs in the genome is significantly higher than those identified in the transcriptome. This discrepancy may be due to the specific expression of these genes in certain tissues or their lack of expression during the experimental stage. Simultaneously, analysis of gene expression profiles across different developmental stages revealed varying periods of peak expression for olfactory-related genes. These results suggest that the identification of olfactory-related genes in booklice on a genome-wide scale is more feasible and reliable than using a transcriptome-based approach. Additionally, compared to parasitic lice, booklice possess significantly more olfactory-related genes. This increase may be due to the inability of parasitic lice to survive without a host, whereas booklice have a wide range of feeding habits and live in complex and variable environments. Furthermore, we observed that the IR gene family in L. tricolor has undergone a certain degree of amplification, which may facilitate its adaptation to diverse environmental conditions.ConclusionsWe identified olfactory-related genes of five Liposcelis species for the first time, providing valuable insights for future functional investigations into olfactory genes associated with pheromone and odorant recognition. These discoveries present promising targets for effectively managing psocid pests.

Predicting patient outcomes with gene-expression biomarkers from colorectal cancer organoids and cell lines.

Colorectal cancer (CRC) is characterized by an extremely high mortality rate, mainly caused by the high metastatic potential of this type of cancer. To date, chemotherapy remains the backbone of the treatment of metastatic colorectal cancer. Three main chemotherapeutic drugs used for the treatment of metastatic colorectal cancer are 5-fluorouracil, oxaliplatin and irinotecan which is metabolized to an active compound SN-38. The main goal of this study was to find the genes connected to the resistance to the aforementioned drugs and to construct a predictive gene expression-based classifier to separate responders and non-responders. In this study, we analyzed gene expression profiles of seven patient-derived CRC organoids and performed correlation analyses between gene expression and IC50 values for the three standard-of-care chemotherapeutic drugs. We also included in the study publicly available datasets of colorectal cancer cell lines, thus combining two different in vitro models relevant to cancer research. Logistic regression was used to build gene expression-based classifiers for metastatic Stage IV and non-metastatic Stage II/III CRC patients. Prognostic performance was evaluated through Kaplan-Meier survival analysis and log-rank tests, while independent prognostic significance was assessed using multivariate Cox proportional hazards modeling. A small set of genes showed consistent correlation with resistance to chemotherapy across different datasets. While some genes were previously implicated in cancer prognosis and drug response, several were linked to drug resistance for the first time. The resulting gene expression signatures successfully stratified Stage II/III and Stage IV CRC patients, with potential clinical utility for improving treatment outcomes after further validation. This study highlights the advantages of integrating diverse experimental models, such as organoids and cell lines, to identify novel prognostic biomarkers and enhance the understanding of chemotherapy resistance in CRC.

Genome-Wide Identification of the Uridine Diphosphate Glucotransferase Gene Family and Expression Profiling Analysis in the Stem Development of Prunus mume

Prunus mume, a traditional ornamental species native to China, is highly valued for both its captivating weeping variety and economic value. The glycosylation of metabolites, which is mediated by UDP-glycosyltransferases (UGTs), is essential for the regulation of secondary metabolic pathways in plants. Here, we systematically identified and analyzed the UGTs in P. mume. A total of 182 PmUGTs were identified using genomic data and categorized into 16 distinct subfamilies (A–P). All PmUGTs were distributed unevenly across the eight chromosomes, with clear evidence of tandem duplication. Additionally, synteny analysis revealed a close evolutionary relationship between P. mume and Prunus persica. A promoter cis-acting element analysis indicated that PmUGTs may respond to light, hormones, and external stresses. A heatmap analysis revealed that PmUGTs had specific expression patterns across different tissues, under various hormone treatments, and in different developmental stages of stem lignification. Notably, qRT-PCR verification showed significant differences in PmUGT163 expression between straight and weeping stems, underscoring its role in regulating plant architecture formation. Taken together, our study elucidates the evolutionary trajectory of PmUGTs and lays the groundwork for the further validation of the candidate genes involved in plant architectural formation.

Study of the SPL gene family and miR156-SPL module in Populus tomentosa: Potential roles in juvenile-to-adult phase transition and reproductive phase.

Populus tomentosa, a deciduous tree species distinguished by its significant economic and ecological value, enjoys a wide-ranging natural distribution. However, its long juvenile period severely restricts the advancement of breeding work. The SPL gene family, a distinctive class of transcription factors exclusive to the plant kingdom, is critical in various processes of plant growth and development. The miR156-SPL molecular module stands as an indispensable regulatory mechanism in the transition from the vegetative juvenile phase to the adult phase in plants. Consequently, this research endeavored a methodical and exhaustive exploration of the SPL gene family within the P.tomentosa species, synergistically integrating the miR156 family into the analysis. A total of 56 PtSPL genes were identified and subjected to a comprehensive analysis of their gene structure, conserved motifs, collinearity relationships, chromosomal localization, and promoter cis-acting elements. Further analysis of gene expression profiles confirmed the pivotal role of PtSPLs in the reproductive phase and tissue development of P. tomentosa. In addition, 11 members of miR156 in P. tomentosa were identified and their sequences analyzed, elucidating the miR156-SPL regulatory network. The target relationship between miR156k and PtSPLs was further validated by detecting the expression levels of PtSPLs in transgenic poplars overexpressing 35S::MIR156k. This comprehensive study lays a robust theoretical foundation for the continued exploration and application of the SPL genes in P. tomentosa, opening avenues for future research and potential advancements in plant biology and breeding strategies.

Genome-wide transcriptome analysis of gene expression profiles in Goose Astrovirus-infected GEF cells.

As a novel emerging pathogen, mainly causing visceral and articular gout in goslings, the pathogenesis of goose astrovirus (GAstV) remains unclear, seriously impeding the development of effective prevention and control methods. To better understand the reprogrammed cellular genes due to GAstV infection, a high-throughput transcriptome analysis was performed with primary goose embryo fibroblasts (GEF) at 48 h after infection. A total of 2324 differentially expressed genes (DEGs) were identified, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that most DEGs were closely associated with immune signal pathway and metabolic process. Subsequently, several immune and metabolic related genes, such as Mx, OAS, STAT1, IFIT5, and ADA, were identified and further validated via quantitative real-time PCR and western blot. This was the first study using GEF as the cell model to explore the host response to GAstV infection, which will undoubtedly provide a solid foundation to elucidate the pathogenesis of GAstV.

Integrated Analysis and Validation of Ferroptosis-Related Genes Associated with Ischemia/Reperfusion Injury in Lung Transplantation.

Lung transplantation is the only effective therapeutic option for patients with end-stage lung disease. However, ischemia/reperfusion injury (IRI) during transplantation is a leading cause of primary graft dysfunction (PGD). Ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation, has been implicated in IRI across various organs. This study aims to explore the role of ferroptosis in lung transplantation-related ischemia/reperfusion injury and to identify its potential molecular mechanisms through bioinformatics analysis. Transcriptome data from lung transplant patients were obtained from the Gene Expression Omnibus (GEO) database. Ferroptosis-related differentially expressed genes (FRGs) were identified by analyzing gene expression profiles before and after reperfusion. Weighted gene co-expression network analysis (WGCNA) was used to identify module genes, and overlapping genes were further analyzed using two machine learning algorithms. The CIBERSORT algorithm was applied to assess immune cell infiltration, while Mendelian randomization (MR) analysis was used to investigate causal relationships between candidate genes and PGD. Finally, Consensus clustering based on FRGs was performed to identify subtypes. We identified four candidate genes associated with ferroptosis during lung reperfusion: tumor necrosis factor alpha-induced protein 3 (TNFAIP3), C-X-C motif chemokine ligand 2 (CXCL2), neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L), and sestrin 2 (SESN2). These genes were closely associated with immune cell infiltration. MR analysis suggested that SESN2 might play a protective role against PGD. Additionally, consensus clustering revealed distinct immune infiltration patterns across subtypes, providing insights for personalized therapeutic approaches to lung ischemia/reperfusion injury (LIRI). This study highlights TNFAIP3, CXCL2, NEDD4L, and SESN2 as candidate genes associated with ferroptosis during LIRI, with SESN2 potentially protecting against PGD. These findings offer promising therapeutic targets for preventing LIRI and improving outcomes in lung transplantation.

MiR-204-5p and miR-130a-3p in Focus: Computational Breakthroughs in Understanding Hypertension Pathogenesis

Hypertension is a multifactorial disorder influenced by complex genetic and epigenetic interactions. Recent advancements in understanding the role of microRNAs (miRNAs) in regulating gene expression have provided new insights into the molecular mechanisms underlying hypertension. This study investigates the involvement of miRNAs in the pathophysiology of hypertension by analyzing gene expression profiles derived from multiple datasets obtained from NCBI and analyzed with GEOR. miR-DEGs were identified and subjected to the DAVID online tool for gene ontology study. BiBiServ2 was queried for miRNA/mRNA homology study. A total of 1,014 overlapping differentially expressed genes (DEGs) were identified across three datasets, revealing a significant dysregulation of the hypertensive transcriptome. The study further highlights the role of miRNAs, such as miR-29a-3p, miR-204-5p, miR-130a-3p, and miR-145-5p, in targeting these DEGs, with a predominant suppression of gene expression observed in hypertensive conditions. Functional enrichment analysis of miRNA-targeted DEGs revealed significant associations with key pathways involved in vascular remodeling, inflammation, and aldosterone regulation, including MAPK signaling, PI3K-Akt signaling, and the renin-angiotensin-aldosterone system (RAAS). Additionally, miRNA/gene homology studies demonstrated strong binding affinities between these miRNAs and genes involved in aldosterone synthesis, suggesting their pivotal role in modulating blood pressure regulation. The findings underscore the critical involvement of miRNAs in hypertension, proposing their potential as biomarkers and therapeutic targets for hypertension management. Future research should focus on validating these miRNA-targeted pathways and exploring miRNA-based therapeutics to restore homeostasis in hypertension.

Single-cell RNA sequencing reveals the critical role of alternative splicing in cattle testicular spermatagonia

Spermatogonial stem cells (SSCs) form haploid gametes through the precisely regulated process of spermatogenesis. Within the testis, SSCs undergo self-renewal through mitosis, differentiation, and then enter meiosis to generate mature spermatids. This study utilized single-cell RNA sequencing on 26,888 testicular cells obtained from five Holstein bull testes, revealing the presence of five distinct germ cell types and eight somatic cell types in cattle testes. Gene expression profiling and enrichment analysis were utilized to uncover the varied functional roles of different cell types involved in cattle spermatogenesis. Additionally, unique gene markers specific to each testicular cell type were identified. Moreover, differentially expressed genes in spermatogonia exhibited notable enrichment in GO terms and KEGG pathway linked to alternative splicing. Notably, our study has shown that the activity of the YY1 regulation displays distinct expression patterns in spermatogonia, specifically targeting spliceosome proteins including RBM39, HNRNPA2B1, HNRNPH3, CPSF1, PCBP1, SRRM1, and SRRM2, which play essential roles in mRNA splicing. These results emphasize the importance of mRNA processing in spermatogonia within cattle testes, providing a basis for further investigation into their involvement in spermatogonial development.

RBIS regulates ribosome biogenesis to affect progression in lung adenocarcinoma.

Increased ribosome biogenesis is required for tumor growth. In this study, we investigated the function and underlying molecular mechanism of ribosome biogenesis factor (RBIS) in the progression of non-small cell lung cancer (NSCLC). In our study, we conducted a comprehensive analysis to identify key genes implicated in ribosome biogenesis by leveraging a Gene Set Enrichment Analysis (GSEA) dataset. Subsequently, we performed a comparative analysis of gene expression profiles by utilizing data from the Gene Expression Omnibus (GEO) datasets to ascertain differentially expressed genes (DEGs) between cancerous and adjacent non-cancerous tissues. Through the intersection of gene sets derived from GSEA and GEO, we identified a cohort of ribosome-associated genes that might exert a substantial influence on the progression of lung adenocarcinoma. Following an extensive literature review, we have identified the RBIS gene as an interesting candidate for further investigation. To elucidate the in vitro functional role of RBIS, several assays was employed, including the Transwell migration and invasion assay, wound healing assay, Cell Counting Kit-8 (CCK-8) proliferation assay, and colony formation assay. Subcutaneous and tail vein injection-based lung metastasis xenograft tumor models were used in evaluating the tumorigenic potential, growth, and metastatic spread of lung cancer cells. Flow cytometry analysis was employed to investigate cell cycle distribution and apoptotic rates. Additionally, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was utilized to quantify the mRNA expression levels ofgenes. To comprehensively assess the translational efficiency of nascent proteins, we employed polysome profiling analysis to provide insights into the cellular translational landscape. Furthermore, we quantified global protein synthesis using a fluorescence-based assay to measure protein synthesis rates. The immunofluorescence technology was utilized to study the subcellular reorganization of the nucleolus. We conducted co-immunoprecipitation (Co-IP) assays followed by Western blot analysis to identify potential proteins interacted with RBIS. The half maximal inhibitory concentration (IC50) was used for evaluating the chemosensitivity of lung cancer cells to gemcitabine. Additionally, the colony formation assay was employed to assess the survival and proliferative capacity post-treatment of gemcitabine. The database analysis showed that RBIS was upregulated in lung adenocarcinoma, and its high expression was associated with poor prognosis; Knockdown of RBIS significantly inhibited NSCLC cell migration, invasion and proliferation in vitro and xenograft tumor growth and metastasis in vivo. Additionally, knockdown of RBIS led to G0/G1 phase arrest and significantly increased apoptosis in lung adenocarcinoma cells. Mechanistically, downregulation of RBIS significantly decreased the expression of 47S ribosomal RNA (rRNA), a component associated with ribosome assembly. Polysome profiling analysis indicated that RBIS knockdown affected protein translation efficiency, and global protein synthesis assay further verified that RBIS knockdown inhibited synthesis of newborn proteins. Additionally, the ribosomal biogenesis-targeting drugs CX-5461 and the loss of RBIS exhibited synergistic effects in inhibiting cell cycle progression and inducing apoptosis. Furthermore, the ribosomal maturation factor GNL2 was identified as the key downstream regulator of RBIS in ribosome biogenesis. Notably, knockdown of RBIS substantially increased the sensitivity of lung adenocarcinoma cells to the chemotherapeutic drug gemcitabine, highlighting its l role in chemotherapy. Collectively, these studies suggested the close involvement of RBIS in the progression of lung adenocarcinoma, providing new insights for targeted therapeutic interventions involving ribosomes.

Physiological, biochemical, and genome-wide expression patterns during graded normobaric hypoxia in healthy individuals.

The regulation of oxygen homeostasis is critical in physiology and disease pathogenesis. High-altitude environment or hypoxia (lack of oxygen) can lead to adverse health conditions such as high-altitude pulmonary edema (HAPE) despite initial adaptive physiological responses. Studying genetic, hematological and biochemical, and the physiological outcomes of hypoxia together could yield a comprehensive understanding and potentially uncover valuable biomarkers for predicting responses. To this end, healthy individuals (n = 51) were recruited and exposed to graded normobaric hypoxia. Physiological parameters such as heart rate (HR), heart rate variability (HRV), oxygen saturation (Spo2), and blood pressure (BP) were constantly monitored, and a blood sample was collected before and after the hypoxia exposure for the hematological and gene-expression profiles. HR was elevated, and Spo2 and HRV were significantly reduced in a fraction of inspired oxygen ([Formula: see text])-dependent manner. After exposure to hypoxia, there was a minimal decrease in HCT, red blood cell distribution width (RDW)-coefficient of variation (CV), mean platelet volume (MPV), platelet distribution width, plateletcrit, eosinophils, lymphocytes, and HDL cholesterol. Additionally, there was a marginal increase observed in neutrophils. The effect of hypoxia was further assessed at the genome-wide expression level in a subset of individuals. Eighty-two genes significantly differed after hypoxia exposure, with 46 upregulated genes and 36 downregulated genes (P ≤ 0.05 and log2-fold change greater than ±0.5). We also conducted an integrative analysis of global gene expression profiles linked with physiological parameters, and we uncovered numerous reliable gene signatures associated with BP, Spo2, HR, and HRV in response to graded normobaric hypoxia.NEW & NOTEWORTHY Our study delves into the multifaceted response to hypoxia, integrating gene expression and hematological, biochemical, and physiological assessments. Hypoxia, crucial in both physiology and pathology, prompts varied responses, necessitating a thorough systemic understanding. Examining healthy subjects exposed to graded normobaric hypoxia, we observed significant shifts in heart rate, oxygen saturation, and heart rate variability. Moreover, genomic analysis unveiled distinct gene signatures associated with physiological parameters, offering insights into molecular perturbations and adaptations to oxygen deprivation.

Denatonium inhibits RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype by blocking p65 signaling pathway

BackgroundBone remodeling is a critical process that maintains skeletal integrity, orchestrated by the balanced activities of osteoclasts, which resorb bone, and osteoblasts, which form bone. Osteoclastogenesis, the formation of osteoclasts, is primarily driven by NFATc1, a process activated through c-Fos and NF-κB signaling pathways in response to receptor activator of nuclear factor κB ligand (RANKL). Dysregulation of RANKL signaling is a key contributor to pathological bone loss, as seen in conditions such as osteoporosis.MethodsWe investigated the effects of denatonium, a known bitter compound, on RANKL-induced osteoclast differentiation. We used RNA sequencing (RNA-seq) to analyze gene expression profiles in osteoclast precursors treated with denatonium. Transcription factor prediction analysis was conducted to identify key targets of denatonium action. Additionally, we performed Western blotting to examine the phosphorylation status of AKT and p65, crucial components of the NF-κB pathway. Chromatin immunoprecipitation (ChIP) assays were employed to assess the binding of p65 to promoter regions of osteoclast-related genes. Finally, we tested the therapeutic potential of denatonium in a mouse model of osteoporosis.ResultsOur findings demonstrated that denatonium significantly inhibited RANKL-induced osteoclastogenesis by targeting the p65 pathway. RNA-seq analysis revealed a downregulation of osteoclast-related genes following denatonium treatment, corroborated by transcription factor prediction analysis, which highlighted p65 as a key target. Denatonium effectively blocked the phosphorylation of AKT and p65, key steps in NF-κB activation. ChIP assays further confirmed that denatonium reduced the enrichment of p65 at promoter regions critical for osteoclast differentiation. In vivo, denatonium treatment in an osteoporosis animal model led to a significant restoration of bone health, demonstrating its potential as a therapeutic agent.ConclusionsThis study identifies denatonium as an inhibitor of RANKL-induced osteoclast differentiation, potentially acting through suppression of the p65 signaling pathway. The ability of denatonium to downregulate osteoclast-related genes and inhibit key signaling events highlights its potential as a candidate for further investigation in the context of bone loss and osteoporosis.

Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells.

Ecotropic viral integration site 1 (EVI1/MECOM) is frequently upregulated in myeloid malignancies. Here, we present an Evi1-transgenic mouse model with inducible expression in hematopoietic stem/progenitor cells (HSPCs). Upon induction of Evi1 expression, mice displayed anemia, thrombocytopenia, lymphopenia, and erythroid and megakaryocyte dysplasia with a significant expansion of committed myeloid progenitor cells, resembling human myelodysplastic syndrome/myeloproliferative neoplasm-like (MDS/MPN-like) disease. Evi1 overexpression prompted HSPCs to exit quiescence and accelerated their proliferation, leading to expansion of committed myeloid progenitors while inhibiting lymphopoiesis. Analysis of global gene expression and Evi1 binding site profiling in HSPCs revealed that Evi1 directly upregulated lysine demethylase 6b (Kdm6b). Subsequently, Kdm6b-mediated H3K27me3 demethylation resulted in activation of various genes, including Laptm4b. Interestingly, KDM6B and LAPTM4B are positively correlated with EVI1 expression in patients with MDS. The EVI1/KDM6B/H3K27me3/LAPTM4B signaling pathway was also identified in EVI1hi human leukemia cell lines. We found that hyperactivation of the LAPTM4B-driven mTOR pathway was crucial for the growth of EVI1hi leukemia cells. Knockdown of Laptm4b partially rescued Evi1-induced abnormal hematopoiesis in vivo. Thus, our study establishes a mouse model to investigate EVI1hi myeloid malignancies, demonstrating the significance of the EVI1-mediated KDM6B/H3K27me3/LAPTM4B signaling axis in their maintenance.

Transcriptome Analysis Provides Insights into the Safe Overwintering of Local Peach Flower Buds.

During the dormant period of peach trees in winter, flower buds exhibit weak cold resistance and are susceptible to freezing at low temperatures. Understanding the physiological and molecular mechanisms underlying the response of local peach buds to low-temperature adversity is crucial for ensuring normal flowering, fruiting, and yield. In this study, the experimental materials included the conventional cultivar 'Xia cui' (XC) and the cold-resistant local resources 'Ding jiaba' (DJB) peach buds. The antioxidant enzyme activity, levels of malondialdehyde (MDA), proline (Pro), and hydrogen peroxide content (H2O2) were determined in peach buds at different dormancy periods. Transcriptome sequencing was performed at three dormancy stages: the dormancy entry stage (FD), deep dormancy release stage (MD), and dormancy release stage (RD). Additionally, transcriptome sequencing was conducted to analyze gene expression profiles during these stages. Our findings revealed that compared with XC cultivars, DJB peach buds exhibited decreased MDA and H2O2 contents but increased superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities as well as Pro content during the dormancy period. These findings suggest that cold-resistant cultivars possess significantly stronger antioxidant capacity than conventional cultivars under low-temperature stress. A total of 10,168 differential genes were annotated through transcriptome sequencing. Among them, 4975 were up-regulated while 5193 were down-regulated. The differentially expressed genes associated with low-temperature response in peach buds are primarily enriched in plant hormone signal transduction pathway and phenylpropane synthesis pathway. Key differentially expressed genes related to cold resistance include ARF2, GH3, and SAPK2, and differentially expressed transcription factors mainly belong to the AP2/ERF-ERF, bHLH, and C2H2 families. This study provides a theoretical foundation for understanding the key genes involved.

Odorant binding protein TcOBPC02 contributes to phytochemical defense in the red flour beetle, Tribolium castaneum

AbstractThe red flour beetle, Tribolium castaneum, is an agricultural and storage pest with a global distribution. Studies have shown that eucalyptol has strong contact toxicity against larvae of this beetle, whereas odorant binding proteins (OBPs) are known to contribute to larval defenses against this phytochemical toxin. However, the mechanisms underlying the protective effect of insect OBPs against eucalyptol remain unclear. Here, TcOBPC02 from T. castaneum was cloned and characterized. Gene expression profile analysis showed that TcOBPC02 is highly expressed at early larval and early pupal stages. Additionally, tissue expression profiling revealed that, in the adult, TcOBPC02 was most highly expressed in the head, followed by the epidermis, whereas in larvae, TcOBPC02 was mainly expressed in hemolymph and the epidermis. These developmental stages and tissues that exhibit high TcOBPC02 expression are closely related to the detoxification of heterologous substances. Furthermore, the mRNA level of TcOBPC02 was significantly increased after exposure to eucalyptol, whereas TcOBPC02‐targeted RNA interference increased the susceptibility of T. castaneum to eucalyptol, indicating that TcOBPC02 participates in the tolerance of this beetle to eucalyptol. Additionally, recombinant TcOBPC02 was expressed in Escherichia coli and isolated, enabling a straightforward fluorescence competition binding assay. In combination, these results have demonstrated that TcOBPC02 is required for defenses against phytochemicals in T. castaneum. This study provides a theoretical basis for understanding the mechanisms underlying the degradation of exogenous toxicants in insects and adds to the repertoire of potential target genes for pest control.

A reactive oxygen species-related signature predicts the prognosis and immunosuppressive microenvironment in gliomas

ABSTRACT Objective: Intracellular redox homeostasis is crucial for a series of physiological processes. Reactive oxygen species (ROS) play important roles in redox processes. ROS can maintain cell reproduction and survival at moderate levels while promoting the initiation and progression of tumors at high levels. Methods: Based on a comprehensive analysis of ROS-related gene expression profiles, we established a gene signature associated with ROS to explore its influence on prognosis and immune microenvironment in gliomas. Results: The ROS-related gene expression profile dichotomized patients into two groups with different clinicopathological features and prognoses. A 19-gene ROS-related signature was used to robustly predict prognosis in both training and validation datasets. Functional analysis indicated an association between ROS levels and the immune microenvironment. The expression of immune checkpoints and M2-type markers was upregulated in the high-risk group, which suggested the immunosuppressive function of ROS. Conclusion: ROS-related signature is an independent prognostic factor in gliomas and could potentially exert immunosuppressive effects on the tumor microenvironment.