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Redox Biology Jun 2024GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein...
GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein signaling is terminated remains largely unknown. In this study, we aimed to investigate the regulatory mechanisms involved in terminating the signaling of Gα subunits from endosomes. Through structural analysis and cell-based assays, we have discovered that SNX25, a protein that targets endosomes via its PXA or PXC domain, interacts with regulator of G protein signaling (RGS) proteins (including RGS2, RGS4, RGS8, and RGS17) in a redox-regulated manner. The interaction between SNX25 and these RGS proteins enhances their GTPase-accelerating activity towards Gα and their ability to bind GDP-bound (inactive form) Gα. As a result, SNX25 recruits these RGS proteins to endosomes, leading to the termination of endosomal Gα signaling. Furthermore, we have found that the SNX25/RGS complex also exerts a negative regulatory effect on Gα signaling from the plasma membrane. This is achieved by recruiting Gα to endosomes and preventing its activation on the plasma membrane. Our findings shed light on the previously unknown role of redox-modulated SNX25 in inhibiting Gα signaling, thereby uncovering a novel mechanism for terminating Gα signaling from endosomes. Importantly, this study expands our understanding of the regulation of GPCR-Gα signaling beyond the plasma membrane.
PubMed: 38936254
DOI: 10.1016/j.redox.2024.103253 -
PLoS Computational Biology Jun 2024Therapeutic interventions are designed to perturb the function of a biological system. However, there are many types of proteins that cannot be targeted with...
Therapeutic interventions are designed to perturb the function of a biological system. However, there are many types of proteins that cannot be targeted with conventional small molecule drugs. Accordingly, many identified gene-regulatory drivers and downstream effectors are currently undruggable. Drivers and effectors are often connected by druggable signaling and regulatory intermediates. Methods to identify druggable intermediates therefore have general value in expanding the set of targets available for hypothesis-driven validation. Here we identify and prioritize potential druggable intermediates by developing a network perturbation theory, termed NetPert, for response functions of biological networks. Dynamics are defined by a network structure in which vertices represent genes and proteins, and edges represent gene-regulatory interactions and protein-protein interactions. Perturbation theory for network dynamics prioritizes targets that interfere with signaling from driver to response genes. Applications to organoid models for metastatic breast cancer demonstrate the ability of this mathematical framework to identify and prioritize druggable intermediates. While the short-time limit of the perturbation theory resembles betweenness centrality, NetPert is superior in generating target rankings that correlate with previous wet-lab assays and are more robust to incomplete or noisy network data. NetPert also performs better than a related graph diffusion approach. Wet-lab assays demonstrate that drugs for targets identified by NetPert, including targets that are not themselves differentially expressed, are active in suppressing additional metastatic phenotypes.
PubMed: 38935814
DOI: 10.1371/journal.pcbi.1012195 -
PloS One 2024Tuberculosis is a serious life-threatening disease among the top global health challenges and rapid and effective diagnostic biomarkers are vital for early diagnosis...
BACKGROUND
Tuberculosis is a serious life-threatening disease among the top global health challenges and rapid and effective diagnostic biomarkers are vital for early diagnosis especially given the increasing prevalence of multidrug resistance.
METHODS
Two human whole blood microarray datasets, GSE42826 and GSE42830 were retrieved from publicly available gene expression omnibus (GEO) database. Deregulated genes (DEGs) were identified using GEO2R online tool and Gene Ontology (GO), protein-protein interaction (PPI) network analysis was performed using Metascape and STRING databases. Significant genes (n = 8) were identified using T-test/ANOVA and Molecular Complex Detection (MCODE) score ≥10, which was validated in GSE34608 dataset. The diagnostic potential of three biomarkers was assessed using Area Under Curve (AUC) of Receiver Operating Characteristic (ROC) plot. The transcriptional levels of these genes were also examined in a separate dataset GSE31348, to monitor the patterns of variation during tuberculosis treatment.
RESULTS
A total of 62 common DEGs (57 upregulated, 7 downregulated genes) were identified in two discovery datasets. GO functions and pathway enrichment analysis shed light on the functional roles of these DEGs in immune response and type-II interferon signaling. The genes in Module-1 (n = 18) were linked to innate immune response, interferon-gamma signaling. The common genes (n = 8) were validated in GSE34608 dataset, that corroborates the results obtained from discovery sets. The gene expression levels demonstrated responsiveness to Mtb infection during anti-TB therapy in GSE31348 dataset. In GSE34608 dataset, the expression levels of three specific genes, GBP5, IFITM3, and EPSTI1, emerged as potential diagnostic makers. In combination, these genes scored remarkable diagnostic performance with 100% sensitivity and 89% specificity, resulting in an impressive Area Under Curve (AUC) of 0.958. However, GBP5 alone showed the highest AUC of 0.986 with 100% sensitivity and 89% specificity.
CONCLUSIONS
The study presents valuable insights into the critical gene network perturbed during tuberculosis. These genes are determinants for assessing the effectiveness of an anti-TB response and distinguishing between active TB and healthy individuals. GBP5, IFITM3 and EPSTI1 emerged as candidate core genes in TB and holds potential as novel molecular targets for the development of interventions in the treatment of TB.
Topics: Humans; Tuberculosis; Protein Interaction Maps; RNA-Seq; Computational Biology; Gene Expression Profiling; ROC Curve; Gene Regulatory Networks; Databases, Genetic; Biomarkers; Gene Ontology
PubMed: 38935691
DOI: 10.1371/journal.pone.0305582 -
PloS One 2024To bolster the dual-circulation development model and green economy, this study delves into the spatiotemporal dynamics of implied carbon transfer in China's...
To bolster the dual-circulation development model and green economy, this study delves into the spatiotemporal dynamics of implied carbon transfer in China's inter-provincial and inter-industrial trade, emphasizing its significance for the "dual carbon" objectives. Utilizing multi-regional input-output data from 2012, 2015, and 2017, we employed the multi-region input-output model to gauge embodied carbon transfers across 31 provinces and 28 industries. The Structural Decomposition Analysis (SDA) model further decomposed the growth of trade-related carbon emissions. Key findings include: (1) The electricity and thermal power sectors dominate carbon transfers, with secondary industries seeing rapid growth; (2) Northern provinces significantly outweigh southern ones in carbon transfers and the main direction of it is towards affluent southern coastal regions; (3) Scale effect plays a pivotal role in these transfers. Conclusively, it is crucial for regulatory authorities to rationally formulate region-specific emission policies for inter-regional coordination, and future studies can focus on industrial and spatial clustering effects.
Topics: China; Carbon; Industry
PubMed: 38935676
DOI: 10.1371/journal.pone.0300478 -
Heliyon Jun 2024Identification of novel biomarkers for prediction of disease course and prognosis is needed to reduce morbidity of liver hepatocellular carcinoma (LIHC/HCC) patients....
Identification of novel biomarkers for prediction of disease course and prognosis is needed to reduce morbidity of liver hepatocellular carcinoma (LIHC/HCC) patients. Although dysregulated Periodic tryptophan protein 1 homolog (PWP1/endonuclein) expression has been detected in several tumors, the potential regulatory effect of PWP1 on LIHC remains uncertain. Here we evaluated the expression of PWP1 using multiple online platforms, and demonstrated that PWP1 upregulation was consistently observed in LIHC relative to non-tumor liver tissues and correlated with unfavorable prognosis. Moreover, HCC prognosis was significantly influenced by the methylation status of various CpG sites in the PWP1 gene. Lastly, we provide direct evidence that PWP1 acts as a driver of HCC progression by showing that siRNA-mediated PWP1 silencing significantly suppressed HCC cell proliferation in vitro. These data strongly suggest that PWP1 silencing may be an effective therapeutic strategy to treat LIHC.
PubMed: 38933950
DOI: 10.1016/j.heliyon.2024.e32409 -
Frontiers in Genetics 2024The single nucleotide polymorphism (SNP) rs4644 at codon 64 of galectin-3 (gal-3, gene name: ), specifying the variant proline (P64) to histidine (H64), is known to...
INTRODUCTION
The single nucleotide polymorphism (SNP) rs4644 at codon 64 of galectin-3 (gal-3, gene name: ), specifying the variant proline (P64) to histidine (H64), is known to affect the protein's functions and has been associated with the risk of several types of cancer, including differentiated thyroid carcinoma (DTC).
MATERIALS AND METHODS
To deepen our understanding of the biological effects of this SNP, we analyzed the proteome of two isogenic cell lines (NC-P64 vs. NA-H64) derived from the immortalized non-malignant thyrocyte cell line Nthy-Ori, generated through the CRISPR-Cas9 technique to differ by rs4644 genotype. We compared the proteome of these cells to detect differentially expressed proteins and studied their proteome in relation to their transcriptome.
RESULTS
Firstly, we found, consistently with previous studies, that gal-3-H64 could be detected as a monomer, homodimer, and heterodimer composed of one cleaved and one uncleaved monomer, whereas gal-3-P64 could be found only as a monomer or uncleaved homodimer. Moreover, results indicate that rs4644 influences the expression of several proteins, predominantly upregulated in NA-H64 cells. Overall, the differential protein expression could be attributed to the altered mRNA expression, suggesting that rs4644 shapes the function of gal-3 as a transcriptional co-regulator. However, this SNP also appeared to affect post-transcriptional regulatory mechanisms for proteins whose expression was oppositely regulated compared to mRNA expression. It is conceivable that the rs4644-dependent activities of gal-3 could be ascribed to the different modalities of self-dimerization.
CONCLUSION
Our study provided further evidence that rs4644 could affect the gal-3 functions through several routes, which could be at the base of differential susceptibility to diseases, as reported in case-control association studies.
PubMed: 38933925
DOI: 10.3389/fgene.2024.1380495 -
Frontiers in Genetics 2024Circular RNAs (circRNAs) play an important role in the occurrence and development of diseases. However, the role of circRNAs in male smokers with chronic obstructive...
BACKGROUND
Circular RNAs (circRNAs) play an important role in the occurrence and development of diseases. However, the role of circRNAs in male smokers with chronic obstructive pulmonary disease (COPD) remains unclear.
METHODS
Stable COPD patients and healthy controls were recruited. Peripheral blood mononuclear cells (PBMCs) were extracted. After high-throughput RNA sequencing (RNA-Seq) of PBMCs, a bioinformatics method was used to analyse differentially expressed (DE) circRNAs (DEcircRNAs) and mRNAs (DEmRNAs).
RESULTS
Total of 114 DEcircRNAs and 58 DEmRNAs were identified. Functional enrichment analysis showed that processes related to COPD include the regulation of interleukin (IL)-18, IL-5 and the NLRP3 inflammasome; differentiation of T helper type 1 (Th1), Th2, and Th17 cells, and the AMPK, Wnt, JAK-STAT, and PI3K-Akt signalling pathways. In the protein-protein interaction (PPI) network, the core genes were MYO16, MYL4, SCN4A, NRCAM, HMCN1, MYOM2, and IQSEC3. Small-molecule prediction results revealed potential drugs for the COPD treatment. Additionally, the circRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory network was constructed.
CONCLUSION
This study identified a set of dysregulated circRNAs and mRNAs and revealed potentially important genes, pathways, new small-molecule drugs and ceRNA regulatory networks in male smokers with COPD. These circRNAs might be prospective biomarkers or potential molecular targets of the ceRNA mechanism for COPD.
PubMed: 38933922
DOI: 10.3389/fgene.2024.1376721 -
Frontiers in Genetics 2024In recent years, burgeoning research has underscored the pivotal role of non-coding RNA in orchestrating the growth, development, and pathogenesis of various diseases...
In recent years, burgeoning research has underscored the pivotal role of non-coding RNA in orchestrating the growth, development, and pathogenesis of various diseases across organisms. However, despite these advances, our understanding of the specific contributions of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) to lens development remains notably limited. Clarifying the intricate gene regulatory networks is imperative for unraveling the molecular underpinnings of lens-related disorders. In this study, we aimed to address this gap by conducting a comprehensive analysis of the expression profiles of messenger RNAs (mRNAs), lncRNAs, and circRNAs at critical developmental time points of the mouse lens, encompassing both embryonic (E10.5, E12.5, and E16.5) and postnatal stages (P0.5, P10.5, and P60). Leveraging RNA-sequencing technology, we identified key transcripts pivotal to lens development. Our analysis revealed differentially expressed (DE) mRNAs, lncRNAs, and circRNAs across various developmental stages. Particularly noteworthy, there were 1831 co-differentially expressed (CO-DE) mRNAs, 150 CO-DE lncRNAs, and 13 CO-DE circRNAs identified during embryonic stages. Gene Ontology (GO) enrichment analysis unveiled associations primarily related to lens development, DNA conformational changes, and angiogenesis among DE mRNAs and lncRNAs. Furthermore, employing protein-protein interaction networks, mRNA-lncRNA co-expression networks, and circRNA-microRNA-mRNA networks, we predicted candidate key molecules implicated in lens development. Our findings underscore the pivotal roles of lncRNAs and circRNAs in this process, offering fresh insights into the pathogenesis of lens-related disorders and paving the way for future exploration in this field.
PubMed: 38933921
DOI: 10.3389/fgene.2024.1405715 -
Frontiers in Endocrinology 2024Exosomes, as pivotal entities within the tumor microenvironment, orchestrate intercellular communication through the transfer of diverse molecules, among which... (Review)
Review
Exosomes, as pivotal entities within the tumor microenvironment, orchestrate intercellular communication through the transfer of diverse molecules, among which non-coding RNAs (ncRNAs) such as miRNAs, lncRNAs, and circRNAs play a crucial role. These ncRNAs, endowed with regulatory functions, are selectively incorporated into exosomes. Emerging evidence underscores the significance of exosomal ncRNAs in modulating key oncogenic processes in thyroid cancer (TC), including proliferation, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, and immunoediting. The unique composition of exosomes shields their cargo from enzymatic and chemical degradation, ensuring their integrity and facilitating their specific expression in plasma. This positions exosomal ncRNAs as promising candidates for novel diagnostic and prognostic biomarkers in TC. Moreover, the potential of exosomes in the therapeutic landscape of TC is increasingly recognized. This review aims to elucidate the intricate relationship between exosomal ncRNAs and TC, fostering a deeper comprehension of their mechanistic involvement. By doing so, it endeavors to propel forward the exploration of exosomal ncRNAs in TC, ultimately paving the way for innovative diagnostic and therapeutic strategies predicated on exosomes and their ncRNA content.
Topics: Humans; Exosomes; Thyroid Neoplasms; RNA, Untranslated; Disease Progression; Tumor Microenvironment; Biomarkers, Tumor; Animals; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic
PubMed: 38933820
DOI: 10.3389/fendo.2024.1337226 -
British Journal of Biomedical Science 2024The Biomedical Scientist (BMS) role is established in healthcare, working in laboratory environments to provide diagnostic testing and to monitor treatment effects on a...
INTRODUCTION
The Biomedical Scientist (BMS) role is established in healthcare, working in laboratory environments to provide diagnostic testing and to monitor treatment effects on a patients' health. The profession is subject to several professional standards which highlight the importance of working in the best interests of the patient and service user. However, Biomedical Scientists have little or no patient contact. This study aimed to determine how Biomedical Scientists evidence that they meet the professional standards and support the achievement of patient outcomes.
MATERIALS AND METHODS
This study utilised a Delphi method to explore the opinions of professional stakeholders to determine whether there was consensus for how this professional group contributes to patient outcomes and offers evidence that they are working in the best interests of the patient. The qualitative 1st round of the study consisted of focus groups and interviews with staff and students on the BSc Biomedical Science awards, Professional, Statutory and Regulatory body (PSRB) representatives and Biomedical Scientists from the National Health Service (NHS). The first-round responses were analysed using thematic analysis which then generated attitude statements which participants scored using a 5-point Likert scale in the 2nd round. Consensus or divergence of opinion was determined based upon a 70% consensus level within each participant group and overall.
RESULTS
Following analysis of the 2nd round data, there was divergence of opinion across all stakeholders, with consensus rates being highest in the Biomedical Scientist group (72.7% of statements reached 70% consensus), followed by the student group (54.5% of statements reached 70% consensus) and lowest in the academic group (40.9% of statements reached 70% consensus).
DISCUSSION
This demonstrates a theory-practice gap in both the academic and student groups, suggesting that graduates are insufficiently prepared for their post-graduate role. This gap was particularly evident when discussing topics such as how Biomedical Scientists contribute to patient care, professional registration and working as part of the multi-disciplinary team (MDT). The identification of a theory-practice gap in the education of Biomedical Scientists is a novel finding, indicating that students may graduate with insufficient understanding of the Biomedical Scientist role.
Topics: Humans; Biomedical Research; Delphi Technique; Focus Groups; Consensus; Research Personnel; Male; Female
PubMed: 38933755
DOI: 10.3389/bjbs.2024.12629