Systematic investigation of global coordination among mRNA and protein in cellular society

<p>Abstract</p> <p>Background</p> <p>Cell functions depend on molecules organized in the cellular society. Two basic components are mRNA molecules and proteins. The interactions within and between those two components are crucial for carrying out sophisticated cell functions. The interplay can be analyzed by comparing expression levels of mRNA and proteins. This is critical for understanding the molecular interactions, (post-) transcriptional regulations and conservation of co-expression between mRNAs and proteins. By using high-throughput transcriptome and proteome data, this study aims to systematically investigate the general picture of such expression correlations. We analyze four groups of correlations: (i) transcript levels of different genes, (ii) protein levels of different genes, (iii) mRNA levels with protein levels of different genes and (iv) mRNA levels with protein levels of same genes. This helps to obtain global insights into the stability and variability of co-expression and correlation of mRNA and protein levels.</p> <p>Results</p> <p>Analysis of the simultaneous co-expression of mRNAs and proteins yields mainly weak correlations. Therefore we introduce the concept of time-delayed co-expression patterns. Based on a time-course dataset, we obtain a high fraction of time-delayed correlations. In group (i), 67% of different transcripts are significantly correlated. At the protein level (ii), 68% of different proteins are significantly correlated. Comparison of the different molecular levels results in a 74% fraction of correlated transcript and protein levels of different genes (iii) and 56% for the same genes (iv). Furthermore, a higher fraction of protein levels (simultaneously 20% and short time-delayed 29%) is correlated than at the transcript level (10% and 18% respectively). Analysis of the dynamics of the correlation shows that correlation at the transcript level is largely passed to the protein level. In contrast, specific co-expression patterns are changed in multiple ways.</p> <p>Conclusions</p> <p>Our analysis reveals that the regulation of transcription and translation contains a time-delayed component. The correlation at the protein level is more synchronous or delayed by shorter time than those at the transcript level. This supports the hypothesis that a higher degree of direct physical interactions require a higher synchronicity between the interacting partners. The conservation of correlation between the transcript level (i) and the protein level (ii) sheds light on the processes underlying transcription, translation and regulation. A future investigation of the conditions of conservation will give comprehensive insights in the complexity of the regulatory mechanisms.</p

FH535, a β-catenin Pathway Inhibitor, Represses Pancreatic Cancer Xenograft Growth and Angiogenesis

The WNT/β-catenin pathway plays an important role in pancreatic cancer carcinogenesis. We evaluated the correlation between aberrant β-catenin pathway activation and the prognosis pancreatic cancer, and the potential of applying the β-catenin pathway inhibitor FH535 to pancreatic cancer treatment. Meta-analysis and immunohistochemistry showed that abnormal β-catenin pathway activation was associated with unfavorable outcome. FH535 repressed pancreatic cancer xenograft growth in vivo. Gene Ontology (GO) analysis of microarray data indicated that target genes responding to FH535 participated in stemness maintenance. Real-time PCR and flow cytometry confirmed that FH535 downregulated CD24 and CD44, pancreatic cancer stem cell (CSC) markers, suggesting FH535 impairs pancreatic CSC stemness. GO analysis of β-catenin chromatin immunoprecipitation sequencing data identified angiogenesis-related gene regulation. Immunohistochemistry showed that higher microvessel density correlated with elevated nuclear β-catenin expression and unfavorable outcome. FH535 repressed the secretion of the proangiogenic cytokines vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, and tumor necrosis factor-α, and also inhibited angiogenesis in vitro and in vivo. Protein and mRNA microarrays revealed that FH535 downregulated the proangiogenic genes ANGPT2, VEGFR3, IFN-γ, PLAUR, THPO, TIMP1, and VEGF. FH535 not only represses pancreatic CSC stemness in vitro, but also remodels the tumor microenvironment by repressing angiogenesis, warranting further clinical investigation

From multi-omics approaches to personalized medicine in myocardial infarction

Myocardial infarction (MI) is a prevalent cardiovascular disease characterized by myocardial necrosis resulting from coronary artery ischemia and hypoxia, which can lead to severe complications such as arrhythmia, cardiac rupture, heart failure, and sudden death. Despite being a research hotspot, the etiological mechanism of MI remains unclear. The emergence and widespread use of omics technologies, including genomics, transcriptomics, proteomics, metabolomics, and other omics, have provided new opportunities for exploring the molecular mechanism of MI and identifying a large number of disease biomarkers. However, a single-omics approach has limitations in understanding the complex biological pathways of diseases. The multi-omics approach can reveal the interaction network among molecules at various levels and overcome the limitations of the single-omics approaches. This review focuses on the omics studies of MI, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, and other omics. The exploration extended into the domain of multi-omics integrative analysis, accompanied by a compilation of diverse online resources, databases, and tools conducive to these investigations. Additionally, we discussed the role and prospects of multi-omics approaches in personalized medicine, highlighting the potential for improving diagnosis, treatment, and prognosis of MI

Investigation of the Acetylation Mechanism by GCN5 Histone Acetyltransferase

The histone acetylation of post-translational modification can be highly dynamic and play a crucial role in regulating cellular proliferation, survival, differentiation and motility. Of the enzymes that mediate post-translation modifications, the GCN5 of the histone acetyltransferase (HAT) proteins family that add acetyl groups to target lysine residues within histones, has been most extensively studied. According to the mechanism studies of GCN5 related proteins, two key processes, deprotonation and acetylation, must be involved. However, as a fundamental issue, the structure of hGCN5/AcCoA/pH3 remains elusive. Although biological experiments have proved that GCN5 mediates the acetylation process through the sequential mechanism pathway, a dynamic view of the catalytic process and the molecular basis for hGCN5/AcCoA/pH3 are still not available and none of theoretical studies has been reported to other related enzymes in HAT family. To explore the molecular basis for the catalytic mechanism, computational approaches including molecular modeling, molecular dynamic (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) simulation were carried out. The initial hGCN5/AcCoA/pH3 complex structure was modeled and a reasonable snapshot was extracted from the trajectory of a 20 ns MD simulation, with considering post-MD analysis and reported experimental results. Those residues playing crucial roles in binding affinity and acetylation reaction were comprehensively investigated. It demonstrated Glu80 acted as the general base for deprotonation of Lys171 from H3. Furthermore, the two-dimensional QM/MM potential energy surface was employed to study the sequential pathway acetylation mechanism. Energy barriers of addition-elimination reaction in acetylation obtained from QM/MM calculation indicated the point of the intermediate ternary complex. Our study may provide insights into the detailed mechanism for acetylation reaction of GCN5, and has important implications for the discovery of regulators against GCN5 enzymes and related HAT family enzymes

Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary

AbstractThe indifferent mammalian embryonic gonad generates an ovary or testis, but the factors involved are still poorly known. The Wnt-4 signal represents one critical female determinant, since its absence leads to partial female-to-male sex reversal in mouse, but its signalling is as well implicated in the testis development. We used the Wnt-4 deficient mouse as a model to identify candidate gonadogenesis genes, and found that the Notum, Phlda2, Runx-1 and Msx1 genes are typical of the wild-type ovary and the Osr2, Dach2, Pitx2 and Tacr3 genes of the testis. Strikingly, the expression of these latter genes becomes reversed in the Wnt-4 knock-out ovary, suggesting a role in ovarian development. We identified the transcription factor Runx-1 as a Wnt-4 signalling target gene, since it is expressed in the ovary and is reduced upon Wnt-4 knock-out. Consistent with this, introduction of the Wnt-4 signal into early ovary cells ex vivo induces Runx-1 expression, while conversely Wnt-4 expression is down-regulated in the absence of Runx-1. We conclude that the Runx-1 gene can be a Wnt-4 signalling target, and that Runx-1 and Wnt-4 are mutually interdependent in their expression. The changes in gene expression due to the absence of Wnt-4 in gonads reflect the sexually dimorphic role of this signal and its complex gene network in mammalian gonad development

The management of change: Strategic design for historic urban quarters of Guangzhou

This paper will discuss the conflict between designers and other actors in urban regeneration processes in China’s historic quarters. It does this because the role of mediation is missing. Based on observation and analysis, it will be shown how urban design can address this problem, both theoretically and in practice.As an increasingly popular discipline, urban design has been having a positive role in urban-regeneration processes in the West. However, this is not the case in the Chinese context. Urban planning and architecture have not been using mediation to try and solve the conflicts that can arise where there is urban regeneration. From a theoretical perspective, urban designers’ roles as potential mediators in regeneration processes will be highlighted by a review of relevant literature; while from a practical perspective, the potential of mediating, and creating dialogues of urban design, will be analyzed and tested by my thesis design project later on.The main aim of this paper (and my graduation project) is to address the theoretical gap that exists regarding mediation within existing professional approaches (namely urban planning and architecture), and at the same time provide an alternative regeneration model for historic urban quarters in China.Design of the urban fabricArchitecture, Urbanism and Building Sciences | Design of the Urban Fabri

Performance of ChatGPT on Chinese national medical licensing examinations: a five-year examination evaluation study for physicians, pharmacists and nurses

Abstract Background Large language models like ChatGPT have revolutionized the field of natural language processing with their capability to comprehend and generate textual content, showing great potential to play a role in medical education. This study aimed to quantitatively evaluate and comprehensively analysis the performance of ChatGPT on three types of national medical examinations in China, including National Medical Licensing Examination (NMLE), National Pharmacist Licensing Examination (NPLE), and National Nurse Licensing Examination (NNLE). Methods We collected questions from Chinese NMLE, NPLE and NNLE from year 2017 to 2021. In NMLE and NPLE, each exam consists of 4 units, while in NNLE, each exam consists of 2 units. The questions with figures, tables or chemical structure were manually identified and excluded by clinician. We applied direct instruction strategy via multiple prompts to force ChatGPT to generate the clear answer with the capability to distinguish between single-choice and multiple-choice questions. Results ChatGPT failed to pass the accuracy threshold of 0.6 in any of the three types of examinations over the five years. Specifically, in the NMLE, the highest recorded accuracy was 0.5467, which was attained in both 2018 and 2021. In the NPLE, the highest accuracy was 0.5599 in 2017. In the NNLE, the most impressive result was shown in 2017, with an accuracy of 0.5897, which is also the highest accuracy in our entire evaluation. ChatGPT’s performance showed no significant difference in different units, but significant difference in different question types. ChatGPT performed well in a range of subject areas, including clinical epidemiology, human parasitology, and dermatology, as well as in various medical topics such as molecules, health management and prevention, diagnosis and screening. Conclusions These results indicate ChatGPT failed the NMLE, NPLE and NNLE in China, spanning from year 2017 to 2021. but show great potential of large language models in medical education. In the future high-quality medical data will be required to improve the performance

Prostate cancer management with lifestyle intervention: From knowledge graph to Chatbot

Abstract Background Personal lifestyle is an important cause of prostate cancer (PCa), hence establishing a corresponding knowledge graph (KG) and a chatbot is a convenient way for preventing and assessing risks. The chatbot based on a KG of PCa‐associated lifestyles will be helpful to PCa management, then save health care resources in the ageing society. Results Based on our established knowledge base, we define entities and corresponding relationships to construct the PCa‐associated lifestyles KG for visualization by importing the triples into the Neo4j graph server. The dialogue system uses the Flask framework to determine the classification of questions through entity recognition and relationship extraction and later uses the query template to search the answers from the PCa‐associated lifestyles KG. The PCa‐associated lifestyles KG contains 11 types of entities and 14 types of relationships, the total number of nodes and links is 21 546 and 66 493, respectively. Also, the entity “Lifestyle”, “Paper”, “Baseline” and “Outcome” contain multiple attributes. The established chatbot can answer 12 types of basic questions and predict the probability of a certain lifestyle resulting in a certain PCa. The chatbot is available at http://sysbio.org.cn:5000/Pca/chatbot. Conclusion A chatbot based on PCa‐associated lifestyles KG was constructed to help researchers, physicians or patients learn more about PCa lifestyle management interactively