Integrated Analysis Research Articles

Integrative analysis of the immunological significances of guanylate binding protein family genes in microsatellite stability colorectal cancer

BackgroundMicrosatellite stability (MSS) colorectal cancer (CRC) has poor sensitivity to immunotherapy and its underlying mechanisms are still unclear. Guanylate binding proteins (GBPs) are a family of GTPase involving innate immune responses by providing defense against invading microbes and pathogens. However, the immunological significances of GBPs in MSS CRC remain unknown. MethodsWe utilized bioinformatic tools to comprehensively analysis the expression pattern, clinical relevance, prognostic value, biological function, and immunoregulation effect of distinct GBP members in MSS CRC. ResultsThe expression of all seven GBPs in MSS samples are remarkably decreased compared to microsatellite instability-high (MSI-H) samples. Among them, GBP1/2/4/5 are obviously correlated with distant metastasis status. High expression of GBP1/4/5/6 was remarkably related to favorable overall survival (OS) and progression-free survival (PFS) in CRC patients with MSS tumor. Subsequent enrichment analysis revealed that Interferon-gamma (IFN-γ) and NOD-like receptor signaling are the most relevant functions. Besides, the expression patterns of GBPs are remarkably associated with several tumor infiltrated immune cells (e.g. regulatory T cells, CD4+ T cells, and macrophages) and diverse immunoregulatory molecules (e.g. immune checkpoint biomarkers (ICBs) and major histocompatibility complex (MHC) molecules). Moreover, high GBP1/2/4/5 expression predicted better immunotherapy responsiveness in immunotherapy cohorts. ConclusionThese findings might provide novel insights for the identification of therapeutic targets and potential prognostic biomarkers of GBP family in CRC with MSS samples.

Study on the prediction model of liver cancer based on chronic liver disease and the related molecular mechanism

Introduction and objectiveDue to the high heterogeneity of HCC, which leads to poor prognostic outcomes for patients, there is a need to develop a novel predictive model for accurate classification of HCC in order to improve patient survival rates. Materials and methodsThe data of the HCV, cirrhosis, and HCC were obtained from TCGA and GEO databases. Multivariable Cox regression analysis and survival analysis was conducted to assess the prognostic relevance of these differentially expressed genes. Single-cell sequencing was used to explore the intercellular interaction patterns and identify relevant signaling pathways. Drug sensitivity analysis was conducted to determine personalized treatment strategies for patients. ResultsIn this study, we conducted integrated analysis of hepatitis, cirrhosis, and hepatocellular carcinoma datasets and identified 10 liver disease progression genes associated with prognosis. These genes exhibited significant downregulation in expression as the disease advanced, suggesting their crucial involvement in HCC development. By performing multivariable Cox analysis, we established a prognostic model for liver disease progression to predict the prognosis of HCC patients. The model was validated using ROC analysis, demonstrating good accuracy and stability in prognostic evaluation. Single-cell sequencing analysis revealed that these genes primarily exert their effects through the MIF signaling pathway during HCC progression. Furthermore, we observed that patients in the low-risk group exhibited higher sensitivity to TACE treatment, while patients in the high-risk group showed better response to sorafenib treatment. ConclusionsIn summary, we have elucidated the key genes involved in the progression of liver diseases and established a precise prognostic model for assessing the prognosis of HCC patients. Our study provides novel insights and strategies for the treatment of HCC.

A new sexually dimorphic Diploechiniscus species (Tardigrada: Echiniscidae) from Calvert Island (British Columbia, Canada)

An important, but generally overlooked source in intraspecific variability of characters used in tardigrades taxonomy is sexual dimorphism. Dioecious tardigrades species with unisexual or bisexual populations are common, but external sexual dimorphism is rarely observed. The discovery and integrative analysis of a Diploechiniscus species population with high sexual dimorphism from Calvert Island (Canada) has allowed its description as a new species. Diploechiniscus dimorphus n. sp. is characterized by a different chaetotaxy in males and females, and by enlarged cephalic sensory appendages in the males. The discovery of this new species shows that it is important to consider sexual dimorphism as a source of intraspecific variability in tardigrade taxonomy due to its implications on the use of traits commonly used to delineate species such as chaetotaxy. Lastly, the finding of individuals of Diploechiniscus horningi ( Schuster and Grigarick, 1971 ), a species previously synonymized with Diploechiniscus oihonnae ( Richters, 1903 ), allows us to prove that it is genetically a separate species and to reinstate it.

1956P Integrative analysis of 26848 human transcriptomes reveals cancer-defining transcriptional architecture at the isoform resolution

1956P Integrative analysis of 26848 human transcriptomes reveals cancer-defining transcriptional architecture at the isoform resolution

Integrated ultrasensitive metabolomics and single-cell transcriptomics identify crucial regulators of sheep oocyte maturation and early embryo development in vitro

IntroductionDevelopmental competence of oocytes matured in vitro is limited due to a lack of complete understanding of metabolism and metabolic gene expression during oocyte maturation and embryo development. Conventional metabolic analysis requires a large number of samples and is not efficiently applicable in oocytes and early embryos, thereby posing challenges in identifying key metabolites and regulating their in vitro culture system. ObjectivesTo enhance the developmental competence of sheep oocytes, this study aimed to identify and supplement essential metabolites that were deficient in the culture systems. MethodsThe metabolic characteristics of oocytes and embryos were determined using ultrasensitive metabolomics analysis on trace samples and single-cell RNA-seq. By conducting integrated analyses of metabolites in cells (oocytes and embryos) and their developmental microenvironment (follicular fluid, oviductal fluid, and in vitro culture systems), we identified key missing metabolites in the in vitro culture systems. In order to assess the impact of these key missing metabolites on oocyte development competence, we performed in vitro culture experiments. Furthermore, omics analyses were employed to elucidate the underlying mechanisms. ResultsOur findings demonstrated that betaine, carnitine and creatine were the key missing metabolites in vitro culture systems and supplementation of betaine and L-carnitine significantly improved the blastocyst formation rate (67.48% and 48.61%). Through in vitro culture experiments and omics analyses, we have discovered that L-carnitine had the potential to promote fatty acid oxidation, reduce lipid content and lipid peroxidation level, and regulate spindle morphological grade through fatty acid degradation pathway. Additionally, betaine may participate in methylation modification and osmotic pressure regulation, thereby potentially improving oocyte maturation and early embryo development in sheep. ConclusionTogether, these analyses identified key metabolites that promote ovine oocyte maturation and early embryo development, while also providing a new viewpoint to improve clinical applications such as oocyte maturation or embryo culture.

Ichnological indicators of physico-chemical stresses in wave- to tide-dominated Miocene shallow marine environments (argentine Patagonia)

An integrated analysis of ichnological and sedimentological features in ancient successions provides for a robust dataset for high-resolution interpretations of environmental parameters, encompassing both depositional and ecological aspects. By characterizing discrete and recurring bioturbation patterns in the Puerto Madryn Formation (Late Miocene, Argentine Patagonia), we arrive at key knowledge about predominant environmental stresses within transgressive phase shallow marine and estuarine systems, shedding light on their palaeoenvironmental implications. Given the inherent complexities of coastal settings, including the challenges posed by omission/erosion surfaces, it becomes imperative to consider the intricate interplay of multiple depositional processes and environmental factors.Through a detailed integration of sedimentological and ichnological approaches, we discern the establishment of a wave-dominated system overlain by a tide-dominated estuarine system.The wave-dominated marine system involves tabular bodies extending laterally over tens of kilometres, with upward fining and coarsening successions from the mid- to lower-shoreface to offshore-shelf environments. The influence of waves and tides on these systems is discussed in the absence of physical sedimentary structures and the need to find elements that bring us closer to elucidating whether waves or tidal processes influence shoreface to offshore systems. The ichnological assemblages allow for the characterization of Cruziana ichnofacies with proximal (Taenidium and Thalassinoides), archetypal (Asterosoma, Chondrites, Cylindrichnus, Ophiomorpha,?Rhizocorallium, Rosselia, Scolicia, Sinusichnus, Siphonichnus, Teichichnus, and Thalassinoides), and distal expressions (Chondrites, Helicodromites, Phycodes, Thalassinoides, and?Zoophycos) in the lower shoreface to lower offshore and transitional settings with the shelf. However, the transition from these deposits to Chondrites-dominated beds associated with lower offshore to shelf environments —determined by changes in oxygenation, nutrients, and energy conditions— impedes assignment of all the successions to a particular ichnofacies.The tide-dominated estuarine system features wide, channel-shaped bodies filled with sandy to heterolithic facies, are interpreted as intertidal and subtidal deposits. To differentiate between estuary mouths and other settings, the analysis involved characterization of transgressive and regressive surfaces, ichnological assemblages, and facies distribution, determining net sediment movement —whether landward or seaward— and its influence on system classification. The ichnological assemblages could be assigned to the Skolithos (Arenicolites, Gyrolithes, Maiakarichnus, Ophiomorpha, Schaubcylindrichnus, Skolithos, and Thalassinoides) and Cruziana ichnofacies (Ophiomorpha, Rosselia, Scolicia, and Siphonichnus). Variations in diversity and abundance often help to determine certain stressful conditions, although the transition to more open areas is discussed, addressing how it could modify the typical models linked with a direct relationship between abundance/diversity and physico-chemical stress.

Overexpression of SLC2A1, ALDOC, and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids.

The 3D multicellular tumor spheroid (MTS) model exhibits enhanced fidelity in replicating the tumor microenvironment and demonstrates exceptional resistance to clinical drugs compared to the 2D monolayer model. In this study, we used multiomics (transcriptome, proteomics, and metabolomics) tools to explore the molecular mechanisms and metabolic differences of the two culture models. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways revealed that the differentially expressed genes between the two culture models were mainly enriched in cellular components and biological processes associated with extracellular matrix, extracellular structural organization, and mitochondrial function. An integrated analysis of three omics data revealed 11 possible drug resistance targets. Among these targets, seven genes, AKR1B1, ALDOC, GFPT2, GYS1, LAMB2, PFKFB4, and SLC2A1, exhibited significant upregulation. Conversely, four genes, COA7, DLD, IFNGR1, and QRSL1, were significantly downregulated. Clinical prognostic analysis using the TCGA survival database indicated that high-expression groups of SLC2A1, ALDOC, and PFKFB4 exhibited a significant negative correlation with patient survival. We further validated their involvement in chemotherapy drug resistance, indicating their potential significance in improving prognosis and chemotherapy outcomes. These results provide valuable insights into potential therapeutic targets that can potentially enhance treatment efficacy and patient outcomes.

281. PROTEOMIC, TRANSCRIPTOMIC AND GENOMIC ANALYSIS OF ESOPHAGEAL ADENOCARCINOMA UNCOVERS CANDIDATE THERAPEUTIC TARGETS AND CANCER-SELECTIVE POST-TRANSCRIPTIONAL REGULATION

Abstract Background Addressing the poor prognosis associated with esophageal adenocarcinoma (EAC) has been hindered by the absence of biomarkers for early disease detection and therapeutic targets. Despite extensive research on the somatic mutations associated with EAC, the impact of genomic aberrations on protein expression and cancer phenotype remains unclear. Methods We conducted a quantitative proteomic analysis using tumour tissue and patient-matched adjacent normal esophageal and gastric tissues from 23 patients undergoing resection for EAC. We further examined the relationship between transcript and protein levels using patient-matched whole transcriptome RNA sequencing and proteomic data from 7 patients and integrated these findings with data from a cohort of 264 EAC patients with RNA sequencing and 454 patients with whole-genome sequencing, as well as external published datasets. Results We quantified protein expression from 5897 genes in EAC and normal tissues. Several potential biomarkers showing selective expression in EAC, such as the transmembrane protein GPA33, were identified. We validated the EAC-specific expression of GPA33 in an external cohort of 115 patients, suggesting its utility as a diagnostic and therapeutic target. Additionally, integrated analysis of protein and RNA expression in EAC and normal tissues revealed genes with discordant protein and RNA levels, indicating post-transcriptional regulation of protein expression. These outlier genes, including SLC25A30, TAOK2, and AGMAT, exhibited rare somatic mutations, suggesting post-transcriptional mechanisms driving this EAC-specific phenotype. AGMAT, as an example, was found to be overexpressed at the protein level in EAC compared to adjacent normal tissues, with a proposed EAC-selective, post-transcriptional mechanism regulating protein abundance. Conclusion Through quantitative proteomic analysis, we identified GPA33 as a candidate EAC biomarker. Integrated analysis of the proteome, transcriptome, and genome in EAC uncovered genes with tumor-selective post-transcriptional regulation of protein expression, offering potential exploitable vulnerabilities for therapeutic intervention.

53535 Integrative Analysis of Intermediate-to-High Risk Cutaneous Squamous Cell Carcinoma (cSCC)

53535 Integrative Analysis of Intermediate-to-High Risk Cutaneous Squamous Cell Carcinoma (cSCC)

Regulatory mechanisms orchestrating cellular diversity of Cd36+ olfactory sensory neurons revealed by scRNA-seq and scATAC-seq analysis

Recent discoveries have revealed remarkable complexity within olfactory sensory neurons (OSNs), including the existence of two OSN populations based on the expression of Cd36. However, the regulatory mechanisms governing this cellular diversity in the same cell type remain elusive. Here, we show the preferential expression of 79 olfactory receptors in Cd36+ OSNs and the anterior projection characteristics of Cd36+ OSNs, indicating the non-randomness of Cd36 expression. The integrated analysis of single-cell RNA sequencing (scRNA-seq) and scATAC-seq reveals that the differences in Cd36+/- OSNs occur at the immature OSN stage, with Mef2a and Hdac9 being important regulators of developmental divergence. We hypothesize that the absence of Hdac9 may affect the activation of Mef2a, leading to the up-regulation of Mef2a target genes, including teashirt zinc finger family member 1 (Tshz1), in the Cd36+ OSN lineage. We validate that Tshz1 directly promotes Cd36 expression through enhancer bindings. Our study unravels the intricate regulatory landscape and principles governing cellular diversity in the olfactory system.

Integrated analysis reveals an aspartate metabolism-related gene signature for predicting the overall survival in patients with hepatocellular carcinoma.

Deregulating cellular metabolism is one of the prominent hallmarks of malignancy, with a critical role in tumor survival and growth. However, the role of reprogramming aspartate metabolism in hepatocellular carcinoma (HCC) are largely unknown. The multi-omics data of HCC patients were downloaded from public databases. Univariate and multivariate stepwise Cox regression were used to establish an aspartate metabolism-related gene signature (AMGS) in HCC. The Kaplan-Meier and receiver operating characteristic curve analyses were performed to evaluate the predictive ability for overall survival (OS) in HCC patients. Gene set enrichment analysis and immune infiltration analysis were operated to determine the potential mechanisms underlying the AMGS. Single-cell RNA sequencing (scRNA-seq) data of liver cancer stem cells were visualized by t-SNE algorithm. In vivo and in vitro experiments were implemented to investigate the biological function of CAD in HCC. In addition, a nomogram based on the AMGS and clinicopathologic characteristics was constructed by univariate and multivariate Cox regression analyses. Patients in the high-AMGS subgroup exerted advanced tumor status and poor prognosis. Mechanistically, the high-AMGS subgroup patients had significantly enhanced proliferation and stemness-related pathways, increased infiltration of regulatory T cells and upregulated expression levels of suppressive immune checkpoints in the tumor immune microenvironment. Notably, scRNA-seq data revealed CAD, one of the aspartate metabolism-related gene, is significantly upregulated in liver cancer stem cells. Silencing CAD inhibited proliferative capacity and stemness properties of HCC cells in vitro and in vivo. Finally, a novel nomogram based on the AMGS showed an accurate prediction in HCC patients. The AMGS represents a promising prognostic value for HCC patients, providing a perspective for finding novel biomarkers and therapeutic targets for HCC.

Mechanical integrity analysis of caprock during the CO2 injection phase

Abstract CO2 geological storage is one of the important means to mitigate the greenhouse effect. The safe underground storage of CO2 largely depends on the mechanical integrity of the caprock. This paper establishes a fluid-solid coupling model for CO2 geological storage to study the changes in pore pressure, vertical displacement, and effective stress in the caprock during the CO2 injection process. Combined with the Mohr-Coulomb criterion, the study determines whether mechanical failure occurs in the caprock. The results indicate that, at the beginning of CO2 injection, significant changes occur in the pore pressure, vertical displacement, and effective stress at the bottom of the caprock near the injection well, which then tend to stabilize; the maximum pore pressure at the bottom of the caprock reaches 36.08 MPa; the caprock near the injection well is considered the most critical area, where the risk of mechanical failure is highest; at the end of CO2 injection, the stress state does not reach the limit, and the caprock remains stable.

57P Integrative analysis of the genomic and transcriptomic landscape identifies ciliary genes as a therapeutic target in bile duct cancer

57P Integrative analysis of the genomic and transcriptomic landscape identifies ciliary genes as a therapeutic target in bile duct cancer

Towards circular manufacturing systems implementation: An integrated analysis framework for circular supply chains

The transition to circular manufacturing systems (CMS) is crucial for achieving sustainable growth, addressing the environmental concerns and resource scarcity challenges. Shifting towards CMS requires a systemic approach that integrates value proposition models, product design, and supply chains (SCs). Circular supply chains (CSCs) emerge as a core pillar of CMS, incorporating value delivery, use, recovery, and reuse. CSCs are inherently more complex and dynamic than linear SCs requiring a holistic analysis approach to capture their complex and dynamic attributes. This research proposes an integrated analysis framework combining qualitative and quantitative approaches to explore the complexities and dynamics of CSCs and assess their economic, environmental, and technical performance. Through the lens of two different CMS implementation case studies, one in automotive parts remanufacturing and one in white goods manufacturing, this research illustrates the framework's applicability. In the automotive case, centralizing core management activities was found to improve economic performance by 50-54 %. However, the introduction of regional logistics hubs, while economically efficient, led to a 20 % increase in CO2-equivalent emissions. On the other hand, the white goods case study highlighted the trade-offs in centralizing end-of-life recovery facilities, where financial savings of up to 60 % were offset by increased transportation costs and increased CO2 emissions. The analysis of CSCs in these two distinct manufacturing sectors underscores the relevance and flexibility of the proposed framework, providing decision-makers with a tool to examine how different CSCs configurations and strategies impact overall performance. This guidance is crucial for developing optimal CSCs design and implementation strategies.

Dissecting the molecular basis of the ultra-large grain formation in rice.

The shape of rice grains not only determines the thousand-grain weight but also correlates closely with the grain quality. Here we identified an ultra-large grain accession (ULG) with a thousand-grain weight exceeding 60 g. The integrated analysis of QTL, BSA, de novo genome assembled, transcription sequencing, and gene editing was conducted to dissect the molecular basis of the ULG formation. The ULG pyramided advantageous alleles from at least four known grain-shaping genes, OsLG3, OsMADS1, GS3, GL3.1, and one novel locus, qULG2-b, which encoded a leucine-rich repeat receptor-like kinase. The collective impacts of OsLG3, OsMADS1, GS3, and GL3.1 on grain size were confirmed in transgenic plants and near-isogenic lines. The transcriptome analysis identified 112 genes cooperatively regulated by these four genes that were prominently involved in photosynthesis and carbon metabolism. By leveraging the pleiotropy of these genes, we enhanced the grain yield, appearance, and stress tolerance of rice var. SN265. Beyond showcasing the pyramiding of multiple grain size regulation genes that can produce ULG, our study provides a theoretical framework and valuable genomic resources for improving rice variety by leveraging the pleiotropy of grain size regulated genes.

Educational Interventions for Individuals with Insulin-Treated Type 2 Diabetes Mellitus: A Systematic Review.

To evaluate and synthesize evidence on the impact of educational interventions for individuals with insulin-treated type 2 diabetes mellitus (T2DM). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, five electronic databases (Scopus, PubMed, Medline, CINAHL Plus with Full Text, and Web of Science) were systematically searched in February 2024. The search focused on studies published between 2019 and 2024 that investigated the impact of educational interventions on individuals with insulin-treated T2DM. Reference lists of the included studies were also manually searched. Titles and abstracts were screened for eligibility, and relevant full texts were assessed. Out of 1,032 identified records, 11 studies met the inclusion criteria. According to the data synthesized using a convergent integrated analysis framework, five major themes have emerged: 1) Glycemic control (including subthemes improving HbA1C, decreasing postprandial plasma glucose, and decreasing fasting plasma glucose), 2) Insulin-related complications (including subthemes reducing hypoglycemic events and reducing the size of lipohypertrophy), 3) Knowledge, Attitude, and Practice (including subthemes engaging in self-management, improving insulin injection technique, improving knowledge, and improving attitude toward insulin treatment), 4) Optimal dose of insulin, and 5) Improving quality of life. Educational interventions are crucial for improving diabetes-related outcomes and reducing complications in individuals with insulin-treated T2DM. These interventions enhance knowledge, attitudes, and self-management practices, leading to better glycemic control and quality of life. Healthcare settings should develop and provide tailored educational programs for individuals with insulin-treated T2DM to optimize outcomes and minimize complications.

Integrative analysis of long isoform sequencing and functional data identifies distinct cortical layer neuronal subtypes derived from human iPSCs.

Generation of human induced pluripotent stem cells (iPSCs) through reprogramming was a transformational change in the field of regenerative medicine that led to new possibilities for drug discovery and cell replacement therapy. Several protocols have been established to differentiate hiPSCs into neuronal lineages. However, low differentiation efficiency is one of the major drawbacks of these approaches. Here, we compared the efficiency of two methods of neuronal differentiation from iPSCs cultured in two different culture media, StemFlex Medium (SFM) and Essential 8 Medium (E8M). The results indicated that iPSCs cultured in E8M efficiently generated different types of neurons in a shorter time and without the growth of undifferentiated nonneuronal cells in the culture as compared with those generated from iPSCs in SFM. Furthermore, these neurons were validated as functional units immunocytochemically by confirming the expression of mature neuronal markers (i.e., NeuN, β tubulin, and Synapsin I) and whole cell patch-clamp recordings. Long-read single-cell RNA sequencing confirms the presence of upper and deep layer cortical layer excitatory and inhibitory neuronal subtypes in addition to small populations of GABAergic neurons in day 30 neuronal cultures. Pathway analysis indicated that our protocol triggers the signaling transcriptional networks important for the process of neuronal differentiation in vivo.NEW & NOTEWORTHY Low differentiation efficiency is one of the major drawbacks of the existing protocols to differentiate iPSCs into neuronal lineages. Here, we present time-efficient and robust approach of neuronal differentiation leading to the generation of functional brain units, cortical layer neurons. We found iPSCs cultured in Essential 8 media (E8M) resulted in neuronal differentiation without the signs of growth of spontaneously differentiated cells in culture at any point in 35 days compared with Stemflex media (SFM).

OS03-10 Early biomarkers of cancer susceptibility in benzene-exposed workers: integrated analysis of gene expression, microRNA alterations, and DNA methylation datasets

OS03-10 Early biomarkers of cancer susceptibility in benzene-exposed workers: integrated analysis of gene expression, microRNA alterations, and DNA methylation datasets

Integrative analysis of the efficacy and pharmacological mechanism of Xuefu Zhuyu decoction in idiopathic pulmonary fibrosis via evidence-based medicine, bioinformatics, and experimental verification

Integrative analysis of the efficacy and pharmacological mechanism of Xuefu Zhuyu decoction in idiopathic pulmonary fibrosis via evidence-based medicine, bioinformatics, and experimental verification

Age-dependent genetic architectures of chicken body weight explored by multidimensional GWAS and molQTL analyses

Chicken body weight (BW) is a critical trait in breeding. Although genetic variants associated with BW have been investigated by genome-wide association studies (GWAS), the contributions of causal variants and their molecular mechanisms remain largely unclear in chickens. In this study, we construct a comprehensive genetic atlas of chicken BW by an integrative analysis of 30 age points and 5 quantitative trait loci (QTL) across 27 tissues. We find that chicken growth is a cumulative non-linear process, which can be divided into three distinct stages. Our GWAS analysis reveals that BW-related genetic variations show ordered patterns in these three stages. Genetic variations in chromosome 1 may regulate the overall growth process, likely by modulating the hypothalamus-specific expression of SLC25A30 and retina-specific expression of NEK3. Moreover, genetic variations in chromosome 4 and chromosome 27 may play dominant roles in regulating BW during stage Ⅱ (8-22 weeks) and stage Ⅲ (23-72 weeks), respectively. In summary, our study presents a comprehensive genetic atlas regulating developmental stage-specific changes in chicken BW, thus providing important resources for genomic selection in breeding programs.