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2022 ◽  
Author(s):  
Nurcan Tuncbag ◽  
Seyma Unsal Beyge

Abstract Heterogeneity across tumors is the main obstacle in developing treatment strategies. Drug molecules not only perturb their immediate protein targets but also modulate multiple signaling pathways. In this study, we explored the networks modulated by several drug molecules across multiple cancer cell lines by integrating the drug targets with transcriptomic and phosphoproteomic data. As a result, we obtained 236 reconstructed networks covering five cell lines and 70 drugs. A rigorous topological and pathway analysis showed that chemically and functionally different drugs may modulate overlapping networks. Additionally, we revealed a set of tumor-specific hidden pathways with the help of drug network models that are not detectable from the initial data. The difference in the target selectivity of the drugs leads to disjoint networks despite sharing the exact mechanism of action, e.g., HDAC inhibitors. We also used the reconstructed network models to study potential drug combinations based on the topological separation, found literature evidence for a set of drug pairs. Overall, the network-level exploration of the drug perturbations may potentially help optimize treatment strategies and suggest new drug combinations.


2022 ◽  
Vol 12 ◽  
Author(s):  
Xiaofei Shang ◽  
Xinghui Yuan ◽  
Lixia Dai ◽  
Yang Liu ◽  
Jian He ◽  
...  

Ruangan granules (RGGs) have been used to treat liver fibrosis with good clinical efficacy for many years. However, the potential mechanism of action of RGGs against liver fibrosis is still unclear. In this study, we evaluated the quality and safety of this preparation and aimed to explore the anti-liver fibrosis activity and potential mode of action of RGGs using network pharmacology and metabolomics. The results showed that RGGs contained abundant ferulic acid, salvianolic acid B and paeoniflorin, and at the given contents and doses, RGGs were safe and presented anti-liver fibrosis activity. They presented anti-liver fibrosis activity by improving liver function (ALT and AST, p < 0.01) and pathology and decreasing fibrosis markers in the serum of rats caused by CCl4, including HA, LN, PC III, HYP, CoII-V, and α-SMA, and the oxidant stress and inflammatory response were also alleviated in a dose-dependent manner, especially for high-dose RGGs (p < 0.01). Further studies showed that RGGs inhibited the activation of the PI3K-Akt signaling pathway in rats induced by CCl4, regulated pyrimidine metabolism, improved oxidative stress and the inflammatory response by regulating mitochondrial morphology, and alleviated liver fibrosis. Luteolin, quercetin, morin and kaempferol were active compounds and presented the cytotoxicity toward to LX-02 cells. This study provides an overall view of the mechanism underlying the action of RGGs protecting against liver fibrosis.


2022 ◽  
Vol 30 (12) ◽  
pp. 32-47
Author(s):  
E. M. Kharlanova ◽  
E. V. Shirokova ◽  
O. V. Besschetnova ◽  
A. B. Fedulova

Currently, in the context of the transition to hybrid education, new network forms of communication and interaction of teachers, students as well as specialists are in demand in the framework of personnel training, research and professional activities. The article reveals the main aspects of the integrated network community for training professionals working with youth in the field of educational and youth social policy. Network community can be viewed as an important resource for the development of both the participants themselves and the specific professional sphere. The purpose of the article is to describe the conceptual framework of a professional network community for training personnel for working with youth in the context of social, educational and youth policy and identify the prerequisites for its creation.In the course of the work, we used such methods as structural and functional analysis, system synthesis, modeling and an online survey. The sample comprised university students, faculty members, and youth workers (n = 147) from six federal districts of Russia.The conceptual framework of the professional network community presented on the basis of systemic-synergetic and constructive methodological approaches enables 1) to formulate its idea as a collaboration for personnel training, scientific research, joint projects implementation and self-development of participants; 2) to identify systemic contradictions, the solution of which is directed by the interaction of community members; 3) to determine the axiological basis, purpose, objectives and stages of deployment; 4) to identify the degree of its relevance, the presence of common interests among all its participants on the basis of the results of empirical research that may be useful in the professional network communities design.


Author(s):  
Ashish H Shah ◽  
Robert Suter ◽  
Pavan Gudoor ◽  
Tara T Doucet-O’Hare ◽  
Vasileios Stathias ◽  
...  

Abstract Background Poor prognosis of glioblastoma patients and the extensive heterogeneity of glioblastoma at both the molecular and cellular level necessitates developing novel individualized treatment modalities via genomics-driven approaches. Methods This study leverages numerous pharmacogenomic and tissue databases to examine drug repositioning for glioblastoma. RNAseq of glioblastoma tumor samples from The Cancer Genome Atlas (TCGA, n=117) were compared to “normal” frontal lobe samples from Genotype-Tissue Expression Portal (GTEX, n=120) to find differentially expressed genes (DEGs). Using compound-gene expression data and drug activity data from the Library of Integrated Network-Based Cellular Signatures (LINCS, n=66,512 compounds) CCLE (71 glioma cell lines), and Chemical European Molecular Biology Laboratory (ChEMBL) platforms, we employed a summarized reversal gene expression metric (sRGES) to “reverse” the resultant disease signature for GBM and its subtypes. A multi-parametric strategy was employed to stratify compounds capable of blood brain barrier penetrance with a favorable pharmacokinetic profile (CNS-MPO). Results Significant correlations were identified between sRGES and drug efficacy in GBM cell lines in both ChEMBL(r=0.37,p<.001) and Cancer Therapeutic Response Portal (CTRP) databases (r=0.35, p<0.001). Our multiparametric algorithm identified two classes of drugs with highest sRGES and CNS-MPO: HDAC inhibitors (vorinostat and entinostat) and topoisomerase inhibitors suitable for drug repurposing. Conclusions Our studies suggest that reversal of glioblastoma disease signature correlates with drug potency for various GBM subtypes. This multiparametric approach may set the foundation for an early-phase personalized -omics clinical trial for glioblastoma by effectively identifying drugs that are capable of reversing the disease signature and have favorable pharmacokinetic and safety profiles.


2021 ◽  
Author(s):  
Shuang Li ◽  
Cancan Qi ◽  
Patrick Deelen ◽  
Floranne Boulogne ◽  
Niek de Klein ◽  
...  

Gene co-expression networks can be used to infer functional relationships between genes, but they do not work well for all genes. We investigated whether DNA methylation can provide complementary information for such genes. We first carried out an eQTM meta-analysis of 3,574 gene expression and methylation samples from blood, brain and nasal epithelial brushed cells to identify links between methylated CpG sites and genes. This revealed 6,067 significant eQTM genes, and we observed that histone modification information is predictive of both eQTM direction and presence, enabling us to link many CpG sites to genes. We then generated a co-methylation network - MethylationNetwork - using 27,720 publicly available methylation profiles and integrated it with a public RNA-seq co-expression dataset of 31,499 samples. Here, we observed that MethylationNetwork can identify experimentally validated interacting pairs of genes that could not be identified in the RNA-seq datasets. We then developed a novel integration pipeline based on CCA and used the integrated methylation and gene networks to predict gene pairs reported in the STRING database. The integrated network showed significantly improved prediction performance compared to using a DNA co-methylation or a gene co-expression network alone. This is the first study to integrate data from two -omics layers from unmatched public samples across different tissues and diseases, and our results highlight the issues and potential of integrating public datasets from multiple molecular phenotypes. The eQTMs we identified can be used as an annotation resource for epigenome-wide association, and we believe that our integration pipeline can be used as a framework for future -omics integration analyses of public datasets. We provide supporting materials and results, including the harmonized DNA methylation data from multiple tissues and diseases in https://data.harmjanwestra.nl/comethylation/, the discovered and predicted eQTMs, the corresponding CCA components and the trained prediction models in a Zenodo repository (https://zenodo.org/record/4666994). We provide notebooks to facilitate use of the proposed pipeline in a GitHub repository (https://github.com/molgenis/methylationnetwork).


2021 ◽  
Vol 30 (4) ◽  
pp. 539-565
Author(s):  
Aaron Bramson ◽  
◽  
Kazuto Okamoto ◽  
Megumi Hori ◽  
◽  
...  

Walkability analyses have gained increased attention for economic, environmental and health reasons, but the methods for assessing walkability have yet to be broadly evaluated. In this paper, five methods for calculating walkability scores are described: in-radius, circle buffers, road network node buffers, road network edge buffers and a fully integrated network approach. Unweighted and various weighted versions are analyzed to capture levels of preference for walking longer distances. The methods are evaluated via an application to train stations in central Tokyo in terms of accuracy, similarity and algorithm performance. The fully integrated network method produces the most accurate results in the shortest amount of processing time, but requires a large upfront investment of time and resources. The circle buffer method runs a bit slower, but does not require any network information and when properly weighted yields walkability scores very similar to the integrated network approach.


2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Sarah Pfoser ◽  
Herbert Kotzab ◽  
Ilja Bäumler

PurposeThe aim of this paper is to offer an overview of the current state of research in a specific field of transport, namely synchromodality. This includes a conceptual discussion of this innovative transport concept to differentiate it from previous concepts as well as the identification of the antecedents, mechanisms and effects of synchromodality.Design/methodology/approachThe paper combines systematic and content analysis-based approaches to literature review to analyse and synthesise a final sample of 88 publications related to synchromodality.FindingsSynchromodality is a transport concept in its infancy which suffers from ambiguous definitions and a lack of theoretical grounding. The paper identifies four mechanisms which differentiate synchromodality from other transport concepts: real-time switching, integrated network planning, horizontal collaboration and mode-free booking. Seven technical and six managerial antecedents for these mechanisms of synchromodality are defined.Research limitations/implicationsExisting research on synchromodality is largely focused on technical antecedents (e.g. information and communication technology, sophisticated planning systems). Suggestions for further research include managerial problems such as business models or measures to induce a mental shift and trust.Originality/valueThis paper gives a structured overview of the research field of synchromodality and presents existing research from a content-focused perspective. It also indicates opportunities for future research and contributes to a generally accepted understanding of synchromodality.


Author(s):  
Olena Oliinyk

Abstract. The article substantiates the need to complete the formation of an integrated network of pedestrian spaces in the historic center of Kiev. Now the historic center covers three hills - the Upper Town, Pechersk and Kiev-Pechersk Lavra. However, the problem of creating an integrated network of pedestrian connections in the historic center of Kyiv has not yet been solved, and its formation is one of the urgent tasks today. After all, the creation of a holistic system of pedestrian ways in the historic city makes it possible to increase its tourist potential and ensure the preservation and development of historical and cultural heritage. The author proposes a method of spatial analysis to assess the state of public spaces in the city. The author's comparative analysis of two cities in the UK confirmed the importance and cost-effectiveness of pedestrian public spaces. It is noted that the existing transport infrastructure of the city of Kyiv does not provide for the formation of new pedestrian zones. The author analyzes the central squares of Kyiv: Independence Square, Troitska, Tolstoy, European, Sofiyska, Mykhailivska, Lvivska and Peremohy Squares in terms of comfortable pedestrian movement and the availability of public places. It turned out that in terms of transport accessibility, they are convenient, but not suitable for pedestrians; by use - have mainly administrative, political functions; sometimes - cultural; by category of comfort - are inconvenient, there are no sanitary conditions, places for sitting, rest, greens; these are mainly transport interchanges; by category of social function - meeting places, commercial spaces; there are no signs of identity. Means of forming a network of pedestrian public spaces and proposals for the design of individual fragments of the city are proposed. The author determines how transit space and stationary spaces are used, whether it is possible to use them as a citywide public space and connect it to the main axis along Volodymyrska and Khreschatyk.


2021 ◽  
Author(s):  
Zalina Ali ◽  
Astriyana Anuar ◽  
Nicolas Grippo ◽  
Nurshahrily Emalin Ramli ◽  
Najmi Rahim

Abstract Aging facilities and increasing complexity in operations (e.g., increasing water cut, slugging, sand or wax production) continue to widen the gap between actual production and the full potential of the field. To enable production optimization scenarios within an integrated system comprises of reservoirs, wells and surface facilities, the application of an integrated network modelling has been applied. The highlight of this paper is the synergy of Integrated Production Network Modelling (IPNM) utilizing Steady State Simulator (PROSPER-GAP) and the Transient Simulator (OLGA) tools to identify potential quick gains through gaslift optimization as well as mid and long-term system optimization alternatives. The synergy enables significant reduction in transient simulation time and reduced challenges in OLGA well matching, especially in selecting accurate modelling parameters e.g., well inflow performance (validated well (string) production data, reservoir pressure, temperature and fluid properties and the Absolute Open Flow (AOF) of each well). The paper showcased the successful production gain achieved as well as the workflows and methodologies applied for both Steady State Integrated Production Modelling (IPM Steady State) and Integrated Transient Network Modelling (IPM Transient) as tools for production enhancement. Even though IPM Steady State shows promising results in term of field optimization potential, to increase accuracy and reduce uncertainties, IPM Transient is recommended to be performed to mimic the actual transient phenomena happening in the well to facilities


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