| 1. |
- Bhakat, Soumendranath
(författare)
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Effect of T68A/N126Y mutations on the conformational and ligand binding landscape of Coxsackievirus B3 3C protease.
- 2015
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Ingår i: Molecular BioSystems. - : Royal Society of Chemistry (RSC). - 1742-2051 .- 1742-206X. ; 11:8, s. 2303-2311
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Tidskriftsartikel (refereegranskat)abstract
- 3C protease of Coxsackievirus B3 (CVB3) plays an essential role in the viral replication cycle, and therefore, emerged as an attractive therapeutic target for the treatment of human diseases caused by CVB3 infection. In this study, we report the first account of the molecular impact of the T68A/N126Y double mutant (MutantBound) using an integrated computational approach. Molecular dynamics simulation and post-dynamics binding free energy, principal component analysis (PCA), hydrogen bond occupancy, SASA, Rg and RMSF confirm that T68A/N126Y instigated an increased conformational flexibility due to the loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces, which led to a decreased protease grip on the ligand (). The double mutations triggered a distortion orientation of in the active site and decreases the binding energy, ΔGbind (∼3 kcal mol(-1)), compared to the wild type (WildBound). The van der Waals and electrostatic energy contributions coming from residues 68 and 126 are lower for MutantBound when compared with WildBound. In addition, variation in the overall enzyme motion as evident from the PCA, distorted hydrogen bonding network and loss of protein-ligand interactions resulted in a loss of inhibitor efficiency. The comprehensive molecular insight gained from this study should be of great importance in understanding the drug resistance against CVB3 3C protease; also, it will assist in the designing of novel Coxsackievirus B3 inhibitors with high ligand efficacy on resistant strains.
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| 2. |
- Buetti-Dinh, Antoine, et al.
(författare)
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S100A4 and its role in metastasis : simulations of knockout and amplification of epithelial growth factor receptor and matrix metalloproteinases
- 2015
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 11:8, s. 2247-2254
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Tidskriftsartikel (refereegranskat)abstract
- The calcium-binding signalling protein S100A4 enhances metastasis in a variety of cancers. Despite a wealth of data available, the molecular mechanism by which S100A4 drives metastasis is unknown. Integration of the current knowledge defies straightforward intuitive interpretation and requires computer-aided approaches to represent the complexity emerging from cross-regulating species. Here we carried out a systematic sensitivity analysis of the S100A4 signalling network in order to identify key control parameters for efficient therapeutic intervention. Our approach only requires limited details of the molecular interactions and permits a straightforward integration of the available experimental information. By integrating the available knowledge, we investigated the effects of combined inhibition of signalling pathways. Through selective knockout or inhibition of the network components, we show that the interaction between epidermal growth factor receptor (EGFR) and S100A4 modulates the sensitivity of angiogenesis development to matrix metalloproteinases (MMPs) activity. We also show that, in cells that express high EGFR, MMP inhibitors are not expected to be useful in tumours if high activity of S100A4 is present.
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| 3. |
- Buetti-Dinh, Antoine, et al.
(författare)
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S100A4 and its role in metastasis – computational integration of data on biological networks
- 2015
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 11, s. 2238-2246
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Tidskriftsartikel (refereegranskat)abstract
- Characterising signal transduction networks is fundamental to our understanding of biology. However, redundancy and different types of feedback mechanisms make it difficult to understand how variations of the network components contribute to a biological process. In silico modelling of signalling interactions therefore becomes increasingly useful for the development of successful therapeutic approaches. Unfortunately, quantitative information cannot be obtained for all of the proteins or complexes that comprise the network, which limits the usability of computational models. We developed a flexible computational framework for the analysis of biological signalling networks. We demonstrate our approach by studying the mechanism of metastasis promotion by the S100A4 protein, and suggest therapeutic strategies. The advantage of the proposed method is that only limited information (interaction type between species) is required to set up a steady-state network model. This permits a straightforward integration of experimental information where the lack of details are compensated by efficient sampling of the parameter space. We investigated regulatory properties of the S100A4 network and the role of different key components. The results show that S100A4 enhances the activity of matrix metalloproteinases (MMPs), causing higher cell dissociation. Moreover, it leads to an increased stability of the pathological state. Thus, avoiding metastasis in S100A4-expressing tumours requires multiple target inhibition. Moreover, the analysis could explain the previous failure of MMP inhibitors in clinical trials. Finally, our method is applicable to a wide range of biological questions that can be represented as directional networks.
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| 4. |
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| 5. |
- El-Semman, Ibrahim, 1977, et al.
(författare)
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Systems biology analysis of hepatitis C virus infection reveals the role of copy number increases in regions of chromosome 1q in hepatocellular carcinoma metabolism
- 2016
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry. - 1742-206X .- 1742-2051. ; 12:5, s. 1496-1506
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis C virus (HCV) infection is a worldwide healthcare problem; however, traditional treatment methods have failed to cure all patients, and HCV has developed resistance to new drugs. Systems biology-based analyses could play an important role in the holistic analysis of the impact of HCV on hepatocellular metabolism. Here, we integrated HCV assembly reactions with a genome-scale hepatocyte metabolic model to identify metabolic targets for HCV assembly and metabolic alterations that occur between different HCV progression states (cirrhosis, dysplastic nodule, and early and advanced hepatocellular carcinoma (HCC)) and healthy liver tissue. We found that diacylglycerolipids were essential for HCV assembly. In addition, the metabolism of keratan sulfate and chondroitin sulfate was significantly changed in the cirrhosis stage, whereas the metabolism of acyl-carnitine was significantly changed in the dysplastic nodule and early HCC stages. Our results explained the role of the upregulated expression of BCAT1, PLOD3 and six other methyltransferase genes involved in carnitine biosynthesis and S-adenosylmethionine metabolism in the early and advanced HCC stages. Moreover, GNPAT and BCAP31 expression was upregulated in the early and advanced HCC stages and could lead to increased acyl-CoA consumption. By integrating our results with copy number variation analyses, we observed that GNPAT, PPOX and five of the methyltransferase genes (ASH1L, METTL13, SMYD2, TARBP1 and SMYD3), which are all located on chromosome 1q, had increased copy numbers in the cancer samples relative to the normal samples. Finally, we confirmed our predictions with the results of metabolomics studies and proposed that inhibiting the identified targets has the potential to provide an effective treatment strategy for HCV-associated liver disorders.
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| 6. |
- Figueira, Joao, et al.
(författare)
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NMR analysis of the human saliva metabolome distinguishes dementia patients from matched controls
- 2016
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 12:8, s. 2562-2571
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Tidskriftsartikel (refereegranskat)abstract
- Saliva is a biofluid that is sensitive to metabolic changes and is straightforward to collect in a non-invasive manner, but it is seldom used for metabolite analysis when studying neurodegenerative disorders. We present a procedure for both an untargeted and targeted analysis of the saliva metabolome in which nuclear magnetic resonance (NMR) spectroscopy is used in combination with multivariate data analysis. The applicability of this approach is demonstrated on saliva samples selected from the 25 year prospective Betula study, including samples from dementia subjects with either Alzheimer's disease (AD) or vascular dementia at the time of sampling or who developed it by the next sampling/assessment occasion five years later, and age-, gender-, and education-matched control individuals without dementia. Statistically significant multivariate models were obtained that separated patients with dementia from controls and revealed seven discriminatory metabolites. Dementia patients showed significantly increased concentrations of acetic acid (fold change (fc) = 1.25, p = 2 x 10(-5)), histamine (fc = 1.26, p = 0.019), and propionate (fc = 1.35, p = 0.002), while significantly decreased levels were observed for dimethyl sulfone (fc = 0.81, p = 0.005), glycerol (fc = 0.79, p = 0.04), taurine (fc = 0.70, p = 0.007), and succinate (fc = 0.62, p = 0.008). Histamine, succinate, and taurine are known to be important in AD, and acetic acid and glycerol are involved in related pathways. Dimethyl sulfone and propionate originate from the diet and bacterial flora and might reflect poorer periodontal status in the dementia patients. For these seven metabolites, a weak but statistically significant pre-diagnostic value was observed. Taken together, we present a robust and general NMR analysis approach for studying the saliva metabolome that has potential use for screening and early detection of dementia.
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| 7. |
- Guo, Yongzhi, et al.
(författare)
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Changes in protein expression profiles in bovine endometrial epithelial cells exposed to E. coli LPS challenge
- 2017
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Ingår i: Molecular BioSystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 13, s. 392-405
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Tidskriftsartikel (refereegranskat)abstract
- E. coli is one of the most frequently involved bacteria in uterine diseases. Lipopolysaccharide (LPS) is a component of the outer membrane of Gram-negative bacteria involved in pathogenic processes leading to post-partum metritis and endometritis in cattle. It also causes inflammation of the endometrium. The increase of cell proliferation by LPS is part of the inflammatory process. The aim of this study was to investigate possible changes in protein expression in relation to the proliferative response of bEECs after challenge with E. coli-LPS. In vitro culture of bEECs was performed from cow genital tracts collected at a slaughterhouse. In passage 5, bEECs from each of 9 cows (3 series of 3 cows) were exposed to 0, 8, and 16 mg ml(-1) LPS for 72 h. At time 0 and 72 h later, attached cells/living cells were counted and for each time and LPS dosage, cells were frozen for proteomic analyses. All samples from the 3 series were analyzed by 2-D gel electrophoresis coupled to MALDI-TOF/TOF mass spectrometry. The samples from the first series were subjected to shotgun nLC-MS/MS analysis. From the whole differential proteomics analysis, 38 proteins were differentially expressed (p < 0.05 to p < 0.001) following exposure to LPS. Among them, twenty-eight were found to be up-regulated in the LPS groups in comparison to control groups and ten were down-regulated. Differentially expressed proteins were associated with cell proliferation and apoptosis, transcription, destabilization of cell structure, oxidative stress, regulation of histones, allergy and general cell metabolism pathways. The de-regulations induced by LPS were consistent with the proliferative phenotype and indicated strong alterations of several cell functions. In addition, some of the differentially expressed proteins relates to pathways activated at the time of implantation. The specific changes induced through those signals may have negative consequences for the establishment of pregnancy.
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| 8. |
- Li, Hao, et al.
(författare)
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Computational study on the origin of the cancer immunotherapeutic potential of B and T cell epitope peptides.
- 2017
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 13:11, s. 2310-2322
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Tidskriftsartikel (refereegranskat)abstract
- Immune therapy is generally seen as the future of cancer treatment. The discovery of tumor-associated antigens and cytotoxic T lymphocyte epitope peptides spurned intensive research into effective peptide-based cancer vaccines. One of the major obstacles hindering the development of peptide-based cancer vaccines is the lack of humoral response induction. As of now, very limited work has been performed to identify epitope peptides capable of inducing both cellular and humoral anticancer responses. In addition, no research has been carried out to analyze the structure and properties of peptides responsible for such immunological activities. This study utilizes a machine learning method together with interpretable descriptors in an attempt to identify parameters determining the immunotherapeutic activity of cancer epitope peptides.
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| 9. |
- Marco-Ramell, Anna, et al.
(författare)
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Proteomics and the search for welfare and stress biomarkers in animal production in the one health context
- 2016
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry. - 1742-206X .- 1742-2051. ; 12:7, s. 2024-2035
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Forskningsöversikt (refereegranskat)abstract
- Stress and welfare are important factors to animal production in a context of growing production optimization and scrutiny by the general public. In a context in which animal and human health are intertwined aspects of the one-health concept it is of utmost importance to define markers for stress and welfare. These are important tools for producers, retailers, regulatory agents and ultimately consumers to effectively monitor and assess the welfare state of production animals. Proteomics is the science that studies the proteins existing in a given tissue or fluid. In this review we address this topic by showing clear examples where proteomics has been used to study stress-induced changes at various levels. We adopt a multi-species (cattle, swine, small ruminants, poultry, fish and shellfish) approach under the effect of varied stress inducers (handling, transport, management, nutritional, thermal and exposure to pollutants) clearly demonstrating how Proteomics and Systems Biology are key elements to the study of stress and welfare on farm animals and a powerful tool to animal welfare, health and productivity.
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| 10. |
- Nilsson, R, et al.
(författare)
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Simultaneous tracing of carbon and nitrogen isotopes in human cells
- 2016
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Ingår i: Molecular bioSystems. - : Royal Society of Chemistry (RSC). - 1742-2051 .- 1742-206X. ; 12:6, s. 1929-1937
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Tidskriftsartikel (refereegranskat)abstract
- Analyzing isotopes in multiple elements of metabolites can shed light on the coordination of carbon and nitrogen metabolism.
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